Pathology of Kidney Transplantation

Pathology of Kidney Transplantation

25 Pathology of Kidney Transplantation ALTON B. FARRIS III, LYNN D. CORNELL and ROBERT B. COLVIN CHAPTER OUTLINE Renal Allograft Biopsy Optimal Tis...

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Pathology of Kidney Transplantation ALTON B. FARRIS III, LYNN D. CORNELL and ROBERT B. COLVIN

CHAPTER OUTLINE

Renal Allograft Biopsy Optimal Tissue Microscopy Classification of Pathologic Diagnoses in the Renal Allograft Donor Kidney Biopsy Hyperacute Rejection Acute Renal Allograft Rejection Acute T-Cell-Mediated Rejection Tubulointerstitial Rejection (Type I) Endarteritis (Type II Rejection) Glomerular Lesions Atypical Rejection Syndromes Differential Diagnosis Acute Antibody-Mediated Rejection Diagnostic Criteria Pathologic Features C4d Interpretation C4d Negative Antibody-Mediated Rejection Differential Diagnosis Accommodation Complement Inhibition Classification Systems Late Graft Diseases Chronic Antibody-Mediated-Rejection Transplant Glomerulopathy Peritubular Capillary and Tubulointerstitial Lesions Transplant Arteriopathy Chronic T-Cell-Mediated Rejection Other Specific Diagnoses Interstitial Fibrosis and Tubular Atrophy

Protocol Biopsies Acute Tubular Necrosis Calcineurin Inhibitor Nephrotoxicity Acute Calcineurin Inhibitor Toxicity Toxic Tubulopathy Acute Arteriolar Toxicity and Thrombotic Microangiopathy Differential Diagnosis Chronic Calcineurin Inhibitor Toxicity CNI-Arteriolopathy Glomerular Lesions Tubules and Interstitium Differential Diagnosis Target of Rapamycin Inhibitor Toxicity Drug-Induced Acute Tubulointerstitial Nephritis Infections Polyomavirus Tubulointerstitial Nephritis Adenovirus Acute Pyelonephritis Major Renal Vascular Disease De Novo Glomerular Disease Membranous Glomerulonephritis ANTI-GBM Nephritis De Novo Podocytopathy in Congenital Nephrosis Focal Segmental Glomerulosclerosis Recurrent Renal Disease Posttransplant Malignancy and Posttransplant Lymphoproliferative Disease Future Directions in Biopsy Assessment

ABBREVIATIONS

AMR  antibody-mediated rejection ATN  acute tubular necrosis CAN  chronic allograft nephropathy CMV  cytomegalovirus CNI  calcineurin inhibitor CNIT  calcineurin inhibitor toxicity DGF  delayed graft function DSA  donor-specific antibody

EM  electron microscopy FSGS  focal segmental glomerulosclerosis GBM  glomerular basement membrane HLA  human leukocyte antigen IFTA  interstitial fibrosis and tubular atrophy MGN  membranous glomerulonephritis MPGN  membranoproliferative glomerulonephritis

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PAS  periodic acid-Schiff PTC  peritubular capillary PTLD  posttransplant lymphoproliferative disease PTN  polyomavirus tubulointerstitial nephritis

Renal Allograft Biopsy Renal biopsy remains the “gold standard” for the diagnosis of episodes of graft dysfunction that occur commonly in patients after transplantation. Studies have indicated that the results of a renal allograft biopsy change the clinical diagnosis in 30% to 42% and therapy in 38% to 83% of patients, even after the first year.1–4 Most important, unnecessary immunosuppression was avoided in 19% of patients.3 The biopsy is also a gold mine of information on pathogenetic mechanisms, a generator of hypotheses that can be tested in experimental animal studies and in clinical trials. Finally, the biopsy serves, in turn, to validate the hypothesis tested in such trials. Renal biopsy interpretation currently relies primarily on histopathology complemented by immunologic molecular probes. Quantitative gene expression analysis methods may be implemented more in the future as those techniques are further validated and approved for clinical use.5–8 This chapter describes the relevant light, immunofluorescence, and electron microscopy (EM) findings of the most common lesions affecting the renal allograft and their differential diagnosis, citing references largely limited to human pathologic studies after 1990. The discussion is broadly divided into allograft rejection and nonrejection pathology, with an emphasis on differential diagnosis of acute and chronic allograft dysfunction. Grading systems of acute and chronic rejection are discussed further in those sections. Additional references and details are available in a comprehensive review.9

OPTIMAL TISSUE At least seven nonsclerotic glomeruli and two arteries (bigger than arterioles) must be present in a renal allograft biopsy for adequate evaluation.10,11 Using these criteria, the sensitivity of a single core is approximately 90%, and the predicted sensitivity of two cores is about 99%.11 However, adequacy depends entirely on the lesions seen in the biopsy: one artery with endarteritis is sufficient for the diagnosis of acute cellular rejection (TCMR), even if no glomerulus is present; similarly, immunofluorescence or EM of one glomerulus is adequate to diagnose membranous glomerulonephritis (MGN). In contrast, a large portion of cortex with a minimal infiltrate does not exclude rejection. Subcapsular cortex often shows inflammation and fibrosis and is not representative. Diagnosis of certain diseases is even possible with only medulla (acute humoral rejection [acute AMR], polyomavirus tubulointerstitial nephritis [PTN]). However, a normal medulla does not rule out rejection.12 Frozen sections for light microscopy are of limited value, because frozen artifacts preclude accurate evaluation. The diagnostic accuracy of frozen sections was 89% compared

TCMR  T cell-mediated rejection TG  transplant glomerulopathy TBM  tubular basement membrane TMA  thrombotic microangiopathy

with paraffin sections.13 Rapid (2-hour) formalin/paraffin processing is used at Massachusetts General Hospital for urgent and weekend biopsies. 

MICROSCOPY The biopsy is examined for glomerular, tubular, vascular, and interstitial pathology including: (1) transplant glomerulitis, glomerulopathy, and de novo or recurrent glomerulonephritis; (2) tubular injury, isometric vacuolization, tubulitis, atrophy, or intranuclear viral inclusions; (3) endarteritis, fibrinoid necrosis, thrombi, myocyte necrosis, nodular medial hyalinosis, or chronic allograft arteriopathy; (4) interstitial infiltrates of activated mononuclear cells, edema, or neutrophils, fibrosis, and scarring. Arteries and arterioles are particularly scrutinized, because the diagnostic lesion often lies there. A typical immunofluorescence panel (used at Massachusetts General Hospital) detects IgG, IgA, IgM, C3, kappa and lambda light chains, C4d, albumin, and fibrin in cryostat sections. C4d, a complement fragment, is used to identify AMR; the other stains are primarily for recurrent or de novo glomerulonephritis.14 Immunohistochemistry (IHC) in paraffin sections is indicated in the differential diagnosis of lymphoproliferative or viral diseases and may be used for C4d. EM is valuable when de novo or recurrent glomerular disease is suspected and to evaluate peritubular capillary (PTC) basement membranes.15 

CLASSIFICATION OF PATHOLOGIC DIAGNOSES IN THE RENAL ALLOGRAFT The ideal diagnostic classification of renal allograft pathology should be based on pathogenesis, have therapeutic relevance, and be reproducible. The current classification based on Banff and other systems (Table 25.1), meets these criteria.16,17 

Donor Kidney Biopsy Biopsy of the cadaveric donor kidney is sometimes used to determine the suitability of the kidney for transplantation. Objective pathologic criteria based on outcome that could be applied to the renal biopsy as a screening test have not been fully established, as donor biopsies are not always performed and controlled trials have not been done. One of the major problems in assessing the donor kidney is that this is usually done with cryostat sections, often by local pathologists in the middle of the night. Using arbitrary criteria risks that kidneys will be discarded needlessly. In several large studies, the outcome at 1 to 5 years has not measurably correlated with pathologic lesions.18–20

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TABLE 25.1  Pathologic Classification of Renal Allograft Disease16 I. Immunologic rejection A. Hyperacute rejection B. Acute rejection a. Acute T-cell-mediated rejection (acute cellular rejection, C4d−) i. Tubulointerstitial (Banff type I) ii. Endarteritis (Banff type II) iii. Arterial fibrinoid necrosis/transmural inflammation (Banff type III) iv.  Glomerular (transplant glomerulitis; no Banff type) b. Acute AMR (acute humoral rejection, C4d+) i. Tubular injury ii. Capillaritis/thrombotic microangiopathy iii. Arterial fibrinoid necrosis C. Chronic rejection a. Chronic T-cell-mediated rejection (with T cell activity) b. Chronic antibody-mediated rejection (with antibody activity, C4d+) II. Allo-/autoantibody-mediated diseases of allografts A. Anti-GBM disease in Alport’s syndrome B. Nephrotic syndrome in nephrin-deficient recipients C. Anti-TBM disease in TBM antigen-deficient recipients D. De novo membranous glomerulonephritis E. Antiangiotensin II receptor autoantibody syndrome III. Nonrejection injury A. Acute ischemic injury or other causes of acute tubular injury/ necrosis (ATN) B. Drug toxicity □ Calcineurin inhibitor (cyclosporine, tacrolimus) □ mTOR inhibitors (sirolimus, everolimus, rapamycin) □ Drug-induced interstitial nephritis C. Acute tubulointerstitial nephritis (drug allergy) D. Infection (viral, bacterial, fungal) (e.g., BK virus nephropathy, pyelonephritis) E. Major artery/vein thrombosis F. Mechanical □ Obstruction □ Urine leak G. Renal artery stenosis H. Arteriosclerosis I. De novo glomerular disease/glomerulopathy (other than transplant glomerulopathy) J. Posttransplant lymphoproliferative disease (PTLD) K. Chronic allograft nephropathy, not otherwise classified (interstitial fibrosis and tubular atrophy) IV. Recurrent primary disease A. Immunologic (e.g., IgA nephropathy, lupus nephritis, anti-GBM disease) B. Metabolic (e.g., amyloidosis, diabetes, oxalosis) C. Unknown (e.g., dense deposit disease, focal segmental glomerulosclerosis)

As rejection and patient death from complications diminish, the influence of the quality of the graft is likely to increase. Both donor biopsies and reperfusion biopsies can be quite helpful in assessing the baseline status of the graft, although reperfusion biopsies do not provide aid in donor selection.21 Glomerulosclerosis is one feature that is readily assessed in frozen section, by the most casual observation. Glomerulosclerosis >20% correlates with poor graft outcome In several studies, donor serum creatinine did not distinguish the different degrees of glomerulosclerosis found on biopsy,22–24 although that has been demonstrated by other studies.20 In one study, the odds ratio for poor outcome remained significant after adjustment for donor age, rejection episodes, or panel reactive antibody.23 Five-year graft survival was

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strikingly diminished in recipients of grafts with >20% glomerulosclerosis compared with those 0% sclerosis (35% vs. 80%).24 However, other large studies have failed to detect a major effect of glomerulosclerosis >20%, if adjusted for the age of the donor25 or renal function.26 At least 25 glomeruli are needed to correlate with outcome.27 A wedge biopsy may not be representative, because it includes mostly outer cortex, the zone where glomerulosclerosis and fibrosis due to vascular disease is most severe, therefore a needle biopsy is recommended. Even though many other studies try to correlate fibrosis or vascular disease, reproducibility of scoring these lesions, even on permanent sections in broad daylight, is notoriously poor.28 At this time histologic evaluation is recommended in donors with any evidence of renal dysfunction, a family history of renal disease, or whose age is >60 years. Histologic selection of optimal kidneys from donors over age 60 years can result in a graft survival rate similar to that of grafts from younger patients.29 Other lesions may cause the transplant surgeon or pathologist to argue against use of the graft. Arterial intimal fibrosis increases the risk of delayed graft function (DGF)30 and has a slight effect on 2-year graft survival (6% decrease).31 Thrombotic microangiopathy (TMA) with widespread but less than 50% glomerular thrombi increases the likelihood of DGF and primary nonfunction,25 but unaltered 2-year graft survival can still be observed.32 Likewise, deceased donor kidneys with fibrin thrombi in up to essentially 100% of glomeruli due to presumed disseminated intravascular coagulation have been transplanted successfully with initial DGF but eventual stable allograft function.33 Despite initial DGF, It has been shown that donor-derived glomerular fibrin thrombi can resolve after donor kidney transplantation,34 sometimes quite rapidly.35 Reversal of diabetic glomerulosclerosis36 and IgA nephropathy have been reported,37 as well as membranous glomerulonephritis,38 lupus nephritis,39 membranoproliferative glomerulonephritis (MPGN),40 and endotheliosis due to preeclampsia (personal observation). 

Hyperacute Rejection Hyperacute rejection refers to immediate rejection (typically within minutes to hours) of the kidney upon perfusion with recipient blood, where the recipient is presensitized to alloantigens on the surface of the graft endothelium. During surgery, the graft kidney becomes soft and flabby; and livid, mottled, purple, or cyanotic in color; and urine output ceases. The kidney subsequently swells, and widespread hemorrhagic cortical necrosis and medullary congestion appears. The large vessels are sometimes thrombosed. Early lesions show marked accumulation of platelets in glomerular capillaries’ lumina that appear as amorphous, pale pink, finely granular masses in hematoxylin and eosin (H&E) stained slides (negative on periodic acid Schiff [PAS] stains). Neutrophil and platelet margination then occur over the next hour or so along damaged endothelium of small arteries, arterioles, glomeruli, and PTCs, and the capillaries fill with a sludge of compacted red cells and fibrin.41 The larger arteries are usually spared. The neutrophils do not infiltrate initially but form “chain-like” figures in the PTCs without obvious thrombi.41 The endothelium is stripped off

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the underlying basal lamina, and the interstitium becomes edematous and hemorrhagic. Intravascular coagulation occurs and cortical necrosis ensues over 12 to 24 hours. The medulla is relatively spared, but is ultimately affected as the whole kidney becomes necrotic.42 Widespread microthrombi are usually found in the arterioles and glomeruli and can be detected even in totally necrotic samples. The small arteries may show fibrinoid necrosis. Mononuclear infiltrates are typically sparse. One case showed CD3+ cells in the adventitia of small arteries and in the surrounding interstitium.43 By EM, neutrophils attach to injured glomerular endothelial cells.41 The endothelium is swollen— separated from the glomerular basement membrane (GBM) by a lucent space. Capillary loops and PTCs are often bare of endothelium. Platelet, fibrin thrombi, and trapped erythrocytes occlude capillaries.16 The site of antibody and complement deposition is determined by the site of the target endothelial alloantigens. Hyperacute rejection due to preexisting anti-HLA class I antibodies may show C3, C4d, and fibrin throughout the microvasculature.44 ABO antibodies (primarily IgM) also deposit in all vascular endothelium. Cases with anticlass II antibodies may have IgG/IgM primarily in glomerular capillaries and peritubular capillaries, where class II is normally conspicuous.45 In antiendothelial-monocyte antigen cases, IgG is primarily in PTCs, rather than glomeruli or arteries.46 Often antibodies cannot be detected in the vessels,47 even though they can be eluted from the kidney.48,49 In these cases C4d should be positive in PTCs14 and more useful than immunoglobulin stains. Occasional cases, particularly intraoperative biopsies, may be negative for C4d (A. H. Cohen, Cedar Sinai Hospital, Los Angeles, personal communication), perhaps related to focally decreased perfusion or insufficient time to generate substantial C4d amounts.16 The differential diagnosis of hyperacute rejection includes ischemia and major vascular thrombosis.16 The major diagnostic feature of hyperacute rejection is C4d deposition in PTCs and the prominence of neutrophils in capillaries. Although the finding of antibody and C4d deposition in PTCs is diagnostic when present, negative immunofluorescence stains do not exclude hyperacute rejection. Exogenous antibody (rabbit or horse antilymphocyte serum) can cause severe endothelial injury sometimes with C4d deposition mimicking hyperacute rejection.50 Hyperacute rejection typically has more hemorrhage, necrosis, and neutrophil accumulation in glomeruli and PTCs than acute tubular necrosis (ATN), although glomerular neutrophils alone are associated with ischemia.51 Major arterial thrombosis has predominant necrosis with little hemorrhage or microthrombi and PTC neutrophils are not prominent. Renal vein thrombosis shows marked congestion and relatively little neutrophil response. 

Acute Renal Allograft Rejection Acute rejection typically develops in the first 2 to 6 weeks after transplantation, but can arise in a normally functioning kidney from 3 days to 10 years or more, or in a graft affected by other conditions, such as ATN, calcineurin inhibitor toxicity, or chronic rejection. Acute rejection may be cell mediated, humoral, or both (see Table 25.1). TCMR is mediated primarily by T cells reacting to donor

TABLE 25.2  Summary of Banff/CCTT Types of Acute T-Cell-Mediated Rejection1,16 Suspicious/ borderline2 Type I3 Type II Type III

Tubulitis + infiltrate Tubulitis (t1, t2, or t3) with minor interstitial infiltrate (i0 or i1) or infiltrate (i2, i3) with mild tubulitis (t1) Tubulitis >4 cells/tubule + infiltrate >25% A: with 5–10 cells/tubule (t2), or B: with >10 cells/tubule (t3) Mononuclear cells under arterial endothelium A: <25% luminal area, or B: ≥25% luminal area Transmural arterial inflammation, or fibrinoid ­arterial necrosis with accompanying lymphocytic inflammation4

histocompatibility antigens in the kidney and is much more common than acute humoral rejection, due to donorspecific antibodies (i.e., acute antibody-mediated rejection), although the latter is now recognized with greater frequency and has a worse prognosis. Only since 1999 has the distinction between the two been clearly made in the literature.

ACUTE T-CELL-MEDIATED REJECTION T cells react to donor histocompatibility antigens expressed in the tubules, interstitium, vessels, and glomeruli, separately or in combination (Table 25.2). The donor ureter is also affected but rarely sampled.52

Tubulointerstitial Rejection (Type I) The prominent microscopic feature of TCMR is a pleomorphic interstitial infiltrate of mononuclear cells, accompanied by interstitial edema and sometimes hemorrhage (Fig. 25.1). The infiltrate is typically patchy, both in the cortex and medulla. The infiltrating cells are primarily T cells and macrophages. Activated T cells (lymphoblasts) with increased basophilic cytoplasm, nucleoli, and occasional mitotic figures indicate increased synthetic and proliferative activity.53 Granulocytes are not uncommonly present but rarely prominent. When neutrophils are conspicuous, the possibility of AMR or pyelonephritis should be considered. Eosinophils are present in about 30% of biopsies with rejection and can be abundant, but are rarely more than 2% to 3% of the infiltrate.54,55 Abundant eosinophils (10% of infiltrate) are associated with endarteritis (Banff type II).56 Mast cells increase, as judged by tryptase content, and correlate with edema.57 Acute rejection with abundant plasma cells has been described as early as the first month associated with poor graft survival.58–60 Infiltrating T cells express cytotoxic molecules, namely perforin,61,62 FasL,62,63 granzyme A and B,62,64–66 and TIA-1/GMP-17,66,67 and tumor necrosis factor-β (lymphotoxin).68 Apoptosis of the infiltrating T cells can be demonstrated with the TdT-uridine-nick end label (TUNEL) technique, probably as a result of activation-induced cell death, and would thereby serve to limit the immune reaction.67 Mononuclear cells invade tubules and insinuate between tubular epithelial cells, a process termed “tubulitis” (see Fig. 25.1 inset), which is best appreciated in sections stained with PAS or a silver stain to delineate the tubular basement membrane (TBM). All cortical tubules (proximal and distal) as well as the medullary tubules and the collecting ducts may be affected. Tubular cell apoptosis occurs,67,69–71 which

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Fig. 25.1  Acute cellular rejection type I. (A) Mononuclear cells, composed of activated lymphocytes and macrophages, infiltrate the edematous interstitium and invade tubules. Tubulitis affects proximal and other tubules, where mononuclear cells are interposed between the tubular epithelial cells (inset). The invading mononuclear cells appear dark with scant cytoplasm, which distinguishes them from tubular epithelial cells. The tubular basement membranes are stained red by the periodic acid-Schiff stain, which is useful to delineate the boundary between the tubule and the interstitium.

correlates with the number of cytotoxic cells and macrophages in the infiltrate.67,70 Tubular epithelial cells express human leukocyte antigen–DR (HLA-DR), intercellular adhesion molecule 1 (ICAM 1), and vascular cell adhesion molecule 1 (VCAM-1) in increased amounts in TCMR72–82 and express the costimulatory molecules CD80 and CD86.83 Tubules also synthesize tumor necrosis factor-α,84 transforming growth factor-β1, IL-15, osteopontin, and vascular endothelial growth factor (VEGF).85–87 Increased expression of S100A4 may signal the process of epithelial to mesenchymal transition (EMT),88 which may actually consist of an in situ epithelial response rather than a true emigration of tubular epithelial cells into the interstitium.89 Thus, as suggested by proceedings at a Banff conference on allograft pathology,17 EMT may be better thought of as an epithelial to mesenchymal phenotype (EMP).90 Some tubular cell-derived molecules have the potential to inhibit acute rejection, such as protease inhibitor-9 (PI-9), the only known inhibitor of granzyme B65 and IL-15, which inhibits expression of perforin.85 CD8+ and CD4+ cells invade tubules.91 Intratubular T cells with cytotoxic granules,67 and CD4+FOXP3+ cells92 accumulate selectively in the tubules, compared with the interstitial infiltrate. T cells proliferate once inside the tubule, as judged by the marker Ki67 (MIB-1), which contributes to their concentration within tubules, in addition to selective invasion.67,93 Increased tubular HLA-DR,72,73 tumor necrosis factor (TNF)α,84 IFNγ receptor,68 IL-2 receptor,94 and IL-8 are detectable by immunoperoxidase study in TCMR. Several adhesion molecules are increased on tubular cells during rejection, including ICAM-1 (CD54) and VCAM-1, and correlate with the degree of T cell infiltration.82 Signs of tubular cell injury can be detected by TUNEL apoptosis assay. Increased numbers of TUNEL+ tubular cells are present in acute rejection, compared with normal kidneys.67,69 The frequency was significantly lower in cyclosporin A (CsA) toxicity or ATN.67 The degree of apoptosis correlates with the cytotoxic cells in the infiltrate, consistent with a pathogenetic relationship.67 Prominent apoptosis of the infiltrating T cells has also been detected at a frequency

comparable to that in the normal thymus (1.8% of cells).67 Others have described occasional TUNEL+ lymphocytes.69 Apoptosis probably occurs in infiltrating T cells as a result of activation-induced cell death and would thereby serve to limit the immune reaction.67 Little, if any, immunoglobulin deposition is found by immunofluorescence in TCMR, which is characterized primarily by extravascular fibrin accumulation in the interstitium and not uncommonly increased C3 along the TBM. The C3 is largely derived from tubular cells.95 C3 may have a role in the pathogenesis of acute rejection, because C3-deficient mouse kidneys have prolonged survival.96 C4d deposition in PTCs indicates an antibody-mediated component. Gene expression studies of graft tissue have revealed that transcripts for proteins of cytotoxic T lymphocytes (CTLs), such as granzyme B, perforin, and Fas ligand97–103 and the master transcription factor for CTLs, T-bet, are characteristic of TCMR.101 Graft CTL-associated transcripts (CATs) precede tubulitis in mouse kidney grafts.104 Treatment of rejection is followed by a measurable decrease of CATs.100 However, knockout of either granzyme or perforin does not prevent acute rejection, suggesting they are not essential.105 IFNγ mRNA is detectable in fine needle aspirates 1 week before the clinical onset of rejection.106 Other genes associated with acute rejection are IFNγ, TNFβ, TNFα, RANTES (regulated on activation, normal T cell expressed and secreted, also known as also Chemokine (C-C motif) ligand 5 [CCL5]), and macrophage inflammatory protein 1-alpha (MIP-1-alpha, also known as Chemokine [C-C motif] ligand 3 [CCL3]); no elevation of TGFβ or IL-10 is detected.101 

Endarteritis (Type II Rejection) Infiltration of mononuclear cells under arterial and arteriolar endothelium is the pathognomic lesion of TCMR (Fig. 25.2). Many terms have been used for this process, including “endothelialitis,” “endothelitis,” “endovasculitis,” “intimal arteritis,” or “endarteritis.” We prefer the last term, which emphasizes the type of vessel (artery vs. vein) involved and the site of inflammation. Mononuclear cells

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Fig. 25.2  Acute cellular rejection type II. (A) Endarteritis in a medium sized artery. The endothelium is lifted by undermining mononuclear cells, without involvement of the media. (B) Subendothelial infiltration in a small artery with underlying arteriosclerosis (donor disease). This acute process should be distinguished from chronic transplant arteriopathy.

that are sometimes attached to the endothelial surface are insufficient for the diagnosis of endarteritis; however, they probably represent the early phase of this lesion. Endarteritis in TCMR must not be confused with fibrinoid necrosis of arteries. The latter is characteristic of acute AMR and can also be seen in thrombotic vasculopathy. Regrettably, some still do not separate these lesions, regarding all “vascular rejection” as predominately humoral. Endarteritis has been reported in 35% to 56% of renal biopsies with TCMR.11,55,107–109 Many do not find the lesion as often, which may possibly be ascribed to inadequate sampling, overdiagnosis of rejection (increasing the denominator), patient population with respect to medication adherence (severity of rejection), or the timing of the biopsy with respect to antirejection therapy. Endarteritis lesions affect arteries of all sizes including the arteriole, although the lesions affect larger vessels preferentially. For example, in a detailed analysis, 27% of the artery cross sections were affected, vs. 13% of the arterioles.55 A sample of four arteries would have an estimated sensitivity of about 75% in the detection of type II rejection.55 Thus a sample may not be considered adequate to rule out endarteritis unless several arteries are included. “Arteriolitis” has the same significance as endarteritis.110 Endarteritis can occur in cases with little or no interstitial infiltrate or tubulitis, arguing that it has a distinct pathogenetic mechanism,16,111 and even in cases with “isolated endarteritis,” that finding is an independent risk factor for kidney transplant failure.111 In severe cases, a transmural mononuclear infiltrate affects the media, with focal necrosis of the myocytes, features that constitute type III rejection (transmural inflammation or fibrinoid necrosis). Although this occasionally occurs in the absence of demonstrable antibodies, it is more typical of AMR. Endothelial cells are typically reactive with increased cytoplasmic volume and basophilia. The endothelium shows disruption and lifting from supporting stroma by infiltrating inflammatory cells.112 Occasionally endothelial cells are necrotic or absent, however, thrombosis is rare. Endothelial apoptosis occurs67,69 and increased numbers of endothelial cells appear in the circulation.113 The media usually shows

little change. In severe cases a transmural mononuclear infiltrate may be seen (termed “type III rejection”). The cells infiltrating the endothelium and intima are T cells and monocytes, but not B cells.112 Both CD8+ and CD4+ cells invade the intima in early grafts, but later CD8+ cells predominate,91 suggesting that class I antigens are the primary target.67 Vascular endothelial cell apoptosis can be detected in sites of endarteritis.67,69 Normal arterial endothelial cells express class I antigens, weak ICAM-1, and little or no class II antigens, or VCAM-1. During acute rejection the endothelium of arteries expresses increased HLA-DR74,91 and ICAM-1 and VCAM-1.79,81 This adhesion molecule upregulation occurs in association with CD3+82 and CD25+80 infiltrating mononuclear cells. Endothelial cells also have decreased endothelin expression in rejection with endarteritis, but not in tubulointerstitial rejection.114 

Glomerular Lesions In most TCMR cases, glomeruli are spared or show minor changes, typically a few scattered mononuclear cells (T cells and monocytes) and occasionally segmental endothelial damage (Fig. 25.3).115 A severe form of this glomerular injury, termed “transplant glomerulitis” or “acute allograft glomerulopathy,” develops in a minority of cases (<5%), manifested by hypercellularity, injury, and enlargement of endothelial cells; infiltration of glomeruli by mononuclear cells; and by webs of PAS-positive material.116 Crescents and thrombi are rare. Endarteritis often accompanies the transplant glomerulitis.117 The glomeruli contain numerous CD3+ and CD8+ T cells and monocytes.91,118 Fibrin and scant immunoglobulin and complement deposits are found in glomeruli. This variant of cellular rejection has been associated with certain viral infections, such as cytomegalovirus (CMV) infection and hepatitis C virus,119 although viral antigens are not in the glomerular lesions.  Atypical Rejection Syndromes Unique patterns of rejection have been observed under novel immunosuppression regimens. For example, following pronounced lymphocyte depletion from alemtuzumab

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Fig. 25.3  Acute humoral rejection. (A) Low power shows mild interstitial inflammation, focal hemorrhage, neutrophils and thrombi in glomerular capillaries, and dilated peritubular capillaries with leukocytes. (B) At high power neutrophils can be seen in the peritubular capillaries with little tubulitis. PAS stain. (C) Acute transplant glomerulitis is prominent in this case of acute humoral rejection. Glomerular endothelial cells are swollen and the capillaries are filled with mononuclear cells, probably mostly macrophages. PAS stain. (D) C4d stain of a case of acute humoral rejection, shows prominent, diffuse staining of dilated peritubular capillaries, sometimes containing inflammatory cells, and linear staining along the glomerular basement membrane. Immunohistochemistry with a polyclonal anti-C4d rabbit antibody.

(CAMPATH-1H),53,120,121 TCMR with a prominent monocyte population (i.e., an acute monocytic rejection) has been described. In these cases, much of the interstitial rejection infiltrate stains for CD68, correlating with renal dysfunction and tubular stress, shown by HLA-DR staining of the tubules. Under these conditions, T cells did not correlate with renal dysfunction or HLA-DR staining.120 Studies have included simultaneous bone marrow and kidney transplantation protocols in attempt to induce tolerance to the transplanted organ. In these studies, human leukocyte antigen (HLA)-mismatched renal transplants have been performed; withdrawal of maintenance immunosuppression has been accomplished in some of the patients with relatively preserved renal function.122 In several of these patients, a capillary leak or engraftment syndrome has been observed around 10 days after a simultaneous kidney/bone marrow transplant preceded by a nonmyeloablative conditioning regimen. In this “engraftment syndrome,” acute tubular injury is accompanied by congested PTCs containing mononuclear cells and red blood cells. IHC shows that the cells are primarily CD68+MPO+ mononuclear cells and CD3+CD8+ T cells, the latter with a high proliferation index (Ki67+). XY chromosome fluorescence in situ hybridization (FISH) has been used to demonstrate that the PTC cells are recipient derived, correlating with chimerism studies showing a simultaneous decline in circulating donor cells and recovery of recipient circulating cells. PTC endothelial injury can also be seen on EM in these cases.122,123 The etiology of the syndrome remains undefined, and others have performed combined kidney and bone marrow transplants without observing this phenomenon.124 With

modifications in the combined kidney and bone marrow transplantation protocol, it is possible that the “engraftment syndrome” can be eliminated or at least attenuated; this suggests that “engraftment syndrome” may not be an accurate term for what may actually just be a form of transient acute kidney injury.125 

Differential Diagnosis TCMR typically has a diffuse, interstitial mononuclear cell infiltrate, whereas patients with CNI toxicity (CNIT) and those with stable function have only focal mononuclear cell infiltrates (Table 25.3). Endarteritis or C4d+ is found extremely rarely, if ever, in CNIT and if either is present, is the most discriminating feature for acute rejection.126–128 Prominent tubulitis favors acute rejection, because it is less prominent in acute tubular necrosis, particularly in the proximal tubules.129 However, tubulitis has been documented in renal transplants with dysfunction due to lymphoceles (obstruction) and in urine leaks, possibilities that need to be considered and excluded by other techniques.130 Acute obstruction typically has some dilation of the collecting tubules, especially in the outer cortex. Edema and a mild mononuclear infiltrate are also common.11,129,130 Interstitial mononuclear inflammation and tubulitis occur in a variety of diseases other than acute rejection, such as drug-induced (allergic) or infectious tubulointerstitial nephritis. When eosinophils are more abundant than usual for rejection and eosinophils invading tubules are identified, then drug allergy may be favored over rejection. The presence of endarteritis permits a definitive diagnosis of active rejection.55 Lymphocytes commonly

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TABLE 25.3  Banff Classification (Updated 2017)135,157 (A) CLASSIFICATION CATEGORIES CATEGORY 1: NONSPECIFIC CHANGES OR NORMAL BIOPSY CATEGORY 2: ANTIBODY-MEDIATED CHANGES Acute/active ABMR If all three features are present, they are considered diagnostic. If 1 and 2 or 1 and 3 below are present, a “suspicious” designation can be made.a 1. Histologic evidence of injury: □ Microvascular inflammation (g >0 in the absence of recurrent or de novo glomerulonephritis, and/or ptc >0) □ Intimal or transmural arteritis (v >0)1 □ Acute thrombotic microangiopathy (TMA) in the absence of other causes □ Acute tubular injury in the absence of other causes 2. Evidence of antibody interaction with vascular endothelium: □ Linear C4d staining in peritubular capillariesb □ ≥ moderate microvascular inflammation ([g + ptc] ≥ 2)c □ Increased gene transcript/classifier expressiond 3. Serologic evidence of DSAs (HLA or other antigens)e: Chronic active ABMR If all three features are present, they are considered diagnostic. If 1 and 2 or 1 and 3 below are present, a “suspicious” designation can be made.a 1. Histologic evidence of injury: □ TG (cg >0), if not evidence of chronic TMA [even if by EM only (cg1a)] □ Severe peritubular capillary basement membrane multilayering2 □ Arterial intimal fibrosis of new onset, excluding other causes 2. Evidence of antibody interaction with vascular endothelium: □ Linear C4d staining in peritubular capillariesb □ ≥ moderate microvascular inflammation ([g + ptc] ≥ 2)c □ Increased gene transcript/classifier expressiond 3. Serologic evidence of DSAs (HLA or other antigens)e C4d staining without eviOnly if three features are present: dence of rejection 1. Linear peritubular capillary C4d stainingb 2. Criterion 1 for active or chronic, active ABMR not met 3. No molecular evidence for ABMR (i.e., in criterion 2 for active and chronic, active ABMR 4. No acute or chronic active acute TCMR, or borderline changes CATEGORY 3: BORDERLINE CHANGES SUSPICIOUS FOR ACUTE TCMR □ Foci of tubulitis (t1, t2, or t3), with minor interstitial inflammation (i0 or i1) or interstitial inflammation (i2, i3) with mild (t1) tubulitis; if designated in a report or publication, retaining the i1 threshold from Banff 2005 is permitted □ No intimal arteritis (v = 0) CATEGORY 4: TCMR Acute TCMR (grade/type)

Chronic active TCMR (grade)

Interstitial fibrosis and tubular atrophy (IFTA, grade)

A. Interstitial inflammation (>25% of nonsclerotic cortical parenchyma, i2 or i3) and foci of moderate tubulitis (t2) 1 1B. Interstitial inflammation (>25% of nonsclerotic cortical parenchyma, i2 or i3) and foci of severe tubulitis (t3) 2A. Mild to moderate intimal arteritis (v1) with or without interstitial inflammation and tubulitis 2B. Severe intimal arteritis comprising >25% of the luminal area (v2) with or without interstitial inflammation and tubulitis 3. Transmural arteritis and/or arterial fibrinoid change and necrosis of the medial smooth muscle cells with accompanying lymphocytic inflammation (v3) 1A. Interstitial inflammation [>25% of total cortex (ti score 2 or 3) and >25% of sclerotic cortical parenchyma (i-IFTA score 2 or 3)] with moderate tubulitis (t2) involving ≥1 tubules, not including severely atrophic tubules3 1B. Interstitial inflammation [>25% of total cortex (ti score 2 or 3) and >25% of the sclerotic parenchyma (i-IFTA score 2 or 3)] with severe tubulitis (t3) involving ≥1 tubules, not including severely atrophic tubules3 2. Chronic allograft arteriopathy (arterial neointima, intimal fibrosis with mononuclear cell infiltration)1 I. Mild IFTA (≤25% of cortical area) II. Moderate IFTA (26%–50% of cortical area) III. Severe IFTA (>50% of cortical area)

CATEGORY 6: CHANGES NOT CONSIDERED TO BE CAUSED BY CHRONIC OR ACUTE REJECTION (SEE “NONREJECTION INJURY” IN TABLE 25.1) aDesignate

if C4d positive or C4d negative. or C4d3 by immunofluorescence on frozen sections or C4d0 >0 by immunohistochemistry on paraffin sections. cAt least moderate (≥ moderate ) microvascular inflammation ([g + ptc] ≥2) can be sufficient for this requirement; however, in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥2 alone is not sufficient, and g must be ≥1. dIncreased gene transcript/classifier expression is considered sufficient for this requirement “if thoroughly validated” in biopsy tissue. eDSAs can be substituted by C4d staining or expression of validated transcripts/classifiers in criteria 2; however, extensive DSA testing (including non-HLA antibodies if HLA antibody testing is negative) is still advised if criteria 1 and 2 are not met. ABMR, antibody-mediated rejection; DSA, donor-specific antibody; EM, electron microscopy; HLA, human leukocyte antigen; IFTA, interstitial fibrosis and tubular atrophy; TCMR, T-cell-mediated rejection; TG, transplant glomerulopathy. 1These arterial lesions may be indicative of ABMR, TCMR, or mixed ABMR/TCMR. 2≥ seven layers in one cortical peritubular capillary and five or more in two additional capillaries, avoiding portions cut tangentially. 3Severely atrophic tubules have three features: (1) diameter <25% of unaffected or minimally affected tubules; (2) undifferentiated-appearing, flattened, or cuboidal epithelium; and (3) pronounced wrinkling and/or thickening of the tubular basement membrane. Other known causes of i-IFTA should be excluded. bC4d2

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387

TABLE 25.3  Banff Classification (Updated 2017)135,157—cont’d (B) QUANTITATIVE CRITERIA Quantitative Criteria (Lesion)

0

1

2

3

i (interstitial Inflammation) ti (total interstitial inflammation) i-IFTA (inflammation in interstitial fibrosis and tubular atrophy) t (tubulitis) V (arteritis)

i0: none or trivial (<10% of i1: 10%–25% of unscarred i2: 26%–50% of unscarred unscarred cortex) cortex inflamed cortex inflamed ti0: none or trivial (<10% ti1: 10%–25% of scarred and ti2: 26%–50% of scarred and of cortex) unscarred cortex unscarred cortex

i3: >50% of unscarred cortex inflamed ti3: >50% of scarred and unscarred cortex

i-IFTA0: no inflammation or <10% of scarred cortical parenchyma

i-IFTA1: inflammation in i-IFTA2: inflammation in 10%–25% of scarred corti26%–50% of scarred cal parenchyma cortical parenchyma

i-IFTA3: inflammation in >50% of scarred cortical parenchyma

t0: no tubular mononuclear cells v0: no arteritis

t1: 1–4 cells/tubular cross t2: 5–10 cells/tubular cross section1 section1 v1: mild to moderate v2: severe arteritis with ≥25% arteritis in ≥1 arterial cross luminal area lost in ≥1 artesection rial cross section

g (glomerulitis)3 ptc4 (peritubular capillaritis) ci (interstitial fibrosis) ct (tubular atrophy) cg (transplant glomerulopathy) mm (mesangial matrix increase) cv (arterial fibrous intimal thickening)6 ah (arteriolar hyalinosis) aah (arteriolar hyaline thickening)7 C4d IF by immunofluorescence

g0: none

g1: <25% of glomeruli

ptc0: Absent or < 10% of cortical PTCs ci0: ≤5% of cortical area

ptc1: 3–4 luminal inflammatory cells3 ci1: 6%–25% of cortical area

> 10 cells/tubular cross section2 v3: transmural arteritis and/ or fibrinoid change and medial smooth muscle necrosis with vascular lymphocytic infiltrate g3: mostly global in >75% of glomeruli ptc3: >10 luminal inflammatory cells ci3: >50% of cortical area

ct0: none

ct1: ≤ tubular atrophy

cg0: no GBM double contours

cg1: GBM double contours in ≤25% of capillary loops5

ct2: 26%–50% tubular ct3: >50% tubular atrophy atrophy cg2: Double contours in cg3: Double contours in 26%–50% of capillary loops >50% of capillary loops

mm0: none

mm1: ≤25% of nonsclerotic glomeruli

mm2: 26%–50% of nonsclerotic glomeruli

C4d IHC by immunohistochemistry

C4d0: 0% of biopsy area, considered negative

g2: segmental or global in 25%–75% of glomeruli ptc2: 5–10 luminal inflammatory cells3 ci2: 26%–50% of cortical area

mm3: 50% of nonsclerotic glomeruli

cv0: arterial fibrous intimal thickening

cv1: arterial fibrous intimal cv2: arterial fibrous intimal cv3: arterial fibrous intimal thickening with 1%–25% thickening with 26%–50% thickening with >50% luminal narrowing luminal narrowing luminal narrowing ah0: none ah1: mild-moderate in ≤1 ah2: moderate to severe in >1 ah3: Severe in many arteriarteriole arteriole oles aah0: no lesions typical of aah1: 1 arteriole, not circum- aah2: >1 arteriole, not circum- aah3: Any number of arteriCNI arteriolopathy ferential ferential oles, circumferential C4d0: 0% of biopsy area, considered negative

C4d1: 1 to <10% of biopsy C4d2: 10%–50% of biopsy C4d3: >50% of biopsy area, area, considered minimal/ area, considered focal considered diffuse positive negative unknown C4d1: 1% to <10% of biopsy C4d2: 10%–50% of biopsy area, C4d3: >50% of biopsy area, area, considered minimal/ considered focal positive considered diffuse positive unknown

1Tubulitis

can be considered per tubular cross section or per 10 tubular cells. can also be diagnosed if or ≥ two areas of tubular basement membrane destruction accompanied by i2/i3 inflammation and t2 tubulitis elsewhere in the biopsy. 3Complete or partial occlusion of ≥1 glomerular capillary by leukocyte infiltration and endothelial cell enlargement. 4Comment on extent (focal ≤ 50%; diffuse >50%) and composition (neutrophils and mononuclear cells). 5In the severely affected glomerulus; also note number and percent sclerotic. Furthermore, cg1a denotes no GBM double contours by light microscopy but GBM double contours by electron microcopy (EM) with endothelial swelling and/or subendothelial electron lucent widening, and cg1b can denote ≥1 double contours in ≥1 non-sclerotic glomerulus, confirmed by EM if available. 6Characterized by features of chronic rejection (fibrointimal thickening/neointima formation ± breach of internal elastic lamina or presence of occasional mononuclear or foam cells, ± breaks in elastic lamina). 7Alternate scoring for hyaline arteriolar thickening (not always used diagnostically) due to calcineurin inhibitors (CNI). Adapted from Farris AB. Histopathological syndromes of kidney allograft rejection and recurrent disease. In: Kirk A, Larsen C, Madsen J, Pearson T, Webber S, editors. Textbook of Organ Transplantation. Hoboken, NJ: John Wiley and Sons, Ltd; 2014. Loupy A, Haas M, Solez K, et al. The Banff 2015 kidney meeting report: current challenges in rejection classification and prospects for adopting molecular pathology. Am J Transplant. 2017;17(1):28–41. 2t3

surround vessels (without medial involvement), a nonspecific feature, and must not be confused with endarteritis. Tubulitis is often present in atrophic tubules and does not indicate acute rejection. The diagnosis of acute pyelonephritis should be raised when active inflammation and abundant intratubular neutrophils are present. A note of caution though because in acute AMR, neutrophilic tubulitis with neutrophil casts can be seen; a C4d stain will help in distinguishing between these. A

positive urine culture will also separate infection from rejection.131 Polyoma virus interstitial nephritis (BK virus) is often diagnosed by the presence of the enlarged, hyperchromatic tubular nuclei with lavender viral nuclear inclusions, often in collecting ducts. However, these may be inconspicuous, and diligent study of multiple sections may be required. Other clues are prominent apoptosis of tubular cells and abundant plasma cells, which invade

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tubules. IHC for the polyoma SV40 large T antigen or in situ hybridization for BK polyomavirus and EM (even of paraffin) will confirm the diagnosis. Sometimes BK virus infection, with its exuberant plasmacytic infiltration and activated immunoblasts may be confused with the plasmacytic hyperplasia form of posttransplant lymphoproliferative disease,131 which also should be considered in the differential diagnosis of acute cellular rejection. Rarer infections, including microsporidia, should also be considered in biopsies with interstitial inflammation.132–134 

ACUTE ANTIBODY-MEDIATED REJECTION Acute antibody-mediated rejection (also known as acute humoral rejection, acute AMR, or, as referred to in the latest Banff criteria: “active” AMR135) is a form of renal allograft rejection due to damage by circulating antibodies that react to donor alloantigens on endothelium. These antigens include HLA class I and class II antigens,14,136,137 ABO blood group antigens,138 and other non-major histocompatibility complex (MHC) antigens,108,139 even in HLA-identical grafts.140 The main risk factors for donorspecific antibody (DSA; this term typically refers to antiHLA antibody) are blood transfusion, pregnancy, and prior transplant.141 DSA may arise de novo in the posttransplant period, or alloantibody may be present before transplantation in the case of positive crossmatch (+XM) or ABO blood group incompatible transplants with preconditioning regimens to lower the alloantibody level before transplantation. Hyperacute rejection is an immediate rejection that occurs with high levels of preformed alloantibody directed against the graft. Traditionally, identification of acute AMR in biopsies is difficult because none of the histologic features is diagnostic, and immunoglobulin deposition was usually not detectable in the graft.142–144 Techniques for demonstrating C4d in PTCs, pioneered by Feucht,145 have substantially improved detection of this condition.14,144,146–148 Acute AMR may occur in the absence of evidence for T-cell-mediated injury, particularly in +XM transplants;149–151 however, it is not uncommon for both to be present, particularly in the later posttransplant period (months to years).14 Acute AMR typically presents with clinically severe acute rejection136 1 to 3 weeks after transplantation, but also can arise months to years later, associated with decreased immunosuppression or noncompliance.152 With current therapy, approximately 5% to 7% of recipients develop an episode of acute AMR, and about 25% of biopsies taken for acute rejection have pathologic evidence of an acute AMR component.16 The main risk factor is presensitization by blood transfusion, pregnancy, or prior transplant,141 however, the majority have a negative crossmatch at the time of transplantation.131 Serologic testing for DSA has become more sensitive in the past decade due to the widespread use of solid-phase assays rather than the older cell-based assays.153,154 These assays can be used before transplantation and for posttransplant monitoring for DSA. These more sensitive methods of detecting DSA have brought to light the spectrum of alloantibody-mediated damage (e.g., capillaritis) that may not have been recognized in previous studies.155,156

Diagnostic Criteria The three diagnostic criteria for acute AMR are (1) histologic evidence of acute injury (neutrophils in capillaries, acute tubular injury, fibrinoid necrosis), (2) evidence of antibody interaction with tissue (typically C4d in PTCs), and (3) serologic evidence of circulating antibodies to antigens expressed by donor endothelium (typically HLA).147,148,157 Criteria for the diagnosis of acute AMR have been refined over the years. Generally speaking, if only two of the three major criteria are established (e.g., when antibody is negative or not done), the diagnosis can be considered suspicious for acute AMR. Biopsies meeting criteria for both acute AMR and TCMR type I or II are considered to have both forms of rejection. Biopsies with C4d and no pathology are likely a manifestation of “accommodation” (see later).131  Pathologic Features Histologic findings are typically scant to moderate mononuclear interstitial infiltrates, sometimes with prominent neutrophils115,147,158,159 and increased numbers of macrophages160 (see Fig. 25.3). The extent of mononuclear infiltration often does not meet the criteria for TCMR.159 PTCs have neutrophils in about 50% of cases and are classically dilated (Fig. 25.4A). Interstitial edema and hemorrhage can be prominent. Glomeruli have accumulations of macrophages (∼50% of cases) and neutrophils (∼25% of cases; see Fig. 25.3)115,147,159,161 and occasionally fibrin thrombi or segmental necrosis.115,136,147 Acute tubular injury, sometimes severe, can be identified in many cases and may be the only initial manifestation of acute AMR. Focal necrosis of whole tubular cross sections, similar to cortical necrosis has been reported; 38% to 70% of acute AMR cases may have patchy infarction.115,162 Little mononuclear cell tubulitis is found, although a neutrophilic tubulitis with or without neutrophil casts may be prominent,115 resembling acute pyelonephritis. Plasma cells can be abundant in acute AMR, either early59 or late163,164 after transplantation, sometimes associated with severe edema and increased IFNγ production in the graft.164 B cells can be also present, but have no apparent diagnostic value.131 In about 15% of cases small arteries shows fibrinoid necrosis, with little mononuclear infiltrate in the intima or adventitia but with neutrophils and karyorrhectic debris (Fig. 25.5).115,162 Arterial thrombosis can be found in 10%, and a pattern resembling TMA has also been reported.162 Around 75% of cases with fibrinoid necrosis are C4d positive.115,147,158,161 Presumably the C4d-negative cases had T-cell-mediated rejection or TMA. Antibodies to the angiotensin II type 1 receptor have been detected in a few cases with arterial fibrinoid necrosis, in the absence of capillary C4d deposition.165 The presence of mononuclear endarteritis in cases of acute AMR strongly suggests a component of T-cell-mediated rejection.115 By EM the PTCs are dilated, containing neutrophils. The endothelium is reactive and shows loss of fenestrations. The glomerular endothelium is separated from the GBM by a widened lucent space with endothelial cell swelling115 and loss of endothelial fenestrations, indicative of injury. Platelets, fibrin, and neutrophils are found in glomerular and PTCs. The small arteries with fibrinoid necrosis show marked endothelial injury and loss, smooth muscle necrosis, and deposition of fibrin.131 

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389

B

A

∗ E

D

C

E Fig. 25.4  Chronic allograft glomerulopathy. (A) widespread duplication of the GBM with mild mesangial hypercellularity and increased mononuclear cells in the glomerular capillaries. PAS stain. Inset shows GBM multilamination at high power in a silver stain. (B) EM, high power of a glomerular capillary showing duplication of the GBM; the new or second layer of GBM (short arrow) forms underneath the endothelium (E) and is separated from the old GBM layer (long arrow) by the cellular (mononuclear or mesangial cell) interposition (*). C, capillary lumen; U, urinary space. (C) Immunohistochemistry stain for C4d in paraffin sections shows prominent C4d deposition in glomerular and peritubular capillaries. (D) EM, high magnification of a PTC with multilamination (arrow) of the basement membrane. Inset is a higher magnification of the area marked by arrow. E, endothelium; I, interstitium.

C4d Interpretation Feucht and colleagues first drew attention to C4d as a possible marker of an antibody-mediated component of severe rejection.145 C4d, a fragment of complement component C4, is released during activation of the classical complement pathway by antigen–antibody interaction. Because C4d contains a thioester bond, it binds covalently to tissues at the local site of activation. The covalent linkage explains why C4d remains for several days after alloantibody disappears, because antibody binds to cell surface antigens that can be lost by modulation, shedding, or cell death.

Although immunoglobulin deposition is found in only a minority of cases, C4d is characteristically detected in a widespread, uniform ring-like distribution in the PTCs by immunofluorescence in cryostat sections14,145 (see Fig. 25.4B). Deposition occurs in both the cortex and medulla. Using IHC in formalin-fixed, paraffin embedded tissue, C4d has a similar pattern, although the intensity is variable. “Serum staining” is an artifact of C4d IHC, so PTCs must show clear circumferential staining to be called positive by this technique. Glomerular capillary staining also occurs but is hard to distinguish from C4d normally found in the mesangium in frozen sections stained by

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Fig. 25.5  Fibrinoid arterial necrosis: an arteriole with destruction of the medial wall smooth muscle cells by fibrinoid necrosis. Some neutrophils are present underneath the reactive and swollen endothelium. This vascular change is distinctly different from endarteritis (compare with Fig. 25.2) and can be seen in both acute humoral rejection and type III acute rejection. This case had positive C4d.

immunofluorescence. Formalin fixation eliminates this background staining and demonstrates glomerular C4d in about 30% of acute AMR cases.159 Grafts with focal C4d (<50% of PTC) are of uncertain significance and the patient should be monitored closely for donor-reactive antibodies. Two of three studies have failed to show any significant clinical or pathologic difference between cases with focal and diffuse C4d staining.161,163,166 C4d deposition can precede histologic evidence of acute AMR by 5 to 34 days.167 C4d in 1-week protocol biopsies was followed by clinical acute rejection in 82% of cases168 and was associated with donor-reactive antibodies.169 In the setting of acute rejection, C4d is a specific (96%) and sensitive (95%) marker of circulating antidonor HLAspecific antibodies by the antihuman globulin cytotoxicity test.170 PTC C4d deposition is associated with concurrent circulating antibodies to donor HLA class I or II antigens in 88% to 95% of recipients with acute rejection.147,171,172 Moreover, C4d deposition and the severity of histologic injury by antibody correlates with the serum DSA level in acute humoral rejection.149 False negative antibody assays may be due to absorption by the graft as shown by elution from rejected grafts in patients who had no detectable circulating antibody,173 or it may be due to differences in detection of antibody directed against different HLA alleles and sensitivity of solid-phase methods for particular alloantigens. Alternatively, non-HLA antigens may be the target.16,174–179 C4d-negative acute rejection may show flow cytometry evidence of antidonor reactive antibodies as frequently as 50%,171 due in part to noncomplement fixing antibodies.180 Cell based assays have a false positive rate of <10%.147 In a comparison of methods for C4d, the triple layer immunofluorescence technique14 proved the most sensitive, although the difference with IHC in paraffin embedded tissue was small.181 With fixed tissue, plasma in the capillaries and interstitium may stain for C4d, which interferes with interpretation.131

Other components of the complement system have been sought. C3d, a degradation product of C3, was found in PTCs in 39% to 60% of biopsies from HLA-mismatched grafts with diffuse C4d.158,168,172,182 C3d was usually172 but not always182 associated with C4d. C3d correlated with acute AMR in all studies, and was associated with increased risk of graft loss in two series, compared with C3d-negative cases, but C3d provided no convincing additional risk compared with C4d+. The interpretation of C3d stains is complicated by the common presence of C3d along the TBM.172 Even though C3d should indicate more complete complement activation, it added no diagnostic value to C4d in grafts showing histologic features of acute AMR, except in the setting of ABO-incompatible grafts.172 Other complement components, such as C1q, C5b9, and C-reactive protein (CRP) are not conspicuous in PTCs in acute rejection.183,184 Lectin pathway components, which activate C4 by binding to microbial carbohydrates, are sometimes detected.168,185 Among 18 biopsies with C4d, 16 had diffuse H-ficolin deposition along the PTCs, whereas none of the 42 cases without C4d had H-ficolin. No Mannan-binding lectin serine protease 1 (MASP-1, also known as mannoseassociated serine protease 1) or MASP-2 was detectable.185 The significance of this observation is not clear, because MASP proteins are required to activate C4 via the ficolins or Mannosebinding lectin (MBL).185 Natural killer (NK) cells have been the focus of recent research in graft injury, particularly regarding AMR.186,187 Microarray analysis has indicated that several DSA-specific gene transcripts show high expression in NK cells, and IHC also shows prominent numbers of peritubular capillary NK cells in these cases.188 Depletion of NK cells with antiNK1.1 significantly reduced DSA-induced chronic allograft vasculopathy in a murine cardiac allograft model.186,189 

C4d Negative Antibody-Mediated Rejection Attention has recently been drawn to “C4d-negative” AMR, and recent Banff allograft classification documents encourage that cases be designated as “C4d positive” or “C4d negative.”157,190 These cases have DSA and varying degrees of morphologic evidence of antibody-mediated injury but lack detectable C4d deposition in PTC endothelium.191–193 Morphologic signs of injury with concurrent DSA positivity have been identified, particularly in sensitized patients early after transplantation.191,194 Negativity for C4d in AMR can be explained by various mechanisms: time-dependent degradation of C4d-deposits in the microcirculation, complement independent antibody-mediated injury, lack of sensitivity and reproducibility of the staining methods, arbitrary criteria for defining “positivity,” and acute tissue injury due to nonrejection causes with incidental chronic alloantibody-associated changes (capillaritis; usually C4d negative).193 Molecular studies have uncovered a subset of cases with morphologic features of antibody-mediated injury and DSA showing increased endothelial cell associated transcript expression, indicative of endothelial cell activation and stress. These data suggest that 50% to 60% of AMR cases are missed by current Banff criteria due to C4d negativity,195 although many of these cases may be chronic alloantibody-mediated endothelial

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TABLE 25.4  Differentiation Between Acute Rejection and Acute Calcineurin Inhibitor Toxicity Acute Rejection

CNI Toxicity

INTERSTITIUM Infiltrate Edema

Moderate–marked Absent–mild Usual Can be present

TUBULES Tubular injury Vacuoles Tubulitis

Usual Occasional Prominent

ARTERIOLES Endothelialitis Can be present Smooth muscle degeneration Absent Mucoid intimal thickening Absent with red cells

Usual Common Minimal–absent Absent Sometimes present Sometimes present (TMA)

ARTERIES Endothelialitis

Common

Absent (rare mononuclear TMA)

PERITUBULAR CAPILLARIES C4d

May be positive

Negative

GLOMERULI Mononuclear cells Thrombi

Often Occasional

Rare Occasionally prominent (TMA)

CNI, calcineurin inhibitor; TMA, thrombotic microangiopathy.

injury and represent a different mechanism of injury from acute AMR, which is likely more complement mediated.196 Eventually, C4d-negative AMR will likely be added to the Banff diagnostic armamentarium as a distinct category of AMR; however, data are still being gathered by a respective Banff Working Group regarding the significance of this entity in an attempt to provide diagnostic criteria.17

Differential Diagnosis For differential diagnosis, it is helpful that both ATN144,197 and TMA in native kidneys are C4d negative. Among 26 cases of TMA/hemolytic-uremic syndrome in native kidneys, none had positive C4d, including cases with lupus anticoagulant and antiphospholipid antibodies.144 In five cases of recurrent hemolytic-uremic syndrome in transplant recipients, C4d was also negative.198 Among native kidney diseases, only lupus nephritis144,199 and endocarditis199 have been reported to have PTC C4d. Glomerular C4d deposits are not specific because they occur in many forms of immune complex glomerulonephritis in native kidneys. Arterial intimal fibrosis often stains for C4d, even in native kidneys and should not be taken as evidence of AMR.144 The comparative features of “pure” humoral and TCMR are given in Table 25.4. In acute AMR neutrophils are the predominant inflammatory cells in PTCs, glomeruli, tubules, and the interstitium, with or without accompanying fibrinoid necrosis. The vascular lesion of acute AMR, if present, is fibrinoid necrosis of the wall; whereas, in TCMR, endarteritis is the usual lesion. C4d deposition in PTCs (immunofluorescence microscopy) is typically only present in acute AMR but not in TCMR.131 The prognosis of acute AMR is uniformly worse than TCMR.14,108,115,136,139,162 In one series, 75% of the 1-year graft losses from acute rejection were in the C4d+ acute

391

AMR group.147 However, some of those who recover from the acute episode of acute AMR have a similar long-term outcome,115 suggesting that the pathogenetic humoral response can be transient if treated effectively. 

Accommodation The process termed “accommodation” is a peculiar scenario related to AMR. Accommodation refers to the presence of PTC C4d deposition in the absence of other evidence of antibody-mediated injury and in the presence of normal or stable graft function. Accommodation is thought to represent a process of endothelial cell adaptation to antibody and complement over time. In accommodation, donor-specific antibodies may be detectable; however, morphologic signs of tissue injury are absent. There are no signs of acute or chronic TCMR or AMR; more specifically, there is no ATNlike minimal inflammation, no glomerulitis [g0], no chronic transplant glomerulopathy [cg0], no peritubular capillaritis [ptc0], and no PTC basement membrane multilamination. Current Banff criteria refer to this situation as “C4d deposition without evidence of active rejection.” If there are simultaneous borderline changes, the cases can be considered to be indeterminate.157,190,200 Accommodation is common in the setting of ABO-incompatible allografts, with at least 80% of normal surveillance biopsies showing C4d deposition in PTCs.172 It appears that antibodies against blood group antigens (i.e., ABO-incompatible allografts) are mostly not injurious to allografts with “accommodation”; however, allografts with “accommodation” having anti-HLA antibodies may progress to chronic AMR, given enough follow-up surveillance.157 The long-term significance of these relatively uncommon cases is still under investigation.138,201–203  Complement Inhibition Although most approaches for treatment or prevention of acute AMR involve removing alloantibody from the circulation (by plasmapheresis) or decreasing production of alloantibody (e.g., by antiplasma cell drugs), another technique to prevent graft damage by antibody is by inhibiting complement. Eculizumab, a humanized monoclonal antibody directed against the terminal complement component C5, is now being applied in renal transplantation, particularly in sensitized (+XM) patients at a high risk for early acute AMR. C5 is downstream of C4d in the complement cascade; thus, with DSA activation of complement, diffuse C4d deposition would be expected even with effective C5 inhibition. Early surveillance biopsies in eculizumab-treated patients showed diffuse C4d deposition but absent morphologic signs of acute AMR, including a lack of endothelial cell activation by EM. The absence of respective pathology suggests endothelial protection by eculizumab, and moreover supports the notion that most cases of early acute AMR are complement mediated. However, acute AMR has been observed despite eculizumab therapy and may be due to IgM DSA not detected by the usual DSA testing methods.204,205 Notably, a subset of patients still developed features of chronic humoral rejection (chronic AMR), including transplant glomerulopathy (TG).196 Although effective in preventing early acute AMR in +XM transplants, it appears that complement inhibition alone does not entirely prevent chronic, antibody-mediated microcirculation injury. Furthermore,

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the diagnostic reliability for acute AMR of C4d and serum DSA are apparent in this setting, suggesting that diagnostic criteria refinements are needed (See Chapter 22). 

definitions are faulty. Despite these considerations, Banff is fully accepted as a scoring system of drug trials and is used widely in clinical practice (although not necessarily with an individual score report).131 

CLASSIFICATION SYSTEMS The most widely used system currently is the Banff working schema (Banff). Banff started as an international collaborative effort led by Kim Solez, Lorraine Racusen, and Philip Halloran to achieve a consensus that would be useful for drug trials and routine diagnosis.10,17,206 Banff is still growing and remodeling, undergoing revisions based on data presented, and debated at the biennial Banff meeting. These include restructuring that separated the category of endarteritis, according to the National Institutes of Health (NIH) Cooperative Clinical Trials in Transplantation (CCTT) criteria,11,207 the addition of acute148 and chronic AMR,208 and the birth10 and death208 of chronic allograft nephropathy (CAN).209 Banff scores three elements to assess acute rejection: tubulitis (t), the extent of cortical mononuclear infiltrate (i), and vascular inflammation (intimal arteritis or transmural inflammation) (v). Mononuclear cell glomerulitis (g) is scored but not yet part of the classification of rejection. Banff recognizes three major categories of acute T-cellmediated rejection (tubulointerstitial, endarteritis, and arterial fibrinoid necrosis; see Table 25.2). The threshold for type I (tubulointerstitial) TCMR is >25% cortical mononuclear inflammation in the nonatrophic areas, provided tubulitis of at least 5 to 10 cells/tubule is present.207 Cases with no tubulitis, regardless of the extent of infiltrate, are not considered TCMR. Biopsies with C4d+ PTCs are considered to have an additional component of AMR, which occurs in 20% to 30% of cases.210 Cases with tubulitis are termed “suspicious for rejection” or “borderline” in the current Banff system. Many, but not all, of these cases are early or mild acute rejection: 75% to 88% of patients with suspicious/borderline category and graft dysfunction improve renal function with increased immunosuppression,211,212 comparable to the response rate in type I rejection (86%).211 A minority (28%) of untreated suspicious/borderline cases progress to frank acute rejection in 40 days.213 Almost all with suspicious/borderline findings do well, provided there is no element of concurrent AMR, which commonly has a suspicious/borderline pattern, although care must be taken not to misinterpret peritubular capillaritis as interstitial inflammation.155,159 The suspicious category is not counted as acute rejection in many clinical trials, a major omission in our opinion. The interobserver reproducibility of the present Banff classification is sufficient but needs improvement. In a Canadian study, the agreement rate for rejection was 74%, but there was only 43% agreement on the suspicious/borderline cases,214 similar to a European series.215 Among a group of 21 European pathologists, the agreement rate was poor for all of the acute Banff scores (t, i, v, g) in transplant biopsy slides (all kappa scores <0.4).28 Agreement for t and v scores improved significantly when participants were asked to grade a lesion in a photograph (kappa scores of 0.61 and 0.69, respectively), arguing that the challenge is primarily finding the lesion in the glass slide. Lack of improvement in the other categories (g, i) argues that the

Late Graft Diseases Although acute rejection has diminished in clinical importance in the past decade, allografts are still lost by slow, progressive diseases that cause a 3% to 5% annual attrition rate. The specific causes of this are many and sometimes difficult to ascertain, particularly if only an end-stage kidney is examined. Unfortunately, the two terms “chronic rejection” and “CAN” have been used in past literature to lump together these myriad diseases. The role of the pathologist in interpreting the biopsy is to provide the most specific diagnosis possible and indicate the activity of the process. Although some have argued that the renal biopsy is not useful in analyzing graft dysfunction after 1 year, the data show that in 8% to 39% of patients the biopsy led to a change in management that improved renal function.2,3 Here we will discuss the criteria used to distinguish some of these diseases and those that remain idiopathic. The term “chronic rejection” is best defined as chronic injury primarily mediated by an immune reaction to donor alloantigens.

CHRONIC ANTIBODY-MEDIATED REJECTION Circulating anti-HLA antibodies have been associated with increased risk of late graft loss.216,217 Chronic, active antibody-mediated rejection (chronic humoral rejection, chronic AMR) is now recognized as a separate category in the Banff schema. Chronic AMR differs from acute AMR in the usual lack of evidence of acute inflammation (thrombi, necrosis, mostly neutrophilic capillaritis), and the presence of matrix synthesis (basement membrane multilamination, fibrosis in arterial intima and the interstitium). Chronic AMR commonly arises late (>6 months after transplantation) and may occur in patients with or without a history of acute AMR, although C4d in early biopsies is a risk factor for later TG with C4d.218–221 In the setting of de novo DSA, many patients have reduced levels of immunosuppression (absorption, iatrogenic or noncompliance).222 In these cases, a combination of chronic AMR and acute AMR may be seen, along with a component of T-cell-mediated rejection.151 The criteria of chronic AMR are the triad of: (1) one of the following morphologic features, TG (duplication or “double contours” in glomerular basement membranes), multilamination of the PTC basement membrane, PTC loss and interstitial fibrosis (IF), or chronic arteriopathy with fibrous intimal thickening (without duplication of the internal elastica); (2) diffuse C4d deposition in PTCs; and (3) circulating DSA. If only two elements of the triad are present, the diagnosis is considered “suspicious.” Although helpful when positive, C4d deposition and serum DSA are particularly problematic in the chronic setting. They are less sensitive markers due to serum DSA level variability with time posttransplant. Two features point to ongoing immunologic activity: the presence of C4d and mononuclear cells in glomerular and PTCs. Scoring of multilamination requires

25 • Pathology of Kidney Transplantation

EM, not always available in transplant biopsies, and quantitative assessment of the number of layers, because to distinguish from other common causes of lamination, more than approximately six layers have to be present.223,224 To be specific for AMR, current Banff criteria recommend that seven or more layers should be present in one peritubular capillary and five or more layers be present in two additional capillaries,157,190 and this is largely based on one study.224 In assessing peritubular capillary basement membrane multilamination by EM, peritubular capillary basement membranes cut tangentially should be avoided. A Banff Working Group is currently engaged in efforts to refine the assessment of peritubular capillaries and other features by EM.157 Duplication of the GBM has many other causes, such as TMA and MPGN; however, these do not have C4d in PTC unless there is more than one concurrent pathologic process.225 A sequence of four stages of development of chronic AMR has been demonstrated in protocol biopsies of nonhuman primate renal allografts. The process begins with antibody production, followed by C4d deposition, and later, morphologic and functional changes.226 Validation of these processes has recently been provided by gene expression profiling.227 Proof that antibody is sufficient to initiate allograft arterial intimal fibrosis has been shown by passive transfer of anti-MHC antibody into immunologically deficient mice (RAG-1 knockout) bearing cardiac allografts.228

Transplant Glomerulopathy TG (chronic allograft glomerulopathy, given a cg score in the Banff system) increases in frequency from 1 to 5 years posttransplant (5%–14% of protocol biopsies) and affects graft survival more adversely than IF and inflammation.229 TG has been associated with prior episodes of acute rejection, pretransplant hepatitis C antibody positivity, and anti-HLA antibodies (especially anti-class II), with the risk increasing if the antibodies were donor specific.204,220 Patients with preformed DSA (+XM grafts) have a particularly high risk of TG long term, present in 55% of all surviving grafts at 5 years, and in 85% of surviving grafts with anti-HLA class II DSA.204 TG is defined as duplication of the GBM with modest mesangial expansion, in the absence of specific de novo or recurrent glomerular disease. TG is best revealed in PAS or silver stains (see Fig. 25.4A). The glomeruli may show an increase in mesangial cells and matrix with various degrees of scarring and adhesions. In some cases, mesangiolysis or webbing of the mesangium may be prominent as well as segmental or global sclerosis. EM reveals duplication or multilamination of the GBM (see Fig. 25.4B), often accompanied by cellular (mononuclear or mesangial cell) interposition, widening or lucency of the subendothelial space, and a moderate increase in mesangial matrix and cells.230 Glomeruli may show focal and segmental scarring (FSGS), especially in more advanced TG, and some cases with collapsing FSGS lesions have been observed. EM detects 40% more cases of TG than light microscopy.223 The GBM typically has rarefactions, microfibrils, cellular debris but few or no deposits.231–233 Endothelial cells may appear reactive with loss of fenestrae, probably undergoing “dedifferentiation.”232–234 Podocyte foot process effacement ranges from minimal to quite extensive,232 corresponding to the degree of proteinuria. The nonduplicated GBM may become

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slightly thickened, attributable to compensatory hypertrophy. With immunohistochemical techniques in paraffin sections, C4d is present along the glomerular capillary walls in about 10% to 30% of cases.218,235 Extensive crescents or diffuse immunoglobulin deposits are unusual and suggest recurrent or de novo glomerulonephritis.236–238 It is now recognized that approximately 30% of TG due to chronic AMR are C4d negative.239 Notably, although most cases of TG are due to chronic AMR, this pattern is also seen in allografts with chronic thrombotic microangiopathy and in patients with hepatitis C infection.225 

Peritubular Capillary and Tubulointerstitial Lesions PTCs may be dilated and prominent, with thick basement membranes, or may altogether disappear, leaving only occasional traces of the original basement membrane behind.240,241 In a subset of patients, PTCs have prominent C4d deposition (see Fig. 25.4C), which is associated with circulating antidonor HLA class I or II reactive antibodies.242 Other allografts with chronic AMR features may show focal or multifocal C4d staining of PTCs by immunofluorescence or IHC or dim C4d staining by immunofluorescence. In studies of protocol biopsies in graft recipients with DSA, recognition of peritubular capillaritis has come to light as a feature of early chronic humoral rejection.156,243 Peritubular capillaritis, with or without C4d deposition, is commonly seen as a subclinical rejection feature in patients with DSA in otherwise stable grafts. Peritubular capillaritis is associated with later development of TG, with a greater risk of TG in patients with C4d deposition,156 likely reflecting a more active chronic humoral rejection process in those grafts. EM reveals splitting and multilayering of the PTC basement membrane (see Fig. 25.4D), first described by Monga.244,245 Each ring probably represents the residue of one previous episode of endothelial injury going from oldest (outer) to most recent (inner). Quantitation is necessary to establish diagnostic specificity. Only in chronic rejection were three or more PTCs found with five to six circumferential layers or one PTC with seven or more circumferential layers.223 PTC lamination correlates with TG,223,245 C4d deposition,218 and loss of PTCs.241 Marked multilamination (five to six layers in three capillaries or more than six in one) was found in 50% of cases with IF that lacked arterial or glomerular changes, and may point to past episodes of rejection as the cause of the fibrosis.245 Interstitial fibrosis and tubular atrophy (IFTA) is a regular, but nonspecific feature of chronic AMR and does not serve to distinguish rejection from other causes, such as calcineurin inhibitor (CNI) toxicity or previous BK polyomavirus infection. Atrophic tubules typically have thickened, duplicated TBMs and intratubular mononuclear cells and mast cells.246 This should not be confused with the tubulitis of acute rejection. The TBM not uncommonly has deposition of C3 in a broad segmental pattern. This is an exaggeration of similar changes found in normal kidneys and probably represents a residue from prior episodes of tubular injury, or possibly a persistent chronic injury. The interstitium typically has a sparse mononuclear infiltrate, with small lymphocytes, plasma cells, and mast cells.247 Nodular collections of quiescent-appearing lymphoid cells are sometimes found around small arcuate arteries. Abundant plasma cells may be present.248 

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Transplant Arteriopathy Arterial lesions may be a manifestation of chronic AMR.249 Alloantibodies to graft class I antigens are a specific risk factor for chronic transplant arteriopathy (TA) in human renal allografts.250,251 Typically, TA is recognized by thickening of the arterial intima with mononuclear inflammatory cells (CD3+ T cells or CD68+ monocytes/macrophages) within the thickened intima. In a recent study, patients with preformed DSA showed accelerated arteriosclerosis on serial biopsies.249,252 Although the TA lesions were attributable to DSA on serial biopsies from the same allografts, TA such as that due to chronic AMR may not be distinguishable from the arterial intimal thickening seen in hypertension,249 and other biopsy and serologic features are needed to attribute the lesion to chronic AMR.249,252 Experiments in animals show that TA can be initiated by passive transfer of donorreactive MHC antibodies in recipients with no functional T cells, a complement-independent process mediated by NK cells.218,242 

Fig. 25.6 Chronic allograft arteriopathy: an interlobular artery with prominent intimal fibroplasia. The presence of scattered mononuclear cells in the intima and the lack of duplication of the internal elastica are characteristic of chronic rejection. This biopsy was positive for C4d.

CHRONIC T-CELL-MEDIATED REJECTION This category is not well developed and subject to refinement. Using the chronic AMR model, the current Banff classification defines “chronic active T-cell-mediated rejection” as showing morphologic features of chronicity (arterial intimal fibrosis without elastosis) combined with features indicative of ongoing T cell activity (mononuclear cells in the intima). IF with a mononuclear infiltrate and tubulitis is, in some instances, part of this condition, as surveillance follow-up biopsies after an episode of acute cellular rejection not uncommonly show continued inflammation.253 However, at present the arterial lesions are the most definitive. It is anticipated that molecular gene expression studies will help in the future to document the activity of the infiltrate. Other nonspecific features that are commonly present in association with transplant arteriopathy are loss of PTCs and IFTA.241 Small and large arteries, as early as 1 month after transplantation, can begin to develop severe intimal proliferation and luminal narrowing.249,254,255 The intimal change is most prominent in the larger arteries, but can be seen at all levels, from interlobular arteries to the main renal artery. The intima shows pronounced, concentric fibrous thickening with invasion and proliferation of spindle-shaped myofibroblasts (Fig. 25.6). This vascular change has been termed “chronic transplant arteriopathy” and when combined with an infiltrate of mononuclear cells in the intima, is characteristic of chronic T-cell-mediated rejection (Fig. 25.7). Subendothelial mononuclear cells are one of the most distinctive features, and this suggests that the endothelium itself is a target. T cells (CD4+, CD8+, CD45RO+), macrophages, and dendritic cells infiltrate the intima.256–258 T cells express cytotoxic markers, including perforin259 and GMP-1767 and markers of proliferation (proliferating cell nuclear antigen [PCNA]).258 No B cells (CD20) are detected.258 It is imagined that this is a dampened version of the endarteritis of acute rejection. As noted previously, recent studies have also indicated that chronic vascular lesions can be accelerated by the presence of alloantibody.249,252 The second distinctive feature is the lack of multilamination of the elastica interna (fibroelastosis), best appreciated

in elastin stains. Fibroelastosis, typical of hypertensive, atrophic and aging arterial changes, provides a useful differential diagnostic feature from rejection. Foamy macrophages containing lipid droplets are sometimes seen along the internal elastica and can be found as early as 4 weeks after transplantation. Fibrin is sometimes deposited in a band-like subendothelial location or mural thrombus. Focal myocyte loss from the media occurs, as shown in mouse and rat studies.260 Immunofluorescence often shows IgM, C3, and fibrin (and sometimes IgG) along the endothelium, in the intima, or in the media, as a diffuse blush or focal granular deposits.231,250,261–263 The endothelium expresses increased adhesion molecules, notably ICAM-1 and VCAM-1. Antagonism of ICAM-1 binding/expression inhibits chronic rejection264 and in humans certain ICAM-1 genetic polymorphisms (e.g., exon 4, the Mac-1 binding site) appear to confer higher risk for chronic rejection.265 The endothelium remains of donor origin,266,267 however, some of the spindle-shaped cells that contribute to the intimal thickening are of recipient origin.257,268 The myointimal cells stain prominently for smooth muscle actin, sometimes so strikingly that a “double media” seems to be formed.269 This phenomenon has also been described as the development of a new artery inside and concentric with the old,270 with elastic laminae and a muscular media, separated from the old internal elastic lamina poorly by cellular tissue. By EM, the thickened intima consists of myofibroblasts, collagen fibrils, basement membrane material, and a loose amorphous electron-lucent ground substance.271 The matrix consists of collagen, fibronectin, tenascin, proteoglycans (biglycan and decorin), and acid mucopolysaccarides.272–274 Fibronectin has the extra domain of cellular fibronectin extra domain A (EDA), typical of embryonic or wound healing fibronectin.272 Several growth factors/cytokines have been detected. Plateletderived growth factor (PDGF) A chain protein is primarily in endothelial cells, whereas the B chain is in macrophages and smooth muscle cells.275 Enhanced PDGF B-type receptor protein was found on intimal cells and on smooth muscle cells of the proliferating vessels.276 FGF-1 and its

25 • Pathology of Kidney Transplantation

A

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B

Fig. 25.7  CNI arteriolopathy. (A) Several arterioles with peripheral nodular hyalinosis, where hyalin deposits replace necrotic/apoptotic smooth muscle cells in the outermost media. (B) EM, an artery that has “beads” of hyalin (*) along the outer media. L, arteriolar lumen; T, tubule. (PAS 800×; EM 2700×.)

receptor are present in the thickened intima.277 TNFα is in the smooth muscle of vessels with chronic rejection, in contrast to normal kidneys.278 The T-cell-mediated arterial lesions can be divided into three stages, which probably differ in mechanism and reversibility.234 The stage I lesion is endarteritis, characteristic of type II TCMR. This lesion lacks matrix formation. This acute stage is believed to be T-cell-mediated endothelial injury. Stage II lesions have intimal matrix production and accumulation of myofibroblasts forming a “neointima.” This stage also contains mononuclear cells (T cells and macrophages), believed to be active in the intimal proliferation and accumulation of matrix. Intermediate stages between stage I and II lesions are sometimes found, with lymphocytes admixed with fibrin and fibromuscular proliferation, and are well documented in a nonhuman primate model of chronic rejection.279 Secondary factors probably become increasingly important as the lesion progresses to stage III, where the intima is fibrous and inflammatory cells are scant. A fourth category resembling natural atherosclerosis with cholesterol clefts and calcification has also been proposed.258 A large body of experimental evidence supports the concept that the arterial lesions are immunologically mediated234: (1) the lesions do not routinely arise in isografts; (2) the target antigens can be either major or minor histocompatibility antigens;260,280,281 (3) the specific initiator is probably T cells followed by antibody (antibody is necessary and sufficient for the fibrous lesion in mice); (4) the target cell is probably the endothelium, but the smooth muscle may also be affected; (5) secondary nonimmunologic mechanisms analogous to those in atherosclerosis are important in the progression of the lesion; and ultimately (6) the process may be independent of specific antidonor immunologic activity. T cells are sufficient to initiate cellular vascular lesions in B cell deficient mice, but these lesions do not readily progress to fibrosis in the absence of antibody.282 Fibrous lesions are also markedly reduced in strain combinations that fail to elicit a humoral antibody response. The best evidence for T cell mechanisms of chronic allograft injury in humans is that subclinical or late clinical cellular rejection is associated with progressive graft fibrosis and dysfunction,283–285 and endarteritis is associated with later transplant arteriopathy.286 As mentioned previously,

TABLE 25.5  Differentiation Between Acute Humoral Rejection and Acute Cellular Rejection Acute Humoral Rejection

Acute Cellular Rejection

Variable Present Neutrophils Positive

Moderate–severe Present Mononuclear cells Negative

Can be present Can be neutrophilic

Usually absent Mononuclear cell

VESSELS Endarteritis Fibrinoid necrosis

Can be present Can be present

Present in type II Present in type III

GLOMERULI Inflammatory cells Fibrinoid material/necrosis

Neutrophils Can be present

Mononuclear cells Typically absent

INTERSTITIUM Infiltrate Edema Peritubular capillaries C4da TUBULES Acute tubular necrosis Tubulitis

aC4d

staining in peritubular capillaries indicates activation of the classical complement pathway by humoral antibody (monoclonal antibody, immunofluorescence microscopy).

antibodies likely conspire to accelerate the process of allograft arteriopathy/arteriosclerosis.249,252 Recent data indicate that allograft deterioration is accelerated by inflammation in scarred areas as well as unscarred areas287,288 in contrast to some of the past thought, which tended to disregard inflammation in scarred areas. For this reason, recent Banff classification added a new score, i-IFTA, which takes into account inflammation in areas of interstitial fibrosis and tubular atrophy. Furthermore, a Banff Working Group on T-cell-mediated rejection was formed to consider incorporation of i-IFTA into rejection classification and possible elimination of the “borderline” category; this working group is reevaluating thresholds for inflammation and tubulitis (t) and considering the addition of other findings (e.g., edema) in the diagnosis of rejection.157 Along these lines, as shown in Table 25.5, the most recent Banff meeting has now specified criteria for a diagnosis of chronic active TCMR.135 

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OTHER SPECIFIC DIAGNOSES The other conditions that can be diagnosed by a renal biopsy that cause slowly progressive graft dysfunction and loss are: calcineurin inhibitor toxicity (CNIT), hypertensive vascular disease, PTN, recurrent disease, de novo glomerular disease, obstruction, and renal artery stenosis.16 Chronic CNIT is most specifically diagnosed by the presence of nodular hyaline replacement of individual smooth muscle cells, which may form distinctive deposits on the outer side of the arteriole, as described by Mihatsch as cyclosporin arteriolopathy. Ordinary hyalinosis due to diabetes, hypertension, or aging typically is subendothelial.289–291 To distinguish intimal fibrosis due to hypertension from that due to chronic rejection, an elastin stain is valuable, because in hypertension, but not necessarily in rejection, the elastica interna is multilayered (“elastosis”), and in chronic rejection the elastica is not duplicated, but may be fractured. A recent study, however, suggested that some lesions of vascular intimal thickening due to alloantibody are indistinguishable from those due to hypertension.249 Foam cells and mononuclear cells in the intima also favor rejection. The features that point to a component of chronic AMR were discussed earlier and include, most specifically, the presence of C4d in PTC and/or glomeruli. Multilamination of the GBM or PTC basement membranes is also typical. In the absence of C4d in PTC other causes of lamination of the GBM must be excluded. Demonstration of polyomavirus by IHC in previous biopsies can point to a causal role in the late graft damage, even when the virus is no longer detectable.131 Obstruction, usually difficult to diagnose by histology, archetypically shows dilated collecting ducts, especially in the outer cortex, lymphatics filled with Tamm-Horsfall protein, occasionally ruptured tubules with granulomas, and sometimes acute tubular injury.131 Patients with obstruction may show a completely normal histologic appearance on allograft biopsy, however. Renal artery stenosis causes TA (or even acute injury) accompanied by relatively little fibrosis or intraparenchymal arteriolar/arterial lesions.131 Recurrent and de novo glomerular diseases are generally identified by their light, immunofluorescence, and electron microscopic criteria in native kidneys.131 

INTERSTITIAL FIBROSIS AND TUBULAR ATROPHY There remain cases with IFTA in which no specific diagnosis can be made. Some of these cases may be the end stage of active processes in which the etiologic agent is no longer appreciable (e.g., late effects of polyomavirus or TMA). Others may represent burned out or inactive rejection. This might be the case for TG or arteriopathy without C4d deposition. Animal studies have shown that limited exposure to anti-MHC antibody can cause longstanding arteriopathy, despite only transient C4d deposition.228 The term “CAN” was created in Banff in 1993 to draw attention to the fact that not all late graft injury was due to rejection, and that, to make the diagnosis of rejection, certain more specific features than IF and TA needed to be

present (notably chronic glomerular or arterial lesions). However, the unintended consequence was that “CAN” itself became a diagnosis that inhibited search for specific and perhaps treatable causes. CAN was replaced in Banff 2005 with category 5: “IF and TA, no evidence of any specific etiology.” This now includes only those cases for which no specific etiologic features can be defined, and excludes those with pathologic features of chronic AMR, chronic CNIT, hypertensive renal disease, PTN, obstruction, or other de novo or recurrent renal disease.209 

Protocol Biopsies “Protocol” or “surveillance” biopsies taken at predetermined times for evaluation of the status of the renal allograft, independent of renal function, are currently the standard of care at several leading transplant centers229,283,284,292–295 and widely used in clinical trials to evaluate efficacy.296 Protocol biopsies have the potential ability to reveal mechanisms of late graft loss and to identify active processes that might be interrupted therapeutically before irreversible injury has occurred.297 The risk of protocol biopsy is low. There were no deaths or graft losses in the Hannover series of more than 1000 biopsies298 and graft loss was 0.04% in another protocol biopsy series.299 The current interest in protocol biopsies started with David Rush and colleagues, who made the surprising observation that 30% of biopsies from stable patients 1 to 3 months posttransplant showed histologic rejection300 and those with these lesions show later loss of renal function.284,301 Many other studies have confirmed this result.229,283,284,292–294 Mononuclear inflammation that meet the Banff criteria for TCMR or borderline acute rejection are found in 5% to 50% of protocol biopsies in the first 12 months, depending on therapy and patient populations.302 Those with inflammation have a higher risk of graft dysfunction or fibrosis at later time points.229,283,293,294 Grafts with both inflammation and fibrosis do the worst,229,287,294,303 In one study, the best predictor of allograft function 1 year after transplantation was persistent inflammation, of any type, including those patterns considered in Banff to be irrelevant to the diagnosis of acute rejection (in areas of IF, around large blood vessels, in nodules, or in subcapsular areas).304 Infiltrates in areas of atrophy correlated with IFTA at 6 months and graft dysfunction at 2 years. In another study, protocol biopsies at 1 year posttransplant that showed fibrosis and inflammation predicted a worse GFR at 5 years compared with biopsies with fibrosis and no inflammation and compared with normal biopsies.305 These results and the results of other studies suggest that these infiltrates are part of the pathogenesis of slow, progressive renal injury.287,288,296 What differentiates infiltrates in patients with stable and unstable graft function? In stable grafts endarteritis is found rarely (0.3% in one series)306 and can herald an impeding acute episode.300 Among the interstitial infiltrates, only the diffuse pattern (rich in macrophages and granzyme B cytotoxic T lymphocytes) was more common in biopsies taken for acute dysfunction.304 In contrast, nodular infiltrates (rich in B cells and activated T cells) were more common in protocol biopsies. Similarly, infiltrates rich in activated

25 • Pathology of Kidney Transplantation

macrophages distinguished biopsies with clinical versus subclinical acute rejection.307 Molecular studies have shown that increased levels of transcripts for T-bet (a Th1 master transcription factor), FasL (cytotoxic mediator), and CD152 (CTLA-4, an inhibitory costimulatory molecule) are associated with graft dysfunction.101 Grafts in recipients that are developing tolerance also typically have graft infiltrates, sometimes termed the “acceptance reaction,”308 which spontaneously disappears and is followed by indefinite graft survival.309,310 The acceptance reaction had less infiltration by CD3+ T cells and macrophages, less T cell activation, long lasting apoptosis of graft infiltrating T cells, less IFNγ, and more IL-10 than rejecting grafts.310,311 Recent evidence shows that regulatory T cells (Treg) that express the Foxp3 transcription factor infiltrate tolerated grafts in mice treated with costimulatory blockade.312 Foxp3 cells can also be found in grafts with infiltrates interpreted as acute rejection.92 Although the significance of Foxp3+ cells has yet to be determined, high numbers of such Treg cells are likely beneficial,313 in view of the known suppressor functions of these cells. The hope of much ongoing research is the discovery of markers that predict graft acceptance in a clinical setting.313,314 Subclinical interaction of antibody with graft endothelium (accommodation) has been revealed by the demonstration of diffuse C4d in PTCs, found in 2.0% of routine protocol biopsies,306 and a higher frequency among presensitized patients (17%) or patients with ABO-incompatible grafts (51%).138,172 The stability of such accommodation, referring to the presence of PTC C4d deposition in the absence of other evidence of antibody-mediated injury has not been established. Accommodation is thought to represent a process of endothelial cell adaptation to antibody and complement over time. In accommodation, donor-specific antibodies may be detectable; however, morphologic signs of tissue injury are absent. There are no signs of acute or chronic TCMR or AMR; more specifically, there is no ATNlike minimal inflammation, no glomerulitis [g0], no chronic TG [cg0], no peritubular capillaritis [ptc0], and no PTC basement membrane multilamination. Current Banff criteria refers to this situation as “C4d staining without evidence of active rejection.”157 If there are simultaneous borderline changes, the cases can be considered indeterminate.200 The long-term significance of these relatively uncommon cases is still under investigation.201–203 In nonhuman primates with MHC-incompatible grafts and no immunosuppression, C4d deposition predicts chronic rejection with glomerulopathy and arteriopathy and ultimate graft loss with a high degree of certainty.226 The most important question is whether treatment of subclinical rejection is beneficial (and, if so, what therapy is optimal). No study has dared to randomize treatment in patients with acute rejection on protocol biopsy. The closest to a controlled trial was that of Rush and colleagues, who found that patients with protocol biopsies, treated with steroid boluses if they had subclinical rejection, had a better outcome than a group of patients who declined a renal biopsy (and were presumed to have a similar frequency of subclinical rejection).284 Other diseases revealed by the “eye of the needle” clearly benefit from altered therapy, including CNIT283,315 and polyomavirus infection.316 

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Fig. 25.8  Acute tubular necrosis. Dilated “rigid”-appearing tubular lumens with loss of brush borders, occasional loss of nuclei, and cytoplasmic thinning. Mild edema is present but little inflammation. Glomeruli are normal. PAS stain.

Acute Tubular Necrosis The morphologic basis of DGF is usually acute ischemic injury (ATN). The most common feature histologically is loss of the brush borders of proximal tubular cells, best shown on a PAS stain with focal interstitial edema and mononuclear cell accumulation (Fig. 25.8). The tubular lumen appears larger than normal and lacks the usual artifactual sloughing of the apical cytoplasm in human renal biopsies (this sloughing has occurred in vivo and has washed downstream; Fig. 25.9). The other features of ATN include flattening of the cytoplasm and loss of cell nuclei due to apoptosis/death of individual tubular epithelial cells and covering of the TBM by the remaining cells. The lumina contain individual apoptotic detached cells (“anoikis”) and inflammatory cells. Reactive changes in the tubular epithelium are seen after 24 to 48 hours, including large basophilic nuclei with prominent nucleoli, increased cytoplasmic basophilia and occasionally mitoses. Focal interstitial, PTC, and glomerular capillary neutrophils may be seen but are not as prominent as in acute AMR, and C4d is negative. Mechanical flushing of cadaveric kidneys with organ preservation fluid immediately before transplantation (as advocated by some) was associated with abnormal cellular debris within the tubules and eosinophilic proteinaceous material within Bowman’s capsule and an increased frequency of DGF.317 DGF has other causes, and if function has not recovered in 1 to 2 weeks, a diagnostic biopsy is recommended to ascertain the presence of occult acute rejection, found in 18% of patients with DGF at 7 days.318 

Calcineurin Inhibitor Nephrotoxicity The CNI class of drugs, including cyclosporine and tacrolimus, cause both acute and chronic nephrotoxicity that includes ischemic injury without morphologic features,

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A

B

C

D

Fig. 25.9  Polyoma (BK) virus infection. (A) Low power view showing patchy mononuclear inflammation in the medulla with groups of atypical nuclei in tubular epithelium (arrows) (B) Higher power shows polyomavirus inclusion (arrow), marked tubulitis, and tubular cell apoptosis. (C) Immunohistochemistry, monoclonal antibody to SV40 large T antigen (homologous to BK, JC, and other polyoma viruses), many tubular epithelial cell nuclei appear dark brown due to immunoreactivity for polyoma virus. (D) EM, high magnification of a tubular cell nucleus (N) containing polyoma virions (arrow), that are rounded, 30 to 35 nm in diameter and organized in arrays. (From cynomolgus monkey; van Gorder MA, Della Pelle P, Henson JW, Sachs DH, Cosimi AB, Colvin RB. Cynomolgus polyoma virus infection: a new member of the polyoma virus family causes interstitial nephritis, ureteritis, and enteritis in immunosuppressed cynomolgus monkeys. Am J Path 1999;154(4):1273–84.)

vacuolar tubulopathy, acute endothelial injury (TMA), and arteriolar hyalinosis.290,319 These cause secondary pathologic effects, such as TA, IF, and global or segmental glomerulosclerosis. As judged by protocol biopsies, chronic CNIT is universal in renal transplants after about 5 years according to some studies.283 However, changes attributed to CNIT have been less in later studies.295 Chronic CNIT can also damage native kidneys in patients with other organ transplants and contributes to the 7% to 21% prevalence of end-stage renal disease in nonrenal transplant recipients after 5 years.320

ACUTE CALCINEURIN INHIBITOR TOXICITY Toxic Tubulopathy The biopsy features of acute toxicity are quite variable. A normal biopsy is found in “functional CNIT,” which is due to reversible vasospasm.321 In toxic tubulopathy, proximal tubules show the most conspicuous morphologic changes with loss of brush borders and isometric (uniformly sized), clear, fine vacuolization (or microvacuoles) in the epithelial cells (Fig. 25.10). The microvacuoles contain clear aqueous fluid rather than lipid and are indistinguishable from those caused by osmotic diuretics or ischemia. EM shows that the vacuoles in CsA toxicity are due to dilation of the endoplasmic reticulum and appear empty.322 Isometric vacuolization may begin in the straight portion of the proximal tubule,322 although it can extend to the convoluted

Fig. 25.10  Acute calcineurin inhibitor nephrotoxicity with isometric vacuolization of tubular epithelium. This change can also be seen in other causes of tubular injury, including ischemia, osmotic diuretics, and intravenous immunoglobulin.

portion. The degree of vacuolization does not correlate with drug levels; some patients with CNIT lack the vacuolar change,323 and isometric vacuoles can be found in a minority of patients with stable renal function.324 However, reduction of the CNI dosage causes disappearance of tubular vacuolization.102 

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A

399

B

Fig. 25.11  TMA associated with calcineurin inhibitors. (A) glomerulus with widespread endothelial swelling, segmental GBM duplication, and focal collapse resembling a crescent. Arterioles show endothelial swelling and occasional peripheral hyaline nodules. PAS stain. (B) No glomerular or PTC C4d deposition is detected in this case. Immunohistochemistry for C4d in paraffin, using rabbit polyclonal anti-C4d.

Acute Arteriolar Toxicity and Thrombotic Microangiopathy Arterioles are a significant target of CNIT. The most characteristic acute changes include individual medial smooth muscle cell degeneration, necrosis/apoptosis, and loss.322 The apoptotic smooth muscle cells are later replaced by rounded, “lumpy” protein deposits or hyalinosis, which is the beginning of a more chronic arteriolopathy.322 Accumulation of glycogen (PAS positive, diastase sensitive) in smooth muscle cells has been described on high doses.325 Endothelial cells can have prominent vacuolization and some swelling. Immunofluorescence microscopy of the vessels often shows deposits of IgM, C3, and sometimes fibrin/ fibrinogen, but these changes are nonspecific.326 TMA due to CNI was first reported in bone marrow transplant recipients treated with cyclosporine327 and occurs in about 1% to 4% of renal allograft recipients, even with careful attention to drug levels, suggesting that it is dose independent and probably idiosyncratic.328,329 Most cases present with a delayed onset and a slow loss of function 1 to 5 months posttransplant.330 The pathologic changes are believed to be an exaggeration of CNI induced endothelial and smooth muscle damage. The small arteries and arterioles have mucoid intimal thickening with acid mucopolysaccharides and extravasated red cells and fragments; fibrinoid necrosis and thrombi may be prominent (Fig. 25.11). Apoptosis of endothelial and smooth muscle cells is seen. The medial smooth muscle can develop a mucoid appearance with loss of a clear definition of the cells.126 The arterioles may show hypertrophy of the endothelial cells and have a “constricted” appearance.126 The vascular lumina may be partially or completely obliterated by the intimal proliferation and endothelial swelling. The vascular lesions are most severe in the interlobular and arcuate-sized arteries, and can lead to cortical infarction.330 By immunofluorescence microscopy, the vessels stain with IgM, C3, and fibrin.131 The glomeruli typically have swollen bloodless capillaries with scattered fibrin-platelet thrombi (see Fig. 25.11),

particularly in the hilum,327 the so-called pouch lesion.331 The endothelial cells are swollen and may completely obliterate the capillary lumina. The GBM is segmentally duplicated with cellular (mononuclear or mesangial cell) interposition best seen by EM, which also shows the loss of fenestrae and swelling of the endothelial cytoplasm. Variable mesangial expansion, sclerosis, and mesangiolysis331 may be seen. Marked congestion and focal, global, or segmental necrosis can be present.332 

Differential Diagnosis Acute tubular toxicity of CsA may be indistinguishable from ischemia or tubulopathy from intravenous immunoglobulin (IVIG) or mannitol, which all have vacuoles by light microscopy.333 By EM a more coarse and varied vacuolization is typical of ATN and the periphery of infarcts334 compared with the isometric (uniform) vacuoles of CsA toxicity. The vacuoles of osmotic diuretic injury do not involve the endoplasmic reticulum, as do those of CsA toxicity.331 Necrosis of tubular cells is more common in ATN (0.5% of tubules), characteristically involving whole tubular cross sections.324 Acute medial apoptosis/degeneration in arterioles is the only definitive finding favoring CsA toxicity. Morphology alone cannot distinguish the various etiologies of TMA,335,336 which in renal transplants are most commonly CNI, acute AMR, hepatitis C virus (HCV), and recurrent TMA. Recurrence should be the first choice when the recipient’s original disease was TMA, unless associated with a diarrheal illness. C4d deposition in PTCs is present in acute AMR but absent in CNI-associated TMA (see section on acute AMR). Serum should also be tested for antiHLA class I, class II, and antiendothelial antibodies. HCV(+) renal allograft recipients may develop TMA with associated elevation of circulating anticardiolipin antibody,337 thus hepatitis serology and anticardiolipin antibody determination could help distinguish between HCV versus CNI in the etiology of TMA. The healing phase of TMA may leave intimal fibrosis that resembles chronic rejection, even with a few intimal mononuclear cells.131 

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CHRONIC CALCINEURIN INHIBITOR TOXICITY Irreversible chronic renal failure due to CNIT was first demonstrated in native kidneys of heart transplant patients who received cyclosporine for more than a year.338 Similar lesions arise in patients on tacrolimus.339 Biopsies showed IFTA, arteriolar hyalinosis, and sometimes focal glomerular scarring. These findings have been confirmed and extended in numerous other studies.326 More recent studies of patients mostly on maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone showed less prevalent chronic changes of moderate or severe arteriolar hyalinosis and IFTA than was noted on previous studies of patients on immunosuppressive regimens including cyclosporine.340 Because many features resemble chronic rejection in the kidney, the most convincing pathology data come from nonrenal transplant patients on cyclosporine.341,342

CNI-Arteriolopathy The chronic phase of CNI-arteriolopathy is characterized by replacement of the degenerated medial smooth muscle cells with hyaline-like deposits, in a beaded pattern along the peripheral outer media (see Fig. 25.7). This has been referred to as “nodular protein (hyaline) deposits”289 in a “pearl-like pattern”326 and “peripheral medial nodular hyalinosis,” and is now called “CNI-arteriolopathy.” The current evidence supports the view that this type of arteriolopathy is relatively specific for CNI. In heart and bone marrow transplant recipient autopsy studies, 55% of cases on cyclosporine had this type of arteriolopathy in the native kidneys compared with 0% in those not on CNIs.341 Evidence of apoptosis is sometimes found in the form of karyorrhexic debris in the media, but fibrinoid necrosis is not observed.343 In severe cases the media is nearly devoid of smooth muscle cells.343 EM reveals a distinctive replacement of individual smooth muscle cells of afferent arterioles with amorphous electrondense material, which contains cell debris and protrudes into the adventitia (see Fig. 25.7B).326,344,345 This gives rise to the beaded hyalinosis distribution in the outer media noted by light microscopy. The myocyte nuclei are sometimes condensed (apoptotic) or have two nuclei or mitotic figures.344 The cytoplasm is vacuolated, with dilated endoplasmic reticulum, and has degenerated mitochondria, lipofuscin granules, multivesicular bodies, and a disarray of microfibrils and reduced intercellular junctions. The endothelium sometimes appears “swollen,” protruding into and narrowing the lumen, and having reduced cell junctions; aggregates of platelets are rare.344,346 These findings support the view that the smooth muscle myocyte of the afferent arteriole is a primary target of CNI injury. Immunofluorescence microscopy shows IgM and C3 in a relatively nonspecific, but conspicuous sheathing of the arterioles.326 CNI-arteriolopathy begins and predominates in the afferent arterioles but may progress to the small arteries and efferent arterioles.326,344 Decreased renin immunostaining in the juxtaglomerular apparatus suggests that the prime target of CNI is the renin-producing smooth muscle cell in the afferent arteriole.347 The frequency of arterioles affected with hyalinosis is typically small (<15%), and the lesions can easily be overlooked.348 In renal transplant patients on

cyclosporine, 15% of protocol biopsies at 6 months showed CNI-arteriolopathy which increased to 45% in 18-month protocol biopsies349; “nonspecific” hyalinosis showed no progressive increase. The arteriolar lesions also develop in native kidneys of patients who receive even low doses of cyclosporine for 2 years.350,351 Mihatsch has suggested a scoring system of CNI-arteriolopathy with improved reproducibility.352 

Glomerular Lesions After 1 year on cyclosporine, glomeruli show increased numbers with global or segmental sclerosis.341,342 Focal, segmental sclerosis was more common in CNI-treated bone marrow (13%) and heart transplant (27%) recipients at autopsy than their respective CNI-free controls (0% and 14%).341 Heart transplant recipients have an increase in the heterogeneity of glomerular volume and size, with more small and large glomeruli (compensatory hypertrophy), compared with controls (living kidney donors).343 The shift to smaller glomeruli becomes more extreme with chronic renal failure and the hypertrophied glomeruli disappear.353 Thus hyperfiltration injury probably causes the progressive glomerular proteinuria and sclerosis. Bone marrow and heart transplant patients at autopsy show glomerular collapse in 59% of the patients on CNI versus 8% of those not on CNI.341 This can develop into florid collapsing glomerulopathy, attributed to the severe CNI-arteriolopathy.354 Immunofluorescence findings are nonspecific (IgM and C3 in scarred areas). EM in cardiac and liver transplant recipients showed diffuse expansion of the mesangial matrix, with little hypercellularity, GBM, or podocyte lesions.342,343 Those with frank collapsing glomerulopathy have podocyte foot process effacement and detachment of podocytes from the GBM.354 The endothelium shows loss of its normal fenestrae, perhaps reflecting a component of TMA.131  Tubules and Interstitium IFTA was recognized as a feature of CNIT in the early studies.355 The interstitium had prominent patchy fibrosis, with a scanty infiltrate. Band-like narrow zones of IFTA (“striped fibrosis”) were once regarded as characteristic of CNIT127,356,357; however, indistinguishable “stripes” occur in patients not maintained on CNI,358 casting doubt on the specificity of that pattern. IF also develops in native kidneys in patients on CNI350,359–361 and remains for at least a month after discontinuing the drug.362 Thus even low doses of CsA can cause significant and presumably permanent loss of renal function by inducing chronic tubulointerstitial nephritis.131  Differential Diagnosis Distinction between chronic rejection and chronic CNIT is a challenge (Table 25.6). The finding that favors CNIT most decisively is the arteriolopathy, provided it is distinctive (isolated smooth muscle cell degeneration and string of pearls replacement by hyalinosis in the outer media).319 The arterioles are relatively spared in chronic rejection, compared with chronic CNIT, and the arteries are more affected, with proliferative intimal fibrosis without elastosis.319 PTC C4d deposits or mononuclear cells in the arterial intima are the most useful signs of an active rejection process. An inflammatory infiltrate, including plasma cells,

25 • Pathology of Kidney Transplantation

TABLE 25.6  Differentiation Between Chronic Rejection and Chronic CNI Toxicity Interstitium Infiltrate Fibrosis

Chronic Rejection

CNI Toxicity

Plasma cells Patchy

Mild Patchy, “striped”

PERITUBULAR CAPILLARIES C4d Often positive BM multilamination Usual

Negative Absent

TUBULES Tubular atrophy Vacuoles

Usual Occasional

Usual Occasional

ARTERIOLES Smooth muscle degeneration Absent External nodular hyalinosis Absent

Usual Present

ARTERIES Intimal fibrosis

Usual

Intimal mononuclear cells

Common

Can be present but unrelated Absent

GLOMERULI Duplication GBM Mesangial expansion

Usual Can be present

Absent Can be present

BM, basement membrane; CNI, calcineurin inhibitor; GBM, glomerular basement membrane.

is less common in CNIT than rejection.363 Other features are not decisive. IFTA and glomerular sclerosis are found in either. GBM duplication and endothelial dedifferentiation can also be seen in either, although perhaps more commonly in chronic rejection.131 

Target of Rapamycin Inhibitor Toxicity Inhibitors of the mammalian target of rapamycin (TORi; rapamycin, everolimus, sirolimus) can cause DGF due to tubular toxicity that resembles myeloma cast nephropathy. Pathologically, in addition to acute tubular injury, eosinophilic debris and macrophages were present in tubular lumina, which mimicked myeloma casts, but the casts stain for keratin, rather than immunoglobulin light chains.364 TORi can also cause TMA, indistinguishable from that due to CNI.365 Increased proteinuria is common in patients switched from CNI to TORi because they had developed severe CNIT. In these patients, GFR improves but increased proteinuria develops in about 30%.366 CNI exposure is not necessary for the proteinuric response to TORi. Conversion from azathioprine to TORi can also cause increased proteinuria.367 Patients started on TORi without CNI had double the risk of proteinuria at 6 to 12 months compared with those on CNI.368 Few pathologic studies have been published. One reported a variety of glomerular diseases typical of native kidneys, suggesting recurrent disease.369 A recipient begun on TORi, developed 12 g/day proteinuria in the first week after transplantation, which remitted after the drug was discontinued.370 Biopsy showed that no obvious glomerular disease was evident by light, immunofluorescence, or EM, suggesting the proteinuria was due to failure of tubular

401

reabsorption. One notable case report described collapsing glomerulopathy in a patient with Kaposi’s sarcoma converted to TORi from azathioprine.371 We have seen two cases of focal, segmental glomerulosclerosis, in patients started on TORi; one had collapsing glomerulopathy (Cornell et al., unpublished). More pathology studies are clearly needed, particularly on those patients started on TORi.131 

Drug-Induced Acute Tubulointerstitial Nephritis Drug-induced interstitial nephritis in the allograft is similar to that in the native kidney and resembles tubulointerstitial rejection. Both are characterized by an intense mononuclear interstitial infiltrate and tubulitis, and have variable numbers of eosinophils. Acute rejection occasionally has a prominent eosinophilic infiltrate.54,372–376 Conversely, druginduced interstitial nephritis may have no eosinophils, especially those due to nonsteroidal antiinflammatory drugs.377 Endarteritis, if present, is unequivocal evidence for rejection. Strong, but not absolute, evidence for a drug etiology is the invasion of multiple tubules by eosinophils, and eosinophils in tubular casts (Colvin, unpublished observation), usually attributed to prophylactic trimethoprim-sulfamethoxazole (Bactrim). We have also seen one case of severe acute interstitial nephritis and serum sickness-like syndrome secondary to horse anti-thymocyte globulin (ATG).131 Interstitial nephritis can sometimes have a granulomatous pattern; and this pattern can indicate a variety of potential etiologies, including drugs, infections, and recurrent diseases such as sarcoidosis and granulomatosis with polyangiitis.378 

Infections Many organisms can infect the transplanted kidney, ranging from mycobacteria and Candida,379 to herpes simplex virus380 and human herpesvirus 1 (HHV-1, also known as Herpes simplex virus-1 [HSV-1]).380 In addition, viruses such as CMV and HCV can have indirect effects on the transplant, promoting rejection or immune-mediated disease.91,116,381 CMV can also directly infect the allograft, particularly in glomerular endothelial cells. Here we will discuss the three most important types of infections, polyomavirus, adenovirus, and bacterial pyelonephritis.

POLYOMAVIRUS TUBULOINTERSTITIAL NEPHRITIS PTN has emerged since 1996 as a significant cause of early and late graft damage.382–387 Among various series of patients on tacrolimus/mycophenolate mofetil, PTN arises in about 5%, similar to the prevalence of acute rejection. The virus was originally isolated from B.K., a Sudanese patient who had distal donor ureteral stenosis 3 months after a living related transplant.388 BK virus is related to JC virus (which also inhabits the human urinary tract) and to simian virus SV40. These viruses are members of the papovavirus group, which includes the papilloma viruses. The BK virus commonly infects urothelium but rarely causes morbidity in immunocompetent individuals. However, in

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A

B

Fig. 25.12  Recurrent diabetic nephropathy 12 years after transplant. (A) Glomerulus with prominent Kimmelstiel-Wilson mesangial nodules (arrow) and arteriolar hyalinosis. PAS stain. (B) EM of another case shows homogeneous thickening of the GBM up to 1100 nm. C, capillary lumen; U, urinary space.

renal transplant recipients three lesions have been attributed to BK virus: hemorrhagic cystitis, ureteral stenosis, and interstitial nephritis.389–391 PTN is characterized by a patchy mononuclear infiltrate associated with tubulitis and tubular cell injury.387 The infiltrate often contains plasma cells, which sometimes invade the tubules (see Fig. 25.9). Concurrent TCMR may be present. Tubular cell apoptosis is prominent as well as “dedifferentiation” of tubular epithelial cells, with loss of polarity and a spindly shape. PTN has three recognized stages: stage A has only minimal inflammation; stage B shows marked tubular injury, denudation of the tubular basement membranes, and interstitial edema with a mixed, mild to marked inflammatory cell infiltrate; and stage C has marked IFTA.382,392–395 The recognition of viral nuclear inclusions is the key step in histologic diagnosis. The affected nuclei are usually enlarged with a smudgy, amorphous lavender inclusion (see Fig. 25.9B). Other nuclear changes found less commonly are eosinophilic, granular inclusions with or without a halo and a vesicular variant with coarsely clumped, irregular basophilic material.78,385,396 These nuclear inclusions tend to be grouped in tubules, particularly collecting ducts in the cortex and outer medulla, and can often be spotted at low power. IHC and EM confirm the diagnosis. Monoclonal antibodies are commercially available that react with BK-specific determinants and with the large T antigen of several polyoma species (see Fig. 25.9C). In situ hybridization for BK polyomavirus is used at some centers as an alternative to IHC. EM will reveal the characteristic intranuclear paracrystalline arrays of viral particles of about 40 nm diameter (Fig. 25.12D). Other tests useful for monitoring patients at risk are urine cytology (“decoy cells”) and PCR quantitation of virus in the blood, although these are not specific enough to make a PTN diagnosis.131 Polyomavirus infections may cause an immune complex deposition along the TBM, as described in 43% of cases in a series from Seattle, being the most common cause of IgG deposits in the TBM of transplants.397 Granular IgG, C3, and C4d are focally present by immunofluorescence and amorphous electron-dense deposits by EM. The prognostic significance is not known.131 Late graft fibrosis and scarring “CAN” may be caused by polyomavirus, even though the virus is no longer

demonstrable. The virus is cytopathic for tubular cells and leads to characteristically destructive tubular lesions, with only TBM remaining. The diagnosis is sometimes only possible by review of prior biopsies. Suspicion of PTN is heightened if tubular destruction is severe. The process may be clinically silent: protocol biopsies have shown a subclinical incidence of PTN of 1.2%.316 Furthermore, PTN can affect native kidneys of recipients of nonrenal allografts; only a few cases have been reported, but this may be in part due to a presumption of CNIT and a lack of renal biopsies in this setting.398 

ADENOVIRUS Adenovirus, most frequently serotype 11, causes hemorrhagic cystitis and occasionally tubulointerstitial nephritis in renal allografts, which may resemble a space-occupying lesion by imaging studies.399,400 Biopsy shows necrotizing inflammation with neutrophils and tubular destruction, interstitial hemorrhage and red cell casts, granulomatous inflammation,401–404 or a zonal inflammation localized to the outer medulla.405 Tubular cells have intranuclear ground glass inclusions with a distinct halo surrounded by a ring of marginated chromatin and glassy smudged nuclei. The diagnosis is established by immunoperoxidase stains for viral antigen in tubular cells and EM to reveal the intranuclear crystalline arrays of 75- to 80-nm viral particles. Immune complexes may also contribute to the injury. Decreased immunosuppression has been followed by recovery.131 

ACUTE PYELONEPHRITIS Pyelonephritis is a potentially devastating complication of transplantation. Pyelonephritis can present as acute renal failure406,407 and cause graft loss.408,409 According to one series, pyelonephritis arises most often 1 year or more after transplantation (80% of episodes), and E. coli was the most common organism (80%).410 Acute pyelonephritis is a not an uncommon finding on renal biopsy, despite the expectation that the process is patchy.406 Renal biopsies are not the usual method of diagnosis, however, if neutrophils are abundant, especially if they form destructive abscesses and casts in tubules, the diagnosis should be at the top of the list. Other variants are

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emphysematous pyelonephritis, due to gas-producing organisms,409 xanthogranulomatous pyelonephritis,411,412 and malakoplakia.413 

Major Renal Vascular Disease Most arterial thromboses develop in the early posttransplant period and produce acute infarction with microthrombi and scant inflammation.414 Evidence for underlying rejection should be sought by careful examination of the larger arteries for endarteritis. Renal artery stenosis (typically at the anastomosis site), a cause of late graft dysfunction, can be deceptive clinically and pathologically.415,416 Biopsies show tubular injury or atrophy with relatively little inflammation or fibrosis. Renal vein thrombosis causes a swollen and purple kidney, sometimes with graft rupture.417 The cortex shows severe hemorrhagic congestion and extensive infarction and necrosis418 sometimes with diffuse microcapillary thrombi. Intracapillary leukocytes can be a clue as in native kidneys. Late renal vein thrombosis is associated with proteinuria due to membranous glomerulonephritis or TG, sometimes with graft loss.419 Lupus anticoagulant has been detected in a few patients.420 

De Novo Glomerular Disease Patients without previous glomerular disease occasionally develop lesions in the allograft that resemble a primary glomerular disease, rather than the usual transplant glomerulopathy. Although some are no doubt coincidental, at least three are related to an alloimmune response to the allograft: membranous glomerulonephritis, anti-GBM disease in Alport’s syndrome, and recurrent nephrotic syndrome in congenital nephrosis. A fourth relatively common de novo glomerular disease, FSGS, is believed to be related to hyperfiltration injury of the allograft or marked microvascular compromise due to CNIT.131

MEMBRANOUS GLOMERULONEPHRITIS De novo MGN is typically a late complication, with a prevalence of about 1% to 2%.421–423 In contrast, recurrent MGN can present early.424 The risk factors for de novo MGN include time after transplant, de novo MGN in a first graft,421 and HCV infection.422,423 Light microscopy usually shows rather mild GBM changes. Mesangial hypercellularity is found in about 33%. Mononuclear cells can be abundant in glomerular capillaries, raising the possibility of transplant glomerulitis or renal vein thrombosis.425 Immunofluorescence shows granular deposits along the GBM that stain for IgG, C3, C4d, and factor H426; about 35% are more irregular and segmental in distribution than typical primary (idiopathic) MGN.425,427 By EM, subepithelial electron-dense deposits are present (Fig. 25.13), which are smaller and more irregular in distribution than primary MGN.425,427 Endothelial changes and GBM duplication typical of TG are present in half of the cases.425,427 Repeat biopsies have shown persistence or progression of the deposits in most cases and occasional resolution.425,428

Fig. 25.13 De novo membranous glomerulonephritis: subepithelial electron-dense deposits (arrows) along the GBM with intervening basement membrane spikes. Podocyte (P) foot processes are effaced. C, capillary lumen; U, urinary space.

The pathogenesis of de novo MGN has not been established. The literature supports the hypothesis that de novo MGN may be a form of AMR or directed at minor histocompatibility antigen(s) in the glomerulus, presumably on the podocyte or a special type of chronic rejection.234,427,429 The common presence of TG is consistent with this hypothesis.425,427 Phospholipase A2 receptor (PLA2R) staining can be useful in the evaluation of allograft MGN. In one study, PLA2R staining had a sensitivity of 83% and specificity of 92% (for recurrent MG; PLA2R staining was almost always negative in de novo MGN.430 

ANTI-GBM NEPHRITIS Patients with Alport’s syndrome or hereditary nephritis commonly develop anti-GBM alloantibodies, because they genetically lack self-tolerance to GBM collagen components. However, this leads to glomerulonephritis in only a minority. Overall, de novo crescentic and necrotizing glomerulonephritis due to anti-GBM antibodies after transplantation is uncommon, seen in only 5% of male adult renal allograft recipients with typical Alport’s syndrome431,432 or hereditary nephritis with deafness.433 The pathology is similar to that in native kidney with prominent crescents (not a feature of allograft rejection), segmental necrosis, and red cell casts. Second transplantation with and without recurrent anti-GBM nephritis have both been reported.434–436 The 5-year graft survival may be equal to that of non-Alport’s recipients.437 

DE NOVO PODOCYTOPATHY IN CONGENITAL NEPHROSIS Congenital nephrotic syndrome of the Finnish type, an autosomal recessive disease due to mutations in the nephrin gene NPHS1, paradoxically leads to posttransplant nephrotic syndrome.438,439 The podocyte pathology resembles minimal change disease and usually responds to cyclophosphamide.440,441 De novo “minimal change disease” is thought to be caused by the alloantibodies to nephrin in some cases.442 

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Kidney Transplantation: Principles and Practice

TABLE 25.7  Classification of Recurrent Renal Disease I. USUALLY RECUR (>50% PATIENTS) A. Adverse effecta Primary HUS Dense deposit disease Collapsing FSGSc B. Little or no adverse Immunotactoid/fibrillary glomerulopathyc affect Systemic light chain diseasec Diabetes mellitusd

Fig. 25.14  De novo collapsing glomerulopathy: collapsed glomerular capillaries and prominent podocyte proliferation, hypertrophy, and abundant reabsorption droplets. Severe arteriolar hyalinosis with peripheral nodules typical of CNI arteriolopathy was present. This is a native kidney in a patient with a heart-lung transplant.354 PAS stain.

FOCAL SEGMENTAL GLOMERULOSCLEROSIS De novo FSGS has been described in adult recipients of pediatric kidneys,443,444 in which the presumed pathogenesis is hyperfiltration injury; in long-standing grafts, in which parenchymal loss due to CNIT or chronic rejection leads to hyperfiltration injury of residual glomeruli; and as the collapsing variant of FSGS, probably related to CNI-arteriolopathy.445 De novo collapsing glomerulopathy presents months to years after transplantation with proteinuria (2–12 g/ day).445–447 Diffuse or focal, global or segmental collapse of glomeruli was evident with prominent hyperreactive podocytes (Fig. 25.14). Arteriolar hyalinosis, arteriosclerosis, and IF were also present. A rapid progression to renal failure occurred in 80% of the patients (2–12 months). The cause is unknown; all patients were HIV negative. Collapsing glomerulopathy can also develop in native kidneys in patients on CNI (see Fig. 25.14).354 

Recurrent Renal Disease Recurrent disease is a significant cause of allograft failure.448–450 The frequency and clinical significance of recurrence varies with the disease (Table 25.7). In one study, glomerular diseases, including recurrent and de novo glomerulonephritis and transplant glomerulopathy, were responsible for 37% of cases of graft loss, and 14% of deathcensored graft losses were due to recurrent glomerular disease297 (e.g., recurrent dense deposit disease in Fig. 25.15). Recurrence of immune-mediated disease may become a greater problem in the future with longer graft survival and development of tolerance protocols that require no immunosuppression. The reader is referred to a comprehensive review elsewhere for detailed information regarding specific diseases.9 Transplantation also can uniquely illuminate the early pathologic events that precede clinical signs and determine

II. COMMONLY RECUR (5%–50%) A. Adverse effect Focal, segmental glomerulosclerosis Membranoproliferative GN,b type I Membranous GN ANCA related diseases Wegener’s granulomatosis Pauci-immune GN Microscopic polyarteritis Progressive systemic sclerosis Sickle cell nephropathyc B. Little or no adverse IgA nephropathy affect Henoch-Schönlein purpura Amyloidosis III. RARELY RECUR (<5%) A. Adverse effect Anti-GBM disease B. Little or no adverse Systemic lupus erythematosus affect Fabry’s disease Cystinosis IV. NEVER RECUR (ESSENTIALLY 0%) A. Unique complications Hereditary nephritis/Alport’s syndrome (anti-GBM disease) Congenital nephrosis (nephrotic syndrome; nephrin autoantibody?) B. No unique complicaPolycystic disease (all genetic types) tions Osteo-onychodysplasia (nail-patella)c Acquired cystic disease Secondary HUS (infection) Secondary FGS Familial FGSc Postinfectious acute glomerulonephritisc V. Unclassified, recurrence Thrombotic thrombocytopenic purpura reportede Adenosine phosphoribosyl transferase deficiency Familial fibronectin glomerulopathy Lipoprotein glomerulopathy Malacoplakia aAdverse

effect defined as graft loss of >5% (when disease recurs) antineutrophil cytoplasmic antibody; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; GN, glomerulonephritis; HUS, hemolytic-uremic syndrome. cLimited experience: few cases reported (n < 10). dArteriolar and glomerular lesions will recur to some degree in most if not all cases, but severe form (nodular) delayed until >5 years. eRecurrence occurs, but too few cases reported to classify frequency or consequences. bANCA,

the reversibility of preexisting lesions in the donor kidney (e.g., diabetes, IgA nephropathy). For example, in early recurrent MGN, as early as 2 weeks posttransplant the glomeruli can show staining in a membranous pattern by immunofluorescence for IgG, C4d, and kappa and lambda light chains, but corresponding electron-dense deposits may not be present ultrastructurally; these features can be seen on biopsy without proteinuria clinically.424 Later biopsies of the allografts show a more typical membranous pattern with subepithelial deposits by EM.451 Diabetic nephropathy begins with an increase in allograft glomerular volume at 6 months,452 followed by increases

25 • Pathology of Kidney Transplantation

A

405

B

Fig. 25.15  Recurrent dense deposit disease. (A) EM, widespread very electron-dense deposits that are continuous, linear, and embedded in the GBM proper, (i.e., intramembranous [arrows]). Similar deposits are also seen in the mesangium (M). C, capillary lumen; U, urinary space. (B) immunofluorescence microscopy, staining for C3 shows broad, linear ribbon-like deposits along the GBM and blob-like deposits in the mesangium (mesangial rings).

in mesangial volume453 and mesangial sclerosis, which is present 10 years after transplantation in the majority of patients who had diabetes at baseline, as was nicely demonstrated in one study.454 Thickening of the GBM is first evident after 2 to 3 years453,455 and nodular diabetic glomerulosclerosis at 5 to 15 years posttransplant (see Fig. 25.12).456 Tubulointerstitial diseases may also recur, such as with recurrent oxalate nephropathy in primary hyperoxaluria.457 A chronic tubulointerstitial nephritis mediated by antibodies against the proximal tubule brush border can recur after transplantation. Patients present with renal failure ranging from slowly progressive to acute with little or no proteinuria and a bland urinary sediment. Tubules appear injured, and focal tubulitis may be present amid an infiltrate of lymphocytes, plasma cells, and few eosinophils. On PAS stains, there is a diffuse loss in proximal tubule brush borders. Immunofluorescence shows widespread granular deposits along the TBM that stain for IgG and C3, and prominent amorphous electron-dense deposits are seen in the TBM on EM.458 Recent data indicate that LDL receptor-related protein 2 (LRP2), also known as megalin, is the target in this anti-brush border antibody disease (ABBA disease).459 

Posttransplant Malignancy and Posttransplant Lymphoproliferative Disease Immunosuppression leads to an increased risk of malignancy, particularly those neoplasms caused by viruses and ultraviolet radiation. These malignancies are presumptively suppressed by immune responses that recognize the viral or mutation-derived neoantigens. Immunosuppressive agents may interfere with normal immune surveillance and mechanisms of DNA repair, and some common posttransplant viral infections are associated with malignancy.460 There is an approximately twofold increased risk of common cancers (colon, lung, prostate, and breast) in kidney transplant patients in the first 3 years posttransplant compared with the general population,461 so transplant patients should be part of appropriate cancer screening protocols. End-stage renal disease patients and hemodialysis patients not on

immunosuppression are also at increased risk for malignancy,462 likely in part due to various functional immune system abnormalities related to uremia and dialysis. Those cancers increased in kidney transplant recipients compared with patients on the transplant waiting list include Kaposi’s sarcoma (associated with human herpesvirus-8 [HHV-8]), PTLD (some associated with Epstein-Barr virus [EBV]), genitourinary cancers in women (some associated with human papillomavirus), nonmelanoma skin cancers, melanoma, and mouth and esophageal cancers, among others.460,461 The renal pathologist must be particularly aware of PTLD, as it can affect the graft and cause graft dysfunction. PTLD refers to a spectrum of lymphocytic or plasmacytic proliferations, ranging from EBV-positive polyclonal proliferations of plasmacytic hyperplasia and infectious mononucleosis-like PTLD to EBV-positive or -negative monoclonal lymphomas.463 Early and late-occurring PTLDs are relatively distinct clinicopathologic entities, with late-occurring PTLD resembling lymphoproliferative disorders in immunocompetent patients.464,465 PTLDs that arise relatively early posttransplant (<1 year) tend to be associated with EBV466 and are composed of lymphocytes of donor origin.467 In one study, most donor-origin PTLDs developed in the kidney allograft; 79% of these were EBV-positive.467 PTLDs that arise late posttransplant are less frequently associated with EBV, more likely to be of recipient origin,467 and have a poorer prognosis.464,466 PTLD occurs in approximately 0.3% of kidney transplant recipients by 1 year posttransplant and 1.6% by 10 years.468 Risk factors for development of PTLD in renal transplant patients include recipient EBV seronegativity with an EBV seropositive donor,469 recipient age <18 years470 (due to higher rate of EBV seronegativity in children), age over 60 years at the time of transplantation in adult patients,471 greater degree of immunosuppression, antirejection therapy with OKT3 or antithymocyte globulin,468 use of belatacept (T cell costimulation blocker) for immunosuppression,472,473 and viral coinfection with HCV or CMV. The morphologic appearance of PTLD can vary (e.g., Fig. 25.16). Most (86%–92%) are B cell predominant; 68% to 81% are EBV-positive.471,474 PTLD involves the renal allograft in at least 21% of cases (with or without extrarenal involvement),474 with one study showing graft involvement in 49% of PTLD cases in renal transplant recipients.467 Most PTLDs involving the allograft have a polymorphous

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A

B

Fig. 25.16  Posttransplant lymphoproliferative disease. (A) Dense mononuclear cell infiltrate in the interstitium that permeates between the tubules without tubulitis (although tubulitis may occur in PTLD). The monomorphic infiltrate and the lack of edema distinguish PTLD from the usual cellular rejection. (B) In situ hybridization, nuclei of mononuclear cells stain dark, brown-black for EBER (Epstein-Barr virus encoded RNA), which is the definitive test for the diagnosis of PTLD.

appearance.463 The kidney is infiltrated with cells that include small lymphocytes, plasma cells, and varying numbers of immunoblasts with large nuclei and prominent nucleoli. The plasma cells usually (but not always) have a monotypic staining pattern for kappa or lambda light chain. Rarely, other types of PTLD occur in the kidney, including pure plasmacytic lesions, T cell lymphomas, and NK cell lymphomas.463 If needed, consultation with a hematopathologist can help the renal pathologist make the diagnosis of a PTLD. PTLD involving the kidney can resemble TCMR in having a widespread mononuclear infiltrate invading tubules and even vessels.60,475,476 In TCMR, the infiltrating cells are not positive for EBV, a feature that helps distinguish TCMR and PTLD in the early posttransplant period. EBV is best demonstrated by in situ hybridization for EBER (EBV encoded RNA; see Fig. 25.16). In some cases, a useful clue that favors PTLD is when the infiltrate forms a dense sheet of monomorphic, large lymphoid cells with vesicular chromatin and prominent nucleoli, without accompanying edema or granulocytes (see Fig. 25.16). Serpiginous necrosis of the lymphoid cells (irregular patches) has been described, but is not always present in PTLD.476 Carcinoma of the urinary tract has been associated with polyomavirus infection.477–481 In the past, the possibility that polyomavirus could contribute to tumorigenesis was not widely considered; however, in transplant recipients with a history of polyomavirus-associated nephropathy, expression of the SV40 polyomavirus large T antigen has recently been demonstrated in numerous renourinary tumors (e.g., transplant kidney, native kidney, renal pelvicalyceal system, graft ureter, bladder, and metastases from some of these tumors). In polyomavirus infection, polyomavirus early and late proteins (large tumor antigen [LTag] and viral capsid protein 1 [VP1], respectively) are expressed; and LTag inactivates the p53 tumor suppressor gene, leading to positive P53 staining. As cells become dysplastic and frankly malignant, cells become positive for Ki67, indicating proliferative activity, and both P53 and P16, indicating tumor suppressor gene inactivation and cell cycle regulation loss. Later in the process, VP1 staining can become negative due to a process referred to as early/ late viral gene region (EVGR/LVGR) uncoupling. The retinoblastoma tumor suppressor protein (pRB) is also implicated in the pathogenesis of these tumors. The tumors are

typically high-grade urothelial carcinomas481; however, they may exhibit unique morphologies such as micropapillary479 and giant cell components.478 Collecting duct carcinomas have also been described.482,483 

Future Directions in Biopsy Assessment Biopsy assessment will likely further improve from advances in image analysis techniques and molecular understanding. The contribution from a variety of “-omics” fields and technologies has led to improvements in allograft biopsy assessment.484,485 Molecular phenotypes have been characterized for a variety of pathologic states in renal allograft biopsies; however, the clinical utility of these molecular phenotypes will need additional validation before it is understood the circumstances in which molecular assessment can be superior to histopathology. In addition, before molecular biopsy assessment is clinically feasible as an adjunct to histopathology, additional improvements are needed in molecular method turnaround time, cost, and the reporting required for high-dimensional “-omics” data. Digital microscopic techniques (e.g., whole slide scanning) are also emerging that will likely improve biopsy assessment. Whole histology slide images contain highly detailed image information, allowing data mining through computer-based image analysis techniques. For example, interstitial fibrosis assessment can be automated; and automation can likely make interstitial fibrosis assessment more reproducible.486–488 Algorithms are available for additional features such as inflammatory cell infiltration, microvessel density, and a variety of other parameters.489,490 Multiparameter staining techniques can be coupled with digital imaging and analysis algorithms to provide more objective and quantitative assessment of molecular derangements in the renal biopsies.489 Advancements in technology such as artificial intelligence/machine learning and pathologic understanding will likely provide a more complete picture and allow enhanced patient care.

Acknowledgments Many thanks to a coauthor of a prior version, Shamila Mauiyyedi, MD, and to Dr. Paul J. Kurtin, for his useful suggestions on the manuscript.

25 • Pathology of Kidney Transplantation

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