Nonsteroidal Antiinflammatory Drugs and Opioids in Chronic Kidney Disease


65 Nonsteroidal Antiinflammatory Drugs and Opioids in Chronic Kidney Disease David M. Clivea, Pia H. Cliveb a

University of Massachusetts Medical School, Department of Medicine, Division of Renal Medicine, Worcester, MA, United States; bUMass Memorial Medical Center, Worcester, MA, United States that the consumption of analgesic medications in the US is enormous. It is estimated that 19% of the population regularly use aspirin, albeit not exclusively for pain. Another 12.8% use nonaspirin NSAIDs regularly. These numbers appear to be on the rise.1 Excessive use of opioids is now pervasive due to the prevalence of addiction, as well as profligate overprescription. At the time of this writing, opioid use represents one of the nation’s greatest public health crises. Recent estimates of the prevalence of CKD in this country average around 15%. One may extrapolate from these numbers that the relationship between CKD and analgesic medications is a topic of potentially major clinical significance. In examining this relationship, we will first explore the propensity of these agents to exert adverse effects on the kidney. Next, we will consider the extent to which CKD patients, by virtue of their reduced renal function, have a reduced tolerance for them. We will apply this approach to both the NSAIDs and opiates.

Abstract Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the synthesis of prostaglandins, which comprise an important compensatory mechanism for maintaining renal blood flow, glomerular filtration, and water and electrolyte homeostasis in the setting of a number of pathophysiologic states including chronic kidney disease (CKD). CKD patients are, therefore, at risk for adverse renal side effects of NSAIDs, including acutely worsened renal function, hyperkalemia, hyponatremia, sodium retention, and exacerbation of hypertension. Although these effects are generally reversible on discontinuation of the drugs, patients with CKD must be monitored closely while taking NSAIDs. Evidence suggests that heavy cumulative NSAID consumption is capable of causing chronic kidney injury with manifestations similar to those seen in classic analgesic nephropathy, including chronic interstitial nephritis and papillary necrosis. The pathogenesis of this disorder is probably renal medullary ischemia resulting from diversion of blood flow to the cortex that occurs with suppression of prostaglandin synthesis. CKD due to NSAIDs is probably rare. Extra caution is indicated when (1) committing patients to high-dose, long-term NSAID therapy or (2) recommending NSAID therapy of any duration to patients with CKD or other risk factors for adverse renal side effects including advanced age, use of diuretics, congestive heart failure, cirrhosis, and hypertension. As with NSAIDs, opioid analgesics must be considered from two standpoints: their ability to cause chronic kidney injury, which appears rare if it occurs at all, and the susceptibility of patients with chronically impaired renal function to the hemodynamic and neurotoxic effects of opioids, a problem commonly confronted in the clinic.


INTRODUCTION Because pain is the most common symptom for which people consult their physicians, it is hardly surprising Chronic Renal Disease, Second Edition

The potential for harmful interactions between nonsteroidal antiinflammatory drugs (NSAIDS) and the kidney has been known for 60 years. The earliest reports were of a fulminant form of acute kidney injury (AKI) known as “phenylbutazone anuria.” Although phenylbutazone has virtually disappeared from clinical use in humans, the number of NSAID products available for administration to humans has exploded in the years since. Several different classes of NSAIDs have been marketed (Table 65.1), most recently the coxibs, or selective cyclooxygenase-2 antagonists. NSAIDs may be the


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TABLE 65.1

Nonsteroidal Antiinflammatory Drugs



Indoleacetic acid derivatives

Indomethacin, sulindac, ketorolac

Propionic acid derivatives

Ibuprofen, naproxen


Celecoxib, valdecoxib


Aspirin, salsalate

Fenamic acid derivatives



Meloxicam, piroxicam



most widely used of all drugs, with over 70 million prescriptions written annually in the US.2 Aspirin, the first and most familiar NSAID, was developed in the late 19th century. In the decades since, newer and more potent agents have been introduced, some of which became available as over-the-counter formulations in the late 1980s. Two of these, ibuprofen and naproxen, can produce adverse renal effects. Both are widely advertised and consumed. The proliferation of NSAID products has not been confined to the introduction of new compounds. Newer formulations and delivery systems have also appeared. Adverse renal effects have recently been reported in association with topical NSAID formulations.3,4 The explosion in NSAID consumption in the US has occurred in parallel with a sharp increase in the prevalence of chronic kidney disease (CKD). Although the current epidemiologic trends of CKD doubtless reflect the influence of many factors, it is logical to ask whether NSAID use may be one of them. This is the first of two key issues to be examined in this chapter.

PHARMACOLOGY OF NSAIDS The principal pharmacologic action of all NSAIDs is to alter the metabolism of arachidonic acid. This 20carbon fatty acid, present in all cells, is the precursor of the eicosanoids, a family of physiologically active compounds comprising the prostaglandins and leukotrienes (Figure 65.1). These substances are autocoids, meaning their effects are exerted primarily on the tissue in which they are synthesized. Different cell types have differing proclivities for producing specific eicosanoid end-products. The paradigmatic illustration of this phenomenon is the abundant production by platelets of thromboxane A2, a prostaglandin that

induces platelet aggregation and vasoconstriction. In endothelial cells, the predominant eicosanoid product is prostaglandin I2 (prostacyclin), a vasodilator and inhibitor of platelet aggregation. The opposing effects of these substances lend protective balance to the interaction between blood vessels and thrombocytes. Variability of eicosanoid production is seen among the renal cell types as well. The primary step in the metabolism of arachidonic acid is catalyzed by cyclooxygenase (COX). It is this step that is inhibited by NSAIDs. Mammalian cells express two isoforms of cyclooxygenase, COX-1 and COX-2. COX-1 predominates in gastric mucosa, where prostaglandins confer protection against acid-peptic assault. For this reason, the specific COX-2 inhibiting NSAIDs are felt to be safer for patients at risk for gastric bleeding and ulceration. COX-2 is the predominant cyclooxygenase isoenzyme in the kidney. It is, therefore, not surprising that COX-2 inhibitors are reported to cause renal effects similar to those of the traditional, nonspecific NSAIDs.

PROSTAGLANDINS AND THE KIDNEY: AN OVERVIEW Both COX-1 and COX-2 are present in kidney tissue. COX-1 is constitutively expressed in the distal nephron. Its chief product is prostaglandin E2 (PGE2). COX-2 is more widely distributed throughout the kidney. Like COX-1, it is constitutively expressed, but it is also inducible under conditions of physiologic stress. The inducible expression of COX-2 in the renal cortex and medulla appear to be under independent control.5 The physiologic stresses that lead to enhanced cortical COX-2 activity are those associated with increased activity of the renineangiotensinealdosterone system (RAAS), such as sodium depletion and reduced renal perfusion. A bidirectional stimulatory relationship exists between the two hormonal systems: angiotensin II stimulates production of COX-2 eicosanoid products, and those products, in turn, stimulate renin release. Several generalizations may be made regarding the actions of renal prostaglandins, which are listed in Table 65.2. (1) As autocoids, prostaglandins synthesized in the kidney act on the kidney. Prostaglandins and prostaglandin metabolites excreted in the urine represent mostly those that were produced in the kidney. (2) The importance of prostaglandins affecting compensatory mechanisms in pathophysiologic states exceeds that of their role in normal renal physiology. This assertion is based on two




FIGURE 65.1 Biosynthetic pathway of eicosanoids. The eicosanoid precursor molecule is arachidonic acid, derived from substrate in the cell membrane phospholipid pool. Arachidonic acid may be metabolized by either of two enzymatic pathways. The lipoxygenase pathway produces a family of inflammatory mediators and cytokines known as leukotrienes. The cyclooxygenase (COX) system produces prostaglandins. Cyclooxygenase catalyzes the conversion of arachidonic acid to cyclic endoperoxides, which are short-lived prostaglandin precursors with no intrinsic biologic role other than as parent molecules for the biologically active prostaglandins. There are two isoforms of cyclooxygenase, COX-1 and COX-2; their relative importance varies among different tissues. NSAIDs inhibit cyclooxygenase activity. PGI2 is prostacyclin. PG, prostaglandin; Tx, thromboxane. TABLE 65.2

Major Roles of Prostaglandins in Renal Physiology and Clinical Consequences of Inhibition of Prostaglandin Synthesis



Consequences of Inhibition

Maintenance of renal blood flow

Counterregulate the action of vasoconstrictor hormones

Acute kidney injury (vasomotor nephropathy)

Potassium homeostasis

Promote potassium excretion through stimulation of renin secretion

1) Hyperkalemia 2) Hyporeninemic hypoaldosteronism (type IV renal tubular acidosis)

Water balance

Counterregulate the action of antidiuretic hormone on medullary collecting tubule


Sodium homeostasis

Modulate sodium reabsorption at multiple nephron sites

1) 2) 3) 4)

observations. First, under normal physiologic conditions, people are rarely subject to adverse renal consequences of inhibition of prostaglandin synthesis by NSAIDS. Second, under many of the conditions associated with renal sensitivity to NSAIDs (Table 65.3), urinary excretion of prostaglandin metabolites is above normal,

Edema Exacerbation of congestive heart failure Exacerbation of cirrhotic ascites and edema Exacerbation of hypertension

indicating a high level of renal cyclooxygenase activity. (3) As already noted in relation to the RAAS, prostaglandins serve to counterregulate the actions of other hormones on the kidney. A similar checkand-balance relationship exists between antidiuretic hormone and prostaglandins.


1074 TABLE 65.3


Predisposing Factors for Adverse Renal Effects of NSAIDs

Reduced renal blood flow

changes in intrarenal blood flow with marked reduction in medullary perfusion.6 Prolonged medullary ischemia can lead to atrophy and fibrosis of deep nephron structures and ultimately papillary necrosis.

Volume depletion Congestive heart failure

Importance of NSAID Use as a Causative Factor in CKD

Cirrhosis Chronic kidney disease Hypertension Medications (triamterene, calcineurin inhibitors, ACE inhibitors, ARBs, diuretics) Older age

Table 65.4 lists the various renal abnormalities that have been reported in patients taking drugs that inhibit prostaglandin synthesis. Most of these are predictable given the information in Table 65.2.

NSAIDS AS A CAUSE OF CHRONIC KIDNEY DISEASE Mechanism NSAID nephropathy is thought to be an ischemic, rather than toxic, process. In contrast to phenacetin, implicated in the pathogenesis of classic analgesic nephropathy, NSAIDs and their metabolites are not inherently nephrotoxic. In animal studies, suppression of prostaglandin synthesis by NSAIDs induces regional

TABLE 65.4

Renal Syndromes Attributed to NSAIDs

ACUTE KIDNEY INJURY • Prerenal azotemia • Vasomotor nephropathy • Crystal nephropathy • Acute tubular necrosis • Acute interstitial nephritis and proteinuria FLUID, ELECTROLYTE, AND ACIDeBASE IMBALANCES • Sodium retention • Hyperkalemia • Hyponatremia • Type IV renal tubular acidosis Exacerbation of hypertension Chronic kidney disease

The collective evidence that NSAIDs are capable of causing irreversible renal damage is less robust than that supporting their role in AKI. In the past three decades, isolated reports have imputed such a relationship, but in none of these is the case for direct causality beyond question.7e14 Clinical investigators have attempted to solidify this case. Segasothy and coworkers evaluated renal function and morphology in 94 chronic arthritis patients with a history of relatively heavy NSAID exposure. Of 82 patients who completed the assessment, 12% had radiographic evidence of papillary necrosis and 24% higher than expected serum creatinine concentration (S[Cr]) levels. These findings were distributed among patients with several unrelated forms of arthritis, strengthening the authors’ conclusion that heavy NSAID use, and not the disease process being treated, was culpable in the pathogenesis of their CKD.15 Sandler et al. conducted telephone interviews of 554 North Carolinians with newly diagnosed chronic renal disease to assess their prior intake of NSAIDs, and compared it with that of 516 control subjects. Heavy NSAID use was associated with a twofold risk of renal disease, although the effect was limited to male subjects over the age of 65.16 In another survey, 716 end-stage renal disease (ESRD) patients and 316 control subjects were queried regarding their pattern of use of three types of analgesics: acetaminophen, aspirin, and nonaspirin NSAIDs. The ESRD patients were stratified into three groups according to the etiology of their renal disease: diabetes mellitus, hypertension, and all others. A very strong cumulative dose-dependent interaction was found between NSAID use and prevalence of ESRD. A weaker relationship was found for acetaminophen. It is interesting that no such risk enhancement was seen with aspirin.17 A retrospective analysis of incident Taiwanese dialysis patients between 1998 and 2009 found that use of NSAIDs within the preceding 14 days raised the relative risk for initiation of chronic dialysis by a factor of 2 to 3.18 Renal function was followed over an 11-year period in a cohort of 1697 women enrolled in the national Nurses’ Health Study. These women were asked about their use of aspirin, acetaminophen, and nonaspirin NSAIDs. Their change in renal function over time was



compared with that of non-NSAID users. The only significant interaction between analgesic intake and abnormally rapid decline in renal function was seen with acetaminophen.19 Slightly different results emanated from a similar investigation looking at a healthy male cohort of participants in the national Physicians’ Health Study. Here, a modestly increased risk of reduced renal function was demonstrated among especially heavy users of nonaspirin NSAIDs or acetaminophen, while a possibly protective, albeit minimal, effect was seen with aspirin.20 More conventional usage patterns were not associated with risk enhancement.21 Further attempts have been made to identify an epidemiologic link between NSAID consumption and CKD.22e27 As is often the case with retrospective, casecontrol, and cross-sectional studies, caution is warranted in interpreting these data. Many of these studies relied on estimates and recollections by patients of their pill consumption over many years. The variability of the collective data precludes any meaningful estimate of actual risk. In some studies, interactions of NSAIDs with renal failure were limited to small subsets of subjects. Even in those studies showing an association between NSAID use and CKD, the causal sequence remains unproven, because increased use of NSAIDs may occur as a consequence of musculoskeletal complications of CKD, such as metabolic bone disease and crystal arthropathies. Whether NSAID use is heavier among persons with CKD than in demographically comparable subjects with normal kidney function is unclear.28 One group has attempted to clarify the role of NSAIDs in the pathogenesis of CKD by prospectively examining the incidence of papillary necrosis among 259 people receiving long-term, high-dose NSAIDs for treatment of arthritis.29 Over the 11-year study period, 69 new cases of papillary necrosis were diagnosed and confirmed radiographically. This study, while prospective, poses several impediments to interpretation. First, the population was demographically limited; the subjects were all Malaysian. Second, in addition to nonaspirin NSAIDs, some of the affected patients received other analgesics, including aspirin, phenacetin, paracetamol, and herbal supplements. Third, of the 29 patients who took nonaspirin NSAIDs alone, some received phenylbutazone. Fourth, no longitudinally studied control group of age-matched arthritis patients not receiving NSAIDs was available for comparison. These shortcomings notwithstanding, the incidence of papillary necrosis documented in this study is concerning, particularly in light of the fact that papillary necrosis is not a highly sensitive finding for diagnosing analgesic nephropathy radiographically.30


Relationship between NSAID-Induced CKD and Analgesic Nephropathy The term analgesic nephropathy is traditionally reserved for a syndrome of progressive renal atrophy and failure resulting from long-term use of phenacetin or related compounds, alone or in combination with other drugs. Because NSAIDs have analgesic properties, NSAID-induced CKD is often classified under the same heading. Although classic analgesic nephropathy and chronic NSAID-induced interstitial disease are both characterized by chronic tubulointerstitial nephritis and papillary necrosis, it is unlikely that they share the same pathogenesis. The mechanism by which phenacetin injures kidneys involves accumulation in the medulla of nephrotoxic metabolites and generation of reactive oxygen species (its relative acetaminophen has similar, albeit milder, effects). NSAIDs have minimal cytotoxicity in renal tissue per se. Their damage appears mediated through the previously discussed ischemic mechanism. Despite these differences, the two drug etiologies are closely linked epidemiologically, because patients commonly use both forms of analgesics. It is likely that their respective mechanisms are synergistic in the pathogenesis of CKD in patients taking NSAIDs and acetaminophen or phenacetin in combination.31 Although phenacetin-induced analgesic nephropathy predisposes to the development of renal and urologic neoplasms, this association has not been described with NSAIDs.32,33

Conclusions Although the accrued evidence that NSAID use can induce chronic kidney injury is not ironclad, it is strong enough to support the following conclusions: (a) NSAIDs appear capable of causing a morphologic pattern of renal injury similar to that of classic analgesic nephropathy, with interstitial fibrosis and papillary necrosis; (b) this form of injury appears limited to patients with very high cumulative NSAID exposure; and (c) the toxicity of NSAIDs may be magnified when taken in combination, or in conjunction with other medications such as acetaminophen and caffeine. The possibility that men may be more susceptible than women to NSAID-related CKD, as suggested by two of the individual studies cited, bears further study. Clinicians should be mindful of the likelihood of a causal link between NSAIDs and CKD when committing patients to longterm NSAID therapy. Blood pressure, blood chemistries, and urinalysis should be monitored routinely during treatment. At the earliest sign of change in any of these




FIGURE 65.2 Prostaglandin dependence of renal function. Vasodilatory prostaglandins such as PGI2 and PGE2 offset the actions of circulating and locally produced vasoconstrictors at the afferent arteriole. This modulation of afferent resistance is particularly important in conditions of high vasoconstrictor activity. NSAID use under such conditions can lead to unopposed vasoconstriction and reduction of glomerular perfusion. AFF, afferent arteriole; EFF, efferent arteriole; GC, glomerular capillary.

parameters, alternatives to NSAID therapy should be considered, some of which may be found later in this chapter.

ADVERSE CONSEQUENCES OF NSAID THERAPY IN PATIENTS WITH CKD Are patients with CKD at enhanced risk for adverse renal effects and, if so, which ones? What is known about the pathogenesis of such effects, and how can they be avoided in CKD patients for whom NSAID therapy is indicated? Indeed, an array of renal abnormalities attributable to NSAIDs have been described. These have been reviewed extensively34e41 and are shown in Table 65.4. In normal individuals, NSAIDs rarely evoke significant changes in blood pressure, renal function, water, or electrolyte balance. NSAID-related renal syndromes occur almost exclusively in pathophysiologic settings, an observation that is consistent with the primarily compensatory role of renal prostaglandins. Of these predisposing conditions, which are listed in Table 65.3, CKD was among the first to be reported.

Acute and Acute-On-Chronic Kidney Injury Due to NSAIDs To maintain glomerular blood flow in the face of an activated renineangiotensin system, as occurs in congestive heart failure, cirrhosis, and sodium deprivation, modulation of afferent arteriolar resistance by vasodilatory prostaglandins (PGs) is essential. The prostaglandin dependence of renal function in patients with these conditions is evidenced by their elevated urinary excretion of prostaglandin metabolites, and the observation that NSAIDs can cause AKI in these

conditions. This form of AKI has been variously termed vasomotor nephropathy, autoregulatory failure, functional acute renal failure, or decompensated prerenal azotemia (Figure 65.2). As is characteristic of hemodynamically mediated forms of AKI, the syndrome will usually reverse readily when the offending agent is withdrawn, although if renal perfusion has been sufficiently compromised by the NSAID, frank acute tubular necrosis (ATN) may develop.29 Recent reports have suggested a particularly heightened risk for AKI when NSAIDs are added to the medication regimens of patients already receiving diuretics and ACE inhibitors or ARBs.41e46 This would seem straightforward from a pathophysiologic perspective as this combination of agents could impair autoregulation of vascular tone in both the pre- and postglomerular arterioles. The prevailing hemodynamic adaptations that occur in CKD kidneys are less predictable. Patients with CKD typically have chronic volume expansion and suppression of their renineangiotensin system, yet are still prone to NSAID-induced vasomotor nephropathy. In 1978, Kimberly and Plotz reported several patients with systemic lupus erythematosus who developed reversible AKI while receiving aspirin.47 They subsequently reported the same phenomenon in association with other NSAIDs.48 The best explanation for these findings is that while these patients ostensibly had good baseline renal function, their glomerular filtration rate (GFR) was probably maintained by glomerular hyperfiltration, and that this process is prostaglandindependent. Evidence exists to support this hypothesis. It is known from micropuncture studies in rats that subnormal afferent arteriolar resistance permits hyperfiltration in remnant glomeruli.49,50 In a rodent kidney ablation model, the renal functional changes associated with uninephrectomy were blunted in rats treated with either indomethacin or a selective COX-2 inhibitor.51 In



humans, the hyperfiltration observed in a group of subjects with sickle cell nephropathy was blunted by both indomethacin and sulindac,52 by celecoxib in euglycemic patients with early type 1 diabetic nephropathy,53 and by aspirin in children with chronic obstructive uropathy.54 The observations of Kimberly and Plotz notwithstanding, review of the literature on NSAID-related AKI suggests that this phenomenon occurs much less frequently with salicylates than with other classes of NSAIDs. Early literature suggested that sulindac, too, was less often associated with such cases.55,56 However, a recent meta-analysis of this literature suggests that the relative nephrotoxicity of different NSAIDs, including the selective COX-2 inhibitors, is still not well established.57 The exact risk of acute renal decompensation in a CKD patient at the outset of NSAID exposure is unknown because prospective data from randomized, controlled trials are lacking, and because this risk may be further influenced by multiple factors. In a general population survey among residents of Saskatchewan, current NSAID use was found to raise the risk of hospitalization for AKI fourfold. Age >65 years was likewise an independent risk factor with an associated hazard ratio of 3.5. Unfortunately, baseline level of renal function was not examined as a risk factor in this analysis.58 However, other epidemiologic surveys as well as clinical investigation provide evidence that renal senescence is a risk factor (see below). In patients with glomerular diseases, the sensitivity of renal function to cyclooxygenase-inhibiting drugs was noted by Patrono and colleagues to correlate with basal excretion of 6-keto-PGF1a, the chief metabolite of prostacyclin, suggesting dependence of renal function on prostacyclin. This group found that patients with active lupus nephritis excrete large amounts of not only 6keto-PGF1a, but thromboxane B2, the main metabolite of the vasoconstrictor prostanoid thromboxane A2, as well. Their experience is that renal function in lupus nephritis is less severely affected by NSAIDs than in other glomerular diseases. They posit that, at baseline, lupus patients produce excessive thromboxane A2 which causes chronic afferent vasoconstriction, thus limiting glomerular filtration. When these patients take NSAIDs, the decremental effect on GFR that would be expected from reduced prostacyclin production is offset by the concomitant reduction in thromboxane. Patrono has suggested that the clinical consequences of cyclooxygenase inhibition in the intrarenal microcirculation depend on the net change in the balance between prostaglandins that are vasodilatory and inhibitory of platelet function vs. those that are vasoconstrictive and prothrombotic.59 Further support for this hypothesis


comes from their finding that thromboxane-specific inhibitors raise GFR in SLE.60 In summary, the CKD patient’s renal response to an NSAID may be influenced by several factors: 1) The etiology of the underlying renal disease. 2) The change in the specific pattern of eicosanoid synthesis engendered by cyclooxygenase inhibition. 3) The nature of the NSAID, its pharmacokinetics, and COX-specificity. The pharmacologic effects of NSAIDs vary markedly among specific agents. Sulindac, despite its chemical kinship to indomethacin, is much less nephrotoxic, although probably not totally innocuous as originally thought.50,51 NSAIDs in the salicylate class are the least frequently identified in reports of adverse renal effects, but tend to have lower antiinflammatory potency than other NSAIDs. The interest in COX-2-specific inhibitors derives from the fact that COX-1-generated PGE2 is integral to the protection of the gastric mucosa. The selective COX-2 inhibitors have been implicated in numerous reports of adverse renal side effects, as might be expected given the abundant expression of cyclooxygenase-2 in the kidney.38,61e64 They should be considered no less potentially nephrotoxic than traditional cyclooxygenase inhibitors. This heterogeneity of effects between NSAIDs is well exemplified in the coronary circulation. Aspirin is a pure COX-1 antagonist that binds irreversibly to the membranes of platelets and blocks the synthesis of their principal eicosanoid product, thromboxane A2. This specificity confers on aspirin its balance of antithrombotic and antiinflammatory potency that is unique among NSAIDs and has made aspirin the clinical mainstay in prophylaxis against coronary events.65 A meta-analysis of the effects of other NSAIDs on the risk of atherothrombotic events (chiefly myocardial infarction and stroke) showed a substantially increased risk with rofecoxib, diclofenac, and ibuprofen, but not naproxen or celecoxib.66 The association between rofecoxib and coronary events was sufficiently serious to force the withdrawal of this agent from the market.67,68 Pharmacokinetics may also influence risk. In a German study comparing renal function in NSAID users compared with nonusers undergoing elective orthopedic surgery, the prevalence of renal dysfunction was highest among patients using longer half-life (>4 hours) drugs. This study was a cross-sectional, interview-driven analysis looking at prevalence, not incidence, and thus limited in its ability to establish causality or to differentiate between CKD and AKI.69 A randomized, prospective,




drug challenge study in an elderly cohort demonstrated that the negative effect on GFR of the longer acting NSAIDs sulindac and celecoxib is more sustained than that induced by ibuprofen.70 Similar findings were reported by other investigators.71 4) Timing of drug exposure. The acute renal response to NSAIDs may differ from the chronic response. In the study referenced immediately above, which was designed to delineate the acute and chronic effects of various NSAIDs on renal function in an elderly cohort, while most subjects demonstrated a decline in GFR within an hour of drug challenge, no effects were seen following one-month of sustained exposure to the same agents.72 5) “Host” factors, including patient age. The response of renal function to NSAIDs has been studied extensively in the elderly population, because the prevalence of both CKD and age-related decline in renal function without evidence of discrete renal disease is high. The results have varied from study to study. Caution has been recommended in committing elderly patients to sustained courses of long-acting NSAIDs.73,74 In another drug challenge study with a crossover design comparing the effects of celecoxib vs. naproxen in healthy elderly subjects over periods of up to 10 days, both agents engendered negative changes in GFR and sodium excretion, albeit of minimal magnitude.62 Although the risk of AKI from NSAIDs in the truly healthy elderly is probably very small, the prevalence of comorbidities including unrecognized CKD among the aged warrants close monitoring when prescribing NSAIDs, especially in the very elderly (age >85 years).74

Nonhemodynamically Mediated Acute Kidney Injury Due to NSAIDs Acute interstitial nephritis (AIN) due to NSAIDs is relatively unusual. It differs from typical druginduced AIN in lacking hypersensitivity features such as eosinophilia, eosinophiluria, or rash and is often accompanied by nephrotic-range proteinuria. It is the most idiosyncratic of NSAID-related renal syndromes. Antecedent CKD is not, as far as is known, a risk factor. Tubulointerstitial nephritis was been reported in patients receiving aminosalicylates for inflammatory bowel disease.75,76 Medications with solubility characteristics conducive to intratubular crystallization can cause microobstructive AKI. This phenomenon is rare with NSAIDs, but has been reported with sulindac, and was partly

responsible for the removal of zomepirac from the marketplace in the 1980s. As with AIN, there is no evidence that CKD places the patient at increased risk.

Effect of NSAIDs on the Progression of Established CKD Concern has been expressed in the medical literature that long-term NSAID use may exacerbate the course, or accelerate the progression, of chronic renal parenchymal disease. Gooch et al. evaluated the effects of NSAIDs on kidney function in a large population of older (>66 years) patients with preexisting CKD. Patients in the highest decile of self-reported cumulative NSAID use had a 26% increase in risk of experiencing a mean decline in eGFR of >15 mL/min/1.73 m2 over a two-year study period compared with nonusers.77 A cross-sectional study of over 19,000 CKD patients in a random sampling of Taiwanese National Health Insurance enrollees found that use of aspirin, nonaspirin NSAIDs, and acetaminophen all were associated with markedly increased risk of ESRD in a cumulative dose-dependent manner. Again, the order of causality cannot be strictly established due to limitations inherent to this type of the study and the question raised by the observed interaction with acetaminophen.78 Exactly how serious a threat NSAIDs pose for accelerated progression of CKD, and whether certain etiologies of CKD may be more prone than others, are as yet unknown. From a mechanistic standpoint, it is entirely plausible that NSAIDs could accelerate CKD progression by superimposing an ischemic insult on that of the primary renal disease. However, this same reduction in perfusion might be expected to afford the glomeruli protection from hyperfiltration injury. These effects of NSAIDs on glomerular hemodynamics were the basis for their use years ago in patients with severe and refractory nephrotic syndrome for palliation of proteinuria. Despite sporadic reports of success, this approach has been largely abandoned due to the availability of more reliable alternatives. Consequently, little has been learned about the impact of prolonged, deliberate NSAID exposure on the course of CKD. NSAIDs have also been employed as antithrombotic therapeutic adjuncts in chronic glomerulonephritis, but this experience, too, has added little to our understanding of the net effect of long-term NSAID use on chronic renal disease outcomes. At this time, there is no solid evidence on which to base the use of NSAIDs as a nephroprotective measure in CKD. In fact, based on available data, the clinician is well advised to act on the assumption



that NSAIDs can speed the progression of renal injury and to minimize exposure of CKD patients to them. A recent meta-analysis of the global literature linking NSAIDs and CKD reached similar conclusions.79

Hyperkalemia The overall risk of hyperkalemia among patients taking NSAIDs is unknown and is clearly subject to ancillary host susceptibility factors, many of them the same as those for other renal complications of NSAIDs. In a large, Veterans Administration case-control study, the effect of NSAIDs as a sole, independent risk factor for hyperkalemia was negligible.80 A 1985 Israeli study analyzed changes in renal function and serum electrolytes in 50 elderly inpatients receiving indomethacin for a variety of indications. A minority (z30%) of these patients had underlying renal insufficiency. In all patients, potassium concentration rose steadily until discontinuation of the drug. In 13 patients, the increment in serum potassium concentration (S[K]) exceeded 3.6 mMol/L, and in 23 the peak potassium concentration exceeded 5.0 mMol/L. Not surprisingly, older age and the presence of predrug azotemia correlated with the magnitude of rise in S[K] level. The authors did not report which other medications these patients might have received.81 Although the patients at greatest risk for hyperkalemia are those who sustain AKI from NSAIDs, hyperkalemia can occur even in the absence of a substantial fall in GFR. The pathogenesis of NSAID-related hyperkalemia is felt chiefly to reflect the suppressive effect on the renineangiotensinealdosterone axis of inhibiting prostaglandin synthesis and may present as type IV renal tubular acidosis. In one such case, the patient’s underlying rheumatologic condition necessitated continuation of the NSAID, but the manifestations of type IV RTA were controlled with the addition of fludrocortisone to his therapeutic regimen.82 An identical pattern of hyperkalemic acidosis occurs in congenital hypoprostaglandism.83 Because, in normal subjects, indomethacin impairs neither the disposal of nor the aldosterone response to an acute potassium load,84 one must assume that reduced availability of prostaglandins is somehow deleterious to adrenocortical function in those individuals who develop NSAID-induced hyporeninemic hypoaldosteronism. Other pathogenetic mechanisms of hyperkalemia from NSAIDs have been posited. There is evidence suggesting that function of potassium secretory channels in the distal nephron may be dependent on prostaglandins.85 It has also been speculated, albeit never proved, that prostaglandins may facilitate transcellular disposition of potassium.


NSAID therapy should be approached cautiously in patients with baseline renal insufficiency or other medical conditions that may reduce potassium tolerance. Extreme caution is warranted when adding NSAIDs to regimens that include other medications associated with hyperkalemia, notably ACE inhibitors, ARBs, aliskiren, spironolactone, trimethoprim, and potassiumsparing diuretics.

Hyponatremia Prostaglandins oppose the effects of ADH on the collecting tubule epithelium, thus providing a counterregulatory balance to ADH-induced water reabsorption. It is not surprising that NSAIDs may render patients prone to hyponatremia. At highest risk are patients with preexisting conditions known to limit their water excretion, particularly those characterized by a reduction of effective circulating volume, such as congestive heart failure.86 Even with normal systemic hemodynamics, however, CKD can predispose to NSAID-induced hyponatremia. Clinicians must exercise caution when considering persons with CKD for a course of NSAID therapy, particularly those patients with a prior history of hyponatremia. Blood chemistries should be monitored frequently (about every two weeks or until the stability of blood chemistries has been ascertained) with the expectation of determining the possible need for daily water restriction. Although a synergistic effect of NSAIDs and thiazide diuretics in promoting hyponatremia has not yet been demonstrated, it would seem prudent to avoid this drug combination.

Sodium Retention Antinatriuresis is the most common renal side effect of NSAIDs. In large trials of nonspecific and COX-2specific NSAIDs in patients with osteoarthritis, the incidence of edema, generally mild, ranged from approximately 2e6%.87 Again, the most vulnerable patients are those with sodium retentive conditions such as cirrhosis and congestive heart failure, disorders in which optimization of renal hemodynamics is prostaglandin-dependent. Cyclooxygenase inhibition in these situations lessens glomerular perfusion and filtration, resulting in both a reduction of the filtered load and increased tubular reabsorption of sodium. In addition to altered hemodynamics, sodium retention also reflects the elimination of the natriuretic effects of prostaglandins, which inhibit tubular sodium transport in the normal kidney. This more direct antinatriuretic action of NSAIDs can occasionally have significant impact even in normal individuals. In one investigation in which 36 normal subjects were challenged with




indomethacin or a COX-2-selective NSAID, the antinatriuretic effects of each agent were shown to persist only through the first 72 hours of treatment.88 How this escape natriuresis occurs is unknown nor is it known why it presumably fails to occur in those occasional seemingly normal individuals who develop edema on NSAIDs. Studies have demonstrated NSAIDs are capable of mitigating the natriuretic effects of loop and thiazide diuretics.89e94 Sodium retention, like most other renal side effects of NSAIDS, is reversible. Natriuresis generally occurs on discontinuation of the drug, with restoration of pretreatment sodium balance.

Exacerbation of Hypertension The intimate relationship between hypertension and CKD is familiar to all clinicians and detailed elsewhere in this text. Hypertension is a common primary cause of CKD. Conversely, hypertension is the nearly inevitable result of declining GFR in patients with CKD of most etiologies. Regardless of whether hypertension represents a primary or secondary phenomenon in a given patient with CKD, it can accelerate the course of progressive renal injury. Besides blunting the action of diuretics, NSAIDs can reduce the efficacy of other antihypertensive agents including calcium channel blockers,95 vasodilators,87 and, possibly, beta 96,97 blockers. In a randomized controlled trial in which celecoxib was given to 178 participants already receiving an ACE inhibitor for hypertension, no effect of the NSAID on blood pressure was seen.98 The ability of NSAIDs to mitigate action of some antihypertensive drugs is understandable, given the vasodilatory and natriuretic properties of the predominant renal eicosanoids. In the Success VI trial comparing the vascular effects of rofecoxib and celecoxib, the tendency to cause edema paralleled their tendency to cause increased systolic blood pressure, with rofecoxib exerting greater effects than celecoxib.99 The significance of these observations is threefold. First, they strengthen the contention that antinatriuresis plays a role in NSAIDrelated exacerbation of hypertension. Second, they illustrate that cyclooxygenase-2 specificity may actually enhance the harmfulness of NSAIDs to the kidneys. Third, they underscore the disproportionate morbidity of rofecoxib compared with the closely related compound, celecoxib. This last point was upheld in another similar study comparing the vascular actions of several NSAIDs in type 2 diabetic hypertensive patients receiving NSAIDs for osteoarthritis, which found rofecoxib more apt to exacerbate hypertension than either naproxen or celecoxib.100

Because CKD is so prevalent and so likely to go unrecognized in our population, and because antiinflammatory self-medication use is so abundant, physicians should alert their patients to the potential for untoward interactions.26 The significance of NSAIDs in clinical hypertension resides in their ability to exacerbate preexisting hypertension or to vitiate the actions of antihypertensive drugs. However, evidence from several sources, including the national Nurses Health Study, raises concern about an increased risk of incident hypertension among otherwise healthy persons who use NSAIDs heavily.101e103 In any event, blood pressure, like other parameters of renal function, should be monitored closely throughout the course of NSAID therapy in patients with known hypertension or CKD or both, and appropriate adjustments in antihypertensive regimens made when necessary.

NONRENAL SIDE EFFECTS OF NSAID USE IN PATIENTS WITH CKD NSAIDs can increase the risk of cardiovascular events in patients with atherosclerosis. Given the enormous prevalence of atherosclerosis at all stages of CKD, such patients should be considered at particularly high risk for cardiovascular morbidity when taking NSAIDs. It is important to inform patients of this risk and advise them to seek immediate medical attention if any symptoms suggestive of coronary or cerebrovascular ischemia should arise. The risk of atherothrombotic complications in these patients is another reason why stringent attention must be paid to blood pressure control. Of all NSAID side effects, the most familiar to physicians and patients alike, and the most concerning epidemiologically, are those involving the gastrointestinal tract: dyspepsia, gastritis, peptic ulceration, and upper gastrointestinal hemorrhage. Gastritis and peptic ulcer disease were formerly thought to be more prevalent in CKD patients than in the population at large. Although current consensus challenges this contention, recent evidence suggests that CKD patients with peptic ulcer disease are more prone to complications such as recurrent bleeding.104 Given this, and the clinical observation that peptic ulcer disease tends to be less symptomatic in CKD patients than in others, it is prudent to consider these patients at increased risk of gastrointestinal morbidity from NSAIDs. Although COX-2 inhibitors are safer from the gastrointestinal standpoint, they are no safer for the kidneys than traditional NSAIDs and may pose a higher risk of cardiovascular complications. It is thus impossible to specify a particular NSAID of choice for CKD patients. Agents of either group should be used with extreme caution, and patients should be monitored for the appearance of gastrointestinal



complications. CKD patients receiving NSAIDs should receive proton-pump inhibitors concomitantly for gastrointestinal prophylaxis.

NSAIDS AND CKD: RECOMMENDATIONS FOR THE CLINICIAN The combined prevalence of NSAID use and CKD throughout the modern world represents a substantial hazard for untoward interactions. Fortunately, most adverse renal effects of NSAIDs are reversible, and patients at highest risk are readily identifiable. The presence of risk factors does not categorically preclude the use of NSAIDs when indications arise, as long as careful physician oversight of NSAID therapy is provided. An algorithm illustrating an approach we recommend is shown in Figure 65.3. When NSAID therapy is indicated for a patient with renal risk factors, it may be worth starting with one of the better tolerated agents such as a nonacetylated salicylate. While less often associated with renal side effects, these agents lack the antiinflammatory potency of most other NSAIDs. They are unlikely to be of benefit in a highly active inflammatory state such as acute gouty arthritis


or a flare of systemic lupus. If they are tried, and fail to engender the desired therapeutic response, a trial of a more potent NSAID such as naproxen, indomethacin, or ibuprofen may be considered, provided the patient is closely monitored. NSAIDs are extremely effective in the treatment of a wide variety of inflammatory conditions and have an established role in the palliation of pain. What alternatives are available for patients who cannot tolerate them? The answer to this question clearly depends on the indication for treatment. Corticosteroids offer an alternative option for treating inflammatory disorders. The risks associated with systemic steroid therapy must be weighed if this option is under consideration. A localized inflammatory condition, such as a monoarthritis or bursitis, may respond to direct injection, which lessens systemic exposure. CKD patients with gout or pseudogout can be safely treated with colchicine provided the clinician titrates the dose carefully to minimize gastrointestinal symptoms. If colchicine therapy is to last longer than a week, the white blood cell count should be monitored. Acetaminophen is a good alternative to NSAIDs for management of mild to moderate pain. Although

Establish indicaon for NSAID.

Check baseline BP, renal funcon, blood chemistries. Discuss risks with paent. Begin low-toxicity NSAID (eg, salicylate).

Adequate response to NSAID therapy ?

Determine how long to connue NSAID therapy.

Recheck BP, renal funcon, blood chemistries. Discuss risks with paent. Switch to higher-potency NSAID.

Minimize duraon of therapy; monitor BP, renal funcon, blood chemistries every 1 to 2 weeks throughout. Disconnue NSAID if changes noted.

FIGURE 65.3 Suggested algorithm for safe treatment with NSAIDs in patients with CKD. Patients with known risk factors should be monitored for renal complications throughout course of therapy. Low-toxicity NSAIDs, specifically nonacetylated salicylates, are less apt to cause renal side effects, but often have less therapeutic efficacy. When higher potency nonsteroidals are used in patients at risk, vigilance must be intensified. Alternatives to NSAIDs for the management of pain and inflammation are discussed in text.




acetaminophen does have slight nephrotoxic potential, this does not pose a significant risk until a very high cumulative dose exposure is reached. Opioids represent another option.

OPIOIDS AND CKD Narcotic analgesics can be used as NSAID alternatives in patients with moderate to severe pain provided the clinician and patient are mindful of their risks. Clinical safety of these agents from the renal standpoint will be considered in the following section.

OPIOID-INDUCED NEPHROPATHIES Although the direct nephrotoxicity of opioids is questionable, they have the ability to engender acute effects on prerenal, intrarenal, and postrenal physiology. Understanding these effects is essential to predicting the acute and long-term effects of opioids on kidney function.

Acute Renal Effects of Opioids Prerenal renal azotemia due to opioids occurs as a result of opioid-induced hypotension, which arises through several mu opioid receptor (MOR)-mediated mechanisms. These include suppression of CNS sympathetic outflow, histamine-induced vasodilation, and blunting of reflex vasoconstriction in response to fluctuations in arterial blood gases.105 Recent in vivo studies suggest this effect may also be mediated by nitric oxide106,107, or by indirect activation of the apelin receptor.108 Because of their hypotensive effect, opioids should be used with caution in CKD patients to avoid worsening of intradialytic hypotension and further decrease in renal perfusion in the setting of already compromised renal blood flow. Fentanyl, which has multiple pharmacokinetic properties favorable for use in renal impairment, appears to exert the least hemodynamic impact among opioids. Acute intrarenal effects of opioids. Kidney injury due to rhabdomyolysis is commonly seen with opioid overdoses that result in prolonged immobilization. Animal studies suggest that opioid exposure itself also has the potential to exert physiological damage on the kidney at the cellular level. Morphine has been shown to compromise podocyte integrity, inducing microalbuminuria109 and to induce mesangial cell proliferation and superoxide formation resulting in glomerular injury in vitro.110e112 Perhaps related to these observations, Yatsynovich et al. described a case of a 61-year-old man

with stage IIIa CKD attributed to chronic NSAID use for back pain. After two years of abstention from NSAIDs, during which time the patient had been using oxymorphone for analgesia, he developed proteinuria and acute-on-chronic renal failure. Renal biopsy revealed lamellated, phospholipid-like deposits in podocytes similar to those seen in Fabry’s disease as well as in renal injury from other medications. The patient’s kidneys recovered to baseline following abstinence from oxymorphone.113 Therapeutic doses of tramadol and tapentadol have also been shown to produce histological changes in rat renal tissue mediated by oxidative stress114 although we are unaware of any reports of human renal injury due to these agents. Postrenal effects of opioids. Opioid-induced urinary retention results from MOR-mediated inhibition of the volume-evoked micturition reflex115 and from decreased detrusor contractility via the inhibition of acetylcholine release by parasympathetic sacral neurons.116,117 The anticholinergic activity of opioids does not correlate directly with their narcotic potency. Despite being among the weaker opioids, tramadol tends to exert the most potent anticholinergic effect among drugs in this class.118

Heroin Nephropathy and Other Renal Syndromes Associated with Opioid Abuse “Heroin nephropathy” was widely reported in the 1970s and 1980s, although such reports have become rare in recent years. Whether this syndrome was attributable to the pharmacological properties of the active drug per se, to bulking agents and contaminants within the drug product, or to comorbidities and social factors associated with intravenous drug use (IVDU), has been debated. The preponderance of evidence favors the latter two explanations. Most cases were reported in users of “brown heroin,” a variety originating predominantly in southwest Asia. Its brownish color reflects the specific chemical process by which it is formulated.119 Phenacetin, a commonly used heroin additive, was banned by the FDA in 1983 because of its nephrotoxicity. The withdrawal of phenacetin may have contributed to the waning of the heroin nephropathy phenomenon.120 A patient has been reported who developed acute renal injury due to crystallization of heroin in the renal tubules. Although this mechanism of renal injury is well known in relation to other pharmacologic agents, including NSAIDs, we know of only one such report of tubular injury due to heroin dissolubility.121 Indeed, renal biopsies of patients with “heroin nephropathy” most commonly revealed the lesions of focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis. These are also the lesions seen in the glomerulopathies associated with HIV and HCV infection,




also highly prevalent among IV drug users. It is speculated that advances in the diagnosis and treatment of these diseases have resulted in the reduced frequency with which heroin nephropathy is documented.122e124 Infections associated with IVDU may have additional, indirect renal implications as they often result in exposure to nephrotoxic antiinfective agents. For example, tenofovir, a widely used antiretroviral agent for the treatment of both HIV and HBV infection, is known to cause ATN and Fanconi syndrome.125e127 IVDUassociated bacterial infections such as infective endocarditis may also result in prolonged exposure to highly nephrotoxic antibiotics such as vancomycin and/or aminoglycosides, which may cause AIN and ATN, respectively.128

USE OF OPIOIDS IN PATIENTS WITH CKD Recent evidence suggests that therapeutic use of opioids is widespread among patients with CKD and may even increase in patients with more advanced stages of CKD.129 It behooves the nephrologist to have at least passing familiarity with the clinical pharmacology of these agents.

Agent-specific Considerations As a family, the opioids vary widely in terms of their individual pharmacokinetics and routes of metabolism. This variability markedly influences the safety and proper prescription of each agent for use in patients with CKD. The following paragraphs, and Table 65.5, summarize the key considerations. Morphine130: Morphine’s kinetic and dynamic profiles make it unfavorable for use in patients with kidney disease. Symptoms of neurotoxicity such as cognitive impairment, tremors, and myoclonus can result from the glucuronidated morphine metabolite M3G, which tends to accumulate in patients with impaired renal function.131 Morphine is also especially histaminergic132 and therefore more likely to produce untoward hemodynamic effects than other drugs in this class. TABLE 65.5

Hydromorphone133: Hydromorphone’s active metabolite HM3G has been shown to have neurotoxic effects similar to those produced by toxic morphine metabolites.134,135 However, it is considered safer and possibly more effective than morphine.136,137 Codeine138: Codeine’s metabolism and excretion are quite variable and subject to the influence of factors besides renal function, particularly CYP2D6 activity.139,140 Codeine is converted into multiple metabolites, including morphine, via the CYP2D6 pathway. Given its unpredictable kinetics, and the likelihood of accumulation of downstream toxic metabolites, codeine is not recommended in kidney disease. Hydrocodone,141,142: As hydrocodone is eliminated primarily via the kidneys, patients with renal disease are at increased risk of sedation and respiratory depression. Dosage adjustment and careful titration are warranted. Oxycodone143: Oxycodone is extensively renally eliminated and minimally dialyzable.144 Renal dosing adjustments and careful titration are warranted with its use. Meperidine145: The antinociceptive properties of meperidine have been shown to be minimal relative to the toxicity of its primary metabolite, normeperidine. Its place in pain management is, therefore, limited.146 Because meperidine and normeperidine are extensively renally eliminated, its use is discouraged in renal failure. However, both meperidine and normeperidine are effectively removed by dialysis.147 Tramadol148: Tramadol exerts a weak narcotic effect and was only recently added to the DEA list of controlled substances. Approximately 30% of tramadol is eliminated by the kidney, resulting in its prolonged duration of effect with renal impairment. Because of its structural similarity to meperidine, tramadol shares many of its off-target anticholinergic and serotonergic effects and a propensity to cause seizures. Reduced dosing frequency in patients with renal failure and avoidance of use all together in patients with seizure history are therefore recommended. Fentanyl149,150: Because less than 10% of active drug is excreted in the urine, fentanyl is unlikely to accumulate in patients with mild to moderate renal disease or when given in appropriately adjusted doses to patients with

Suggested Dosing of Opioids as a Function of GFR153e155

GFR (mL/min) Methadone Oxycodone

Hydromorphone Hydrocodone Oxymorphone Fentanyl




5 mg PO 2.5 mg IV

5e10 mg PO 1e2 mg PO 0.25e0.5 mg IV

5e10 mg PO

5 mg PO

25e50 mcg IV 50 mg PO

10 mg PO 2.5e5 mg IV

















Dose q12 hours 25*

Note: Further dose reduction should be considered for patients with eGFR <10 mL/min/1.73 m . Use of codeine, morphine, or meperidine is not recommended in CKD. Dosing recommendations are for immediate release dosage forms only. * Percent of starting dose for GFR >60 mL/min. 2




severe renal disease. The most commonly used nonparenteral formulation is the transdermal patch. Unfortunately, transdermal delivery delays the onset and duration of action by up to 12 hours from the time the patch is applied or removed, making it somewhat more difficult to monitor and titrate. As such, the patch is not recommended in patients who are opioid naı¨ve, and further caution must be exercised when initiating its use in patients with kidney disease. Methadone151: Methadone is notoriously difficult to titrate for several reasons including its tendency to accumulate in tissues, its long elimination half-life relative to duration of analgesia, and its somewhat idiosyncratic doseeresponse relationship. However, like fentanyl, less than 10% of active methadone is excreted in the urine, resulting in pharmacokinetics that are only minimally altered in the setting of renal impairment. Unlike other opioids, methadone can cause cardiac arrhythmias when combined with other QT-interval-prolonging agents. Patients with renal failure may be more susceptible to such drugedrug interactions.152

Dialytic Considerations Because the narcotic effects of opioids, with few exceptions, are readily reversible with naloxone, the safety implications of nondialyzability are generally minimal. As dialyzability is inversely proportional to molecular weight, volume of distribution, protein binding, and water solubility, it is not surprising that pharmacokinetic studies have found methadone and fentanyl concentrations least affected by hemodialysis,156e159 whereas drugs like morphine may be so readily dialyzed that a rebound effect may be observed as the elimination

TABLE 65.6

from the plasma during dialysis may exceed the rate of drug transfer to and from the CNS.160 The chemical properties of each opioid agent that may affect its dialyzability are listed in Table 65.6.

Conclusions The combined prevalence of NSAID use and CKD throughout the modern world represents a substantial hazard for untoward interactions. Fortunately, most adverse renal effects of NSAIDs are reversible, and patients at highest risk are readily identifiable. The presence of risk factors does not categorically preclude the use of NSAIDs when indications arise, as long as careful physician oversight of NSAID therapy is provided. An algorithm illustrating an approach we recommend is shown in Figure 65.3. When NSAID therapy is indicated for a patient with renal risk factors, it may be worth starting with one of the better tolerated agents such as a nonacetylated salicylate. While less often associated with renal side effects, these agents lack the antiinflammatory potency of most other NSAIDs. They are unlikely to be of benefit in a highly active inflammatory state such as acute gouty arthritis or a flare of systemic lupus. If they are tried, and fail to engender the desired therapeutic response, a trial of a more potent NSAID such as naproxen, indomethacin, or ibuprofen may be considered, provided the patient is closely monitored. NSAIDs are extremely effective in the treatment of a wide variety of inflammatory conditions and have an established role in the palliation of pain. What alternatives are available for patients who cannot tolerate them? The answer to this question clearly depends on the indication for treatment. Corticosteroids are an option for treating inflammatory disorders. The risks

Drug-specific Factors Affecting the Dialyzability of Opioids161


Molecular Weight

Volume of Distribution (L)

Protein Binding

Water Solubility


















Not reported
































associated with systemic steroid therapy must be weighed against the use of other approaches if this option is under consideration. If the inflammatory condition is localized (such as a monoarthritis or bursitis), it may respond to direct injection, which lessens systemic exposure. CKD patients with gout or pseudogout can be safely treated with colchicine, provided the clinician titrates the dose carefully so as to minimize gastrointestinal symptoms. If colchicine therapy is to last longer than a week, the white blood cell count should be monitored. Acetaminophen is a good alternative to NSAIDs for management of mild to moderate pain. Although, as noted, acetaminophen does have mild nephrotoxic potential, this does not represent a significant risk until a very high cumulative dose exposure is reached. Narcotic analgesics can be used as NSAID alternatives in patients with moderate to severe pain, provided the clinician and patient are mindful of the well-known risks associated with these agents. Serious problems are associated with the widespread use of opioids, including misuse, abuse, overprescription, and diversion. Nevertheless, these drugs remain a valuable therapeutic tool in the treatment of pain refractory to nonnarcotic analgesics. Pharmacokinetics of many opioids are altered in CKD, and they vary in their dialyzability. For these reasons, dosing modifications are often necessary.

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QUESTIONS AND ANSWERS Question 1 A 64-year-old man is hospitalized for worsening shortness of breath. Ten days ago, he saw his physician for pain due to osteoarthritis of the knees and was given a prescription for naproxen (750 mg twice a day). He has a history of dilated cardiomyopathy felt to be of ischemic etiology, type 2 diabetes mellitus, and hypertension. He has remained on his other medications, which include lisinopril (20 mg a day), furosemide (20 mg twice a day), and glyburide (10 mg a day). On examination, BP ¼ 150/95 mm Hg, heart rate ¼ 98 bpm, respirations ¼ 20/min. His O2 saturation is 88% on room air. He appears short of breath. Crackles are heard over both lung fields, and 2þ pitting edema is present in the ankles and feet. Blood chemistries are as follows: Sodium 133 mEq/L, potassium 6.0 mEq/L, chloride 109 mEq/L, bicarbonate 22 mEq/L, BUN 24 mg/dL, S[Cr] 1.1 mg/dL (baseline ¼ 0.9 mg/dL), and glucose ¼ 140 mg/dL. A urinalysis is unremarkable. ECG reveals no changes from his baseline. Chest Xray reveals incipient pulmonary edema and blunting of the costophrenic recesses bilaterally. Discontinuing his naproxen is unlikely to improve which of the following? A. B. C. D. E.

His His His His His

ventricular function peripheral edema blood pressure hyperkalemia pulmonary edema

Answer: A This 64-year-old man presents with signs and symptoms of decompensated heart failure. This is a well-known phenomenon associated with NSAID use in patients with precarious hemodynamics and chronic prerenal azotemia (“cardiorenal syndrome”). Because of their antinatriuretic effects, NSAIDs may cause peripheral and pulmonary edema. They can also worsen the degree of azotemia by causing autoregulatory failure in the intrarenal circulation. In addition to his worsened renal function, suppression of the renineangiotensine aldosterone axis leads to hyperkalemia. All these effects are mediated by abrogation of the compensatory physiologic effects of prostaglandins. NSAIDs have no direct or indirect effect on ventricular performance.

Question 2 A 35-year-old woman with stage 3 CKD due to reflux nephropathy decides to try ibuprofen in an over-thecounter formulation to relieve her dysmenorrhea. She

has no other medical problems. Her only prescription medications include fosinopril (40 mg a day) and a prenatal-type multivitamin. She gets rapid improvement in her dysmenorrhea, but on the third day of taking it, she develops epigastric pain and nausea. She sees her physician who notes some localized epigastric tenderness on exam. She orders blood tests, recommends discontinuing the ibuprofen, and tells her to return tomorrow for follow-up. Which of the following statements is TRUE? A. Over-the-counter NSAID preparations are too mild to affect her renal function B. The patient’s symptoms probably reflect uremic gastritis C. Stopping ibuprofen will likely resolve her epigastric pain and tenderness D. Substituting a COX-2-specific NSAID is less likely to affect her kidney function E. Substituting a COX-2-specific NSAID is likely to worsen her abdominal complaints Answer: C Gastric upset is one of the most common side effects of NSAIDs and, in contrast to most of the renal complications, may occur in otherwise normal individuals. Gastric symptoms may occur even with low-dose formulations such as those sold over-the-counter. Although this woman has underlying CKD, three days is much too rapid a time course for her to have developed uremic gastritis. There is no reason why she could not have cholelithiasis, but the time course points to the NSAID as the source of her abdominal discomfort. COX-2specific NSAIDs are better tolerated by the GI tract, but just as risky from the renal standpoint.

Question 3 A 42-year-old man has been referred to you for evaluation of stage 4 CKD of unknown etiology. He recently emigrated from east Africa where he did not receive regular healthcare and can provide little information about his personal health history. He does not consume tobacco or alcohol and uses only one medication for aches, pains, and headaches. He shows you a bottle of this drug, but the label is written in his native language, and you cannot read it. The patient appears somewhat malnourished in appearance, but otherwise his examination, including his blood pressure, is unremarkable. Blood chemistries are as follows: sodium 140 mEq/L, potassium 5.4 mEq/L, chloride 100 mEq/L, bicarbonate 24 mEq/L, BUN 30 mg/dL, S[Cr] 1.8 mg/dL, glucose 110 mg/dL, calcium 8.0 mg/dL, and albumin 3.4 g/dL. Urinalysis reveals 1þ proteinuria and no other notable findings.



A sonogram of his kidneys reveals them to be 8 and 9 cm in length with increased echogenicity, irregular contours, and findings consistent with papillary necrosis. Which of the following possible etiologies for his renal disease is the LEAST likely? A. B. C. D. E.

Tuberculosis Schistosomal nephropathy NSAID-induced nephropathy Non-NSAID analgesic nephropathy Sickle cell nephropathy

Answer: B All of the answer options represent diseases a patient with this geographic background could have, and all but one of them can cause papillary necrosis: schistosomal nephropathy, which is a glomerular disease. Renal tuberculosis would be an important “rule-out” in a patient of third-world origin presenting in this fashion. Sickle cell nephropathy must be considered in an African patient. Both of these diseases could account for his cachectic appearance. Lastly, until we have discerned the identity of the medication he takes for chronic aches and headaches, we must consider the possibility that it contains phenacetin or a nonsteroidal drug, either of which (especially the former) might cause papillary necrosis.

Question 4 A 77-year-old woman has a history of hypertension which has been very well controlled on atenolol (25 mg a day) and hydrochlorothiazide (25 mg a day). 5 days ago, she developed a painful monoarthritis of her right food diagnosed as gout. She was given a prescription for indomethacin (75 mg twice a day). Her foot pain improved dramatically, but over the past day-and-a-half she has been feeling “spacey” and a little nauseated. Other than a BP of 160/85 mm Hg, some residual right foot warmth and tenderness, and some subtle signs of confusion, her physical examination is unremarkable. Routine blood chemistries and a CBC are sent. Her serum sodium concentration is found to be 120 mEq/dL. Which of the following statements is FALSE? A. Indomethacin can potentiate the actions of antidiuretic hormone in the distal nephron B. Indomethacin tends to increase urinary sodium excretion C. Indomethacin can exacerbate hypertension even in previously well-controlled patients D. Indomethacin is effective for treating gouty arthritis E. Her indomethacin should be stopped and her hydrochlorothiazide put on hold


Answer: B Indomethacin is effective in treating gouty arthritis and is a satisfactory alternative to steroids and colchicine. It is also a potent NSAID and has been implicated in more reports of renal side effects than any other drug in that family. Because prostaglandins counteract the effects of ADH on the collecting tubule, NSAIDs potentiate the activity of that hormone and can cause hyponatremia. For this reason, medications that can impair urinary dilution, like thiazides, should be avoided by patients taking NSAIDs. Prostaglandins inhibit tubular sodium reabsorption; they are natural natriuretic hormones. For this reason, NSAIDs can cause sodium retention and this can exacerbate hypertension.

Question 5 An 88-year-old woman complains of back pain and is found to have a compression fracture of her thoracic spine. She had tried taking acetaminophen without relief. Because she does not tolerate opiates well, her physician wishes to prescribe ketorolac for analgesia. The patient’s medical history is remarkable for osteoporosis, congestive heart failure, and stage 2 CKD (baseline S[Cr] ¼ 1.1 mg/dL). Her medications include enalapril (10 mg twice a day), furosemide (20 mg twice a day), alendronate (35 mg once every a week), and aspirin (81 mg a day). How many risk factors does she have for untoward renal effects due to the ketorolac and what are they? A. B. C. D. E.

One Two Four Five Seven

Answer: C She has four risk factors for untoward renal effects from the ketorolac: her (1) advanced age, (2) underlying renal insufficiency, (3) history of congestive heart failure, and (4) medications (ACE inhibitor and diuretic).

Question 6 A 29-year-old competitive distance runner collapses at the end of half-marathon and is transported to the emergency room of a local hospital. On arrival, she suffers a generalized seizure, following which she remains unresponsive for several hours. Her medical history is entirely unremarkable; her only medication is diclofenac 75 mg twice a day. On physical examination, BP ¼ 150/100 mm Hg, HR ¼ 110/bpm, regular, and respirations ¼ 14/min. She is afebrile and has a room air oxygen saturation of




99%. She is moving all extremities but is unresponsive. She is diaphoretic but does not appear noticeably volume depleted. A cranial CT scan shows no evidence of trauma or hemorrhage, but there is a suggestion of cerebral edema. A complete blood count, blood chemistry panel, and arterial blood gases are sent. The only abnormality is a serum sodium concentration of 119 mEq/L. Which of the following statements about her presentation is TRUE? A. She has acute hyponatremic encephalopathy B. Diclofenac causes salt wasting by the kidney C. Based on her high blood pressure, it is unlikely she is truly volume depleted D. Diclofenac does not interact with ADH E. Diclofenac probably triggered inappropriate ADH release Answer: A This patient has acute hyponatremic encephalopathy, an emergent and sometimes fatal condition that can occur in distance runners who drink water faster than they can metabolize it. As a result, osmotic dysequilibrium develops between the CNS and the bloodstream, leading to cerebral edema. Although diclofenac does not cause inappropriate ADH release, it, like other NSAIDs, potentiates the action of ADH on the renal collecting duct and can thus exacerbate hyponatremia of any etiology. Diclofenac, like all NSAIDs, is antinatriuretic. Many of the reports of acute hyponatremic encephalopathy in runners involved those who were taking NSAIDs.162e164

Question 7 A 31-year-old man with a longstanding history of intravenous heroin abuse is referred for evaluation of

hematuria and proteinuria. Physical examination is remarkable for BP 140/95 mm Hg, diffuse lymphadenopathy, and scattered maculopapular, purplish lesions over his lower legs. BUN is 30 mg/dL, S[Cr] 1.8 mg/dL. Urinalysis reveals 2 to 3þ proteinuria and 1þ occult blood. Sediment contains 5e10 dysmorphic red blood cells per hpf and occasional finely granular casts. In addition to renal biopsy, which of the following tests is/are indicated? A. B. C. D. E.

HIV serology Cryoglobulins Viral hepatitis panel Urine toxicology Antinuclear antibody

Answer: A, B, and C This patient’s history of intravenous heroin abuse places him at risk for HIV and chronic viral hepatitis infection. Both of these infections are associated with glomerulopathic syndromes. Hepatitis C is associated with membranoproliferative glomerulonephritis and cryoglobulinemic vasculitis, which could account for the lesions on lower extremities as well as the renal abnormalities. HIV-associated nephropathy (HIVAN) could also present in this fashion. The syndrome known as heroin nephropathy presents with FSGS-like histopathology and a similar presentation to this patient’s and is of unclear pathogenesis, possibly representing one of the above viral-associated glomerulopathies or a reaction to impurities in the heroin. Various glomerulonephridites have also been associated with HIV infection. Even if his urine were to test positive for opioids, this would not refine the differential diagnosis at all, nor would it add anything to what we already know about his history. The patient’s presentation makes lupus nephritis unlikely.123,124