More questions than answers

More questions than answers

Kidney International, Vol. 55 (1999), pp. 2072–2073 EDITORIAL More questions than answers The child whose idiopathic nephrotic syndrome (INS) defies...

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Kidney International, Vol. 55 (1999), pp. 2072–2073


More questions than answers The child whose idiopathic nephrotic syndrome (INS) defies treatment presents the greatest of challenges to the skills of the pediatric nephrologist. The majority of such patients, on renal biopsy, are found to have the lesion of focal segmental glomerulosclerosis (FSGS), where segments of one or more glomeruli are sclerotic. The glomeruli in the juxtamedullary region are the most likely to be affected by this lesion. With time, more and more glomeruli are affected, glomeruli become totally sclerotic, and renal failure may develop and progress to end-stage renal disease. Some of the patients will have recurrence of the nephrotic syndrome after transplantation and eventually show this typical sclerotic lesion on biopsy of the transplanted kidney, though early in the evolution of the recurrence, the biopsy is more typical of minimal change nephrotic syndrome (MCNS). It has seemed to many of us over the past few years that we are seeing more children who have difficult nephrotic syndrome and FSGS, and the paper by Bonilla-Felix et al in this issue of Kidney International confirms that feeling [1]. We have no idea why this is happening. In considering the issue, the first questions to ask are: what is this condition called focal segmental glomerulosclerosis? Is it a unique disease, is it a variant of MCNS, or is there a continuum of several related diseases, with MCNS the most benign of the group? If MCNS and FSGS are the same disease and signify different ends of the severity spectrum of a single or related group of diseases, why the increase in severity? The more one reads and asks, the more apparent our lack of understanding becomes; we know very little about INS in childhood. The lesion of FSGS is eventually, but not necessarily initially, present on biopsy in the majority of children with INS who are resistant to steroid therapy, and also is present in many of those who respond to steroids with remission of the nephrotic syndrome but become steroiddependent to sustain that remission [2]. Does prolonged proteinuria in such children cause glomerular injury, resulting in the FSGS lesion, or is the lesion a specific indicator of a unique and more severe disease? McAdams, Valentini and Welch et al argue that the lesion of segmental glomerulosclerosis is not a specific marker for a subtype of INS, but reflects instead the progressive Key words: idiopathic nephrotic syndrome, childhood renal disease, lesions, focal segmental glomerulosclerosis.

 1999 by the International Society of Nephrology

nature of the disease process [3]. This claim that the segmental sclerotic lesion is nonspecific is reinforced by the fact that a similar lesion can be seen in other conditions with persistent proteinuria such as HIV nephropathy, the focal sclerosis of sickle cell disease, and diabetic nephropathy. If MCNS and FSGS are different ends of the spectrum of the same disease, we are left with the question, why is the disease progressing in a larger percentage of children? Is it, as Bonilla-Felix et al suggest, secondary to an environmental factor? Is this environmental factor infectious, related to a virus, or is it related to chemical exposures or, more likely, are many factors involved? Genetic factors appear to play a role, as there is a higher and increasing incidence of the FSGS lesion in African American children, shown not only in the Bonilla-Felix study [1] but in several other studies [4, 5]. Bonilla-Felix also show a lower incidence in Hispanic children. In spite of the predilection of children with the FSGS lesion to respond poorly to therapy, those who do respond tend to have a prognosis more similar to that of the child with MCNS. The achievement of long-term remission is a stronger correlate of a favorable prognosis than is the presence or absence of a specific finding such as segmental sclerosis or mesangial hypercellularity on biopsy [3, 6]. It is clear that we have a very poor understanding of the disease process in children with INS. We know that the condition is associated with multiple abnormalities of the immune system, some likely etiologic and others secondary to the disease process [7], and we know that immunosuppressive therapies are effective in many patients [2, 8], but we frequently fail to predict which therapy will help which patient, or if a given patient will respond to any therapy. As a result, we expose some patients to very toxic therapies such as high dose steroids, alkalating agents and cyclosporine, with no benefit. We don’t know the basic cause or causes of INS, and we don’t understand the role or meaning, if any, of the specific FSGS lesion in the steroid-dependent or resistant patient. Cameron very nicely sums up the situation in his statement: “The most important fact to remember about focal glomerulosclerosis (FSGS) is that it is a glomerular appearance seen on histological examination of the kidney and not a disease entity” [9]. In order to advance our knowledge and better correlate the patho-



logical lesion with clinical course and response to therapy, we need to continue to perform renal biopsies on the children with nephrotic syndrome who are steroiddependent or steroid-resistant. The feeling of many nephrologists that it is not helpful to know the specific pathological lesion when making therapeutic decisions in the clinical care of such patients has a practical basis, but will not help us to solve the mysteries of the disease processes involved, so that we gain the knowledge to determine therapy on a scientific rather than an empiric basis. With modern techniques the risk of percutaneous biopsy is minimal, the procedure can be done on an outpatient basis and should be atraumatic for the patient [10]. We pediatric nephrologists, along with our pathology colleagues, need to work together in multicenter studies to look closer at these patients for clause to the etiologies of their disease processes. Only with studies of large numbers of patients will we be able to better analyze and categorize the disease processes behind the lesion. Susan B. Conley Philadelphia, Pennsylvania, USA Correspondence to Susan B. Conley, MCP Hahnemann School of Medicine, Section of Nephrology, St. Christopher’s Hospital for Children, Erie Avenue at Front Street, Philadelphia, Pennsylvania 19134, USA. E-mail: [email protected]


REFERENCES 1. Bonilla-Felix M, Parra C, Dajani T, Ferris M, Swinford RD, Portman RJ, Verani R: Changing patterns in the histopathology of idiopathic nephrotic syndrome in children. Kidney Int 55:1885– 1890, 1999 2. Niaudet P: Steroid-resistant idiopathic nephrotic syndrome, in Pediatric Nephrology (4th ed), edited by Barratt TM, Avner ED, Harmon WE, Baltimore, Lippincott Williams and Wilkins, 1999, pp 749–764 3. McAdams AJ, Valentini RP, Welch TR: The nonspecificity of focal segmental glomerulosclerosis: The defining characteristics of primary focal glomerulosclerosis, mesangial proliferation, and minimal change. Medicine 46:42–52, 1997 4. Ingulli E, Tejani A: Racial differences in the incidence and renal outcome of idiopathic focal segmental glomerulosclerosis in children. Pediatr Nephrol 5:393–397, 1991 5. Korbet SM, Genchi RM, Borok RZ, Schwartz MM: The racial prevalence of glomerular lesions in nephrotic adults. Am J Kidney Dis 27:647–651, 1996 6. Southwest Pediatric Nephrology Study Group: Focal segmental glomerulosclerosis in children with idiopathic nephrotic syndrome. A report of the Southwest Pediatric Nephrology Study Group. Kidney Int 27:442– 449, 1985 7. Broyer M, Meyrier A, Niaudet P, Habib R: Minimal changes and focal segmental glomerulosclerosis, in Oxford Textbook of Clinical Nephrology, edited by Cameron JS, Davison AM, Gru¨nfeld J-P, Kerr D, Ritz E, Oxford, Oxford Medical Publishers, 1992, pp. 298–339 8. Tune BM, Kripekar R, Sibley RK, Reznik VM, Griswold WR, Mendoza SA: Intravenous methylprednisolone and oral alkylating agent therapy of prednisone-resistant pediatric focal segmental glomerulosclerosis: A long-term follow-up. Clin Nephrol 43:84–88, 1995 9. Cameron JS: The enigma of focal segmental glomerulosclerosis. Kidney Int 50(Suppl 57):S119–S131, 1996 10. Conley SB: Renal biopsy in the 1990s. Pediatr Nephrol 10:412– 413, 1996