Nephrotic focal segmental glomerulosclerosis in 2004: an update

Alain Meyrier

Hôpitaux Broussais et HEGP, Paris, Nephrology and INSERM U430 F-75015 Paris, France

Correspondence and offprint requests to: Alain Meyrier, Service de Néphrologie & INSERM U 430, University Hospitals Broussais & HEGP, 20 rue Leblanc, F-75015 Paris, France. Email: alain.meyrier{at}brs.ap-hop-paris.fr

Keywords: focal segmental glomerulonephritis (FSGS); genetics of FSGS; idiopathic nephrotic syndrome; immunosuppressive therapy; podocyte

Writing on the treatment of primary focal segmental glomerulosclerosis (FSGS) is a challenge. The jaded nephrologist is tempted to consider that the issue could be summarized as ‘Treatment of a disease which is not a disease but a lesion of obscure pathophysiology, with drugs the mechanism of action of which is poorly understood’ and flinch from the task. However, the knowledge on this topic has so tremendously progressed over recent years that obsolescence looms with each passing year. Let us try to analyse the subject using a Cartesian approach, that is, dissecting the problem step by step. This review will focus on the nephrotic forms of this nephropathy, as mildly proteinuric FSGS is probably a different entity in terms of pathophysiology, prognosis and treatment.

FSGS is not a disease but a lesion with no definite prognostic value

The denomination of the lesion is misleading, as it is not always focal, or segmental, or even sclerotic. Hence, there is a multiplicity of terms, none of which is fully satisfactory. Nevertheless, the acronym ‘FSGS’ has the merit of being concise.

A recent working group [1] tackled the issue of classifying FSGS. Five variants have been distinguished: FSGS ‘not otherwise specified’ (classic FSGS), perihilar variant, cellular variant, tip variant and collapsing variant. The interest and the shortcomings of this classification have been discussed elsewhere [2]. The problem at hand is 2-fold. First, the pathologist usually selects one of these subsets on the basis of a renal biopsy. The snag is that the glomerular changes are focal, or ‘zonal’ [3], and that with the exception of a whole transplanted kidney removed for relapse of the primary disease, the number of available glomeruli is too small for classifying the glomerulopathy with certainty. Moreover, the renal pathologist knows that tubulointerstitial lesions are probably more indicative of impending threat to renal function than the glomerular appearance. In this line, it is worth observing that the most recent data regarding the ‘Glomerular tip lesion’ tend to push this ‘One leaf clover’ into the realm of minimal glomerular changes [4]. Secondly, whilst classifying the lesions of lupus nephritis has been extremely rewarding in terms of treatment strategy, this is not the case in nephrotic FSGS, a condition in which the only predictive prognostic element is the response of proteinuria to treatment, irrespective of histology [5,6].

The common denominator of all FSGS variants is a podocyte disease

Until recently, the podocyte was not considered very highly among glomerular cells and the glomerular basement membrane (GBM) was seen as the essential structure barring the egress of albumin into the urinary chamber. The slit diaphragm, a narrow space between foot processes, was reduced to an obscure ZO-1 (zona occludens) molecule. The discovery of nephrin, mutations of which elicit the Finnish-type nephrotic syndrome, opened the way to the identification of a tremendous number of intertwined and interacting podocyte molecules that play an essential role in FSGS. Two recent outstanding reviews [7,8] summarize the current and rapidly growing knowledge in this field. It appears that in a majority of glomerulopathies, from the least proliferative, such as membranous glomerulonephritis [9,10], to the most exuberant crescentic glomerulonephritis [11,12], the lesions comprise a podocyte component and that FSGS is the common final pathway to glomerular obsolescence. Meanwhile, it was shown that, in nephrotic FSGS, especially in forms that relapse on a renal transplant, the elusive circulating factor that induces proteinuria also disrupts the cell cycle [13]. The ‘dysregulated’ podocytes undergo dedifferentiation and transdifferentiation, detach from the GBM and acquire macrophagic features [14–16]. FSGS starts with podocyte injury [8], which drives the glomerular lesions from cellular proliferation to the build up of fibrosis and scarring.

These fundamental observations lead to questions regarding treatment. Does it address the cause of the podocyte disease? Does it aim at controlling podocyte dysregulation, at arresting the build-up of extracellular matrix leading to renal insufficiency or at reducing nephrotic proteinuria, a major prognostic factor in FSGS? Simply put, is treatment aetiological, symptomatic or both? Let us first consider the rationale for treating FSGS with a plausible aetiology and remind ourselves that the terms ‘primary’ or ‘idiopathic’ illustrate our ignorance, until each new advance pushes an item into the ‘secondary’ list and gives hope of new treatment strategies.

FSGS, an immunological podocyte disease

The ‘Shalhoub hypothesis’ [17] most probably applies to many cases of nephrotic FSGS. It is beyond the scope of this Editorial to analyse the clinical and experimental arguments in favour of an immunological background of this clinical variant (for review see [18]). Nonetheless, this concept justifies the rationale to treat it with corticosteroids and immunosuppressive agents. Failure to induce remission might indicate that non-immunological factors are at work and foster future research to a pluralistic view [19] regarding the cause(s) of massive proteinuria.

FSGS, a viral podocyte disease

The identification of HIV-associated nephropathy showed that collapsing glomerulopathy may be caused by viral infection. Subsequently, a possible viral aetiology of FSGS has been suggested by evidence of parvovirus B19 in renal biopsies of patients with FSGS [20,21]. Similarly, the simian virus SV40 was found to be associated with FSGS [22]. It is, therefore, conceptually possible that some forms of FSGS are of viral origin. The first contact with the virus might injure the podocyte. Alternatively, viral infection might adopt the course of herpes zoster resurgent decades after varicella. So far, these stimulating observations have not led to specific antiviral therapy, but this might be the case in the future. In the same line, Shono et al. [23] presented in abstract form at the 2003 Annual Meeting of the American Society of Nephrology, experimental data indicating that an adhesion molecule, i.e. the coxsackievirus and adenovirus receptor (CAR), is involved in the formation of tight junctions between podocytes. CAR interacts with podocin. This binding partner shares common trafficking machinery with podocin. Future studies might then disclose a relationship between these preliminary data and new viral aetiologies of FSGS. Finally, a few observations seem to indicate that hepatitis C virus infection may be complicated by FSGS [24,25].

FSGS, a toxic podocyte disease

Adriamycin and the puromycin aminonucleoside induce FSGS in the experimental animal. Heroin has the same effect in drug users [26]. Pamidronate may induce collapsing glomerulopathy [27]. Retrospective epidemiological studies found that the incidence of FSGS has increased over recent decades [28,29]. This might indicate that some environmental factor(s) is involved in this trend and its identification might help reduce the soaring incidence of FSGS.

FSGS, an inherited podocyte disease

The most spectacular breakthrough was brought about by the identification of nephrin, podocin, CD2AP and {alpha}-actinin-4, to cite four molecules, whose mutations are responsible for FSGS, amongst the array of those that have been identified in the podocyte cell body and its foot processes [7]. Conlon et al. [30] screened 60 families with familial FSGS. The mean age at presentation in multigeneration forms was 32.5±14.6 years and in single generation forms was 20.1±12.1 years. This indicates that FSGS due to germline mutations may become apparent late in life, which sheds a new and somewhat ironic light on our treatment strategies based on the ‘Shalhoub hypothesis’. Ruf et al. [31] presented data on 29 steroid-resistant patients with podocin mutations. None responded convincingly to cyclophosphamide or cyclosporin A (CsA).

It is known now that various mutations of podocin (NPHS2 mutations) lead to sporadic, corticosteroid-resistant FSGS [32–35]. Not all are characterized by the onset of nephrotic syndrome in childhood. The most common NPHS2 mutation maps to chromosome 1q25–31. In nine families, Tsukagushi et al. [36] found that the R229Q heterozygous variant (which is found with the same frequency as in a normal population) appeared not to cause FSGS, but rather to enhance susceptibility to FSGS in association with a second mutant NPHS2 allele. There were 11/91 adults with sporadic mutations associated with an apparently ‘primary’ form of FSGS. The mean age of disease onset was 21.8 years and the oldest age at presentation was 34 years. Huber et al. [34] showed that the association of podocin with specialized lipid-raft microdomains of the plasma membrane was a prerequisite for recruitment of nephrin into lipid rafts and that R138Q and R138X mutations entailed failure of this recruitment. Such failure might be essential for inducing NPHS2-linked FSGS. Mutations in ACTN4 encoding {alpha}-actinin-4 were also shown to cause familial FSGS, with a dominant inheritance and a slowly developing renal disease [37,38] (Table 2).


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Table 2. Current knowledge on genetic profiling of INS with histological lesions of FSGS

 
What are the implications of these genetic disorders in terms of therapy? Some paediatric units systematically seek podocin mutations in children suffering from this subset of idiopathic nephrotic syndrome (INS) in order to avoid a useless course of corticosteroids [39]. A test is available in the US that allows identification of this mutation and can be applied to predict steroid resistance (Athena Diagnostics, Worchester, MA).

A podocin mutation identified in a family should lead to circumspection regarding kidney donation from a relative (for review see [40]). It is clear that in the near future molecular genetic profiling will more precisely define the incidence of podocyte mutations in larger series of patients with FSGS and at least preclude useless and hazardous regimens in cases linked to these mutations.

Treatment of FSGS with corticosteroids

Corticosteroids remain the mainstay of treatment, but this applies to the nephrotic forms of FSGS. Mildly proteinuric FSGS is a different entity and it would be of no avail, and in most cases harmful, to treat it with steroids.

It is essential to remember that the definition of steroid resistance is not the same in children and in adults. Whereas paediatricians consider that the absence of remission after 4 weeks of prednisone at a dosage of 60 mg/m2/day and a last attempt using three pulses of methylprednisolone indicates steroid resistance [19], it has been shown repeatedly that remission is slower in adults [41].

Korbet et al. [42] analysed the initial response to treatment in adults with FSGS before and since 1980. The dosage of prednisone ranged from 0.5 to 2 mg/kg/day. However, the highest complete remission rates, >30%, were observed in cases treated for >5 months and the lowest, ≤20%, in patients treated ≤2 months.

It is now established that corticosteroid treatment must be sufficiently long. Full-dose (1 mg/kg/day) prednisone is given for 8–12 weeks followed, in case of even partial remission, by a slow tapering dose over months to avoid a rebound effect.

This period is, in fact, critical, as only a minority of patients with nephrotic FSGS achieve complete and stable remission after tapering corticosteroids to a stop. Most are corticosteroid-dependent, some of them to a high threshold dose. On the other hand, pursuing indefinite treatment with a high maintenance dosage of steroids leads to steroid toxicity.

Nonetheless, reducing proteinuria, even partially, is the only means of slowing or arresting the progression to chronic renal insufficiency [42–45] and there is no doubt that prolonged treatment improves the prognosis of nephrotic FSGS [45]. In steroid-responsive cases, the rate of complete remission, partial remission and failure is, respectively, in the order of 50, 25 and 25% of cases. Complete remission portends a favourable outcome, almost comparable to that of steroid-responsive minimal change disease. However, in steroid-dependent cases, when prednisone dosage is tapered slowly, in most instances abundant proteinuria reappears. Such steroid dependency leads to discussing the pros and cons of further therapeutic strategy, aiming at reducing proteinuria, but trading steroid toxicity for other complications.

Treatment of FSGS with alkylating agents

The rationale for treating FSGS with cytotoxic drugs is based on the postulate that the lesion and the attending proteinuria are due to an immunological background, that is, secretion of a lymphokine by a clone of T lymphocytes. The foregoing data regarding the pathophysiology of FSGS indicate that genetic, viral and toxic aetiologies of FSGS could be failures of alkylating agents. These drugs target cells of the immune response, including those that have nothing to do with the disease, and might be considered as very elementary tools to sort out cases due to an immunological process.

Cyclophosphamide or chlorambucil have been used since the 1950s in the treatment of nephrotic FSGS. It has been established in children [46] that a 12 week course is more effective than a shorter treatment. It is common practice to add a maintenance dosage of steroids in the hope of increasing efficacy. The results of cytotoxic agents largely depend on the previous response to steroids. The best indication of alkylating agents is corticosteroid dependency, which is not common in this form of INS. It is difficult to determine the long-term efficacy of cytotoxic drugs in this subset, as data in the literature usually indicate the results of the first course and very rarely provide longitudinal studies. A rough idea, however, can be drawn from retrospective publications [47]. In steroid responsive cases, the rate of complete remission, partial remission and failure is, respectively, 51, 23 and 26% of cases [42]. The main advantage of cytotoxic agents is that, in steroid-dependent and multirelapsing forms, the remission they yield is long lasting. Conversely, steroid resistance is highly predictive of resistance to alkylating agents with the corresponding figures of 17, 15 and 69%. In fact, considering that steroid-resistant FSGS is the most problematic form in terms of treatment, cytotoxic agents do not seem to benefit these patients, as emphasized by a controlled study emanating from the International Study of Kidney Disease in Children [48].

Treatment of FSGS with CsA

Two decades following the first publications in adults [49] and in children [50–52], CsA is now considered amongst the most useful agents in the treatment of INS, including FSGS [53]. The rationale for trying this molecule was initially blindly based on the hope that CsA might inhibit the production of ‘the responsible cytokine’ as it does for interleukin-2 and {gamma}-interferon. It is clear that complete remission obtained within weeks in minimal change disease is in keeping with this theory. This is also likely in case of such a success in steroid-responsive FSGS. In fact, the efficacy of CsA depends more on the previous response to steroids than on glomerular histology. In steroid-responsive cases, the percentages of complete remission, partial remission and failure are, respectively, 73, 7 and 20%. In steroid-resistant cases, the respective figures are 29%, 22% and 49% [44]. In addition, paediatricians showed that a combination of steroids and CsA pushed a significant additional subset of patients into remission [52]. Thus, CsA has the major advantage of being a steroid-sparing agent. Furthermore, steroids enhance the efficacy of CsA (Table 1).


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Table 1. Improved efficacy of CsA associated with steroids compared to CsA alone. Summarised from Meyrier A, Niaudet P, Brodehl J: Optimal use of Sandimmum in Nephrotic Syndrome. Berlin, Springer Verlag, 1992 (monograph) 34 p. [Reporting Sandoz-Pharma, data on file]. The same was observed in children by Niaudet et al. [52]

 
However, the mode of action of CsA in FSGS is far from simple. CsA was tried haphazardly in a host of glomerulopathies that have little to do with an immunological background, such as diabetic glomerulopathy and Alport's syndrome, and was shown to significantly reduce proteinuria. This effect was attributed to renal vasoconstriction, especially of the glomerular afferent arteriole, and could be considered as a more noxious than beneficial side-effect of the drug, a forerunner of ischaemic striped fibrosis.

There are, in fact, good reasons to believe that, aside from its immunological action, the CsA molecule is endowed with pharmacological properties that interfere with the glomerular permeability to albumin (for review see [54,55]). Zietse et al. [56] using dextran clearances in human glomerulopathies concluded that CsA increases charge selectivity in minimal change disease and pore size selectivity in idiopathic membranous glomerulonephritis. Schrijver et al. [57] induced an anti-GBM glomerulonephritis in the mouse. CsA significantly diminished proteinuria along with declining glomerular filtration rate (GFR). However, when the glomerular vasoconstriction was abolished by the vasodilator phenoxybenzamine, diminution of albuminuria persisted, showing that CsA interfered with glomerular permeability to albumin independently from a mere haemodynamic effect. Changes in the tubular reabsorption of albumin were also ruled out [58]. Ambalavanan et al. [59] treated nephrotic patients suffering from idiopathic membranous glomerulonephritis with CsA; proteinuria diminished significantly and the GFR was unchanged. Repeat renal histology showed that the lesions had not regressed. Dextran sieving curves led to the conclusion that CsA restored the sieving curves towards normal, lowering the computed fraction of shunt-like pores by 25%, indicating enhanced barrier size selectivity.

The most striking data regarding an antiproteinuric effect of CsA, independent from immunosuppression, were provided by Chen et al. in a model of Alport's syndrome in the dog [60]. CsA reduced the urinary albumin/creatinine ratio and preserved durably renal function, despite the fact that repeat renal histology showed that the GBM lesions of Alport's syndrome were progressing with time.

Thus, there is substantial evidence that CsA exerts a pharmacological antiproteinuric effect that might explain partial but clinically beneficial remissions in FSGS. The results of CsA treatment of FSGS have been the subject of numerous publications since 1986. Ten years ago, the results of CsA treatment of steroid-resistant FSGS were considered as more or less disappointing [61,62]. Caveats were formulated regarding nephrotoxicity that was not easy to distinguish from the natural history of the primary renal disease [61,62]. Subsequently, CsA has acquired a definite role amongst the few available treatments of FSGS. First, as stated above, it appears that the drug, when used at low doses in combination with steroids, has increased efficacy and lower toxicity (Table 1). Second, as emphasized by Fritsche et al. [63] on behalf of the German Cyclosporin in Nephrotic Syndrome Group, remission of proteinuria in patients suffering from causes of nephrotic syndrome other than minimal change disease may require >18 months of CsA regimen. This is, apparently, the case in FSGS, as shown by Ponticelli et al. [45]. Finally, the randomized study carried out by Cattran et al. [64] showed that long-term CsA treatment improved renal function in FSGS. This finding, unexpected for a drug with a nephrotoxic potential, might be interpreted as indicating a favourable effect of reduced proteinuria on the tubules, more than reflecting an improvement of the glomerular lesions of FSGS, which are irreversible.

Guidelines regarding Sandimmune® dosage formulated a decade ago [61,62] still apply. The better bioavailability of Neoral® leads to recommending dosages distinctly lower than 5 mg/kg/day [19]. Serum cholesterol levels should be taken into account to adapt dosage. Ingulli and Tejani [65] showed that in nephrotic children with unusually high serum cholesterol levels, who did not respond to CsA, increasing the dosage to 10–12 mg/kg/day led to remission of INS without renal toxicity. It is likely that part of the highly lipophilic CsA molecule is bound to serum lipids and that the active and nephrotoxic moiety is low in hyperlipidaemic nephrotics. In this line, one could hypothesize that nephrotoxicity that is paradoxically higher in diseases with no renal involvement, such as psoriasis [66], than in INS is simply explained by the fact that non-nephrotic patients run normal serum cholesterol levels.

CsA dependency was observed from the very first trials of treatment, where results were usually published at 1 year [67]. Tapering the drug to a stop after complete remission resulted in 50% recurrence of nephrotic syndrome within 2 months. The probability of remaining in remission after abruptly stopping CsA was 50% at 2 months, 30% at 4 months, 20% at 6 months and nil at 9 months. This left the prescribing nephrologist with the disquieting prospect of indefinite treatment with a nephrotoxic drug, hence, trading extrarenal steroid toxicity for renal cyclosporin toxicity. However, the notion of CsA dependency was partly reconsidered when we analysed a series of 36 adults, selected among the 150 cases of the Société de Néphrologie trial as having undergone repeat renal biopsies after 1–5 years of cyclosporin treatment [61,62]. Fourteen out of 36 had been treated for 26±14.5 months (10 with minimal change disease and four with FSGS). After a long period of remission, CsA was very progressively tapered to a stop and in these 14 patients remission was durable and maintained without steroids in 11 and with low-dose steroid treatment in three. At the time of this writing, the longest follow-up starting at the end of CsA treatment is in the order of 12 years. However, in ~20% of the cases, very slow tapering of cyclosporin dosage after 1 year showed that although CsA-dependent, these patients remained in remission with extremely low dosages, <3 mg/kg/day, and even in one case with 1 mg/kg/day. In such cases, CsA dependency to a very low dosage most probably entails very little risk of toxicity over years and maybe decades.

Treatment of FSGS with other immunophillin modulators

Tacrolimus (FK-506)
Trials of treatment of FSGS with FK-506 are anecdotal. McCauley et al. treated seven cases of various glomerulopathies with tacrolimus, including four children with FSGS [68]. All four had previously received prednisone, associated with cyclophosphamide in one, cyclophosphamide and CsA in two and CsA in one. The first case was resistant to treatment; the three others experienced a partial response on CsA. FK-506 induced complete remission in one case and a significant decline in proteinuria with a rise in serum albumin levels in the three others. Renal function declined in all and returned towards pre-treatment values when dosage was reduced or after stopping the drug. The first case was followed up for 14 months and two attempts to stop FK-506 induced a flare in proteinuria that resolved within days of resuming the drug. This report left the impression that, similarly to CsA, FK-506 may induce complete remission in some cases and fail in others. The authors speculated that differing responses to T cell-directed therapy might indicate that nephrosis with lesions of FSGS might be the consequence of various pathogenetic mechanisms.

Segarra et al. [69] presented the results of combined therapy with tacrolimus and steroids in 25 patients with nephrotic FSGS, in whom CsA had not obtained remission. The results of a 6 month trial with FK-506 and steroids were rather impressive: 10 patients enjoyed complete remission, two partial remission and five significant reduction of proteinuria. Time to remission was very long (112±24 days). Reversible nephrotoxicity was observed in 40%. A majority of their patients were tacrolimus-dependent.

Loeffler et al. recently published their experience with tacrolimus therapy in 16 paediatric patients with nephrotic syndrome resisting other treatments [70]. Thirteen had lesions of FSGS. The dosage of FK-506 utilized was 0.1 mg/kg/day and the follow-up period ranged from 0.5 to 18 months. The complete remission rate was 81% and partial remission 13%. Despite side effects comprising anaemia (n = 1), seizures (n = 1), hypertension (n = 5) and sepsis (n = 1), the authors concluded that ‘Tacrolimus is an effective and well-tolerated medication for treatment-resistant forms of nephrotic syndrome in children’. Duncan et al. [71] presented in abstract form at the 2003 Annual meeting of the American Society of Nephrology, four cases of FSGS in whom conversion from CsA to tacrolimus improved renal function.

Sirolimus (rapamycin)
Considering its lack of nephrotoxicity and its efficacy in the field of transplantation, it would be understandable that sirolimus be tried in the treatment of INS. At the time of writing, a Medline search did not find any article on this issue. The Paris Necker Hospital transplantation team carried out a trial of sirolimus and observed fulminant ‘de novo’ FSGS in eight patients, including only one whose primary renal disease was FSGS [72]. Conversely, Tumlin et al. [73] found that sirolimus reduced proteinuria in 12 patients with steroid-resistant, FK-506-dependent FSGS.

Treatment of FSGS with mycophenolate mofetil

Since preliminary publications dating back to 1998 [74], mycophenolate mofetil (MMF) has been tried in a few cases of FSGS, amongst other causes of nephrotic syndrome [75–78]. Of 11 adults with FSGS, two went into remission with stable renal function. In the others, proteinuria diminished whilst renal function declined. In three recent paediatric series [76–78], a total of four children were treated with MMF. The drug allowed corticosteroid sparing and seemed to be beneficial in terms of renal function. Butani et al. presented in abstract form at the 2003 Annual meeting of the American Society of Nephrology [79] six cases of children with FSGS treated with FK-506. Two went into remission. It is a bit too soon to draw conclusions from such limited experience.

Relapse on transplanted kidney

Relapse of nephrotic syndrome and glomerular lesions is observed in 30% of patients undergoing renal transplantation for end-stage FSGS. In ~5% of cases, recurrence leads to loss of the transplant. In some reports, increased immunosuppressive dosage and repeated sessions of plasmapheresis seemed to have partially controlled an unfavourable evolution. In this line, it should be stressed that plasmapheresis is of no avail in primary FSGS, that is, outside the special case of nephrotic syndrome recurring after transplantation. So far, plasma protein adsorption on columns coated with staphylococcal protein A [80] appear to have led up a blind alley. The issue of recurrent FSGS on transplanted kidneys is covered in a comprehensive review by Ghiggeri et al., which recently has appeared in NDT [40].

Conclusion

The treatment of nephrotic FSGS in 2004 has not substantially changed over the last decade. Corticosteroids and CsA remain the mainstay of therapy. Alkylating agents have limited indications and a disappointing success rate. Tacrolimus with steroids seems to push patients who had not responded to CsA into remission. MMF might be of value, but large-scale studies are lacking. Clearly, the main progress to be expected in the next few years is more based on fundamental research focused on the genetics and the pathophysiology of this multifaceted podocyte disease than on trying the efficacy of each new drug used in the field of renal transplantation in the hope of a serendipitous beneficial effect. A spectacular advance has been made by identifying cases due to a genetic defect. This, along with the desperately awaited characterization of the elusive substance(s) that induces podocyte foot process flattening, proteinuria and podocyte cell-cycle dysregulation, is without doubt the most promising approach to base the treatment of FSGS on reason rather than chance.

Conflict of interest statement. Since 1986 the author was often invited to present data on cyclosporine A in the treatment of idiopathic nephrotic syndrome and received speakers honoraria from Sandoz-Pharma and Novartis.

Acknowledgments

The author gratefully acknowledges the help of Stephen Korbet, MD, for critical and thoughtful revision of this manuscript.

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