Childhood minimal change disease and focal segmental glomerulosclerosis: a continuous spectrum of disease? Pathologic study of 33 cases with long-term follow-up.

Thirty-three children with idiopathic nephrotic syndrome who underwent kidney needle biopsy were reevaluated. The male to female ratio was 2:1, and a preponderance of North-African Jewish and Arab origin over Ashkenazi Jewish origin was noted. There was a positive correlation between the severity of glomerular changes and prognosis among the 10 cases with minimal change disease (MCD) and the 23 with focal segmental glomerulosclerosis (FSGS). On long-term follow-up (mean over 11 years) chronic renal failure developed in none of 10 MCD patients, 1 of 12 FSGS patients with mild glomerular sclerosis, 1 of 7 FSGS patients with moderate glomerular sclerosis and 3 of 4 FSGS patients with severe glomerular sclerosis. Prognosis of patients with mild glomerular sclerotic lesion on light microscopy was substantially not worse than the prognosis of patients with mild glomerular alterations only on the electron microscopic study (MCD-B). Thus, both pathologically and prognostically, there was a continuous spectrum from 'pure' MCD (MCD-A) to FSGS with severe glomerular sclerosis. Glomerular changes confined to the origin of the proximal tubule ('tip' changes) were seen only in 4 patients and did not have a distinct prognostic significance. No case of peripheral location of the sclerotic segment within the glomerulus was found in our series of FSGS, and therefore no correlation between location of segmental sclerosis and prognosis was feasible.     

Glomerular tip lesion: a distinct entity within the minimal change disease/focal segmental glomerulosclerosis spectrum

BACKGROUND: The glomerular tip lesion (GTL) is a distinctive but controversial histopathologic lesion occurring in patients with idiopathic nephrotic syndrome. The relationship of GTL to minimal change disease (MCD) and idiopathic focal segmental glomerulosclerosis (FSGS) has been disputed. METHODS: In order to define the clinical features and natural history of GTL, we retrospectively reviewed the presenting clinical features, biopsy findings and outcome of 47 cases. Presenting clinical features of GTL were compared to those of controls with MCD (N= 61) or idiopathic FSGS (N= 50). RESULTS: The cohort of GTL consisted of 45 adults and two children (mean age 47.5 years; range 12 to 79 years), including 76.6% Caucasians and 53% males. At presentation, 93.6% of patients had edema, 89.1% had nephrotic syndrome (mean urine protein 8.31 g, mean serum albumin 2.27 g/dL, and mean cholesterol 340.6 mg/dL), and 34.8% had renal insufficiency. Mean time from onset of renal disease to biopsy was 2.4 months. At biopsy, glomerular segmental lesions included GTL alone in 26%, GTL and peripheral lesions in 6%, GTL and indeterminate lesions in 36%, and GTL with peripheral and indeterminate lesions in 32%. No initial biopsy contained perihilar sclerosis and most (81%) segmental lesions were cellular. Follow-up data were available in 29 patients, of whom 21 received steroids alone and eight received sequential therapy with steroids and a cytotoxic agent. At a mean follow-up of 21.5 months, 58.6% of patients achieved complete remission of nephrotic syndrome, 13.8% had partial remission, and 27.6% had persistent nephrotic proteinuria. Only one patient progressed to end-stage renal disease (ESRD). Predictors of nonremission included severity of proteinuria at presentation and % peripheral lesions. When compared to controls with MCD and idiopathic FSGS, GTL more closely resembled MCD with respect to high incidence of nephrotic syndrome (P < 0.001), severity of proteinuria (P < 0.05), short duration from onset to biopsy (P < 0.001), and absence of chronic tubulointerstitial disease (P < 0.0054). CONCLUSION: Within the MCD/FSGS spectrum, GTL is a distinctive and prognostically favorable clinical-pathologic entity whose presenting features and outcome more closely approximate those of MCD.     

Reduced podocin expression in minimal change disease and focal segmental glomerulosclerosis is related to the level of proteinuria

Background

Glomerular podocyte molecules are involved in the pathogenesis of congenital nephrotic syndrome. However, their role in primary nephrotic syndrome is not clear. This study investigated the expression of nephrin, podocin and synaptopodin in primary nephrotic syndrome.

Methods

Eighty-seven patients with primary nephrotic syndrome including minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN) and membranoproliferative glomerulonephritis Type I (MPGN) were included in the study. Glomerular expression of nephrin, podocin and synaptopodin was studied in renal biopsies by immunofluorescence and immunohistochemistry. Correlation of expression with clinical and biochemical parameters was performed.

Results

The pattern of expression for all podocyte proteins in controls was uniform fine granular along the capillary walls towards the visceral epithelial cell aspect. Glomerular expression of nephrin was present in all renal biopsies and was similar to that in controls. Glomerular synaptopodin expression was seen in all MN and MPGN patients, while it was seen in 74 % (17/23) MCD and 93.5 % (29/31) FSGS. Reduced synaptopodin expression showed no correlation with clinical and biochemical factors. Podocin expression was present in 5/23 MCD (22 %), 3/31 FSGS (9.6 %), 13/17 MN (76.4 %) and 13/16 MPGN (81 %) patients. The reduced expression of podocin significantly correlated with the degree of proteinuria (p = 0.032). No correlation with age, gender and serum creatinine level was observed.

Conclusion

Reduction of glomerular podocin expression found in MCD and FSGS is related to the amount of proteinuria. Our findings suggest that alteration in podocyte phenotype may not be a primary event and may reflect the degree of podocyte injury in primary nephrotic syndrome.     

Glomerular volume and renal function in children with different types of the nephrotic syndrome

Glomerular hypertrophy has been suggested to be an important factor in the pathogenesis of focal glomerular sclerosis. The aim of the present study was to analyse retrospectively the renal biopsies of 58 children (0.2–16.1 years of age) with different types of the nephrotic syndrome, minimal change nephrotic syndrome (MCNS), diffuse mesangial proliferation (DMP) and focal segmental glomerulosclerosis (FSGS). Glomerular surface area was measured and glomerular volume was calculated and related to steroid responsiveness and to renal function, measured by clearances of inulin and para-aminohippuric acid. Glomerular volume correlated with body surface area (BSA) and age. Because of this, patients with FSGS and DMP were matched according to BSA and age, with corresponding MCNS patients. Glomerular volumes of FSGS and DMP patients were significantly larger than those of MCNS patients. In the MCNS patients, significant correlations were found between glomerular volumes and glomerular filtration rate and effective renal plasma flow. Steroid-dependent and steroid-resistant patients showed larger glomeruli than the steroid-responsive children. We suggest that hyperfiltration and hyperperfusion, among other factors, may contribute to glomerular hypertrophy, mesangial proliferation and glomerulosclerosis.     

Synaptopodin expression in idiopathic nephrotic syndrome of childhood

BACKGROUND: Synaptopodin is a proline-rich protein intimately associated with actin microfilaments present in the podocytes' foot processes. We investigated for synaptopodin expression in children with idiopathic nephrotic syndrome (INS), including minimal change disease (MCD), diffuse mesangial hypercellularity (DMH), and focal segmental glomerulosclerosis (FSGS); in children with congenital nephrotic syndrome of the Finnish type (CNF); and in normal kidney tissue. In particular, we examined whether an association exists between synaptopodin expression in podocyte cells and the response to steroids in INS, and whether synaptopodin expression can predict FSGS upon the initial kidney biopsy in children who progress from MCD or DMH to FSGS. METHODS: Immunohistochemistry was performed for synaptopodin expression on renal tissues from MCD (N = 18), DMH (N = 7), FSGS (N = 13), CNF (N = 9), and normal children (N = 7). Synaptopodin expression in nonsclerosed glomeruli was quantitated by computerized image analysis on the Optimastrade mark software for both luminance (L) and percentage of glomerular area (A). RESULTS: Synaptopodin expression was absent in areas of sclerosis. In nonsclerosed glomeruli, synaptopodin was significantly less expressed in all groups of INS and in CNF compared with normal (P < 0.0001 for both L and A, in each MCD, DMH, FSGS, and CNF). In INS, synaptopodin expression decreased in order from MCD to DMH to FSGS, reaching statistical significance between MCD and FSGS (P = 0.001 for L and P = 0.05 for A). Greater synaptopodin expression in podocytes was associated with a significantly better response to steroid therapy (P < 0.05 for both L and A). On the other hand, the expression of synaptopodin did not predict progression of MCD or DMH to FSGS. CONCLUSION: We conclude that measurement of synaptopodin has the potential to be used as a marker to study the alteration in podocyte cell and response to therapy in INS.     

Does cyclosporine achieve a real advantage for treatment of idiopathic nephrotic syndrome in children? A long-term efficacy and safety study

Background Cyclosporine (CsA) was found to be efficient in decreasing proteinuria in both steroid-dependent and steroid-resistant nephrotic patients. We aimed to explore the potential long-term benefits and hazards of CsA and their predictors among a large group of nephrotic patients. Methods In this retrospective analysis, we included 197 pediatric patients with idiopathic nephrotic syndrome (INS) of whom 103 were steroid dependent and 94 steroid resistant. Results CsA induced complete remission in 132 (67%) and partial response in 13 (6.6%). Cyclosporine was received for a period of 22.16 ± 12.21 months. Univariate analysis showed that the response to CsA was significantly better in steroid-dependent children, in minimal change disease (MCD), diffuse mesangial proliferative glomerulonephritis (DMP) and focal segmental glomerulosclerosis (FSGS) than in other pathological lesions and in those who had lower quantities of pretreatment proteinuria. Only the prior response to steroids and concomitant use of ketoconazole with CsA were valid predictors for better response to CsA with multivariate analysis. Discontinuation of the drug in 40 patients resulted in relapse in 26 patients while the remaining 14 patients maintained remission. Renal dysfunction developed in 18 patients of whom 12 recovered completely on drug discontinuation. Thirty-seven patients developed hypertension. Multivariate analysis showed that all side-effects were significantly more prevalent in CsA-resistant patients. Conclusion CsA is effective and well tolerated in the long-term treatment of INS in children, however two thirds of cases showed relapse after CsA discontinuation     

Do current recommendations for kidney biopsy in nephrotic syndrome need modifications?

The current recommendations of kidney biopsy in childhood idiopathic nephrotic syndrome (CINS) were put forward to minimize unnecessary kidney biopsies in underlying minimal change disease (MCD). However, there remains a diversity of opinion about the criteria for biopsying children with idiopathic nephrotic syndrome. This study was conducted to prospectively study their usefulness in avoiding biopsies in MCD and to evaluate further modifications for minimizing biopsies in CINS. Of 400 consecutive CINS patients, 222 patients were subjected to kidney biopsy according to the current recommendations. The histopathology spectrum of these selectively biopsied children revealed focal segmental glomerulosclerosis (FSGS) in 39%, MCD in 34.2%, membranoproliferative glomerulonephritis (MPGN) in 16.2%, mesangioproliferative glomerulonephritis (MesPGN) in 7.6%, membranous nephropathy (MN) in 1.8%, and diffuse mesangial sclerosis (DMS) in 0.9%. We observed that despite the current recommendations and efforts to minimize biopsy, 34% of children had MCD on histopathology. Two or more clinical (hematuria and hypertension) or biochemical (renal insufficiency) parameters were present in all children with MPGN. Low C3 was present only in children with MPGN. All the steroid responders were found to have MCD, FSGS, or MesPGN on biopsy. Cyclophosphamide response correlated better with steroid responsiveness (P=0.02) than with histo- pathology (P=0.80) in MCD, FSGS, and MesPGN. Based on these observations, we suggest some modifications in current recommendations for kidney biopsy to minimize biopsying children with MCD. These are (1) biopsies in children (age 1–16 years) should be restricted (a) to a subgroup with two or more clinical and biochemical parameters and (b) in steroid non-responders, (2) the decision to administer cyclophosphamide should be based on steroid response pattern without requiring a prior routine biopsy. Received: 16 July 1999 / Revised: 20 November 2001 / Accepted: 24 November 2001     

Is single-daily low-dose cyclosporine therapy really effective in children with idiopathic frequent-relapsing nephrotic syndrome?

BACKGROUND: A recent study on renal transplant patients has shown that a single dose of cyclosporine (CsA) has added the advantage of decreasing dosages and adverse effects, while maintaining graft function. However, the efficacy of this regimen in children with idiopathic frequent-relapsing nephrotic syndrome (NS) remains controversial. METHODS: 20 children with steroid-dependent NS or CsA-dependent NS (18 with minimal change disease, MCD and 2 with focal segmental glomerulosclerosis, FSGS) were enrolled in this prospective study. CsA was commenced at 1.5 a 2 mg/kg, given as a single daily dose before breakfast, and the dose was adjusted to reach 2 hours post-dose CsA levels (C2) of 600 - 800 ng/ml. RESULTS: In 9 out of 18 patients with MCD, treatment with single-daily CsA for a median of 13 months (range 7 - 21) resulted in a reduction of mean minimum prednisolone (PSL) dose from 1.1 A+/- 0.55 to 0.04 A+/- 0.09 mg/kg on alternate days (p < 0.01), and the median relapse rate from 1.3 (1.1 - 2.5) to 0 (0 - 0.2) episodes/6 months (p < 0.01). Of them, PSL could be weaned off in 7 patients (4 of 6 with steroid-dependent NS, only 3 of 14 with CsA-dependent NS) without relapse of NS while on this therapy. However, 11 out of 20 were considered to have treatment failure: 1 with steroid-dependent NS and 10 with CsA-dependent NS. In 2 patients having FSGS, this method showed no beneficial effects. In 18 patients with MCD, relapse free ratio on single-daily CsA therapy was significantly higher in patients whose average C2 levels were greater than 700 ng/ml (p < 0.05). CONCLUSIONS: Our experience demonstrates that single-daily low-dose CsA therapy maintaining C2 levels greater than 700 ng/ml may be effective in children with steroid-dependent NS or MCD, with no relapse. In contrast, the usefulness of this regimen in children with CsA-dependent NS appears to be limited.     

Role of cyclosporin A in remitting nephrotic syndrome in a Japanese patient infected with human immunodeficiency virus type 1

We report here the case of a 57-year-old Japanese man who developed nephrotic syndrome during the course of human immunodeficiency virus type 1 (HIV-1) infection. Histological examination revealed focal segmental glomerular sclerosis (FSGS), suggesting that HIV-associated nephropathy (HIVAN) was a possible diagnosis. However, he was initially treated with glucocorticoid plus immunosuppressants for primary FSGS, without knowledge that he was seropositive for HIV-1. Of importance, the nephrotic syndrome entered remission after treatment with cyclosporin A (CsA), and there was no recurrence of the nephropathy over the following 4 years. The patient eventually died due to opportunistic infection. This case is the first report of FSGS in a Japanese HIV patient, and also serves to illustrate the potential risks and benefits of CsA for the treatment of nephrotic syndrome associated with HIV-1 infection. Received: December 9, 1998 / Accepted: March 15, 1999     

High incidence of focal segmental glomerulosclerosis in nephrotic syndrome of childhood

In recent adult literature, there have been reports of an increasing incidence of focal segmental glomerulosclerosis (FSGS) among patients with nephrotic syndrome. To examine whether this observation is also relevant to the pediatric population we utilized our hospital computerized database to analyze the data on children with primary nephrotic syndrome seen first between the years 1984 and 1995. A questionnaire was also sent to all metropolitan Kansas City pediatricians to identify possible patients outside the database. The inclusion criteria were clinical nephrotic syndrome or proteinuria with a kidney biopsy. A total of 148 patients (group A) were identified; 86 of them from metropolitan Kansas City (group B). In group A the incidence of minimal change disease (MCD) and FSGS was 52.7% [95% confidence interval (CI) 44%-60%] and 23.0% (95% CI 16-29%), respectively and in group B 54.7% (95% CI 44%-65%) and 24.5% (95% CI 15%-33%), respectively. Those numbers were significantly different from the International Study of Kidney Disease in Children (IS-KDC) reported incidence of 76.4% for MCD and 6.9% for FSGS. Similar to the ISKDC, in our population children over 6 years had a higher incidence of FSGS than younger children (32.8% vs. 16.7%, P = 0.028). The annual incidence rate for nephrotic syndrome in group B was 2.2 cases/10(5) children per year, of which MCD comprised 1.22 cases/10(5) children per year and FSGS 0.5 cases/10(5) children per year. The annual incidence rates of both primary nephrotic syndrome (3.6) and FSGS (1.6) were significantly higher in African-Americans, than Caucasians (1.8 and 0.3 cases/10(5) children per year, respectively). Our study indicates nearly no change in the annual incidence of pediatric primary nephrotic syndrome, but a higher incidence of FSGS with reciprocal decline in the incidence of MCD. The possibility of primary nephrotic syndrome being caused by a non-MCD entity is further raised among African-American and in children over 6 years. We conclude that our perception of primary nephrotic syndrome of childhood as a benign condition has to be carefully reexamined and a more-guarded prognostic approach adopted in our geographic area.     

Nephrotic syndrome in Namibian children.

BACKGROUND AND OBJECTIVES: Patterns of nephrotic syndrome vary between regions and countries, and influence approaches to management. In the mid-1970s the University of Stellenbosch became involved in providing tertiary care to Namibia, including a paediatric nephrology service. The aim of this study was to document the clinical, pathological and outcome features of nephrotic syndrome in Namibian children. SUBJECTS: Seventy black Namibian children with nephrotic syndrome were managed from 1975 to 1988. Sixty-eight renal specimens (67 biopsies and 1 autopsy specimen) were evaluated. RESULTS: Twenty-nine of the 70 children (41.4%) were hepatitis B virus (HBV) carriers, of whom 25 (86.2%) were male. Of the 29, 26 had predominantly membranous glomerulonephritis (MGN), 1 mesangiocapillary glomerulonephritis (MCGN), and 1 focal segmental glomerulosclerosis (FSGS); 1 child in advanced renal failure was not biopsied. Five children (7.4%) showed minimal change disease (MCD), 11 (16.2%) FSGS and 15 (22.1%) diffuse mesangial proliferative glomerulonephritis (DMP). The remaining 10 children showed diffuse glomerulosclerosis (6), MCGN (3) and endocapillary proliferative GN (1). Four of the 5 children with MCD went into remission on immunosuppressive treatment. Of the 15 with DMP, 4 improved spontaneously and only 1 of those treated did not improve. Only 2 of those with FSGS improved on treatment. The children with HBV-associated MGN and MCGN were offered symptomatic rather than specific treatment. Thirteen children presented with degrees of chronic renal failure. Eight are known to have died, 3 of relentless nephrotic syndrome and 4 (of whom 3 were HBV carriers) of end-stage renal failure. One child died of penicillin anaphylaxis. CONCLUSIONS: The pattern of nephrotic syndrome in black Namibian children differed greatly from the non-African pattern elsewhere in that MCD was uncommon and HBV-associated GN was the most common single group. The most frequent pattern of HBV-associated GN was MGN with some mesangiocapillary features showing marked male predominance. MCD and DMP were potentially treatable and could only be identified by biopsy. HBV carrier rates exert a major influence on the proportions of morphological subgroups of nephrotic syndrome in children. As these HBV carrier rates alter in future due to the influence of vaccination and urbanisation, the relative size of nephrotic subgroups seems likely to alter.     

Single-centre experience with cyclosporin in 106 children with idiopathic focal segmental glomerulosclerosis.

BACKGROUND: Although remission is achieved in most children with nephrotic syndrome by treatment with corticosteroids, a significant proportion of patients experience relapses. Continuous or repeated use of corticosteroids inevitably induces features of steroid side-effects. Cyclosporin (CsA) has been used in the treatment of idiopathic steroid-dependent and -resistant nephrotic syndrome. However, relapse often occurs shortly after the CsA treatment is terminated. Furthermore, long-term clinical outcome of patients treated with CsA is unclear. METHODS: We retrospectively reviewed the data of 106 nephrotic children having primary focal segmental glomerulosclerosis (FSGS) who received CsA between 1993 and 2002. Indications of CsA therapy were steroid resistance (n = 45) and steroid dependence with steroid toxicity (n = 61). Fifty-four patients received cyclophosphamide prior to CsA therapy. CsA starting dose was 6 mg/kg/day to be readjusted to maintain a whole blood trough level of 80-150 ng/ml. The drug was received for 6-48 months (mean: 22.1+/-11 months). The observation period was 5.8+/-3 and 6.1+/-1.9 years before and after CsA treatment, respectively. RESULTS: Complete remission [proteinuria <4 mg/h/m2 body surface area (BSA)], partial remission (proteinuria 4.1-40 mg/h/m2 BSA) and resistance to CsA (proteinuria > or =45 mg/h/m2 BSA) were observed in 71.7, 7.5 and 20.8% of patients, respectively. CsA-sensitive and -resistant patients differed only in the percentage of steroid responsiveness, being 66.7% in the former group and 22.7% in the later (P<0.0001). Logistic regression analysis identified steroid resistance as the only predictor of resistance to CsA (odds ratio: 12.9; P = 0.03). Hypertension, renal impairment (>30% rise of serum creatinine), gingival hyperplasia and hypertrichosis occurred in 12.3, 6.6, 22.6 and 51.9% of patients, respectively. With the exception of hypertrichosis, side effects were significantly more frequent among CsA-resistant children. We were able to stop steroids in 91 patients, of whom 31 patients relapsed. Out of 20 patients for whom CsA was intentionally discontinued while in remission, 16 patients relapsed. Of these, four (25%) were resistant to a second course of CsA. At the last follow-up, one child had developed end-stage renal failure and three had chronic renal insufficiency. CONCLUSIONS: CsA is effective in the treatment of children with idiopathic FSGS, but with a high relapse rate on drug withdrawal. Renal dysfunction and hypertension, which may be drug-induced or natural progression, are the most serious complications; therefore, close monitoring is essential.     

A simple method to detect an albumin permeability factor in the idiopathic nephrotic syndrome

BACKGROUND: Several investigators have detected an albumin permeability factor in the serum of patients with the idiopathic nephrotic syndrome (INS), that is, minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), but the methods used have been complex. METHODS: We describe here a simpler method using cultured rat glomerular epithelial cell monolayers grown to confluence on Millicell filters, which allow sampling of apical and basolateral media. 125I-labeled human serum albumin (125I-HSA) was added to the basolateral compartment, and its leakage across the epithelial cell monolayer into the apical compartment was measured. RESULTS: In untreated cells (negative control), the albumin leakage reached 5.3% at 18 hours. Cell monolayers fixed with 95% ethanol (positive control) showed 62% leakage. Sera from three out of four patients with MCD and three out of four with FSGS resulted in considerable albumin leakage, whereas sera from nine patients with other types of nephrotic renal disease and five normal subjects caused no leakage. CONCLUSION: This study shows that the Millicell system provides a simple and useful method to screen for permeability factors in the INS.     

Histopathological spectrum of childhood nephrotic syndrome in Indian children

Nephrotic syndrome in children is a clinical manifestation of different histopathological subtypes. There is a paucity of recent large studies dealing with the histopathological spectrum from developing countries. A prospective study was performed from January 1990 to December 2000 at our center, involving 600 children (with age of onset up to 16 years) with idiopathic nephrotic syndrome (INS). The objectives were: (1) to study the histopathological distribution of different subtypes of INS and (2) to compare the clinical and biochemical parameters at the time of diagnosis of minimal change disease (MCD) with non-MCD subtypes. For the purpose of this study we analyzed only those children with INS who underwent biopsies. The study group included 290 children in which adequate biopsy reports were available. There were 213 males and 77 females. Mean age at onset of INS was 7.9+5.1 years. Facial edema was found in 286 (98.6%), microhematuria in 120 (41.3%), gross hematuria in 7 (2.5%), and hypertension in 77(26.8%) patients. All patients of the study group were seronegative for HBsAg and HIV. Focal and segmental glomerulosclerosis (FSGS) was the most common histopathological subtype, occurring in 110 of 290 children (38%). Other subtypes included MCD in 95 children (32%), membranoproliferative glomerulonephritis (MPGN) in 44 children (15%), mesangioproliferative glomerulonephritis in 33 children (11%), membranous glomerulonephritis in 5 children (2%), and diffuse mesangial sclerosis in 3 children (1%). In children under 8 years of age, MCD was the most common entity, whereas FSGS predominated in children with age at onset greater than 8 years. The age at onset of nephrotic syndrome was significantly higher in the non-MCD group than the MCD group. The incidence of hypertension, microhematuria, and gross hematuria was significantly lower in the MCD group. MCD remains the most common histopathological subtype in Indian children with INS and onset under 8 years of age. The incidence of MPGN continues to be high. MCD can be differentiated from non-MCD subtype by younger age at onset, absence of hypertension, and absence of microscopic hematuria.     

Is rituximab effective in childhood nephrotic syndrome? Yes and no

The idiopathic nephrotic syndrome (i.e. MCNS and FSGS) in children has been regarded as a disorder of T-cell function. Recent studies, however, also describe abnormalities of B-cell function. This supports the use of B-cell modulating treatment for idiopathic nephrotic syndrome (INS), especially rituximab, which has been used in other glomerular disorders as well. Many studies indicate that rituximab is effective in steroid-sensitive and -dependent nephrotic syndrome, by either inducing long-term remission or reducing relapses. In most series, children with primary (and recurrent) focal segmental glomerulosclerosis (FSGS) do not respond as well. The exact mechanisms of action of rituximab (as well as those of the other treatment options) in INS are as yet unclear. In addition to hosting mechanisms a direct stabilizing effect on the podocyte may also be of relevance, especially in FSGS. Although results are encouraging especially in steroid-sensitive patients, further studies on the clinical use of rituximab and the short- and long-term immunological effects and side-effects are necessary.     

Changing patterns in the histopathology of idiopathic nephrotic syndrome in children

BACKGROUND: It is widely accepted that minimal change nephrotic syndrome (MCNS) is the most common cause of nephrosis in children. Recent studies have demonstrated an increasing incidence of focal segmental glomerulosclerosis (FSGS) in adults. METHODS: To determine possible changes in the etiology of childhood nephrosis, the clinical charts of 152 pediatric patients diagnosed with idiopathic nephrotic syndrome between 1978 and 1997 were reviewed. Histopathological diagnosis was available in 105 patients. RESULTS: MCNS was present in 35% of all biopsies, whereas FSGS was observed in 31%. Even if we assume that all patients without a histological diagnosis had MCNS (presumptive MCNS), the total incidence of MCNS (biopsy proven + presumptive) in our population was only 55%. We observed a dramatic increase in the incidence of FSGS during recent years. Before 1990, FSGS was diagnosed in 23% of all renal biopsies but increased to 47% afterward (P = 0.02). This pattern was observed in all ethnic groups. In African Americans, there was a trend for an increase in the incidence of FSGS from 38% before 1990 to 69% after 1990. A similar trend was observed in Caucasians (from 20 to 45%) and Hispanics (from 8 to 33%) Hispanics had the highest incidence of MCNS (biopsy proven + presumptive: 73%), followed by Caucasians (53%) and African Americans (37%). The mean age for presentation of nephrotic syndrome in African Americans (8.0 +/- 0.9 years) was higher than in Caucasians (4.1 +/- 0.05) and Hispanics (3.3 +/- 0.5). CONCLUSIONS: Our study showed that the incidence of FSGS in children with idiopathic nephrotic syndrome has increased recently. Furthermore, in African American children. FSGS is the most common cause of nephrotic syndrome. These findings may have significant implications in the management of childhood nephrotic syndrome.     

Treatment of steroid-resistant nephrotic syndrome with cyclosporine: study of 17 cases and a literature review

BACKGROUND: Cyclosporine (CsA) has been used in steroid-resistant idiopathic nephrotic syndrome (INS) in many previous studies. OBJECTIVE: To evaluate if CsA is a therapeutic option for steroid-resistant nephrotic syndrome. METHODS: We performed a retrospective cohort study to evaluate the effects of CsA in 17 steroid-resistant INS patients.The main laboratorial data, before and after the use of CsA, and the response to CsA were evaluated. A literature review on this subject was also done. RESULTS: Patient age ranged from 2-43 yrs. Pre-treatment renal biopsy demonstrated focal segmental glomerulosclerosis (FSGS) (64%), membranous nephropathy (MGN) (12%), mesangial glomerulonephritis (MSGN) (12%) and minimal change disease (MCD) (12%). Pre-treatment laboratory tests showed a mean 24-hr proteinuria of 4372 +/- 2686 mg/dL. Treatment with CsA was given for a minimum of 3 months and a maximum of 98 months. Mean 24-hr proteinuria declined from 3181 +/- 2277 before CsA to 915 +/- 1140 mg/24 hr after CsA (p<0.001). Remission was seen in 70.5% of patients, being 52.9% complete and 17.6% partial. The adverse effects observed were nephrotoxicity (11.7%), hypertrichosis (5.8%) and gingival hyperplasia (5.8%). Relapses were seen in eight patients (47%), with posterior remission in six patients (75%). CONCLUSION: Data from the literature suggest that CsA is a good therapeutic option for patients with steroid-resistant INS, being effective in reducing proteinuria. The beneficial effect of CsA demonstrated in our study was limited due to its design and the small sample size.     

Effect of concomitant administration of cyclosporine and ketoconazole in children with focal segmental glomerulosclerosis

BACKGROUND: Focal segmental glomerulonephritis (FSGS) is now the most common primary glomerulonephritis that leads to end-stage renal disease in both adults and children. Cyclosporine (CsA) is a well-known and effective immunosuppressive agent that has become a cornerstone of immunotherapy in solid organ transplantation and it has been used in the treatment of FSGS for over 15 years. The deliberate use of ketoconazole (keto) to reduce the need for CsA is not new, but it is particularly relevant because of the high cost of CsA. Many studies have documented this benefit in renal and cardiac transplants, but this co-administration has not been reported in children with nephrotic syndrome (NS). METHODS: This study included 116 children (below 18 years of age) with primary FSGS who were steroid resistant or dependent and received CsA therapy. Among them, 88 received daily keto therapy (keto group) in a dose of 50 mg with concomitant decrease of CsA dose by one third, while 28 patients received CsA alone (non-keto group). Mean (+/-SD) age was 6.17 +/- 4.68 years and male to female ratio was 1.9:1. The great majority of the study population received the drugs for 1-2 years. The characteristics of both groups were comparable. RESULTS: Co-administration of keto significantly reduced mean doses of CsA by 46% at 1 year with overall net cost savings of 36%. It also significantly improved the response to CsA therapy and decreased the frequency of renal impairment. No significant side effects for keto were observed. CONCLUSION: Co-administration of keto and CsA in idiopathic FSGS children is safe. This combination not only reduces the costs but also may improve the response to CsA and stabilize the renal function.     

Nephrotic urine prevents increased rat glomerular albumin permeability induced by serum from the same patient with idiopathic nephrotic syndrome.

BACKGROUND: The putative humoral mediator thought to be involved in the pathogenesis of idiopathic nephrotic syndrome has not yet been identified. However, components exist in normal serum that block the permeability activity of FSGS serum in vitro. The potential of FSGS serum to increase glomerular albumin permeability may result from an imbalance between permeability factors and naturally occurring inhibitors. We hypothesized that this imbalance may be favoured by loss of inhibitory factors in nephrotic urine. METHODS: The study population consisted of seven patients with biopsy-proven FSGS, one with IgM nephropathy, and three with idiopathic nephrotic syndrome without biopsy, from whom frozen serum and dialysed and lyophilized urine samples were available.Glomerular albumin permeability (P(alb)) was determined from the change in glomerular volume induced by applying oncotic gradients across the basement membrane of normal isolated rat glomeruli pre-incubated with patient serum, normal control serum, patient serum mixed with an equal volume of urine from the same patient, or patient serum mixed with normal urine. Serum and urine apolipoproteins J and E were measured by dot-blot, utilizing peroxidase-labelled antibodies. The urinary capacity to scavenge oxygen radicals was determined after exposure of isolated glomeruli to superoxide generated by xanthine and xanthine oxidase. RESULTS: The mean P(alb) of the patients was markedly elevated at 0.74+/-0.08. The addition of urine from the same patient significantly reduced P(alb) (mean 0.15+/-0.23) in all but one of the patients with FSGS. Normal urine had no inhibitory effect in the 10 patients in which it was tested (mean 0.71+/-0.09). Serum apo J was slightly decreased and serum apo E was slightly increased compared with controls. Urine levels of both lipoproteins were significantly decreased compared with controls. Urine from FSGS patients effectively neutralized superoxide, whereas normal urine did not. CONCLUSIONS: Nephrotic urine but not normal urine contains components that block increased albumin permeability in isolated rat glomeruli induced by serum from patients with the idiopathic nephrotic syndrome. The inhibitory function of these components, which appear not to include apolipoproteins J and E, may involve scavenging of superoxide as a final common pathway. Loss in the urine from the serum of naturally occurring inhibitors in the initial stages of the disease may propagate proteinuria and glomerular injury.     

Long-term effects of cyclosporine in children with idiopathic nephrotic syndrome: a single-centre experience

Background. Because of its potential nephrotoxicity, the long-termuse of cyclosporine (CsA) as treatment for nephrotic syndrome(NS) is controversial. The clinical outcome of the patientswith NS treated with CsA is unclear. Methods. This study reports the results of long-term CsA treatmentin 117 children with idiopathic NS, who received CsA therapyfor more than 2 years (median, 34 months). The mean age of childrenat initiation of CsA therapy was 11±4 years. The startingdose of CsA was 5 mg/kg/day, adjusted to maintain a trough levelof 100–150 ng/ml in the first 2 months, 50–100 ng/mlthereafter. Later, a level as low as 30 ng/ml was accepted solong as it maintained remission. All patients received CsA between1993 and 2003. Indications for treatment included steroid-dependentnephrotic syndrome (SDNS) in 74 patients and steroid-resistantnephrotic syndrome (SRNS) in 43 patients. Initial renal histologyshowed minimal change disease (MCD) in 38 patients and focalsegmental glomerulosclerosis (FSGS) in 79 patients. Most patientswere receiving moderate doses of prednisone. Sixty patientsreceived cyclophosphamide prior to CsA. The observation periodswere 5.8±3 years and 6.1±1.9 years before andafter CsA treatment, respectively. Results. Complete remission [proteinuria <4 mg/h/m²/bodysurface area (BSA)], partial remission (proteinuria between4.1 and 40 mg/h/m²/BSA) and resistance to CsA (proteinuria 45mg/h/m²/BSA) were observed in 82.1, 5.1 and 12.8%, respectively.Hypertension, renal impairment (>30% rise of serum creatinine),gingival hyperplasia and hypertrichosis occurred in 10.3, 6.0,32.5 and 70.1%, respectively. Steroids were stopped in 102 patients,of which 31 relapsed. Out of 29 patients for whom CsA was intentionallydiscontinued while in remission, 22 relapsed. Of these, sixpatients were resistant to a second course of CsA. Post-therapybiopsies, performed in 45 patients (33 with SDNS and 12 withSRNS), showed mild stripped interstitial fibrosis and tubularatrophy in two SDNS patients (4.4%). At the last follow-up,one child had developed end-stage renal failure and two hadchronic renal insufficiency. Conclusions. Long-term CsA therapy in low doses is effectivein the treatment of children with idiopathic NS, but the rateof relapse is high after drug withdrawal. Hypertension developedin 10% of patients and renal insufficiency in 6% (most patientswith FSGS).