Idiopathic Focal Segmental Glomerulosclerosis Research Articles

Genetic Podocyte Lineage Reveals Progressive Podocytopenia with Parietal Cell Hyperplasia in a Murine Model of Cellular/Collapsing Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a progressive renal disease, and the glomerular visceral cell hyperplasia typically observed in cellular/collapsing FSGS is an important pathological factor in disease progression. However, the cellular features that promote FSGS currently remain obscure. To determine both the origin and phenotypic alterations in hyperplastic cells in cellular/collapsing FSGS, the present study used a previously described FSGS model in p21-deficient mice with visceral cell hyperplasia and identified the podocyte lineage by genetic tagging. The p21-deficient mice with nephropathy showed significantly higher urinary protein levels, extracapillary hyperplastic indices on day 5, and glomerular sclerosis indices on day 14 than wild-type controls. X-gal staining and immunohistochemistry for podocyte and parietal epithelial cell (PEC) markers revealed progressive podocytopenia with capillary collapse accompanied by PEC hyperplasia leading to FSGS. In our investigation, non-tagged cells expressed neither WT1 nor nestin. Ki-67, a proliferation marker, was rarely associated with podocytes but was expressed at high levels in PECs. Both terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and electron microscopy failed to show evidence of significant podocyte apoptosis on days 5 and 14. These findings suggest that extensive podocyte loss and simultaneous PEC hyperplasia is an actual pathology that may contribute to the progression of cellular/collapsing FSGS in this mouse model. Additionally, this is the first study to demonstrate the regulatory role of p21 in the PEC cell cycle.

A novel multidrug therapy for difficult cyclosporine-resistant focal segmental glomerulosclerosis

Sirs,Since unremitting proteinuria itself is harmful to thekidney of patients with focal segmental glomerulosclerosis(FSGS) [1], patients with idiopathic FSGS which does notrespond to treatment with prednisolone (PDN) or cyclo-sporine A (CsA) have a high risk of progressing to renalfailure [2]. Thus, aggressive immunosuppressive therapyhas been conducted for the treatment of FSGS [3, 4].However, therapy-related adverse events, such as oppor-tunistic infection and calcinurin inhibitor-related nephro-toxicity, remain major concerns in the treatment of somepatients with refractory nephrotic syndrome (NS). Thus,we hypothesized that multidrug therapy consisting of twoimmunosuppressive drugs with different modes of actionadministered at relatively low doses, in combination withPDN, would be an effective and safe treatment in selectpatients with refractory FSGS, as postulated in a recentreport concerning the successful treatment of adult NSusing a multidrug therapy comprising tacrolimus (Tac),mycophenolate mofetil (MMF) and PDN [5].Case 1A 4-year-old boy with a 4-week history of generalizededema associated with persistent proteinuria was referred toour hospital because the NS proved to be steroid-resistant.An initial percutaneous renal biopsy revealed minorglomerular abnormalities with no segmental or tubulointer-stitial lesions (glomeruli number=40). Therefore, CsAadministration was initiated as a single dose of 25 mg(1.8 mg/kg) daily. The calculated 0-h to 4-h area under thetime–concentration curve (AUC

Polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9) are strongly associated with end-stage renal disease historically attributed to hypertension in African Americans

African Americans have high incidence rates of end-stage renal disease (ESRD) labeled as due to hypertension. As recent studies showed strong association with idiopathic and HIV-related focal segmental glomerulosclerosis and non-muscle myosin heavy chain 9 (MYH9) gene polymorphisms in this ethnic group, we tested for MYH9 associations in a variety of kidney diseases. Fifteen MYH9 single-nucleotide polymorphisms were evaluated in 175 African Americans with chronic glomerulonephritis-associated ESRD, 696 African Americans reportedly with hypertension-associated ESRD, and 948 control subjects without kidney disease. Significant associations were detected with 14 of the 15 polymorphisms in all 871 non-diabetic patients with ESRD. In hypertension-associated ESRD cases alone, significant associations were found with 13 MYH9 polymorphisms and the previously reported E1 haplotype. Thus, hypertension-associated ESRD in African Americans is substantially related to MYH9 gene polymorphisms and this may explain the poor response to blood pressure control in those diagnosed with hypertensive nephrosclerosis. It is possible that many African Americans classified as having hypertension-associated ESRD have occult MYH9-associated segmental or global glomerulosclerosis. Our study shows that gene-environment and/or gene-gene interactions may initiate kidney disease in genetically susceptible individuals, because African Americans homozygous for MYH9 risk alleles do not universally develop kidney disease.

An update on the treatment options for focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is not a disease but a lesion initially affecting the podocyte. Various factors may induce ‘secondary’ FSGS, including defects in molecules that contribute to the podocyte slit diaphragm permselectivity to albumin. They do not represent indications for immunosuppression and require symptomatic treatment only, comprising angiotensin 2 and endothelin antagonists. Primary (idiopathic) FSGS is possibly but not certainly of immunologic origin, owing to an elusive glomerular permeability factor (GPF), explaining relapse on a renal transplant and justifying an immunosuppressive treatment. The best prognostic feature of primary nephrotic FSGS is its response to corticosteroids. Alkylating agents are mostly ineffective in steroid-resistant forms. An association of corticosteroids and cyclosporine A (CsA) remains the mainstay of treatment, with a good tolerability when CsA dosage is low. A definite advantage of tacrolimus on CsA has not yet been established. Sirolimus appears ineffective and potentially harmful. Azathioprine is not indicated. A number of mostly uncontrolled trials indicate that mycophenolate mofetil might find an adjunctive place in the treatment. Plasmapheresis is of no avail outside the special case of relapse in a transplanted kidney. Immunoabsorption of the GPF has not led to practical treatment options. Anecdotal reports on rituximab are as yet too few to determine whether this monoclonal anti-CD20 antibody will find a place in the treatment of primary FSGS.

Polymorphisms in the Nonmuscle Myosin Heavy Chain 9 Gene (MYH9) Are Associated with Albuminuria in Hypertensive African Americans: The HyperGEN Study

Background:MYH9 is a podocyte-expressed gene encoding nonmuscle myosin IIA that is associated with idiopathic and human immunodeficiency virus-associated focal segmental glomerulosclerosis (FSGS) and hypertensive end-stage renal disease in African Americans. Methods: Four single nucleotide polymorphisms comprising the major MYH9 E1 risk haplotype were tested for association with estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (ACR) in 2,903 HyperGEN participants (1,458 African Americans (AA) in 895 families and 1,445 European Americans (EA) in 859 families) to determine the role of MYH9 in subclinical nephropathy. Association analyses employed general linear models in unrelated probands and generalized estimating equations in families. Adjustment was performed for age, sex, diabetes, BMI, medications, and mean arterial pressure separately in each race. Results: Mean (SD) eGFR and ACR were 74.3 (16.0) ml/min/1.73 m² and 20.3 (119.9) mg/g in EA, and 88.6 (20.9) ml/min/1.73 m² and 76.8 (394.5) mg/g in AA (both p < 0.0001 across ethnicities). Urine ACR was associated with rs3752462 (p = 0.01) and rs4821481 (p = 0.05) in unrelated AA and with rs4821481 (p = 0.03), rs2032487 (p = 0.04) and the E1 3224 haplotype (p = 0.013) in AA families. Single nucleotide polymorphisms and the haplotype were not associated with ACR in EA or with eGFR in either ethnic group. Conclusions:MYH9 variants are associated with albuminuria in hypertensive AA. The strength of the association was weaker than that in FSGS and hypertensive end-stage renal disease. MYH9 risk variants appear to be associated with primary FSGS with secondary hypertension, although nephrosclerosis may develop in response to hypertension in subjects homozygous for the MYH9 E1 risk haplotype.

ACTN4 Gene Mutations and Single Nucleotide Polymorphisms in Idiopathic Focal Segmental Glomerulosclerosis

Aim: To investigate the association between mutations or single nucleotide polymorphisms (SNPs) of the gene ACTN4 in Chinese patients with idiopathic focal segmental glomerulosclerosis (FSGS). Materials and Methods: Genomic DNA of 82 Chinese idiopathic FSGS patients and 70 healthy people were used to analyze ACTN4 gene mutations by polymerase chain reaction, direct sequencing and GenBank matching. Hair follicle DNA of novel mutated patients’ parents were sequenced and α-actinin-4 expression in patients’ kidney was examined by immunofluorescence. For SNPs, after the Hardy-Weinberg equilibrium test, allele association and the frequencies of genotypes were analyzed, followed by association analysis between genotypes and clinical diagnosis. Results: We found a heterozygous candidate mutation 184T>A (S62T) in 1 patient and a 5′ UTR candidate mutation 1-34C>T in another patient. Both patients had non-nephrotic syndrome FSGS with reduced kidney α-actinin-4 expression. Promoter activity analysis suggests that the 1-34C>T candidate mutation may affect the transcriptional regulation of ACTN4 gene. Additionally, 6 novel silent variants and 2 novel SNPs were also found in this study. Novel SNP 484 + 87C>G had a significant association with the level of urine protein excretion in these idiopathic FSGS patients. Conclusions: Our data suggest that mutations and SNP of ACTN4 gene may contribute to be associated with Chinese idiopathic FSGS.

Morphometric and immunohistochemical insight into focal segmental glomerulosclerosis in obese and non-obese patients.

A number of studies have reported an alarming increase in the incidence of obesity related-glomerulopathy. Focal segmental glomerulosclerosis has recently been shown to be key lesion leading to end-stage renal disease in these cases. Nineteen patients with obesity-related focal segmental glomerulosclerosis (O-FSGS) and 16 with idiopathic focal segmental glomerulosclerosis (I-FSGS) were examined by percutaneous renal biopsy. Glomerular and interstitial parameters in O-FSGS and I-FSGS were compared morphometrically as well as immunomorphological study was done to evaluate immunohistochemical profile of TGFbeta- 1, monocytes/macrophages, T lymphocytes and alpha-SMA in these groups. The total glomerular cells, mesangial areas, glomerular alpha-SMA staining, glomerular monocytes/macrophages and glomerular T-cells were in IFSGS increased in comparison with O-FSGS, most of them significantly, whereas total glomerular area was significantly greater in O-FSGS patients. The tubular immunoexpression of TGF-beta-1, interstitial volume and interstitial alpha-SMA staining were significantly increased in I-FSGS cases in comparison with O-FSGS group, but interstitial CD68+ and CD3+ cells did not differ significantly. Moreover, we found in both O-FSGS and I-FSGS groups significant positive correlations between glomerular immunoexpression of alpha-SMA and glomerular CD 68+ cells, tubular immunoexpression of TGF-beta-1 and interstitial immunoexpression of alpha-SMA as well as tubular immunoexpression of TGF-beta-1 and interstitial volume. Negative correlation between tubular immunoexpression of TGF-beta-1 and interstitial CD3+ cells was significant only in IFSGS group. Our morphometric and immunohistochemical study suggests that O-FSGS and I-FSGS are separate morphological entities whereas mechanisms of glomerular and interstitial injury in these cases seem to be rather similar.

Podocyte foot process effacement as a diagnostic tool in focal segmental glomerulosclerosis

Podocyte foot process effacement is characteristic of proteinuric renal diseases. In minimal change nephrotic syndrome (MCNS) foot processes are diffusely effaced whereas the extent of effacement varies in focal segmental glomerulosclerosis (FSGS). Here we measured foot process effacement in FSGS and compared it to that in MCNS and in normal kidneys. A clinical diagnosis was used to differentiate idiopathic FSGS from secondary FSGS. Median foot process width, determined morphometrically by electron microscopy, was 3236 nm in 17 patients with idiopathic FSGS, 1098 nm in 7 patients with secondary FSGS, and 1725 nm in 15 patients with MCNS, as compared to 562 nm in 12 control patients. Multivariate analysis showed that foot process width did not correlate with proteinuria or serum albumin levels but was significantly associated as an independent factor with the type of disease. Foot process width over 1500 nm differentiated idiopathic from secondary FSGS with high sensitivity and specificity. Our results show that quantitative analysis of foot processes may offer a potential tool to distinguish idiopathic from secondary FSGS.

Angiotensin‐converting enzyme gene polymorphism and the progression rate of focal segmental glomerulosclerosis in Iranian children

Focal segmental glomerulosclerosis (FSGS) is one of the most common forms of glomerulonephritis leading to end-stage renal disease (ESRD). A few clinical and paraclinical factors are considered as contributing factors in progression rate. However, there are controversial reports on the relationship between ACE gene polymorphism and rapidity of progression of FSGS to ESRD in different populations. To elucidate this issue, we investigated the relationship between the insertion (I) and deletion (D) ACE gene polymorphism and rapidity of progression of FSGS to ESRD in Iranian children. Forty-one children aged 1-18 years admitted to St AlZahra Hospital, Isfahan, and St Ali Asghar Hospital, Tehran, Iran, with idiopathic FSGS were enrolled. Renal death was defined as a glomerular filtration rate (GFR) of less than 50 mL/min per 1.73 m(2) or a decreased GFR to less than 50% compare to baseline. Reaching renal death in less or more than 2 years were labelled as rapid progressors (RP) or slow progressors (SP), respectively. Intron 16 of the ACE gene was amplified by the polymerase chain reaction technique. Twenty-eight patients were male and 13 were female. In 15 RP patients, the genotype distribution was 26.6% DD, 6.7% II and 66.7% ID. In 26 SP patients, the genotype was similar (38.6% DD, 7.6% II and 53.8% ID, P > 0.05). There were no statistically significant differences for ACE I/D gene polymorphism between the two groups of patients (P > 0.05). Our study revealed no correlation between ACE I/D gene polymorphism and rapidity of progression of FSGS to ESRD in Iranian children.

Differential chemokine expression in tubular cells in response to urinary proteins from patients with nephrotic syndrome

Background and aim: Comparison of urine proteins in idiopathic minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) patients has been previously conducted, but the relationship between the severity of tubular injury and the composition of urine proteins in various kidney diseases is unknown. This study aimed to investigate the chemokine expression in human tubular cells in response to urine proteins from patients with nephrotic syndrome. Methods: Urine proteins collected from patients with MCD or FSGS were extracted by ultrafiltration and coincubated with HK-2 cells. The expression of the RANTES and MIF genes and the activation of p38 and extracellular regulated kinase were determined. Results: The urine proteins from both MCD and FSGS patients contained a primary band of proteins with Mr of ∼62kDa. The major cytokines present in urine proteins from MCD and FSGS patients were IL-6 and IL-8, while IL-1β, IL-10, IL-12p70 and TNF-α were only detectable. We observed time- and dose-dependent increases in RANTES and MIF expression with urine protein treatment in HK-2 cells. The urine proteins from FSGS patients induced a higher expression of these two chemokines in HK-2 cells compared to the urine proteins from MCD patients. ERK and p38 were activated by urine proteins from either MCD or FSGS patients. Pretreatment with SB203580 or PD98059 abolished the increase in RANTES and MIF expression induced by urine proteins from FSGS patients, while only SB203580 suppressed the high expression induced by urine proteins from MCD patients. Conclusion: These findings indicate that the urine proteins from MCD and FSGS patients induce a differential expression of RANTES and MIF in tubular cells through distinct activation of MAPK-related signaling pathways.

Mycophenolate mofetil or standard therapy for membranous nephropathy and focal segmental glomerulosclerosis: a pilot study

The current treatment regimes for patients with nephrotic syndrome due to idiopathic membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS) are based on steroids and/or cytotoxic agents. Data on the effect of mycophenolate mofetil (MMF) for these conditions are scarce and confounding. We compared the efficacy of an MMF-based therapy with standard therapies in inducing remission in adult nephrotics with MN and FSGS in a randomized pilot study. MMF was given at 2 g/day for 6 months along with prednisolone at 0.5 mg/kg/day for 2-3 months. Conventional therapy was prednisolone 1 mg/kg/day for 3-6 months for FSGS and alternating monthly cycles of steroids and cyclophosphamide for 6 months for MN. The primary end point was change in urinary protein/creatinine ratio. A total of 54 patients (21 MN and 33 FSGS) were recruited; 28 were randomized to receive MMF (group A) and 26 were on conventional treatment (group B). There was no difference in the proportion of patients achieving remission in two groups (64 and 80% in MN and 70 and 69% in FSGS). The frequency of relapses and incidence of infections was also similar. FSGS patients in group A achieved remission faster and received a lower cumulative steroid dose. A 6-month treatment with MMF is as effective as the conventional treatment for primary treatment of MN and FSGS in the short term. It induces remission faster and reduces steroid exposure in FSGS patients. Studies with more cases and longer follow-up are required to evaluate its impact on preservation of kidney function.

Recurrence of Nephrotic Proteinuria in Children With Focal Segmental Glomerulosclerosis After Renal Transplantation Treated With Plasmapheresis and Immunoadsorption: Case Reports

Idiopathic focal segmental glomerulosclerosis (FSGS) is believed to be caused by a circulating permeability factor. FSGS recurrence is common after transplantation. The treatment is still a matter of debate; plasmapheresis (PE) and immunoadsorption (IA) are often used. We report on PE and IA in the treatment of two children with recurrent nephrotic proteinuria. Patient 1 was a 16-year-old girl who had recurrence of nephrotic proteinuria on the first day after transplantation (proteinuria-19 g/d). Primary immunosuppressive therapy was changed to high-dose cyclosporine and cyclophosphamide; plasmapheresis was started on day 4. Altogether we performed 53 PE and 38 IA procedures. During the first month, PE procedures were performed with no more than a 2-day interval between sessions, and the girl achieved partial remission (proteinuria 3 g/d). PE was then stopped. After 2 months, a relapse of heavy proteinuria occurred. This relapse was successfully treated again with intensified PE treatment. After achieving remission, a chronic PE regimen was started (PE once a week), similar to the previous series. The child remained in partial remission. Seven months after renal transplantation, she was switched from PE to IA, because of severe hypoproteinemia. Graft biopsy performed at 4 months showed effacement of the foot processes. At the present time she has a good graft function and 3 g/d proteinuria. Patient 2 was a 13-year-old girl with FSGS since 9 years. On the second day after renal transplantation she developed nephrotic proteinuria (proteinuria-14 g/d), which was treated with 39 PE and 16 IA treatments. She went into complete remission on the intensified PE regimen, had one relapse, and was switched to chronic IA. Graft biopsy performed at 2 weeks after transplantation showed effacement of the foot processes. At the present time she has good graft function and low proteinuria (0.3 g/d). In conclusion, intensified PE or IA treatments induced remission of recurrent nephrotic range proteinuria. Chronic PE or IA can maintain patients with frequent relapses in long-term remission.

Pirfenidone Slows Renal Function Decline in Patients with Focal Segmental Glomerulosclerosis

Pirfenidone is an orally available antifibrotic agent that has shown benefit in animal models of pulmonary and renal fibrosis and in clinical trials of pulmonary fibrosis, multiple sclerosis, and hepatic cirrhosis. Our objective was to determine whether pirfenidone slows the loss of renal function in focal segmental glomerulosclerosis. An open-label trial was performed to evaluate the safety and efficacy of pirfenidone in patients with idiopathic and postadaptive focal segmental glomerulosclerosis. The monthly change in estimated GFR, expressed as ml/min per 1.73 m2, was compared between the baseline period and the treatment period. During both periods, patients received angiotensin antagonist therapy if tolerated. Twenty-one patients were enrolled, and 18 patients completed a median of 13 mo of pirfenidone treatment. The monthly change in GFR improved from a median of -0.61 ml/min per 1.73 m2 (interquartile range -1.31 to -0.41) during the baseline period to -0.45 ml/min per 1.73 m2 (interquartile range -0.78 to -0.16) with pirfenidone therapy. This change represents a median of 25% improvement in the rate of decline (P < 0.01). Pirfenidone had no effect on BP or proteinuria. Adverse events attributed to therapy included dyspepsia, sedation, and photosensitive dermatitis. It is concluded that pirfenidone is an attractive candidate for placebo-controlled trials in patients with progressive chronic kidney disease.

Steroid-resistant idiopathic childhood nephrosis: overdiagnosed and undertreated

The rate of complete remission after induction therapy for steroid-resistant nephrotic syndrome (SRNS) due to either focal segmental glomerulosclerosis (FSGS) or minimal change nephrotic syndrome (MCNS) has been reported to be <50%. The present retrospective study investigated 86 children with SRNS due to FSGS and MCNS and found improved rates of complete remission in children with idiopathic FSGS and MCNS after combination therapies using ciclosporin A (CSA) and prednisolone (PRED). Eighty-six children with FSGS or MCNS and with SRNS receiving standard oral PRED therapy were analysed in a retrospective, non-randomized study. Fifty-two patients had idiopathic FSGS (group 1), 14 patients had MCNS (group 2), and 20 patients had genetic FSGS or syndrome-associated FSGS (group 3). In group 1A (n = 25), induction therapy consisted of CSA (initial dose 150 mg/day/m(2) divided into two doses) given in combination with intravenous methylprednisolone (IV-MPRED 300-1000 mg/day/m(2) for 3-8 days) and oral PRED. In group 1B (n = 27), CSA was combined with oral PRED (40 mg/m(2) on alternate days). In group 1, patients with idiopathic FSGS receiving IV-MPRED + oral PRED + CSA had a significantly better outcome than patients treated with oral PRED + CSA (84 vs 64% cumulative proportion of sustained complete remission, respectively; P = 0.02, log-rank test). Sixteen (40%) out of 40 children entering complete remission had a first relapse after a median interval of 1 year. All relapses were successfully treated with IV-MPRED + oral PRED + CSA or oral PRED + CSA. Three out of forty responding children developed stage 2 chronic kidney disease (CKD), and none advanced to stage 3-5; in contrast, 9 out of 12 children with persistent nephrotic syndrome (NS) developed CKD stage 2-5 (8 vs 75%, respectively; P < 0.001, Fisher's exact test). In group 2, all 14 children with steroid-resistant MCNS went into remission after receiving PRED + CSA (n = 11) or IV-MPRED + oral PRED + CSA (n = 3). No patient developed CKD. In group 3, NS persisted in all 20 children having a genetic or syndromic type of FSGS receiving either PRED + CSA (n = 9) or PRED alone (n = 11). Seventeen out of 20 patients entered stage 5 CKD and were successfully transplanted; one patient developed recurrent NS. Prolonged and intensified treatment of children with idiopathic non-genetic SRNS (FSGS or MCNS) with combined PRED + CSA therapy including IV-MPRED pulses resulted in a higher rate of remission when compared with previous reports on using CSA mono-therapy or other immunosuppressive combination therapies.

Idiopathic collapsing focal segmental glomerulosclerosis in pediatric patients.

The aim of this study was to evaluate the clinical outcome of our patients with idiopathic collapsing focal segmental glomerulosclerosis (FSGS) as compared to those with non-collapsing FSGS. The study included a total of 39 patients with idiopathic FSGS. Of these, 11 had collapsing FSGS and the remaining 28 were collectively grouped as non-collapsing FSGS. The mean ages, gender ratio (M:F), and percentage of African-American patients in collapsing versus non-collapsing FSGS groups were 12.7+/-3.1 and 8.9+/-5.1 years, 1.2:1 and 4.6:1, and 90.9 and 53.6%, respectively. After a mean followup period of 31.5+/-22.3 months, 8 patients (73%) with collapsing FSGS had chronic renal impairment as compared to 8 (29%) patients with non-collapsing FSGS group after a mean follow-up period of 18.7+/-12.9 months. However, the cumulated renal survival at 30 months did not reveal a significant difference. In comparison to non-collapsing FSGS, collapsing FSGS in our study was equally common in females as in males and occurred predominantly in African Americans. The outcome of our patients with collapsing FSGS at 30 months was better than in previous reports.

The nephrologist in the HAART era

The nephrologist in the HAART era

Predictors of long-term outcome of children with idiopathic focal segmental glomerulosclerosis

Clinical and histological data of children presenting with steroid-resistant nephrotic syndrome and renal biopsy showing focal and segmental glomerulosclerosis from 1980 with a follow-up of over 10 years were reviewed. There were 66 patients; 38 male and 28 female. Age at onset ranged from 0.4-14.1 years (mean 6.4). Tubular atrophy was present at first biopsy in 50/66, capsular adhesions in 35/66, glomerular tip lesions in 8/66 and mesangial expansion in 31/66 patients. In 51 children, cyclophosphamide was prescribed as the first cytotoxic agent, while 15 received cyclosporine A and complete remission was induced in 43 and 40% of the children, respectively. Complete and stable remission was maintained in 35 children, while 22 had reduction of proteinuria with symptomatic relief. Nine were refractory to cytotoxic therapy. Of the 35 patients who entered complete and stable remission, the renal survival was over 90%, while in the 31 non-responders it was 48% in 10 years. The multivariate analysis using unconditional logistic regression method identified the presence of mesangial expansion (p=0.011) and tip lesions (p=0.005) as the independent predictors of favourable response to cytotoxic therapy and the presence of renal impairment (p=0.008) and extensive focal segmental sclerosis (p=0.025) as independent predictors of unfavourable response.

Sirolimus Therapy of Focal Segmental Glomerulosclerosis Is Associated With Nephrotoxicity

To evaluate the safety and efficacy of sirolimus in treating patients with focal segmental glomerulosclerosis (FSGS), we performed a phase 2, open-label clinical trial. Inclusion criteria were adults and children 13 years and older with biopsy-proven idiopathic FSGS, proteinuria with protein of 3.5 g/d or greater while on angiotensin antagonist therapy, glomerular filtration rate (GFR) of 30 mL/min/1.73 m(2) or greater (>or=0.50 mL/s), and failure to achieve sustained remission with at least 1 immunosuppressive agent. Eligible patients received sirolimus doses adjusted to achieve trough levels of 5 to 15 ng/mL during the first 4 months and 10 to 20 ng/mL for the subsequent 8 months. The primary outcome was decrease in proteinuria, expressed as complete remission (protein < 0.3 g/d) or partial remission (protein >or= 50% decrease and <3.5 g/d). Six adult patients with FSGS were enrolled in the study; they had median disease duration of 4.0 years, mean age of 39 +/- 11 years, mean baseline Modification of Diet in Renal Disease-estimated GFR of 52 +/- 15 mL/min/1.73 m(2) (0.87 +/- 0.25 mL/s), and median baseline proteinuria with protein of 6.6 g/d (interquartile range, 4.2 to 9.4). Five patients had received cyclosporine. No patient experienced a complete or partial remission. Sirolimus therapy was stopped prematurely in 5 patients for the following reasons: (1) precipitous decrease in GFR in 4 patients after 7 to 9 months of therapy with a greater than 2-fold increase in proteinuria in 3 patients and (2) hypertriglyceridemia with triglyceride levels greater than 1,600 mg/dL (>18 mmol/L) at 5 months in 1 patient. Because of a rapid decrease in GFR with worsening proteinuria, the protocol was closed to further recruitment. We conclude that sirolimus may be associated with nephrotoxicity in some patients with FSGS, particularly those with prolonged disease duration and prior cyclosporine therapy.

Cellular focal segmental glomerulosclerosis: Clinical and pathologic features

Five pathologic variants of idiopathic focal segmental glomerulosclerosis (FSGS) are recognized: collapsing (COLL), cellular (CELL), glomerular tip lesion (GTL), perihilar, and not otherwise specified (NOS). The prognostic significance of CELL FSGS has not been determined. We compared the presenting clinical and pathologic characteristics in 225 patients with CELL (N=22), COLL (N=56), GTL (N=60), and NOS (N=87) variants of idiopathic FSGS. CELL, COLL, and tip lesion all showed greater frequency and severity of nephrotic syndrome, and shorter time to biopsy compared to NOS. Predictors of end-stage renal disease (ESRD) for all FSGS patients included initial serum creatinine, % global sclerosis, % COLL lesions, chronic tubulo-interstitial injury score, and lack of remission response. COLL FSGS had the highest rate of renal insufficiency at presentation, most extensive glomerular involvement and chronic tubulo-interstitial disease, fewest remissions (13.2%), and highest rate of ESRD (65.3%). GTL patients were older and showed the highest remission rate (75.8%) and lowest rate of ESRD (5.7%). CELL variant showed intermediate rates of remission (44.5%) and ESRD (27.8%) compared to COLL and tip lesion. CELL variant may include cases of unsampled tip or COLL lesion, underscoring the importance of adequate sampling. Our data support the view that CELL and COLL FSGS are not equivalent and validates an approach to pathologic classification that distinguishes between COLL, CELL, and tip lesion variants of FSGS.

Immunosuppressive Treatment of Idiopathic Focal Segmental Glomerulosclerosis: A Five-Year Follow-Up Study

Background/Aims: Focal segmental glomerulosclerosis (FSGS) is a common type of glomerular disease that can lead to chronic renal failure. Various therapeutic regimens have been used in nephrotic FSGS patients. The effect of treatment with prednisolone alone or its combination with azathioprine and cyclosporin and parameters related to a poor outcome are studied. Methods: Fifty-one patients with idiopathic FSGS and a follow-up period of 5 years were included. Twenty-five were treated with prednisolone alone (1 mg/kg BW/day) or combination of prednisolone (0.5 mg/kg BW/day) with azathioprine (2 mg/kg BW/day) or cyclosporine (3 mg/kg BW/day) in gradually reduced doses whereas 26 patients received no immunosuppressive drugs. Lower prednisolone dose regimens were used as initial treatment in obese, borderline diabetics or patients with bone disease. The clinical course was estimated using the end-points of 50% or doubling of baseline serum creatinine and/or end-stage renal failure. The contribution of clinical and histological parameters in the clinical outcome was estimated by univariate and multivariate analyses. Results: Increase of baseline serum creatinine by 50% during the follow-up period was observed in 2 treated and 9 untreated patients (8% vs. 35%, p = 0.03) whereas doubling of serum creatinine in 2 and 5 patients respectively (8% vs. 19%, p = NS). End-stage renal failure developed in 4 of 51 patients (8%), 2 treated and 2 untreated (p = NS). Parameters related to a poor outcome were baseline serum creatinine and severity of glomerulosclerosis (multivariate analysis OR = 1.08, p = 0.01). Most of patients (68%) who reached end-points had persistent nephrotic syndrome during the follow-up. Remission of nephrotic syndrome was observed more frequently among treated (75 vs. 30.7%, p = 0.05). Prednisolone alone was followed by remission of nephrotic syndrome in 62.5% whereas combination of lower prednisolone dose with azathioprine and cyclosporin in 80 and 85.7% of patients. No serious side-effects were observed. Conclusion: This and previous studies suggest that steroid and/or immunosuppressive therapy have a role in amelioration of the clinical course and remission of nephrotic syndrome in patients with FSGS A combination of low predisolone dose with cyclosporine could be used as initial treatment in patients with higher risk for side-effects from the usual prednisolone dose.