Focal Segmental Glomerulosclerosis Group Research Articles

Primary focal segmental glomerulosclerosis – Long‐term outcome after pediatric renal transplantation*

Recurrence of the primary disease is a significant issue in pediatric renal transplantation (RTx). According to data reported by the North American Pediatric Renal Transplantation Cooperative Study, patients with focal segmental glomerulosclerosis (FSGS) as primary renal disease have a recurrence rate of 30% after the first RTx. The relative risk of an early graft loss because of recurrent disease is increased to 1.6-3.1 in pediatric patients with FSGS. In a German open multicenter study, which was initiated to investigate mycophenolate mofetil (MMF) after pediatric RTx [Transplantation 2001:71:638, Transplantation 2003:75:454], patients with FSGS were evaluated for recurrence rate, risk factors for recurrence, long-term graft function, glomerular filtration rate and transplant survival. All patients received immunosuppression with MMF, cyclosporine A and prednisone without induction therapy. Renal function and survival data for FSGS patients were compared with the results of patients with other primary renal diseases within the same study population. Among 86 patients transplanted between 1996 and 1999 eight patients suffered from FSGS as primary disease. Recurrence was diagnosed in two of the eight patients. One out of these two patients lost his graft as a result of recurrence. Risk factors such as time between diagnosis and end stage renal disease (ESRD) and age at onset did not predict recurrence. A three-year patient survival in the FSGS group was 100%, graft survival 87% vs. 97% in the non-FSGS group. Acute rejections occurred in three out of eight FSGS patients and in 37 out of 78 among the non-FSGS group. Long-term renal function, calculated using mathematical modeling based on glomerular filtration rate (GFR) data during 3 yr after RTx, was similar in FSGS patients - including a patient who had recurrence with a functioning graft - and those without FSGS. In patients with FSGS, recurring disease after RTx remains an important cause of graft loss (one of two patients in this population) even under modern immunosuppressants. Nevertheless, the immunosuppressive regimen used was associated with a similar graft survival rate and long-term renal function of FSGS patients compared with patients with other primary diseases.

Mycophenolate mofetil treatment for primary glomerular diseases

Treatment of primary glomerular diseases may be unsuccessful or have potential toxicities. Therefore, we evaluated the use of mycophenolate mofetil (MMF) for empirical treatment of primary glomerulopathies. Forty-six patients with biopsy-proven primary glomerulopathies received MMF for > or =3 months as adjunctive or primary treatment. Median (range) 24-hour urine protein to creatinine ratio (Up/c) and serum creatinine at the start and end of MMF therapy were compared using the Wilcoxon signed-ranks test. Overall, the median Up/c decreased from 4.7 (range <0.1, 20.3) to 1.1 (<0.1, 14.3; P < 0.001) at the end of MMF treatment with no significant change in median serum creatinine 1.3 (0.6 to 6.1) to 1.2 (0.5 to 6.5) mg/dL. Median serum albumin increased from 3.4 (1.4, 4.6) to 4.1 (1.7, 48) g/dL (P < 0.001) and the median serum cholesterol decreased from 270 (148, 795) to 220 (140, 309) mg/dL (P < 0.001) post-treatment. For those with minimal change disease, a complete steroid withdrawal was accomplished in 5/6 steroid dependent patients. Focal segmental glomerulosclerosis (FSGS) patients had a median Up/c that decreased from 2.7 (0.1, 20.3) to 0.8 (<0.1, 8.2; P = 0.001) in 18 patients. In membranous nephropathy (MN) patients, the median Up/c decreased from 7.3 (0.1, 18.5) to 1.5 (<0.1, 14.3) (P = 0.001) in 17 patients. No significant change in median serum creatinine was detected in FSGS or MN patient groups during treatment. Empirical MMF therapy in the majority of patients with primary glomerulopathies was well tolerated and achieved the goals of steroid withdrawal, improvement of nephrotic syndrome, and stabilization of renal function.

Loss of living donor renal allograft survival advantage in children with focal segmental glomerulosclerosis

Because of concerns of increased risk of graft loss with recurrent disease, living donor (LD) transplantation in children with focal segmental glomerulosclerosis (FSGS) has been controversial. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database from January 1987 to January 2000 was examined to determine differences in demographics, treatment, and outcomes in children with FSGS compared with other renal diseases. Data on 6484 children, 752 (11.6%) with FSGS, demonstrated that FSGS patients were more likely to be older and black, and were less likely to receive either pre-emptive or LD transplant (P < 0.001). No differences existed in human lymphocyte antigen (HLA) matching or immunosuppression regimens. Acute tubular necrosis occurred in more FSGS patients following LD (11.8 vs. 4.6%) or cadaveric (CD; 27.9 vs. 16.3%) transplants (P < 0.001). Graft survival was worse for LD FSGS patients (5 years 69%) compared with no FSGS (82%, P < 0.001) and was not significantly different than CD graft survival in the FSGS (60%) and No FSGS groups (67%). The LD to CD ratios of relative risk of graft failure were higher in FSGS patients (test for interaction, P = 0.01). Recurrence of original disease was the only cause of graft failure that differed between groups (P < 0.001). A greater percentage of LD FSGS graft failures was attributed to recurrence (P = 0.06). The impact of FSGS on graft survival in children is greatest in LD transplants, resulting in loss of expected LD graft survival advantage. The rationale for LD grafts in children with FSGS should be based on factors other than better outcomes typically associated with LD transplantation.

Significance of ACE Genotypes and Medical Treatments in Childhood Focal Glomerulosclerosis

Backtround: There is little information on the significance of angiotensin-converting enzyme (ACE) genotypes and medical treatments in children with primary focal segmental glomerulosclerosis (FSGS). Methods: A multicenter retrospective study was performed on the role of ACE genotypes and medical treatments in 43 Japanese children with FSGS (20 males and 23 females), including 17 children who progressed to end-stage renal failure during the mean observation period of 6.9 ± (SD) 5.0 years. Results: The incidence of the D allele of the ACE gene was higher in the whole group of 43 children with FSGS and in a subgroup of 28 steroid-resistant FSGS children (p < 0.05) than in the 130 children of the healthy control group (0.48, 0.48, and 0.33, respectively). ACE genotypes did not affect renal survival in the whole FSGS group nor in the steroid-resistant subgroup. Among the 28 steroid-resistant children, treatment with ciclosporin was effective in delaying the development of end-stage renal failure (p = 0.044), independently of other treatment regimens. Conclusion: The present study of Japanese children with FSGS showed that the D allele of the ACE gene is associated with the development of FSGS, but not associated with the progression of FSGS which was greatly ameliorated with ciclosporin, irrespective of ACE genotypes.

Racial differences between patients with focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis from the State of Bahia

To assess the association between race and type of glomerulonephritis, taking into account age, gender and the presence of hepatosplenic schistosomiasis mansoni. Patients from the Renal Service of the Federal University of Bahia, Brazil, 80 with focal segmental glomerulosclerosis (FSG) and 50 with membranoproliferative glomerulonephritis (MPGN) were compared regarding the distribution of the racial types (black, mulatto, white). Patients with systemic lupus erythematosus or any kind of autoimmune disease were not included in the present analysis. Adjusted comparisons were performed using the Mantel-Haenszel method and a multivariate logistic regression model. Race was significantly associated with histologic type; the odds of being classified as black or mulatto were approximately 2.4 times higher (odds ratio = 2.43; IC 95% = 1.09-5.45) in patients with FSG than in those with MPGN. The association between race and histologic type was not influenced by the potential effects of age, gender and hepatosplenic schistosomiasis. In the multivariate logistic regression model, race was significantly associated (p = 0.037) with type of glomerulonephritis (odds ratio = 2.54; IC 95% = 1.06-6.06). A higher frequency of negroes and mulattoes in the FSG group (compared with MPGN) in this sample from the State of Bahia is consistent with findings of previous studies from the United States. The data support the possibility of a greater susceptibility to FSG among negroes and mulattoes, independently of age, gender and schistosomiasis. The identification of the mechanisms that determine this racial difference represents an important question for future investigations.

Living-Related-Donor Kidney Transplantation Outcome in Recipients with Primary Focal-Segmental Glomerulosclerosis

We studied the outcome of renal transplantation in 30 patients with primary focal-segmental glomerulosclerosis (FSGS) and in 30 controls in whom renal failure was secondary to nonglomerular renal diseases. All patients received living-related-donor kidneys, and the majority had one-haplotype HLA matching. Within the follow-up period, the mean serum creatinine values were significantly higher in FSGS recipients as compared with the control group (p = 0.02). However, the frequency of acute rejection episodes and the mean blood pressure values were not significantly different between the two groups. There was a tendency of a higher incidence of proteinuria among FSGS recipients in comparison with the controls. Moreover, nephrotic-range proteinuria occurred only in 3 recipients of the FSGS group. Recurrence of FSGS was morphologically documented in 2 recipients 7 and 18 months, respectively, after transplantation. It is concluded that FSGS as the primary disease has a negligible impact on the living-related-donor kidney transplantation in the Egyptian population. Therefore, this disease should not discourage transplantation for this group of patients.

Identification of oxidized low density lipoprotein in human renal biopsies

Intraglomerular lipid deposition is frequently observed in routine renal biopsies, and it has been suggested that lipid peroxidation of low density lipoprotein (LDL) may be implicated in the pathogenesis of progressive glomerulosclerosis. We have examined whether oxidized LDL (Ox-LDL) is present in the glomeruli of patients with renal disease and whether intrinsic human glomerular cells express NADPH-oxidase (a superoxide-generating enzyme found in professional phagocytes). Immunocytochemical study was performed on 939 renal biopsy specimens, using monoclonal antibodies (mAbs) OL-10, 48 and 449, and polyclonal antibody against human apolipoprotein (apo) B. Mouse mAb OL-10 recognizes malondialdehyde (MDA)-modified peptide epitope, and mAbs 48 and 449 react with alpha and beta subunits of cytochrome b558, an essential component of NADPH-oxidase. Sixty-two (6.6%) of the 939 patients with renal disease exhibited a staining for MDA-altered protein or Ox-LDL in the glomeruli, mainly in the sclerotic segments or mesangial areas. Group 1 patients with heavy Ox-LDL deposition mainly in the sclerotic segments showed a higher frequency of renal insufficiency and heavy proteinuria and a greater degree of glomerulosclerosis, compared to those in group 2 with mesangial Ox-LDL staining. The distribution of MDA protein epitopes, in general, paralleled the deposition of apo B epitopes. Immunoelectron microscopy of ultrathin frozen sections showed the presence of immunogold particles for mAbs 48 and 449 in the cytoplasm of resident glomerular cells of both normal and diseased kidneys. When immunoblotted with mAb OL-10, one band from the IgA nephropathy and focal segmental glomerulosclerosis groups at approximately 260 kD was labeled, whereas immunostaining of normal control samples revealed no staining. These results indicate that Ox-LDL is present mainly in the lesions of glomerulosclerosis and mesangial areas in human renal biopsies. They also suggest that patients with heavy Ox-LDL accumulation in the sclerotic segments of glomeruli have more advanced renal disease than those with mesangial Ox-LDL and that resident glomerular cells generate cytochrome b558, the potential of which may not suffice to induce peroxidation of LDL in the diseased glomeruli.

A quantitative analysis of the glomeruli in focal segmental glomerulosclerosis.

Quantitative analysis of the glomerular area, mesangial matrix and mesangial cells was performed using renal biopsy specimens from 22 children with focal segmental glomerulosclerosis (FSGS) and 20 with minimal change nephrotic syndrome (MCNS). Non-sclerotic glomeruli were examined. All children in both groups showed nephrotic syndrome at the time of biopsy. Children with benign haematuria were examined as controls. Glomerular area increased with age in the FSGS, MCNS and control groups. The glomerular area was significantly greater in FSGS (1.5 +/- 0.4 x 10(4) microns 2) than in MCNS (1.2 +/- 0.2 x 10(4) microns 2) or in controls (1.2 +/- 0.3 x 10(4) microns 2) (P < 0.05). Mesangial matrix was increased with age in the three groups. The mesangial matrix was significantly increased in FSGS (28.3 +/- 4.0%; mesangial matrix area/glomerular area) compared with MCNS (24.9 +/- 4.1%) and controls (23.0 +/- 3.0%) (P < 0.01). These findings suggest that both glomerular hypertrophy and mesangial matrix increase in non-sclerotic glomeruli in FSGS may lead to glomerular sclerosis.

Glomerular tip lesions in renal biopsies with focal segmental IgM

Renal biopsies in which immunohistologic examination had shown the presence of glomerular focal segmental IgM were reviewed in order to investigate the histology and clinical course in these patients. Among 19 such biopsies, 12 had focal segmental glomerulosclerosis (FSGS), whereas seven had only so-called glomerular tip lesions (GTL). GTL also occurred moreover in four of the patients with FSGS. Clinical data suggest a somewhat milder course of disease in the seven patients with GTL as the sole lesion than in the patients of the FSGS group. The nature of GTL is at present unclear. We suggest that GTL may be an initial stage of FSGS, being a lesion that may or may not develop towards FSGS in its typical form. Regardless of its origin, attention is directed to the GTL as a characteristic histologic glomerular lesion, which may be the only significant histologic change in the renal biopsy from a patient with nephrotic syndrome or severe proteinuria.