Idiopathic Focal Segmental Glomerulosclerosis Research Articles

Roles of Mast Cells and Monocyte Chemoattractant Protein-1 in the Renal Injury of Obesity-related Glomerulopathy

BackgroundInflammation contributes to renal injury of obesity-related glomerulopathy (ORG). As mast cells are regarded as regulators of inflammation, this study aimed to investigate whether mast cell infiltration is involved in renal damage of ORG. MethodsForty patients with ORG, 18 with idiopathic focal segmental glomerulosclerosis and 10 normal controls were included in this study. Tryptase and CD68 were used for detecting mast cells and macrophages, respectively, by immunohistochemistry. Associations between mast cells and inflammation as well as clinicopathological parameters were assessed. ResultsTubulointerstitial mast cell infiltration increased in the ORG group compared with that in the focal segmental glomerulosclerosis and the control groups. The number of mast cells was positively correlated with body mass index (r=0.432, P=0.006), systolic blood pressure (r=0.445, P=0.005), serum creatinine (r=0.489, P=0.002), tubular atrophy (r=0.470, P=0.003) and interstitial fibrosis (r=0.669, P<0.001). Increased expression of monocyte chemoattractant protein-1, which was partly colocalized with tryptase, was observed. CD68-positive macrophages were also found to be increased and distributed around the mast cells. The area of tubulointerstitial monocyte chemoattractant protein-1 was correlated with the number of mast cells (r=0.695, P<0.001) and interstitial fibrosis (r=0.327, P=0.042). Multivariate regression showed that the number of mast cells was an independent predictor for epidermal growth factor receptor (R2 =0.313, P<0.001). ConclusionsMast cell infiltration is involved in renal damage of ORG, and inflammation may contribute to such a process.

Podocyte expression of nonmuscle myosin heavy chain-IIA decreases in idiopathic nephrotic syndrome, especially in focal segmental glomerulosclerosis

Previous studies have identified significant associations between the development of idiopathic focal segmental glomerulosclerosis (FSGS) and MYH9 encoding nonmuscle myosin heavy chain-IIA (NMMHC-IIA). However, these studies focused only on the linkage of MYH9 polymorphisms and development of FSGS. There have been no reports on pathological changes of NMMHC-IIA in human glomerular diseases. Here we report on the precise localization of NMMHC-IIA in podocytes and changes in NMMHC-IIA expression in pathological states in rats and humans. Immunocytochemical (immunofluorescence and immunoelectron microscopy) studies were performed to determine the precise localization of NMMHC-IIA. Expression levels of NMMHC-IIA were investigated in puromycin aminonucleoside (PAN)-treated rats; and expression levels of NMMHC-IIA and other podocyte-related proteins were investigated in glomeruli of patients with idiopathic FSGS and other heavy proteinuric glomerular diseases. NMMHC-IIA was located primarily at the cell body and primary processes of podocytes; this localization is distinct from other podocyte-related molecules causing hereditary FSGS. In PAN-treated rat kidneys, expression levels of NMMHC-IIA in podocytes decreased. Immunohistochemical analysis revealed that expression levels of NMMHC-IIA markedly decreased in idiopathic nephrotic syndrome, especially FSGS, whereas it did not change in other chronic glomerulonephritis showing apparent proteinuria. Changes in NMMHC-IIA expression were observed in glomeruli where expression of nephrin and synaptopodin was maintained. Considering previous genome-wide association studies and development of FSGS in patients with MYH9 mutations, the characteristic localization of NMMHC-IIA and the specific decrease in NMMHC-IIA expression in idiopathic nephrotic syndrome, especially FSGS, suggest the important role of NMMHC-IIA in the development of FSGS.

The expression of podocyte-specific proteins in parietal epithelial cells is regulated by protein degradation

The role of parietal epithelial cells (PECs) in glomerular disease is unclear because they also express podocyte proteins under pathophysiological conditions. To help resolve this, we established a novel PEC isolation technique in rats and mice to investigate which regulatory mechanisms lead to podocyte protein expression in PECs. This pure pool of naive PECs was then compared with PECs in primary culture and immortalized PECs in permanent culture. The naive PECs expressed low levels of podocyte-specific mRNA. Accordingly, in crescentic glomerulonephritis, single PECs activated the podocin promoter in vivo. In primary culture, PECs expressed a distinct morphology from podocytes but with high transcript and protein levels of PEC markers. In contrast to naive PECs, cultured PECs also expressed podocyte proteins, and this correlated with reduced proteolytic activity but not with increased transcript levels. Activation of autophagy or proteasomal degradation decreased the levels of podocyte proteins in PECs, whereas inhibition of proteasomal degradation led to the stabilization of podocyte proteins in PECs. Thus, naive PECs express podocyte transcripts physiologically and these podocyte proteins are stable under pathological conditions through decreased proteolysis.

A retrospective study of focal segmental glomerulosclerosis: clinical criteria can identify patients at high risk for recurrent disease after first renal transplantation

BackgroundFocal segmental glomerulosclerosis (FSGS) is a frequent cause of end-stage renal disease. Renal transplantation in patients with FSGS is often complicated by disease recurrence, which is associated with poor outcome. There are no tests that reliably predict recurrence of FSGS after transplantation. The aim of this study was to evaluate if clinical criteria can identify patients at high risk for recurrent disease.MethodsWe retrospectively studied 94 patients who received a first renal transplant at a median age of 37 years (range 5–69 years). Patients were assigned to one of three groups: familial or genetic FSGS (group I; n=18), secondary FSGS (group II; n=10) and idiopathic FSGS (group III; n=66). Pretransplant clinical characteristics were analyzed to determine predictors of a recurrence after transplantation.ResultsFSGS only recurred in patients with idiopathic FSGS (group III; 42%). Patients with a recurrence had a significantly lower serum albumin, higher 24-hour proteinuria and higher estimated glomerular filtration rate at diagnosis. Serum albumin at diagnosis was the only independent predictor of a recurrence in patients with idiopathic FSGS. Patients with recurrent FSGS had more acute rejection episodes (54% vs. 27%, P =0.02) and lower five year graft survival compared to patients without a recurrence (50 vs. 82%, P <0.01).ConclusionsClinical criteria allow identification of patients at high risk of recurrent FSGS after renal transplantation. This information can be used in the counseling and management of patients with FSGS.

A Form of Apolipoprotein A-I Is Found Specifically in Relapses of Focal Segmental Glomerulosclerosis Following Transplantation

Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) following kidney transplantation occurs in a large percentage of patients. Accurate prediction of recurrence and elucidation of its pathogenesis are major therapeutic goals. To detect differential proteins related to FSGS recurrence, proteomic analysis was performed on plasma and urine samples from 35 transplanted idiopathic FSGS patients, divided into relapsing and nonrelapsing. Several proteins were detected increased in urine of relapsing FSGS patients, including a high molecular weight form of apolipoprotein A-I, named ApoA-Ib, found exclusively in relapsing patients. This finding was verified by Western blot individually in the 35 patients and validated in an independent group of 40 patients with relapsing or nonrelapsing FSGS, plus two additional groups: FSGS-unrelated patients showing different proteinuria levels (n = 30), and familial FSGS transplanted patients (n = 14). In the total of 119 patients studied, the ApoA-Ib form was detected in 13 of the 14 relapsing FSGS patients, and in one of the 61 nonrelapsing patients. Only one of the 30 patients with FSGS-unrelated proteinuria tested positive for ApoA-Ib, and was not detected in familial patients. Urinary ApoA-Ib is associated with relapses in idiopathic FSGS and warrants additional investigation to determine its usefulness as biomarker of relapse following transplantation.

Urinary IgG andα2-Macroglobulin Are Powerful Predictors of Outcome and Responsiveness to Steroids and Cyclophosphamide in Idiopathic Focal Segmental Glomerulosclerosis with Nephrotic Syndrome

Objective. To assess whether high-molecular-weight proteins excretion predicts outcome and therapy-responsiveness in patients with FSGS and nephrotic syndrome. Research Design and Methods. Thirty-eight patients measured at biopsy fractional excretion of IgG (FEIgG) and urinary α2-macroglobulin/creatinine ratio (α2m/C). Low and high risk groups were defined by cutoffs assessed by ROC analysis. In all patients first-line therapy was with steroids alone or in combination with cyclophosphamide. Results. α2m/C and FEIgG were correlated with segmental sclerosis (r = 0.546; r = 0.522). Twenty-three patients (61%) entered Remission and 9 (24%) progressed to ESRD. Comparing low and high risk groups, by univariate analysis remission was predicted by FEIgG (77% versus 25%, P = 0.016) and α2m/C (81% versus 17%, P = 0.007) and ESRD at best by FEIgG (0% versus 75%, P < 0.0001) and α2m/C (4% versus 67%, P < 0.0001). By multivariate analysis FEIgG was the only independent predictor of remission and α2m/C the most powerful predictor of ESRD. Low and high risk groups of FEIgG and α2m/C in combination had very high predictive value of sustained remission and ESRD in response to therapy. Conclusions. FEIgG and α2m/C are powerful predictors of outcome and responsiveness to steroids and cyclophosphamide; their predictive value, if validated in prospective studies, may be useful in clinical practice suggesting first-line alternative treatments in high risk patients.

Treatment of idiopathic focal segmental glomerulosclerosis: options in the event of resistance to corticosteroids and calcineurin inhibitors.

Half of patients with nephrotic syndrome caused by primary focal segmental glomerulosclerosis (FSGS) have resistance to treatment with steroids. In the case of corticosteroid resistance, &nbsp;the best evidence-based option has classically been treatment with calcineurin inhibitors, &nbsp;although recent studies indicate that mycophenolate may have similar efficacy. In patients with resistance to calcineurin inhibitors, &nbsp;there is no option that allows the clinical course of the disease to be modified, and this is supported by appropriately designed clinical trials, although observational studies have suggested the potential usefulness of mycophenolate, sirolimus, rituximab, apheresis or high galactose doses as treatment options. In FSGS of idiopathic origin, resistant to steroids and calcineurin inhibitors, before taking the decision whether or not to test other immunosuppressive drugs, it might be appropriate to conduct a systematic analysis that considers: 1) evaluating whether the dose and duration of treatment with steroids and calcineurin inhibitors were suitable, 2) analysing the level of P-glycoprotein expression in lymphocytes, 3) performing a new renal biopsy if there is no electron microscopic study available for the first, 4) in young patients, &nbsp;considering a genetic study to rule out the presence of the podocin variant pR229Q in combination with heterozygous mutations in NPHS2, &nbsp;and 5) evaluating the seriousness and difficulty of managing the nephrotic syndrome and the likelihood of progressive loss of renal function. Currently, there are multiple study avenues that attempt to identify the pathogenic mechanisms that cause podocyte injury and there are also several studies underway to analyse the efficacy of drugs such as adalimumab, fresolimumab, rosiglitazone, ACTH (corticotropin) or galactose at high doses, whose preliminary results have generated expectations that require confirmation in larger-scale clinical studies. &nbsp;In the future, it is possible that a better understanding of the pathogenic pathway or pathways that cause FSGS may allow differentiation between immunomodulable and non-immunomodulable forms, &nbsp;however, this continues to be a challenge currently.

Comments on renal abnormalities of sickle cell disease

Comments on renal abnormalities of sickle cell disease

Impact of the National Institutes of Health Focal Segmental Glomerulosclerosis (NIH FSGS) clinical trial on the treatment of steroid-resistant FSGS

Idiopathic focal segmental glomerulosclerosis (FSGS) is among the most common, morbid and treatment-resistant conditions faced by nephrologists. While glucocorticoids have traditionally been the mainstay of initial treatment, they induce remission in only a minority of patients. A variety of other immunosuppressants have been utilized against steroid-resistant FSGS, but few have been rigorously examined in well-controlled trials. Recently, the results were published from a National Institutes of Health (NIH)-sponsored multicenter randomized trial comparing cyclosporine (CSA) with a combination of mycophenolate mofetil (MMF) and pulse dexamethasone (DEX) for the treatment of steroid-resistant FSGS. No difference in treatment effectiveness was shown between the two groups, and adverse effects were comparable. This was the largest randomized trial ever undertaken in FSGS, but it was unfortunately underpowered to show clinically relevant differences in response rates. This shortcoming, along with particularities of the study population and outcome measures, makes it challenging to draw definitive conclusions from the trial results. Despite these limitations, the trial does provide valuable insights into treatment strategies for FSGS and offers important lessons for planning future research.

A Tale of Five Kidneys and One Heart Transplants

Background: Idiopathic focal segmental glomerulosclerosis (FSGS) recurrence occurs in 20-30% of first renal transplant recipients and >80% after a re-transplant after a previous recurrence. Relapse often means graft failure. Case report: A 40-yr-old white female with primary, idiopathic FSGS diagnosed at the age of five years underwent a paired living donor kidney transplantation (her husband having blood group incompatibility). She had already received 4 previous kidney transplants at the age of 9 (mother's kidney), 11, 18 and 32 (cadaver kidneys) years old, the last one simultaneously with a heart transplant. Nephrotic syndrome was immediately diagnosed after the first, third and fourth transplantation, with consequent graft failure secondary to FSGS recurrence (histologically documented) at 6 months, 10 years and 7 years, respectively. The second transplant was lost 24-hour after surgery due to unclear reasons. Considering her past medical history, and the presence of a donor-specific antibody (DSA) (anti-DQ7, MFI 10,500) against the swapped donor (positive B-cell flow cytometry crossmatch, negative CDC crossmatch), we implemented a desensitization/preventive protocol including: plasmapheresis at day -7, -5, -4, -3 and -1 before the transplant; rituximab (375 mg/m2) at days -3, +4, +17; IVIg 1 g/kg at day -1, +1, +2, +3, +4 and +16; and occlusion of native renal arteries. Basiliximab was used for induction, and maintenance immunosuppression consisted of cyclosporine (doses adjusted to maintain C2 levels between 700-800 ng/ml), mycophenolate mofetil (2 g/die) and prednisone (5 mg/day). Serum creatinine was 0.4 mg/dl on day +3. The hightest value of proteinuria was 1.283 g/24h on day 3; the next values reduced progressively and proteinuria was 0.224 g/24h at discharge. The patient was discharged on p.o.d. 18. After 7 months of follow-up, the patient has normal renal function (creatinine level of 0.7 mg/dl), no proteinuria, and a very low titer anti-DQ7 antibody (MFI 1,800). Conclusion: This case reflects the possibility to perform a succesful fifth renal transplant in a patient with FSGS and DSA with a new immunosuppressive and surgical approach.

Oral bisphosphonate use in the elderly is not associated with acute kidney injury

Intravenous bisphosphonates can cause acute kidney injury; however, this risk was not found with oral bisphosphonates in randomized clinical trials with restrictive eligibility criteria. In order to provide complementary safety data, we studied the risk of acute kidney injury in a population-based cohort of 122,727 patients aged 66 years and older discharged from hospital following a new fragility fracture and no history of bisphosphonate use in the prior year. Bisphosphonate treatment was identified within 120 days after discharge and event rates were measured from 90 days of therapy initiation. The primary outcome was hospitalization with acute kidney injury with secondary outcomes of new nephrology consultation and, in a subset of patients with laboratory values, acute kidney injury was defined as an increase in serum creatinine. We identified 18,286 bisphosphonate users and 104,441 non-users with a mean age of 81 years. Of 5772 patients with laboratory values, 40% had chronic kidney disease (eGFR <60 ml/min per 1.73 m(2)). Overall, there was no statistically significant difference in the risk of acute kidney injury among bisphosphonate users compared to non-users (adjusted odds ratio 1.03), and no significant differences in other outcomes or in subgroups of patients with baseline chronic kidney disease. Thus, in this older population-based cohort, oral bisphosphonate use was not associated with acute kidney injury.

Podocytes: A new player for glutamate signaling

In the renal glomerulus, podocytes envelop the external side of the capillary basement membrane with their intertwining ramifications, and ensure elimination of metabolic waste within the urine, while proteins and important blood components are retained into the circulation.To preserve the integrity of the glomerular filter, which is constantly exposed to a high variety of stimuli, podocytes need to communicate by rapid and precise signaling, likely similar to that used by neuronal cells.In the last years, we and others have shown that podocytes are indeed molecularly equipped for communicating in a synaptic-like way, where glutamate and its receptors seem to have a pivotal role, because altering glutamatergic communication leads to podocyte damage and increased filter permeability. Major components of glutamatergic signaling are organized at foot process junctions by adhesion molecules, chiefly by nephrin, and are connected to the actin cytoskeleton, that governs the health of podocytes.Further advances in understanding podocyte physiological behavior and signaling properties have the potential to improve the knowledge of podocyte diseases, first among them idiopathic focal segmental glomerulosclerosis that still needs more precise molecular-based diagnosis and targeted treatment.

Investigation of polyomaviruses replication in pediatric patients with nephropathy receiving rituximab

Rituximab is a chimeric monoclonal antibody reacting with the CD20 antigen on B cells. It has been proposed as treatment for the idiopathic nephrotic syndrome, recurrent idiopathic nephropathy, and focal segmental glomerulosclerosis refractory to steroids. Rituximab influences T-cell immunity and may predispose the patients to opportunistic infections, such as progressive multifocal leukoencephalopathy caused by the polyomavirus JC (JCV). The risk of latent viruses infections/reactivations in pediatric patients receiving monoclonal antibodies is not well known yet. In this longitudinal 6-month study, the effects of rituximab on JCV and BK virus (BKV) replication have been investigated. Blood, serum, and urine samples have been collected monthly from 11 pediatric patients (mean age: 11 years) with the idiopathic nephrotic syndrome and recurrent idiopathic nephropathy, under rituximab therapy. JCV and BKV real-time PCRs and sequencing of the viral protein 1 and the non-coding control region have been conducted. The same investigations have been undertaken on samples collected from eight pediatric patients (controls, mean age: 6 years), with idiopathic nephrotic syndrome or focal segmental glomerulosclerosis, treated with conventional chemotherapy. JCV was detected in the urine of one patient (9%), and one control (12.5%); BKV was found in the urine of 7/11 patients (63.6%) and 2/8 controls (25%) and in blood samples from four patients. No significant difference was found in the mean viral loads and in the viral molecular characterizations between the two groups. The polyomaviruses replication was not associated with rituximab therapy in children.

Krüppel-like Factor 15 (KLF15) Is a Key Regulator of Podocyte Differentiation

Podocyte injury resulting from a loss of differentiation is the hallmark of many glomerular diseases. We previously showed that retinoic acid (RA) induces podocyte differentiation via stimulation of the cAMP pathway. However, many podocyte maturity markers lack binding sites for RA-response element or cAMP-response element (CREB) in their promoter regions. We hypothesized that transcription factors induced by RA and downstream of CREB mediate podocyte differentiation. We performed microarray gene expression studies in human podocytes treated with and without RA to identify differentially regulated genes. In comparison with known CREB target genes, we identified Krüppel-like factor 15 (KLF15), a kidney-enriched nuclear transcription factor, that has been previously shown to mediate cell differentiation. We confirmed that RA increased KLF15 expression in both murine and human podocytes. Overexpression of KLF15 stimulated expression of differentiation markers in both wild-type and HIV-1-infected podocytes. Also, KLF15 binding to the promoter regions of nephrin and podocin was increased in RA-treated podocytes. Although KLF15(-/-) mice at base line had minimal phenotype, lipopolysaccharide- or adriamycin-treated KLF15(-/-) mice had a significant increase in proteinuria and podocyte foot process effacement with a reduction in the expression of podocyte differentiation markers as compared with the wild-type treated mice. Finally, KLF15 expression was reduced in glomeruli isolated from HIV transgenic mice as well as in kidney biopsies from patients with HIV-associated nephropathy and idiopathic focal segmental glomerulosclerosis. These results indicate a critical role of KLF15 in mediating podocyte differentiation and in protecting podocytes against injury.

Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure

Retinoic acid decreases proteinuria and glomerulosclerosis in several animal models of kidney disease by protecting podocytes from injury. Our recent in vitro studies suggest that all-trans retinoic acid induces podocyte differentiation by activating the retinoic acid receptor-α (RARα)/cAMP/PKA/CREB pathway. When used in combination with all-trans retinoic acid, an inhibitor of phosphodiesterase 4 further enhanced podocyte differentiation by increasing intracellular cAMP. Additionally, we found that Am580, a specific RARα agonist, has similar renal protective effects as all-trans retinoic acid in a rederived colony of HIV-1 transgenic mice with rapidly progressive renal failure (HIV-Tg) that mimics human HIV-associated nephropathy. Treatment with either the inhibitor of phoshodiesterase 4, roflumilast, or Am580 significantly reduced proteinuria, attenuated kidney injury, and improved podocyte differentiation in these HIV-Tg mice. Additional renal protective effects were found when roflumilast was combined with Am580. Consistent with the in vitro data, glomeruli from HIV-Tg mice treated with both Am580 and roflumilast had more active phosphorylated CREB than with either agent alone. Thus, phosphodiesterase 4 inhibitors could be used in combination with RARα agonists to provide additional renal protection.

Novel pharmacological TRPC inhibitors block hypoxia-induced vasoconstriction

The Ca2+-permeable, nonselective cation channel TRPC6 is gated via phospholipase C-activating receptors and has recently been implicated in hypoxia-induced pulmonary vasoconstriction (HPV), idiopathic pulmonary hypertension and focal segmental glomerulosclerosis (FSGS). Therefore, TRPC6 is a promising target for pharmacological interference. To identify and develop TRPC6-blocking compounds, we screened the Chembionet library, a collection of 16,671 chemically diverse drug-like compounds, for biological activity to prevent the 1-oleoyl-2-acetyl-sn-glycerol-triggered Ca2+ influx in a stably transfected HEKTRPC6-YFP cell line. Hits were validated and characterised by fluorometric and electrophysiological methods. Six compounds displayed inhibitory potency at low micromolar concentrations, lack of cytotoxicity and blocked the receptor-dependent mode of TRPC6 activation. The specificity was tested towards closely (TRPC3 and TRPC7) and more distantly related TRP channels. One of the compounds, 8009-5364, displayed a 2.5-fold TRPC6-selectivity compared to TRPC3, and almost no inhibition of TRPC7 or the other TRP channels tested. Block of native TRPC3/6-like responses was confirmed in dissociated pulmonary artery smooth muscle cells. Two non-polar blockers effectively suppressed the HPV responses in the perfused mouse lung model. We conclude that pharmacological targeting of TRPC6 is feasible and provide a promising concept to treat pulmonary diseases that are characterised by excessive hypoxic vasoconstriction.

Immunosuppressive treatment in primary focal segmental glomerulosclerosis

The therapeutic effects of immunosuppressive agents such as cyclosporin A, mycophenolate mofetil, rituximab and sirolimus on primary focal segmental glomerulosclerosis (FSGS) remain controversial. The present study was intended to review and analyze the treatment results of immunosuppressive agents for primary FSGS in child and adult patients. Complete remission rates and partial remission rates were extracted from published articles and analyzed using statistical tests. Cyclosporin A was effective in the treatment of child and adult patients with idiopathic FSGS. Rituximab therapy displayed a higher complete remission and partial remission rate in children than in adult FSGS patients. Multiple-center large-scale rigorous trials should be considered to evaluate the risk-benefit ratio of immunosuppressive treatment in patients with primary FSGS.

Focal Segmental Glomerulosclerosis and Parvovirus B19

Focal segmental glomerulosclerosis (FSGS) is a glomerular disease with a characteristic pathologic presentation that includes segmental scarring involving some but not all glomeruli. On immunofluorescence, deposits of immunoglobulin (Ig) M and C3 may be found in the areas of segmental scarring. Electron microscopy typically demonstrates diffuse epithelial cell foot process effacement and focal areas of retraction of glomerular basement membrane with collapse of the involved tuft (1). Due to the focal nature of the process, it is sometimes challenging to recognize this lesion in the biopsy specimen. Accordingly, special attention needs to be directed at the corticomedullary regions of the kidney where FSGS is more likely to be found. Otherwise, an errant diagnosis of minimal change disease could be made. Once underlying causes of this particular glomerular presentation are ruled out (such as obesity, sleep apnea, heroin abuse, reflux nephropathy, and HIV), one is left with a diagnosis of primary or idiopathic FSGS. It is important to identify patients who present with nephrotic-range proteinuria and have FSGS because early treatment of these patients may alter the course of the disease and prevent relentless progression to terminal renal failure (2). The collapsing form of FSGS, which occurs more commonly in African American patients than in Caucasians, carries a particularly poor prognosis with respect to renal survival (3). This variant is morphologically similar to the glomerular lesion often associated with HIV infection. However, the term idiopathic collapsing glomerulopathy is reserved for patients who are HIV negative. Collapsing glomerulopathy has been associated with non–HIV-related pathologies. These include associations with medications like pamidronate and interferon-alfa and with viral infections like parvovirus B19, cytomegalovirus, and hepatitis C (4, 5). Rarely, multiple myeloma has been associated with this lesion (6, 7). A case of collapsing FSGS in a patient with parvovirus B19 infection is presented with review of the known literature.

Histomorphological classification of focal segmental glomerulosclerosis: A critical evaluation of clinical, histologic and morphometric features

Primary focal segmental glomerulosclerosis (FSGS) has recently been divided into five subtypes by the Columbia classification. However, little is known about the incidence of these subtypes in the Indian population. In addition, there are very few studies evaluating the clinico-pathologic features with morphometric parameters in these subtypes. This study was aimed at evaluating the clinical, histopathological and morphometric parameters in various subtypes of FSGS at our referral center. Sixty-five (65) cases of idiopathic FSGS, diagnosed over two years (2006-2007), were included in the study. Detailed clinical and biochemical investigations were noted. Histological sections were reviewed and cases classified according to the Columbia classification and various glomerular and tubulo-interstitial features were noted. Glomerular morphometry on digitized images was performed using image analysis software. Renal biopsies with minimal change disease were used as controls for morphometric evaluation. In this study, FSGS not otherwise specified (NOS) was the most common subtype (44.6%), followed by perihilar FSGS (24.6%), collapsing (13.8%), tip (12.3%) and cellular FSGS (4.6%). Collapsing subtype showed significantly shorter duration of symptoms and higher degree of proteinuria, mean serum urea and creatinine compared with the other subtypes. On histologic analysis, features like glomerular hyalinosis, capsular adhesion, mesangial proliferation and visceral epithelial cell prominence (VEP) were frequently seen. The cases with VEP had a shorter duration of symptoms and a higher mean serum creatinine and 24-h urine protein excretion compared with those without VEP. The morphometric study revealed a significant higher mean glomerular area in the NOS, perihilar and collapsing variants as compared with the control biopsies. The present study highlights the differences in the prevalence in the FSGS subtypes in our population compared with the western data. Also, the significant differences in the clinical, biochemical and histological parameters reaffirm the utility of the Columbia classification of FSGS in routine reporting of renal biopsies. We found VEP (without causing collapse of the tuft) to be associated with higher serum creatinine at presentation. This feature needs to be evaluated in further studies for its potential significance.

Outcome of kidney allograft in patients with adulthood-onset focal segmental glomerulosclerosis: comparison with childhood-onset FSGS

Idiopathic focal segmental glomerulosclerosis (FSGS) occurring at young age is known to predispose to poor graft outcome, but the outcome of adulthood-onset FSGS (A-FSGS) has not been thoroughly investigated. Here, we compared the graft outcomes between kidney recipients with A-FSGS and childhood-onset FSGS (C-FSGS). We enrolled 47 A-FSGS recipients and 60 C-FSGS recipients with an onset age of ≤ 15, from four of the largest transplant centers in Korea. The baseline characteristics were similar between two groups. The 1- and 3-year cumulative recurrence rates were 20.0 and 22.1%, respectively. FSGS was recurrent in 19 C-FSGS patients [median duration, 2 months (interquartile range, IQR, 1-35)], and 11 patients had recurrent disease in A-FSGS [5 months (IQR, 3-37)]. The recurrence rate was similar between two groups (P = 0.126). The 5- and 10-year graft survival rates were 90.0 and 78.5%, respectively. The overall graft survival rates were not different between two groups. After adjusting baseline characteristics, the development of major outcomes was similar between two groups except acute rejection that was more frequent in A-FSGS. The age of disease onset did not affect recurrence in both groups. While grafts with recurrence had poorer graft survival in the A-FSGS group (P = 0.005), the recurrence was not associated with graft loss in the C-FSGS group (P = 0.558). The onset age did not affect the graft outcome in patients with FSGS, and the recurrence significantly affected graft survival in A-FSGS. Therefore, the main focus should aim for the management of recurrence.