Treatment Of Focal Segmental Glomerulosclerosis Research Articles

Population pharmacokinetic analysis of sparsentan in healthy volunteers and patients with focal segmental glomerulosclerosis.

Sparsentan is a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) currently under investigation as a treatment for focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). A population pharmacokinetic (PK) analysis was performed to characterize the PKs of sparsentan and to evaluate the impact of FSGS disease characteristics and co-medications as covariates on sparsentan PKs. Blood samples were collected from 236 healthy volunteers, 16 subjects with hepatic impairment, and 194 primary and genetic FSGS patients enrolled in nine studies ranging from phase I to phase III. Sparsentan plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry with a lower limit of quantitation of 2 ng/mL. Modeling was conducted with the first-order conditional estimation with η-ϵ interaction (FOCE-1) method in NONMEM. A total of 20 covariates were tested using a univariate forward addition and stepwise backward elimination analysis with significance level of p < 0.01 and p < 0.001, respectively. A two-compartment model with first-order absorption and an absorption lag time with proportional plus additive residual error (2 ng/mL) described sparsentan PKs. A 32% increase of clearance due to CYP3A auto-induction occurred at steady-state. Covariates retained in the final model included formulation, cytochrome P450 (CYP) 3A4 inhibitor co-administration, sex, race, creatinine clearance, and serum alkaline phosphatase. Moderate and strong CYP3A4 inhibitors comedications increased area under the concentration-time curve by 31.4% and 191.3%, respectively. This population PK model of sparsentan suggests that dose adjustments may be warranted for patients taking moderate and strong CYP3A4 inhibitors concomitantly, but other covariates analyzed may not require dose adjustments.

Effect of Multiple Doses of Sparsentan on the Single-Dose Pharmacokinetics of Dapagliflozin: An Open-Label Drug-Drug Interaction Study in Healthy Adults.

Sparsentan is a single-molecule dual antagonist of the endothelin type A receptor and angiotensin II type 1 receptor under investigation for the treatment of focal segmental glomerulosclerosis and immunoglobulin A nephropathy. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, has recently been indicated in chronic kidney disease. Sparsentan may be considered for concomitant use with dapagliflozin. The purpose of this open-label, 1-sequence crossover study was to determine whether drug-drug interactions between sparsentan and dapagliflozin affect dapagliflozin pharmacokinetics (PK). In addition, exposure to the inactive metabolite of dapagliflozin, dapagliflozin-3-O-glucuronide, was used to evaluate the effect of sparsentan on the primary metabolizing enzyme of dapagliflozin, uridine 5'-diphospho-glucuronosyltransferase 1A9. The study included 22 healthy adults treated with 10mg of dapagliflozin on day 1, and 800mg/day of sparsentan on days 5-14, with a 10-mg dose of dapagliflozin coadministered on day 11. PK samples were taken for dapagliflozin, dapagliflozin-3-O-glucuronide, and sparsentan before and after treatment throughout the study. Steady-state concentrations of sparsentan following daily dosing did not affect the PK of single-dose dapagliflozin in healthy adults. Dapagliflozin-3-O-glucuronide PK suggests a minimal effect of sparsentan on metabolism of dapagliflozin by uridine 5'-diphospho-glucuronosyltransferase 1A9. No deaths, serious adverse events, or unusual safety signals occurred. Results suggest dapagliflozin PK is not affected by sparsentan daily dosing.

Renal tubular gen e biomarkers identification based on immune infiltrates in focal segmental glomerulosclerosis

Objective The present study identified novel renal tubular biomarkers that may influence the diagnosis and treatment of focal segmental glomerulosclerosis (FSGS) based on immune infiltration. Methods Three FSGS microarray datasets, GSE108112, GSE133288 and GSE121211, were downloaded from the Gene Expression Omnibus (GEO) database. The R statistical software limma package and the combat function of the sva package were applied for preprocessing and to remove the batch effects. Differentially expressed genes (DEGs) between 120 FSGS and 15 control samples were identified with the limma package. Disease Ontology (DO) pathway enrichment analysis was conducted with statistical R software to search for related diseases. Gene set enrichment analysis (GSEA) was used to interpret the gene expression data and it revealed many common biological pathways. A protein-protein interaction (PPI) network was built using the Search Tool for the Retrieval of Interacting Genes (STRING) database, and hub genes were identified by the Cytoscape (version 3.7.2) plug-in CytoHubba. The plug-in Molecular Complex Detection (MCODE) was used to screen hub modules of the PPI network in Cytoscape, while functional analysis of the hub genes and hub nodes involved in the submodule was performed by ClusterProfiler. The least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination (SVM-RFE) analysis were used to screen characteristic genes and build a logistic regression model. Receiver operating characteristic (ROC) curve analyses were used to investigate the logistic regression model and it was then validated by an external dataset GSE125779, which contained 8 FSGS samples and 8 healthy subjects. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was used to calculate the immune infiltration of FSGS samples. Results We acquired 179 DEGs, 79 genes with downregulated expression (44.1%) and 100 genes with upregulated expression (55.9%), in the FSGS samples. The DEGs were significantly associated with arteriosclerosis, kidney disease and arteriosclerotic cardiovascular disease. GSEA revealed that these gene sets were significantly enriched in allograft rejection signaling pathways and activation of immune response in biological processes. Fifteen genes were demonstrated to be hub genes by PPI, and three submodules were screened by MCODE linked with FSGS. Analysis by machine learning methodologies identified nuclear receptor subfamily 4 group A member 1 (NR4A1) and dual specificity phosphatase 1 (DUSP1) as sensitive tubular renal biomarkers in the diagnosis of FSGS, and they were selected as hub genes, as well as hub nodes which were enriched in the MAPK signaling pathway. Immune cell infiltration analysis revealed that the genetic biomarkers were both correlated with activated mast cells, which may amplify FSGS biological processes. Conclusion DUSP1 and NR4A1 were identified as sensitive potential biomarkers in the diagnosis of FSGS. Activated mast cells have a decisive effect on the occurrence and development of FSGS through tubular lesions and tubulointerstitial inflammation, and they are expected to become therapeutic targets in FSGS.

MO254: Baseline Characteristics of Patients Enrolled in the Ongoing Phase 3 Randomized, Double-Blind, Active-Control Trial of Sparsentan for the Treatment of Focal Segmental Glomerulosclerosis (DUPLEX)

Abstract BACKGROUND AND AIMS Uncontrolled focal segmental glomerulosclerosis (FSGS) often follows a progressive course to end-stage kidney disease and has a profound negative impact on patient quality of life and long-term survival. Treatments that reduce proteinuria and risk of kidney disease progression are urgently needed. Sparsentan is a novel dual endothelin angiotensin receptor antagonist (DEARA) being investigated for FSGS. The Phase 3 DUPLEX study is examining the potential long-term antiproteinuric and nephroprotective potential and safety of sparsentan compared with an active control, angiotensin receptor blocker (ARB) irbesartan in adults and pediatric patients with FSGS. Here we report the baseline characteristics for all patients enrolled in the DUPLEX trial. METHOD DUPLEX is an ongoing, global, Phase 3, multicenter, randomized, double-blind, active-controlled study designed to evaluate the efficacy and safety of sparsentan versus irbesartan in adult and pediatric patients (≥8–75 years old) with FSGS. The study duration is 268 weeks: a 112-week double-blind period followed by an open-label extension period of up to 156 weeks. The primary efficacy endpoint is the slope of eGFR over approximately 2 years of randomized treatment. Key inclusion and exclusion criteria are shown in Table 1. Patients receiving renin–angiotensin–aldosterone system (RAAS) inhibitors underwent a 2-week washout prior to randomization. Patients were randomized 1:1 to sparsentan or irbesartan (target dose 800 and 300 mg/day, respectively), stratified by screening eGFR and urine protein/creatinine ratio (UP/C). The blinded and aggregated baseline characteristics of all patients enrolled in the DUPLEX trial are summarized descriptively. RESULTS The DUPLEX study is fully enrolled with 371 patients (336 adult and 35 pediatric) across 179 study sites in 22 countries. Selected demographic and clinical characteristics in the total population are reported in Table 2. CONCLUSION DUPLEX is the largest randomized controlled trial to date in FSGS. Patients with FSGS enrolled in the DUPLEX trial display demographic and clinical characteristics consistent with the profile previously reported in the broader population of patients globally with FSGS not in remission.

MO261: Sparsentan, The Dual Endothelin Angiotensin Receptor Antagonist (DEARA), Attenuates Albuminuria and Protects from the Development of Renal Injury to a Greater Extent Than Losartan in the GDDY Mouse Model of IGA Nephropathy: A 16-Week Study

Abstract BACKGROUND AND AIMS gddY mice are an IgA nephropathy (IgAN)-prone mouse model that develops albuminuria by 8 weeks (wks) of age with glomerular IgA, IgG and C3 deposits and progressive mesangioproliferative glomerulonephritis. We have previously shown that sparsentan (SP), a novel, highly selective, first-in-class, single-molecule dual endothelin angiotensin receptor antagonist (DEARA) being developed for the treatment of focal segmental glomerulosclerosis and IgAN, protected gddY mice from the development of albuminuria and glomerulosclerosis in an 8-week study. Here we compare the impact of SP and losartan (LS), an angiotensin II subtype 1 receptor antagonist (AT1R), on albuminuria, % of sclerotic glomeruli (GS), podocyte number, and glycocalyx damage in gddY mice treated for 16 weeks. METHOD gddY mice at 4 weeks of age were treated for 8 or 16 weeks either with chow as a control (C) (n = 10) or containing SP at 900 ppm (SP900) (n = 12) or with control chow and LS in drinking water to deliver 30 mg/kg of LS (LS30) (n = 12). Systolic blood pressure (BP) was measured by tail-cuff plethysmography at 8, 12 and 18 weeks of age. Albuminuria/creatinine ratio (ACR) was assessed every 2 weeks until 20 weeks of age. Kidney biopsies (n = 4–5 per group) were taken from a subset of mice sacrificed at age 12 weeks and at the end of the study at 20 weeks of age (5–7 per group) and processed for determination of GS, the number of podocytes assessed by immunohistochemistry using an anti-WT-1 antibody (30 glomeruli per animal), and measurement of the glycocalyx area using FITC-labeled lectin (10 glomeruli per animal). RESULTS gddY mice treated with SP900 or LS30 had an equivalent and significant (P &amp;lt; .01) reduction in BP compared with C mice at 12 and 18 weeks of age (18 weeks of age mean BP ± SD mmHg: C, 147 ± 28; SP900, 100 ± 6; LS30, 101 ± 8). Despite similar systemic hemodynamic effects, SP900 treatment resulted in a greater and more rapid reduction in ACR from baseline compared with either mice treated with C or LS30 during the first 4 weeks of treatment (Fig. 1). Development of GS was significantly attenuated in mice at 20 weeks of age treated with SP900 (P &amp;lt; .001) compared with C mice, but not in those treated with LS30 (mean sclerosis score ± SD: C, 28 ± 17; SP900, 3 ± 1; LS30, 19 ± 21). Compared with C mice at 20 weeks of age, SP900 (P &amp;lt; .0001) and LS30 (P &amp;lt; .05) significantly prevented the reduction in WT-1 immunoreactivity (WT-1 positive cells/glomerulus, mean ± SD: C, 7.3 ± 0.5; SP900, 10.0 ± 0.5; LS30 8.1 ± 0.8). Notably, SP900-treated mice had significantly greater WT-1 staining (P &amp;lt; .0001) and glycocalyx area (Fig. 2) than LS30 mice. CONCLUSION gddY mice treated from 4–20 weeks of age with sparsentan demonstrated a more rapid attenuation of ACR and greater protection from GS than mice treated with losartan. Sparsentan protected the glomeruli from loss of podocytes and glycocalyx to a greater extent than losartan despite equivalent lowering of BP. These results suggest that the ability of sparsentan to protect gddY mice from progression of IgAN nephropathy may go beyond effects mediated through reduction in blood pressure and antagonism of AT1R alone and may be attributed to its dual mechanism of action. If translated to the clinic, these data may support sparsentan as a new approach to the treatment of IgAN.

Outcomes of Different Immunosuppressive Regimen in Adult Biopsy Proven Idiopathic Focal Segmental Glomerulosclerosis: A Retrospective Analysis at a Single Center.

Treatment of focal segmental glomerulosclerosis (FSGS) is frustrating, especially for steroid-resistant FSGS. Different immunosuppressive agents have been used with inconsistent outcome. We analyzed the data in our FSGS patients who, in addition to steroid, were treated with cyclosporine (CYA), cyclophosphamide (CYP), and mycophenolate mofetil (MMF) along with the long-term follow-up. This is a retrospective analysis of 113 patients diagnosed to have FSGS with 11 years' follow-up carried out at The Kidney Center Post Graduate Training institute. Among 113 patients, 51.3% were male with a mean age of 34.4 ± 11.8 standard deviation. Patients who achieved complete remission with steroid alone and steroid with combination of CYA, CYP, and MMF were 38 (26%), 19 (16.8%), and six (5.3%), respectively, similarly those who got partial remission were three (3.6%), five (4.4%), three (2.6%), and eight (7.0%), respectively. The factors which affected the outcome were serum creatinine (SCr), tubulointerstitial fibrosis (TIF), and the treatment. In adjusted analysis, increase in 1 mg of SCr reduces the patient recovery by 56%, while the absence of TIF increases recovery by 80.75%. Taking steroid as reference category, steroid + CYA found 2.03 times more effective as compared with steroid alone. Seven patients developed end-stage renal disease (ESRD) and three died due to disease during the follow-up. CYA comes out as the most effective treatment for steroid-resistant FSGS followed by MMF and CYP. The long-term outcome of all modalities is the same in terms of mortality and developing ESRD. The degree of TIF and renal failure has strong influence on the course of the disease.

Expert consensus on diagnosis and treatment of focal segmental glomerulosclerosis in adults

Focal segmental glomerular sclerosis (FSGS) is a clinicopathological syndrome. The prognosis of FSGS patients is very heterogeneous, urging for personalized therapy to improve the long-term prognosis of patients. It provides FSGS clinical diagnosis and treatment workers with a masterable and practical treatment plan to help clinicians further improve their comprehensive diagnosis and treatment capabilities and levels. This collaborative group compiles the Chinese FSGS diagnosis and treatment expert consensus.

Efficacy of abatacept treatment for focal segmental glomerulosclerosis and minimal change disease: A systematic review of case reports, case series, and observational studies .

The efficacy of abatacept has been demonstrated mainly in case reports, case series, and observational studies with small sample size. With current evidence, it is premature to conclude that abatacept is an effective treatment for nephrotic syndrome. We searched MEDLINE, SCOPUS, and Cochrane Library until December 2019 for studies including patients with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) treated with abatacept. Proteinuria recovery and remission were outcomes of interest. Presence of urinary CD80 level of B7-1 staining on kidney biopsies was also reported. A total of 11 studies (n = 32) were included in the systematic review. 60% of patients were male. The median age was 27.5 years (range 5.2-72 years). Approximately 90.6% had FSGS, while 9.4% had MCD. With median follow-up of 12 months (IQR 6.38), only 15 patients (46.9%) showed response in proteinuria reduction, and 12 patients (43.8%) achieved remission with abatacept. Serious adverse events were reported in 12.5%. Additionally, we observed that patients with positive B7-1 staining on kidney biopsies had higher odds of achieving remission with abatacept (likelihood ratio 18.25; p<0.001). We found no significant correlation between elevated CD80 levels and remissions. The efficacy of abatacept therapy for FSGS or MCD was only 43.8%. Serious adverse effects are common. However, our study suggested that abatacept should be considered only in patients with positive B7-1 staining on kidney biopsy because these patients tend to respond to treatment.

Adrenocorticotropic Hormone in the Treatment of Focal Segmental Glomerulosclerosis Following Kidney Transplantation

This retrospective study examined the effect of adrenocorticotropic hormone therapy on remission of recurrent focal segmental glomerulosclerosis (FSGS) in patients with history of kidney transplant (KT) treated at 2 transplant centers. Patients with biopsy-confirmed FSGS following KT who received Acthar Gel (Mallinckrodt ARD, Bedminster, New Jersey, United States) treatment for ≥1 month were eligible. A total of 14 patients with idiopathic FSGS were included. Acthar Gel treatment resulted in complete remission of FSGS in 3 patients and partial remission in 2 patients for a total treatment response rate of 36% (5/14) of patients. Among patients showing complete or partial remission, Acthar Gel treatment duration ranged from 6 months to 2 years and 60% (3/5 patients) had serum creatinine ≤ 2 mg/dL at the start of Acthar Gel treatment. Patient outcomes suggest Acthar Gel may be an effective and tolerable treatment for recurrent FSGS in patients with history of KT. Early initiation of Acthar Gel treatment and therapy duration of at least 6 months may be needed for optimal response to Acthar Gel in patients with history of KT and recurrent FSGS.

SUN-037 NO IMPACT OF NEWLY INITIATED IMMUNOSUPPRESSIVE THERAPY OBSERVED ON LONG-TERM ANTIPROTEINURIC EFFECT OF SPARSENTAN IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS: INTERIM 84-WEEK ANALYSIS OF THE DUET TRIAL

Sparsentan, a first-in-class, orally active, dual-acting, selective antagonist of the angiotensin II type 1 receptor and the endothelin type A receptor, is in development for the treatment of focal segmental glomerulosclerosis (FSGS). In the ongoing DUET trial in patients with FSGS, sparsentan 200, 400, and 800 mg/d resulted in greater reduction in proteinuria versus irbesartan 300 mg/d over an 8-week double-blind period. Sparsentan continues to be evaluated in an open-label extension (OLE) of the DUET trial. Treatment with sparsentan alone in the OLE resulted in further decline in proteinuria over a total of 84 weeks. The current interim 84-week analysis examined whether newly initiated immunosuppressive therapy (IST) in some patients during the OLE contributed to the observed long-term benefits of sparsentan. DUET patients were aged 8-75 years in the US or 18-75 years in the EU and had biopsy-proven FSGS, baseline (BL) urinary protein-to-creatinine ratio (UP/C) ≥1 g/g, and estimated glomerular filtration rate (eGFR) >30 mL/min. In the OLE, patients randomized to double-blind treatment with sparsentan continued sparsentan (SPAR:SPAR) and those randomized to irbesartan were switched to sparsentan (IRB:SPAR). UP/C, FSGS partial remission endpoint (FPRE; UP/C ≤1.5 g/g and >40% UP/C decrease from BL), eGFR, and blood pressure (BP) were measured every 12 weeks to Week 84 and were compared with BL (Week 0 for SPAR:SPAR; Week 8 for IRB:SPAR). Treatment-emergent adverse events (TEAEs) were examined from first dose of sparsentan through Week 84. Data from all patients and from the remaining population after exclusion of data obtained from patients after initiation of new IST in the OLE were analyzed separately. At Week 84, a total of 22% (22/102) of patients in the OLE safety population had initiated a new IST, including cyclosporine, fluorouracil, prednisone, dexamethasone, hydrocortisone, methylprednisolone, mycophenolate mofetil, rituximab, tacrolimus, and triamcinolone. In the SPAR:SPAR group (n=67), sparsentan resulted in rapid, sustained reduction in UP/C from BL (Table). Sixteen (24%) SPAR:SPAR patients received newly initiated IST during the OLE, which had no effect on UP/C decline. In the IRB:SPAR group (n=35), switching to sparsentan resulted in significant reduction in UP/C (Week 16), which was sustained in the OLE, suggesting additional effect of sparsentan following irbesartan cessation (Table). Similar to the SPAR:SPAR group, the IRB:SPAR group showed no effect of newly initiated IST (n=6; 17%) on UP/C decline. The proportion of patients reaching FPRE was similar over the 84 weeks, regardless of use of newly initiated IST, in both the SPAR:SPAR and IRB:SPAR groups. Newly initiated IST had no effect on the course of eGFR or BP in the SPAR:SPAR or IRB:SPAR groups. Sparsentan was well tolerated through Week 84 with similar or slightly lower frequency of TEAEs in SPAR:SPAR and IRB:SPAR patients not initiating new IST versus total patients. Sparsentan in FSGS resulted in sustained and progressive antiproteinuric effects, early BP reduction, and stable eGFR over 84 weeks. Newly initiated IST had no meaningful impact on the effects of sparsentan over 84 weeks of sparsentan treatment in patients with FSGS.

Diagnosis and primary care management of focal segmental glomerulosclerosis in children.

Focal segmental glomerulosclerosis (FSGS) is a pattern of kidney damage that can occur in individuals at any age, including children. Pediatric patients with FSGS require medication monitoring, growth, and psychological health. This article discusses the NP's role in the clinical presentation, diagnostic workup, and treatment of FSGS in pediatric patients.

Moxibustion Alleviates Injury in a Rat Focal Segmental Glomerulosclerosis Model.

Objectives To evaluate the therapeutic effects of moxibustion at Shenshu (BL-23) and Geshu (BL-17) acupoints in a focal segmental glomerulosclerosis (FSGS) model in rats. Methods A FSGS rat model was established by single nephrectomy and repeated injection of doxorubicin. The FSGS rats were randomly divided into the model group, losartan (positive control) group, Shenshu moxibustion group, and Geshu moxibustion group. Molecular indicators of kidney function and renal pathological changes were monitored. Results Urinary protein, serum creatinine, urea nitrogen, and serum uric acid were significantly reduced after 12-week intervention with losartan, Shenshu, or Geshu moxibustion. Renal α-SMA, FN, and TGF-β were also decreased, while podocin and nephrin protein and mRNA were increased. The pathological damage in renal tissue was obviously alleviated by all three treatments, which suggests that moxibustion may have similar efficacy to losartan in the treatment of FSGS. Conclusion Moxibustion alleviates podocyte injury and inhibits renal interstitial fibrosis in the FSGS rat model, thereby minimizing the progression of glomerular sclerosis and improving renal function.

Successful Treatment of Focal Segmental Glomerulosclerosis after Kidney Transplantation with Plasma Exchange and Abatacept in a Patient with Juvenile Rheumatoid Arthritis.

Recurrent focal segmental glomerulosclerosis (FSGS) after renal transplantation is difficult to treat. Recently a series of four patients unresponsive to plasma exchange (PE) and rituximab, who were successfully treated with abatacept, has been reported. We present a 26-year-old Caucasian patient who suffered from juvenile rheumatoid arthritis and developed severe proteinuria eleven days after transplantation. An allograft biopsy was suggestive of recurrent focal segmental glomerulosclerosis. He did not respond to PE therapy. A first dose of abatacept produced partial remission. Four weeks later proteinuria again increased and a second biopsy showed progression of disease. After another ineffective course of PE he was given a second dose of abatacept, which was followed by rapid, complete, and sustained resolution of proteinuria. This treatment caused a significant increase in BK and JC viremia. Whether abatacept ameliorated proteinuria via an effect on podocytes or on the patient's primary disease remains speculative.

Oligomeganephronia in an Adult Presenting With Features of Chronic Kidney Disease

We report the case of a 29-year-old man with oligomeganephronia (OMN) who presented with symptoms of chronic kidney disease (CKD). Radiological and ultrasound images showed bilateral mildly small and uneven kidneys. Right renal biopsy was performed. Under light microscopy, the number of glomeruli in histological samples was decreased and the remaining glomeruli were markedly enlarged without mesangial proliferation. The obsolescent glomeruli had findings compatible with segmental sclerosis. Tubules were dilated and enlarged, and there was a presumptive primitive duct enclosed by a smooth muscle collar. Dysplastic changes in the biopsy specimen suggested that the cause of the patient’s small kidneys was a congenital anomaly rather than acquired kidney disease. OMN is one of the probable causes of CKD in adults. Angiotensin type II receptor blockers may be an effective treatment for focal segmental glomerulosclerosis due to OMN. J Med Cases. 2015;6(8):362-366 doi: https://doi.org/10.14740/jmc2212w

Focal segmental glomerulosclerosis: molecular genetics and targeted therapies.

Recent advances show that human focal segmental glomerulosclerosis (FSGS) is a primary podocytopathy caused by podocyte-specific gene mutations including NPHS1, NPHS2, WT-1, LAMB2, CD2AP, TRPC6, ACTN4 and INF2. This review focuses on genes discovered in the investigation of complex FSGS pathomechanisms that may have implications for the current FSGS classification scheme. It also recounts recent recommendations for clinical management of FSGS based on translational studies and clinical trials. The advent of next-generation sequencing promises to provide nephrologists with rapid and novel approaches for the diagnosis and treatment of FSGS. A stratified and targeted approach based on the underlying molecular defects is evolving.

Oligomeganephronia in an Adult Presenting With Features of Chronic Kidney Disease

We report the case of a 29-year-old man with oligomeganephronia (OMN) who presented with symptoms of chronic kidney disease (CKD). Radiological and ultrasound images showed bilateral mildly small and uneven kidneys. Right renal biopsy was performed. Under light microscopy, the number of glomeruli in histological samples was decreased and the remaining glomeruli were markedly enlarged without mesangial proliferation. The obsolescent glomeruli had findings compatible with segmental sclerosis. Tubules were dilated and enlarged, and there was a presumptive primitive duct enclosed by a smooth muscle collar. Dysplastic changes in the biopsy specimen suggested that the cause of the patient’s small kidneys was a congenital anomaly rather than acquired kidney disease. OMN is one of the probable causes of CKD in adults. Angiotensin type II receptor blockers may be an effective treatment for focal segmental glomerulosclerosis due to OMN. J Med Cases. 2015;6(8):362-366 doi: https://doi.org/10.14740/jmc2212w

Urokinase-type plasminogen activator receptor in IgA nephropathy

Urokinase-type plasminogen activator receptor in IgA nephropathy

Pathophysiology and treatment of focal segmental glomerulosclerosis: the role of animal models

Focal segmental glomerulosclerosis (FSGS) is a kidney disease with progressive glomerular scarring and a clinical presentation of nephrotic syndrome. FSGS is a common primary glomerular disorder that causes renal dysfunction which progresses slowly over time to end-stage renal disease. Most cases of FSGS are idiopathic Although kidney transplantation is a potentially curative treatment, 40% of patients have recurrence of FSGS after transplantation. In this review a brief summary of the pathogenesis causing FSGS in humans is given, and a variety of animal models used to study FSGS is discussed. These animal models include the reduction of renal mass by resecting 5/6 of the kidney, reduction of renal mass due to systemic diseases such as hypertension, hyperlipidemia or SLE, drug-induced FSGS using adriamycin, puromycin or streptozotocin, virus-induced FSGS, genetically-induced FSGS such as via Mpv-17 inactivation and α-actinin 4 and podocin knockouts, and a model for circulating permeability factors. In addition, an animal model that spontaneously develops FSGS is discussed. To date, there is no exact understanding of the pathogenesis of idiopathic FSGS, and there is no definite curative treatment. One requirement facilitating FSGS research is an animal model that resembles human FSGS. Most animal models induce secondary forms of FSGS in an acute manner. The ideal animal model for primary FSGS, however, should mimic the human primary form in that it develops spontaneously and has a slow chronic progression. Such models are currently not available. We conclude that there is a need for a better animal model to investigate the pathogenesis and potential treatment options of FSGS.

Immunosuppressive treatment of focal segmental glomerulosclerosis: lessons from a randomized controlled trial

Patients with steroid-resistant focal segmental glomerulosclerosis (FSGS) may benefit from treatment with calcineurin inhibitors. A National Institutes of Health-funded FSGS multicenter study has suggested that a combination of mycophenolate mofetil and oral dexamethasone pulses was equivalent to cyclosporine. However, since the study was underpowered, one cannot draw firm conclusions from this study. The FSGS trial underscores that FSGS is not one disease and that better predictors of outcome and response to therapy are needed.

Nephrotische Erkrankungen im Fokus - Minimal-Change-Glomerulopathie und fokal segmentale Glomerulosklerose

Als nephrotisches Syndrom bezeichnet man den Symptomkomplex aus erhöhtem Eiweiß im Urin (Proteinurie > 3,5 g/d), reduzierter Albuminkonzentration im Blut (Hypalbuminämie), erhöhten Blutfettwerten und peripheren Ödemen. Dabei zählen die Minimal-Change-Glomerulopathie und die fokal segmentale Glomerulosklerose, neben der membranösen Glomerulonephritis, zu den häufigsten primären glomerulären Ursachen des nephrotischen Syndroms. Während die Minimal-Change-Glomerulopathie meist gut auf eine Steroidtherapie anspricht und in der Regel benigne verläuft, ist die idiopathische fokal segmentale Glomerulosklerose eine therapeutische Herausforderung: Da Patienten mit dieser Erkrankung selten alleine auf Steroide ansprechen, ist sie häufig von einem Nierenfunktionsverlust begleitet und die Gabe zusätzlicher Immunsuppressiva oder alkylierender Agenzien in der Regel erforderlich. Bei beiden Erkrankungen liegt ein primärer Schaden von hoch spezialisierten Zellen des Nierenglomerulus, den Podozyten, vor. In dieser Übersicht erläutern wir kurz die pathophysiologischen Grundlagen der Podozytenschädigung und stellen einen Therapiealgorithmus vor.