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Focal segmental glomerulosclerosis (FSGS) is not a disease, rather a pattern of histological injury occurring from a variety of causes. The exact pathogenesis has yet to be fully elucidated but is likely varied based on the type of injury and the primary target of that injury. However, the approach to treatment is often based on the degree of podocyte foot process effacement and clinical presentation without sufficient attention paid to etiology. In this regard, there are many monogenic causes of FSGS with variable presentation from nephrotic syndrome with histological features of primary podocytopathy to more modest degrees of proteinuria with limited evidence of podocyte foot process injury. It is likely that genetic causes are largely underdiagnosed, as the role and the timing of genetic testing in FSGS is not established and genetic counseling, testing options, and interpretation of genotype in the context of phenotype may be outside the scope of practice for both nephrologists and geneticists. Yet most clinicians believe that a genetic diagnosis can lead to targeted therapy, limit the use of high-dose corticosteroids as a therapeutic trial, and allow the prediction of the natural history and risk for recurrence in the transplanted kidney. In this manuscript, we emphasize that genetic FSGS is not monolithic in its presentation, opine on the importance of genetic testing and provide an algorithmic approach to deployment of genetic testing in a timely fashion when faced with a patient with FSGS.

Background Focal segmental glomerulosclerosis (FSGS, OMIM®#603 965) is an overriding cause that leads to end-stage renal disease (ESRD). As a member of TRP superfamily, mutations of TRPC6 gene are closely linked to FSGS. By now, 20 missense mutations have been reported, among them, nine gain-of-function (GOF), and five loss-of-function (LOF) mutations have been recognized according to the effect on TRPC6 channel activity. Systematic investigations of functional mutations will provide valuable evidences for understanding the pathophysiology of TRPC6 involved in FSGS. The aim of this study is to investigate the pathogenicity of a novel TRPC6 mutation p.Q134P in FSGS. Methods High-throughput sequencing was performed to analyse 436 genes which are associated with hereditary kidney diseases in a Chinese pedigree. Then we constructed TRPC6 expression plasmids of wide type and variant. Immunofluorescence, cell-surface biotinylation assays and electrophysiology were used to analyse the localization, cell surface expression, and calcium transport activity of TRPC6. Results A novel variant c.401A>C (p.Q134P) in exon 2 of TRPC6 gene was found. There was no significant difference between the expression levels of p.Q134P mutant and WT TRPC6 protein in the whole cell lysate and cell-surface fraction. Q134P mutant-bearing TRPC6 elicited much higher Ca+ current amplitude than WT. Conclusion We identified a novel GOF mutation p.Q134P of TRPC6 which contributed to late-onset FSGS. Our study expands the mutational spectrum of TRPC6 associated with FSGS and furtherly supports the hypothesis of calcium dose-response dependency that a moderate increased calcium influx elicited a mild FSGS phenotype.

Animal pollinators directly affect plant gene flow by transferring pollen grains between individuals. Pollinators with restricted mobility are predicted to limit gene flow within and among populations, whereas pollinators that fly longer distances are likely to promote genetic cohesion. These predictions, however, remain poorly tested. We examined population genetic structure and fine-scale spatial genetic structure (FSGS) in six perennial understory angiosperms in Andean cloud forests of northwestern Ecuador. Species belong to three families (Gesneriaceae, Melastomataceae, and Rubiaceae), and within each family we paired one insect-pollinated with one hummingbird-pollinated species, predicting that insect-pollinated species have greater population differentiation (as quantified with the F

OBJECTIVE Late-onset neutropenia (LON) is an underrecognized complication of rituximab treatment. We undertook this study to describe its incidence, risk factors, clinical features, management, and recurrence. METHODS We conducted a single-center retrospective cohort study of 738 adult patients with autoimmune disease who were treated with rituximab to induce continuous B cell depletion. The primary outcome measure was LON, defined as an unexplained absolute neutrophil count of

FSGS is a common indication for kidney transplant with a high-risk of posttransplant recurrence.In this review, we summarize current knowledge about FSGS recurrence after kidney transplantation, including epidemiology, pretransplant planning, posttransplant management, and investigational treatments.FSGS recurs in 14%-60% of first transplants, likely associated with a circulating permeability factor. Pretransplant counseling regarding recurrence is critical, and patients with FSGS should undergo pretransplant genetic screening. Rapid progression to ESKD, initial steroid responsiveness, younger age at diagnosis, race/ethnicity, and mesangial hypercellularity or minimal change histology on native biopsy may be associated with recurrence. Living donation is not contraindicated but does not result in improved graft survival relative to deceased donation. Pretransplant nephrectomy may be performed for a variety of reasons, but does not decrease recurrence. Pretransplant therapy with rituximab and/or PE is understudied but not clearly effective at preventing recurrence. Patients with FSGS typically present early with rapid-onset severe proteinuria. Diagnosis can be confirmed by biopsy showing foot process effacement; typical FSGS lesions are not seen on light microscopy in the early stages. There is no established effective treatment for recurrent FSGS, but renin-angiotensin-aldosterone system inhibition and extracorporeal therapies, including PE and IA, are most commonly used. Adjunct or alternative therapies may include rituximab, lipopheresis, and cyclosporine.

Kidney transplantation in small children is technically challenging. Consideration of whether to use intraperitoneal versus extraperitoneal placement of the graft depends on patient size, clinical history, anatomy, and surgical preference. We report a large single-center experience of intraperitoneal kidney transplantation and their outcomes.We conducted a retrospective review of pediatric patients who underwent kidney transplantation from April 2011 to March 2018 at a single large volume center. We identified those with intraperitoneal placement and assessed their outcomes, including graft and patient survival, rejection episodes, and surgical or non-surgical complications.Forty-six of 168 pediatric kidney transplants (27%) were placed intraperitoneally in children mean age 5.5 ± 2.3 years (range 1.6-10 years) with median body weight 18.2 ± 5 kg (range 11.4-28.6 kg) during the study period. Two patients (4%) had vascular complications; 10 (22%) had urologic complications requiring intervention; all retained graft function. Thirteen patients (28%) had prolonged post-operative ileus. Eight (17%) patients had rejection episodes ≤6 months post-transplant. Only one case resulted in graft loss and was associated with recurrent focal segmental glomerular sclerosis (FSGS). Two patients (4%) had chronic rejection and subsequent graft loss by 5-year follow-up. At 7-year follow-up, graft survival was 93% and patient survival was 98%.The intraperitoneal approach offers access to the great vessels, which allows greater inflow and outflow and more abdominal capacity for an adult donor kidney, which is beneficial in very small patients. Risk of graft failure and surgical complications were not increased when compared to other published data on pediatric kidney transplants.

Background and objectives Glomerulopathies affect kidney glomeruli and can lead to end-stage renal disease if untreated. Clinical and experimental evidence have identified numerous (>20) genetic mutations in the mitochondrial coenzyme Q8B protein (COQ8B) primarily associated with nephrotic syndrome. Yet, little else is understood about COQ8B activity in renal pathogenesis and its role in mitochondrial dysfunction. We identified additional novel COQ8B mutations in a glomerulopathy patient and aimed to define the potential structural and functional defects of COQ8B mutations. Design, setting, participants, and measurements Whole exome sequencing was performed on a Hispanic female presenting with proteinuria. Novel mutations in the COQ8B gene were identified. The effects of mutation on protein function, mitochondrial morphology, and disease progression were investigated by histopathology, transmission electron microscopy, homology modeling, and in silico structural analysis. Results We have characterized the pathophysiology of novel COQ8B mutations, compound heterozygous for two alterations c.1037T>G (p.I346S), and c.1560G>A (p.W520X), in the progression of proteinuria in a Hispanic female. Histopathology revealed defects in podocyte structure and mitochondrial morphology. In silico and computation analyses highlight possible structural origins of COQ8B dysfunction in the presence of mutations. Conclusions Novel mutations in COQ8B present promising biomarkers for the early detection and therapeutic targeting of mitochondrial glomerulopathy. Insights from structural modeling suggest roles of mutation-dependent alterations in COQ8B allosteric regulation, protein folding, or stability in renal pathogenesis.

AIMS An important role of native kidney biopsy evaluation is to predict renal prognosis. We aimed to develop a simplified chronicity score based solely on pathological features that are easily recognisable and can be found in all glomerular nephropathies (GN). In this retrospective study, observational cohort study we included 625 patients with GN diagnosis after native kidney biopsy in a tertiary unit between 1 January 2010 and 31 December 2015. METHODS AND RESULTS Presence of global glomerulosclerosis (GG), tubular atrophy (TA), interstitial fibrosis (IF) and fibrocellular/fibrous crescents (FC) in any grade was scored with one point; a final score was between 0 and 4 (i.e. 'absent' 0 score, 'moderate' 1-2 score, 'severe' 3-4 score). The primary endpoint was renal replacement therapy (RRT) initiation. Mean baseline estimated glomerular filtration rate (eGFR) was 55.9 ± 29.6 ml/min; during the follow-up (median = 27 months), 78 patients started RRT. The total mean renal survival time was 60.1 (58.0-62.1) months. GG (41%) was the most frequent lesion, followed by IF (25%), TA (18%) and FC (17%). Patients with absent (65.7; 63.6-67.8 months) chronicity had better renal survival than those with moderate (59.1; 56.1-62.2 months) or severe (42.7; 35.6-49.7 months) chronicity. The score was associated with renal survival [hazard ratio (HR) = 1.33; 1.08-1.64)] independently of the classical prognostic factors. Patients with moderate and severe chronicity had a two- and threefold increase in risk of RRT initiation. CONCLUSION Our score was correlated with renal survival independently of the traditional risk factors, and could improve outcome prediction in patients with GN by reducing the interobserver variability.

Rituximab is currently used after the conventional agents have failed in the management of steroid-dependent (SD)/ steroid-resistant (SR) podocytopathies and have a safer toxicity profile. We report 53 adults with podocytopathies who were managed effectively with CD19-targeted rituximab therapy. METHODS This was a prospective study carried out at a tertiary care centre in India between January 2014 and June 2019. Adults between 16 and 60 years with SD, frequently relapsing (FR), and SR nephrotic syndrome (NS) due to podocytopathy received rituximab in a CD19-targeted approach. PRIMARY OUTCOME Percentage of patients who were in remission at 6 and 12 months. Secondary outcome: Percentage of patients in remission at the last follow-up, rituximab dose and adverse events of rituximab therapy. RESULTS Fifty-three adults with SD/FR/SR NS received CD19-targeted rituximab. The median age at the time of first rituximab injection was 30.09 ± 13.21 (16.53) years. At the time of first rituximab infusion, all patients were in remission with steroids and/or calcineurin inhibitors (CNIs). Fifty (94.33%) patients were in remission at the end of 6 and 12 months and the last follow-up (median: 36 months). The mean total dose of rituximab at 1 year was 788.7 ± 128.1 (6 001 100) mg. At last follow-up (median 36 months), 42 (79%) patients did not require any additional CNI or steroids therapy. No serious adverse events to rituximab were noted. CONCLUSION CD19-targeted rituximab therapy is safe and efficacious in the management of SD/SR adult podocytopathy. Also, rituximab is effective in maintaining remission in treatment naive adult SD or FR podocytopathy.

Focal segmental glomerulosclerosis (FSGS) can be separated into primary, genetic or secondary causes. Primary disease results in nephrotic syndrome while genetic and secondary forms may be associated with asymptomatic proteinuria or with nephrotic syndrome. Overall only about 20% of patients with FSGS experience a partial or complete remission of nephrotic syndrome with treatment. FSGS progresses to kidney failure in about half of the cases. This is an update of a review first published in 2008.To assess the benefits and harms of immunosuppressive and non-immunosuppressive treatment regimens in adults with FSGS.We searched the Cochrane Kidney and Transplant Register of Studies to 21 June 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.Randomised controlled trials (RCTs) and quasi-RCTs of any intervention for FSGS in adults were included. Studies comparing different types, routes, frequencies, and duration of immunosuppressive agents and non-immunosuppressive agents were assessed.At least two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random-effects model and results were expressed as a risk ratio (RR) for dichotomous outcomes, or mean difference (MD) for continuous data with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.Fifteen studies (560 participants) were included. No studies specifically evaluating corticosteroids compared with placebo or supportive therapy were identified. Studies evaluated participants with steroid-resistant FSGS. Five studies (240 participants) compared cyclosporin with or without prednisone with different comparators (no specific treatment, prednisone, methylprednisolone, mycophenolate mofetil (MMF), dexamethasone). Three small studies compared monoclonal antibodies (adalimumab, fresolimumab) with other agents or placebo. Six single small studies compared rituximab with tacrolimus, cyclosporin plus valsartan with cyclosporin alone, MMF with prednisone, chlorambucil plus methylprednisolone and prednisone with no specific treatment, different regimens of dexamethasone and CCX140-B (an antagonist of the chemokine receptor CCR2) with placebo. The final study (109 participants) compared sparsentan, a dual inhibitor of endothelin Type A receptor and of the angiotensin II Type 1 receptor, with irbesartan. In the risk of bias assessment, seven and five studies were at low risk of bias for sequence generation and allocation concealment, respectively. Four studies were at low risk of performance bias and 14 studies were at low risk of detection bias. Thirteen, six and five studies were at low risk of attrition bias, reporting bias and other bias, respectively. Of five studies evaluating cyclosporin, four could be included in our meta-analyses (231 participants). Cyclosporin with or without prednisone compared with different comparators may increase the likelihood of complete remission (RR 2.31, 95% CI 1.13 to 4.73; I² = 1%; low certainty evidence) and of complete or partial remission (RR 1.64, 95% CI 1.10 to 2.44; I² = 19%) but not of partial remission (RR 1.36, 95% CI 0.78 to 2.39, I² = 22%). In Individual studies, cyclosporin with prednisone versus prednisone may increase the likelihood of partial (49 participants: RR 7.96, 95% CI 1.09 to 58.15) or complete or partial remission (49 participants: RR 8.85, 95% CI 1.22 to 63.92) but not of complete remission. The remaining individual comparisons may make little or no difference to the likelihood of complete remission, partial remission or complete or partial remission compared with no treatment, methylprednisolone, MMF, or dexamethasone. Individual study data and combined data showed that cyclosporin may make little or no difference to the outcomes of chronic kidney disease or kidney failure. It is uncertain whether cyclosporin compared with these comparators in individual or combined analyses makes any difference to the outcomes of hypertension or infection. MMF compared with prednisone may make little or no difference to the likelihood of complete remission (33 participants: RR 1.05, 95% CI 0.58 to 1.88; low certainty evidence), partial remission, complete or partial remission, glomerular filtration rate, or infection. It is uncertain whether other interventions make any difference to outcomes as the certainty of the evidence is very low. It is uncertain whether sparsentan reduces proteinuria to a greater extent than irbesartan.No RCTs, which evaluated corticosteroids, were identified although the KDIGO guidelines recommend corticosteroids as the first treatment for adults with FSGS. The studies identified included participants with steroid-resistant FSGS. Treatment with cyclosporin for at least six months was more likely to achieve complete remission of proteinuria compared with other treatments but there was considerable imprecision due to few studies and small participant numbers. In future studies of existing or new interventions, the investigators must clearly define the populations included in the study to provide appropriate recommendations for patients with primary, genetic or secondary FSGS.

Background: Prevalence and characteristics of non-diabetic renal diseases (NDRD) in patients with type 2 diabetes mellitus is different between populations, and seems to be largely dependent on biopsy policies. Aim: To investigate clinical clues for NDRD in patients with type 2 diabetes mellitus and to analyse renal prognosis of patients based on pathological diagnosis. Methods: We retrospectively searched medical records of 115 patients with type 2 diabetes who underwent a renal biopsy between 2004 and 2018. Patients were divided into three groups as diabetic nephropathy (DN), NDRD + DN or NDRD based on histopathological examination. Results: Thirty-six (31.3%) patients had DN, 33 (28.7%) had DN + NDRD and 46 (40%) had NDRD. The absence of diabetic retinopathy, recent onset of diabetes, abnormal disease chronology, and blood haemoglobin was associated with the presence of NDRD in univariate analysis. Abnormal disease chronology which was defined as the presence of acute proteinuria and/or acute kidney injury that are unexpected to be related to evolution of diabetic nepropathy (odds ratio 4.65, 95% confidence interval 1.44-15.00; P = 0.010) and absence of diabetic retinopathy (odds ratio 3.44, 95% confidence interval 1.32-8.98; P = 0.012) were independently associated with the presence of NDRD in multivariate analysis. Focal segmental glomerulosclerosis was the most frequent type of NDRD. Diseases that affect tubulointerstitial area were more prevalent in the DN + NDRD group compared to the NDRD group (P = 0.001). Renal survival, which was defined as evolution to end-stage renal disease, was 59.5 +/- 14.4 months, 93.7 +/- 11.7 months and 87.2 +/- 2.6 months for DN, DN + NDRD and NDRD groups, respectively (P = 0.005). Conclusions: Renal biopsy is essential in certain clinical conditions as diagnosis of NDRD is vital for favourable renal survival. DN may facilitate superimposed tubular injury in the presence of toxic insults.

Glomerular podocytes play a key role in proteinuric diseases. Accumulating evidence suggests that cGMP signaling has podocyte protective effects. The major source of cGMP generation in podocytes is natriuretic peptides. The natriuretic peptide clearance receptor (NPRC) binds and degrades natriuretic peptides. As a result, NPRC inhibits natriuretic peptide‐induced cGMP generation. To enhance cGMP generation in podocytes, we blocked natriuretic peptide clearance using the specific NPRC ligand ANP(4‐23). We then studied the effects of NPRC blockade in both cultured podocytes and in a mouse transgenic (TG) model of focal segmental glomerulosclerosis (FSGS) created in our laboratory. In this model, a single dose of the podocyte toxin puromycin aminonucleoside (PAN) causes robust albuminuria in TG mice, but only mild disease in non‐TG animals. We found that natriuretic peptides protected cultured podocytes from PAN‐induced apoptosis, and that ANP(4‐23) enhanced natriuretic peptide‐induced cGMP generation in vivo. PAN‐induced heavy proteinuria in vehicle‐treated TG mice, and this increase in albuminuria was reduced by treatment with ANP(4‐23). Treatment with ANP(4‐23) also reduced the number of mice with glomerular injury and enhanced urinary cGMP excretion, but these differences were not statistically significant. Systolic BP was similar in vehicle and ANP(4‐23)‐treated mice. These data suggest that: 1. Pharmacologic blockade of NPRC may be useful for treating glomerular diseases such as FSGS, and 2. Treatment outcomes might be improved by optimizing NPRC blockade to inhibit natriuretic peptide clearance more effectively., The effects of blocking natriuretic peptide clearance from the circulation was examined in a mouse model of focal segmental glomerulosclerosis (FSGS). We found that blockade of the natriuretic clearance receptor protected glomerular podocytes from apoptosis and inhibited albuminuria in FSGS.

BACKGROUND The recurrence rate of focal segmental glomerulosclerosis (FSGS) post-renal transplantation is as high as 30%-50%. However, the pathogenesis is unclear. At present, there is no unified standard for the treatment of recurrent FSGS post-transplantation. Its treatment is full of risks and challenges. METHODS We report a child with recurrent FSGS with massive proteinuria 6~9 g/m2 /day and resistance to plasma exchange (PE) and rituximab (RTX). On the basis of receiving anti-rejection therapy of prednisone, tacrolimus, and mycophenolate mofetil (MMF), we treated the child with adrenocorticotropic hormone (ACTH), and reviewed the literature on the application of ACTH in the recurrence of FSGS post-transplantation. RESULTS After 1 year of treatment with ACTH, the patient's urinary protein decreased and fluctuated between 0.6 and 1.1 g/m2 /day. The albumin (ALB) and cholesterol (CHOL) returned to the normal range. The patient achieved complete remission after 19 months of ACTH treatment and maintained until now. There was no obvious adverse reaction. Literature review showed that up to February 2021, a total of 8 studies showed the use of ACTH in kidney transplant patients, and all the patients in the study achieved remission. CONCLUSIONS ACTH is a potential option for treating recurrent FSGS post-transplantation with fewer side effects and relatively safe for patients. However, further evaluation is needed to better adapt to different populations.

Clinical studies have shown that hyperglycemia can induce early-stage diabetic nephropathy (DN). Furthermore, oxidative stress, tubular epithelial-mesenchymal transition and extracellular matrix accumulation promote the progression of DN to chronic kidney disease and tubulointerstitial fibrosis. It is necessary to initiate treatment at the early stages of DN or even during the early stages of diabetes. In this work, rats with streptozotocin (STZ)-induced diabetes mellitus (DM) presented early DN symptoms within 45 days, and collagen accumulation in the glomerulus of the rats was primarily mediated through the RhoA/ROCK pathway instead of the TGF-β signaling pathway. Resveratrol (15 mg/kg/day) and ramipril (10 mg/kg/day) co-treatment of STZ-induced DN rats showed that glomerulosclerosis in early-stage DN was reversible (P < .05 compared with that in STZ-induced DM rats). The results of this study support early intervention in diabetes or DN as a more efficient therapeutic strategy.

Aim: A significant proportion of patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are either steroid dependent (SD) or resistant (SR), requiring long-term calcineurin inhibitors (CNIs) use. Rituximab has more favourable safety profile. The present study was undertaken to evaluate the efficacy and safety of rituximab in CNI dependent patients.Methods: This was a prospective observational study conducted from July 2014 to February 2018. SD-NS or SR-NS (biopsy proven MCD/FSGS), who were CNI dependent were enrolled. Mean age at enrolment was 22.77±7.45 years. All patients received rituximab at a dose of 375 mg/m2 at entry in the study. CD-19 levels were monitored monthly and patients having CD-19 levels >5/μL and/or >1% received additional low-dose (100 mg) of rituximab.Results: A total of 24 patients were followed up for 12 months. At the end of 6 and 12 months, 87.5 and 79.16% of the patients achieved remission, respectively. Eight (33.33%) patients developed relapse. The mean dose of rituximab in the first year was 791 mg. The average cost of rituximab in the first year was 487.17$. Rituximab was well- tolerated, with mild infusion reactions, respiratory tract infection and oral candidiasis in 5 (20.83%), 5 (20.83%) and 1 (4.17%) patient, respectively.Conclusions: CD-19 targeted rituximab is a safe and cost-effective agent in remission maintenance in adults with CNI dependent. Over three-fourths of the patients with CNI dependent podocytopathy maintain clinical remission with CD-19 targeted rituximab therapy

To investigate the utility of a sensitive platform using electrochemiluminescence (ECL) for the identification of low-abundance urinary protein biomarkers in lupus nephritis (LN).Forty-eight urine samples were obtained from subjects in 2 independent cohorts, each consisting of 3 groups (matched for age, sex, and race) of 8 patients with active LN (renal Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]0), 8 patients with inactive SLE (renal SLEDAI 0), and 8 healthy controls. Samples were tested using a preexisting 40-plex ECL panel. A custom 5-plex ECL panel was then developed for further validation studies and used to test 140 urine samples (from 44 patients with active LN, 41 patients with inactive SLE, 28 healthy controls, and 27 patients with other kidney diseases).Levels of 17 urinary proteins were elevated (P0.05 by 2-tailed Mann-Whitney U test) in samples from patients with active LN compared to samples from patients with inactive SLE and healthy controls in cohort 1, while 9 were similarly elevated in cohort 2. Of these, interleukin-7 (IL-7), IL-12p40, IL-15, interferon-γ-inducible protein 10 (IP-10), and thymus and activation-regulated chemokine (TARC) were chosen for further validation. These 5 proteins were undetectable by enzyme-linked immunosorbent assay (ELISA). Hence, a custom 5-plex ECL panel was developed and used to validate the results from the initial 40-plex screening panel. Urinary IL-7, IL-12p40, IL-15, IP-10, and TARC levels were again significantly elevated in patients with active LN compared to those with inactive SLE and healthy controls, and correlated well with the renal SLEDAI and physician's global assessment of disease activity (R0.67, P0.05). All 5 urinary proteins were more frequently elevated in LN compared to controls with other chronic kidney diseases, although overall group differences attained significance only for urinary IL-7 and IL-15.Urinary levels of IL-7, IL-12p40, IL-15, IP-10, and TARC are potentially useful diagnostic tools in LN. The use of ECL assays may allow detection of urinary biomarkers that are below ELISA detection limits.

Focal segmental glomerulosclerosis (FSGS) is a scarring process associated with chronic low‐grade inflammation ascribed to toll‐like receptor (TLR) activation and monocyte migration. We developed synthetic, small‐molecule lecinoxoids, VB‐201 and VB‐703, that differentially inhibit TLR‐2‐ and TLR‐4‐mediated activation and monocyte migration. The efficacy of anti‐inflammatory lecinoxoid treatment on FSGS development was explored using a 5/6 nephrectomy rat model. Five‐sixths of nephrectomized rats were treated with lecinoxoids VB‐201, VB‐703 or PBS, for 7 weeks. Upon sacrifice, albumin/creatinine ratio, glomerulosclerosis, fibrosis‐related gene expression and the number of glomerular and interstitial monocyte were evaluated. Treatment of nephrectomized rats with lecinoxoids ameliorated glomerulosclerosis. The percentage of damaged glomeruli, glomerular sclerosis and glomeruli fibrotic score was significantly reduced following VB‐201 and VB‐703 treatment. VB‐703 attenuated the expression of fibrosis hallmark genes collagen, fibronectin (FN) and transforming growth factor β (TGF‐β) in kidneys and improved albumin/creatinine ratio with higher efficacy than did VB‐201, but only VB‐201 significantly reduced the number of glomerular and interstitial monocytes. These results indicate that treatment with TLR‐2, and more prominently, TLR‐4 antagonizing lecinoxioids, is sufficient to significantly inhibit FSGS. Moreover, inhibiting monocyte migration can also contribute to treatment of FSGS. Our data demonstrate that targeting TLR‐2‐TLR‐4 and/or monocyte migration directly affects the priming phase of fibrosis and may consequently perturb disease parthogenesis.

Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder caused by a partial deletion of chromosome 4 (4p16.3p16.2). We describe a case of a male 9 years old children with WHS proteinuria and hypertension. Laboratory data showed creatinine 1.05 mg/dl, GFR 65.9 ml/min/1.73 m2 , cholesterol 280 mg/dl, triglyceride 125 mg/dl with electrolytes in the normal range. Urine collection showed protein 2.72 g/L with a urine protein/creatinine ratio (UP /UCr ratio) of 4.2 and diuresis of 1,100 ml. Renal ultrasound showed reduced kidney dimensions with diffusely hyperechogenic cortex and poorly visualized pyramids. Renal biopsy showed oligonephronia with focal segmental glomerulosclerosis associated with initial tubulointerstitial sclerotic atrophy. The child began therapy with Angiotensin-converting enzyme inhibitors (ACE-inhibitors) to reduce proteinuria and progression of chronic kidney disease. In the literature the anomalies of number of glomeruli oligonephronia and oligomeganephronia (OMN) are described in two forms, one without any associated anomalies, sporadic, and solitary and the other with one or more anomalies. Our review of the literature shows that the pathogenesis of this anomaly is unknown but the role of chromosome 4 is very relevant. Many cases of OMN are associated with anomalies on this chromosome, in the literature cases series we observed this association in 14/48 cases (29.2%) and in 7 of these 14 cases with WHS. Our case and the review of literature demonstrate how periodic urinalysis and renal ultrasound monitoring is recommended in patients affected by WHS and the renal biopsy must be performed when there is the onset of proteinuria.

Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies.

Primary focal and segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome. The pathogenic steps leading to primary FSGS are still obscure, although evidence suggests that circulatory factor(s) are involved in onset of disease. Recent technical advances allow the analysis of miRNA expression in tissues and body fluids, leading to reports of miRNAs involved in the molecular mechanisms of FSGS-aetiopathogenesis. Moreover, investigations have also highlighted miRNAs that might serve as biomarkers for primary FSGS. The aim of this review was to summarise reports showing a direct relation between miRNAs and primary FSGS. In addition, the impact of identified miRNAs on treatment response, prediction of disease onset as well as regulation in different disease activities is summarised.. This article is protected by copyright. All rights reserved.

From 1982 to 2011, 53 kidney transplantations (KT) for pediatric focal segmental glomerulosclerosis (FSGS) were recorded in the National Israeli Kidney Transplant Registry (NIKTR): 22—primary (1◦) FSGS, 25—proved/suspected genetic-secondary (2◦) FSGS, six lost/incomplete files/other. Half (56%) of 23 patients with 2◦ FSGS were Israeli-Arabs vs 29% of 1◦ FSGS KT recipients. 1◦ FSGS recurrence occurred in 64% (14/22) of 22 KT in 17 patients aged (median) 14 years vs 1/25 of 2◦ FSGS (P

It is well established that racial differences exist in kidney transplant outcomes; however, there are no studies which focus on the role of race in transplant outcomes specifically in children diagnosed with FSGS. Associations between race and transplant outcomes in FSGS children were evaluated using the Organ Procurement and Transplantation Network database from 2000 to 2012. Recipients aged 2-21 years who received a kidney-only transplant were included. Multivariate regression models were used to evaluate transplant outcomes by race. Five hundred and thirty-six recipients (59.7% male, 15.6±3.9 years) were black and 1134 (55.7% male, 14.3±5.0 years) were non-black. Graft survival was significantly shorter in the black group (4.2±3.1 vs 4.6±3.3 years, P=.005). Black race was associated with significantly higher risk of graft failure (HR 1.34, 95% CI=1.21-1.49, P

Outcome of patients with transplant glomerulopathy (TG) is poor. Using B-cell targeting molecules represent a rational strategy to treat TG during chronic antibody-mediated rejection. In this pilot study, 21 patients with this diagnosis received four doses of intravenous immunoglobulins and two doses of rituximab (IVIG/RTX group). They were retrospectively compared with a untreated control group of 10 patients. At 24 months post-biopsy, graft survival was similar and poor between the treated and the untreated group, 47% vs. 40%, respectively, p = 0.69. This absence of response of IVIG/RTX treatment was observed, regardless the phenotype of TG. Baseline estimated glomerular filtration rate (eGFR) and decline in eGFR during the first six months after the treatment were risk factors associated with 24-month graft survival. The IVIG/RTX therapy had a modest effect on the kinetics of donor-specific alloantibodies at M24, compared to the untreated group, not associated with an improvement in graft survival. The mean number of adverse events per patient was higher in the IVIG/RTX group than in the control group (p = 0.03). Taken together, IVIG/RTX treatment for severe TG during chronic antibody-mediated rejection does not seem to change the natural history of TG and is associated with a high incidence of adverse events.

Background MicroRNAs (miRNAs) are noncoding RNA molecules that play important roles in the pathogenesis of various kidney diseases. We investigated whether patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) have distinct circulating and urinary miRNA expression profiles that could lead to potential development of noninvasive biomarkers of the disease. Materials and methods Exosome miRNAs were extracted from plasma and urine samples of patients with primary FSGS (n = 16) or MCD (n = 5) and healthy controls (n = 5). Differences in miRNA abundance were examined using Affymetrix GeneChip miRNA 3.0 arrays. QRT-PCR was used to validate the findings from the array. Results Comparison analysis of FSGS versus MCD revealed 126 and 155 differentially expressed miRNAs in plasma and in urine, respectively. Only 38 of these miRNAs were previously cited, whereas the remaining miRNAs have not been described. Comparison analysis showed that a significant number of miRNAs were downregulated in both plasma and urine samples of patients with FSGS compared to those with MCD. Plasma levels of miR-30b, miR-30c, miR-34b, miR-34c and miR-342 and urine levels of mir-1225-5p were upregulated in patients with MCD compared to patients with FSGS and controls (P

Mutations in the inverted formin-2 (INF2) gene were recently identified in patients with autosomal dominant intermediate Charcot-Marie-Tooth (DI-CMT) disease and focal segmental glomerulosclerosis (FSGS). Here, we identified a novel p.L132P INF2 mutation in a Korean family with DI-CMT and FSGS by whole-exome sequencing. This mutation was cosegregated with affected individuals in the family and was not found in the 300 controls. The two affected members exhibited juvenile onset sensorimotor polyneuropathy and FSGS. Nerve conduction studies showed an intermediate range of motor nerve conduction velocities. We report a novel INF2 mutation in a family with DI-CMT and FSGS as the first case in Koreans. The INF2 mutation appears to be a major cause of CMT with FSGS.

Background We investigated circulating levels of individual soluble urokinase plasminogen activation receptor (suPAR) forms to determine if specific circulating fragments of suPAR (II-III) and (I) can better serve as clinical biomarkers for focal segmental glomerulosclerosis (FSGS) and the risk of recurrence after transplantation. Materials and methods Serum levels of intact suPAR and its cleaved forms were measured with two assays, ELISA and TR-FIA. Results suPAR levels in healthy controls were significantly lower than those who had glomerular diseases but were not significantly different between FSGS patients and glomerular controls. Intact suPAR (I-II-III) levels were noted to be elevated in glomerular diseases including FSGS. uPAR fragment (I) levels measured with the TR-FIA 4 assay were significantly higher in FSGS (695.4 + 91.29 pMol/L) than glomerular controls (239.1 + 40.45 pMol/L, P = 0.001). However, suPAR(I) levels were not significantly different between recurrent FSGS and nonrecurrent FSGS patients. Conclusion Our analysis of suPAR using the ELISA assay used in all previous studies does not appear to be a useful marker for FSGS nor serve as a predictor for its recurrence after transplantation. The TR-FIA assay results suggest that uPAR(I) is a potential biomarker for FSGS but not of its recurrence.

Background Recurrence of focal segmental glomerulosclerosis (FSGS) in pediatric kidney allografts is associated with poor graft survival. Several therapeutic regimens have been proposed, with conflicting results. Methods Ten pediatric patients with recurrent FSGS after kidney transplantation were treated with a protocol of methylprednisolone (MP) infusions in combination with cyclosporine (CsA)-based immunosuppression. The patients received a drug regimen with infusions of 20 mg/kg MP on three consecutive days at week 1, week 3, and week 5, and then monthly until six months after transplantation. If a complete or partial remission (PR) was obtained, MP pulse continued every three months until 24 months after transplantation. The CsA dose was adjusted according to AUC0–4. Results Seven of 10 patients (70%) achieved complete remission (CR) with stable renal function within 18 months of beginning of treatment. One of two patients with PR entered CR 3.5 yr after transplantation. One patient lost her graft due to recurrence four months after transplantation. After observation for 26–119 months, seven patients maintained remission with normal glomerular filtration rate. Few major side effects were observed in association with the high-dose MP infusion therapy. Conclusions MP infusion therapy in combination with CsA-based immunosuppression could be safe and effective in treating recurrent FSGS after kidney transplantation.

Mesenchymal stem cells (MSCs) have been shown to improve the outcome of acute renal injury models; but whether MSCs can delay renal failure in chronic kidney disease (CKD) remains unclear. In the present study, the were cultured in media containing various concentrations of basic fibroblast growth factor, epidermal growth factor and ascorbic acid 2-phosphate to investigate whether hepatocyte growth factor (HGF) secretion could be increased by the stimulation of these growth factors. Then, TGF-β1-treated renal interstitial fibroblast (NRK-49F), renal proximal tubular cells (NRK-52E) and podocytes were co-cultured with conditioned MSCs in the absence or presence of ascorbic acid 2-phosphate to quantify the protective effects of conditioned MSCs on renal cells. Moreover, male Sprague-Dawley rats were treated with 1 × 10(6) conditioned MSCs immediately after 5/6 nephrectomy and every other week through the tail vein for 14 weeks. It was found that basic fibroblast growth factor, epidermal growth factor and ascorbic acid 2-phosphate promoted HGF secretion in MSCs. Besides, conditioned MSCs were found to be protective against TGF-β1 induced epithelial-to-mesenchymal transition of NRK-52E and activation of NRK-49F cells. Furthermore, conditioned MSCs protected podocytes from TGF-β1-induced loss of synaptopodin, fibronectin induction, cell death and apoptosis. Rats transplanted with conditioned human MSCs had a significantly increase in creatinine clearance rate, decrease in glomerulosclerosis, interstitial fibrosis and increase in CD4(+)CD25(+)Foxp3(+) regulatory T cells counts in splenocytes. Together, our studies indicated that conditioned MSCs preserve renal function by their anti-fibrotic and anti-inflammatory effects. Transplantation of conditioned MSCs may be useful in treating CKD.

A 64-yr-old man with end-stage kidney disease caused by hypertensive nephrosclerosis underwent living-unrelated ABO-identical kidney transplantation (KTx) at the age of 60 yr from his 60-yr-old wife. Maintenance trough concentration of cyclosporine A (CsA) was 100 ± 30 ng/mL. Five months after KTx, proteinuria gradually increased to around 1 g/d. TRBx at eight months after KTx revealed the new-onset alteration of mild arteriolosclerosis with intimal hyalinosis, which might reflect calcineurin inhibitor (CNI)-associated arteriopathy (CAA). Nearly one and half years after KTx, urinary protein excretion became nearly 2 g/d. TRBx revealed the advanced CAA and findings of focal segmental glomerulosclerosis (FSGS). Then, CNI was switched from CsA to tacrolimus (TAC). TRBx at two and half years after KTx revealed progressed arteriolar transmural thickening and striped fibrosis, which were supposed to be induced by an increase in serum TAC concentration because of acute enterocolitis. Then, TAC dose was reduced to serum trough concentration 5-8 ng/mL, but urinary protein excretion was increased up to 10 g/d. Reduction of TAC to trough concentration 2.0 ± 0.5 ng/mL reduced urinary protein excretion. Attempts to elevate TAC trough concentration within normal range (4-8 ng/mL) reproducibly induced the recurrence of an increase in sCr or urinary protein excretion. All these findings supported the etiology of graft dysfunction, and proteinuria of this case was FSGS.

We present a patient with optic nerve hypoplasia, secondary strabismus, mild deafness, abnormal external ear helices, and renal hypoplasia. The clinical phenotype was consistent with renal-coloboma syndrome, but no point mutation in the PAX2 gene could be identified. High-resolution array comparative genomic hybridization (aCGH) analysis showed that this patient has a submicroscopic deletion on chromosome 10, affecting the entire coding region of the PAX2 gene. This finding provided the molecular confirmation of the patient's clinical diagnosis and showed that, in addition to point mutations, deletions of the PAX2 gene contribute to the etiology of the renal-coloboma syndrome.

Over the past 37 year the role of plasma exchange in the treatment of patients with renal disease has undergone several changes. The majority of the changes for the use of plasma exchange relied on randomized control trials and delineations of mechanisms that potentially would benefit from the use of plasma exchange. Over the past 11 years plasma exchange indications for renal disease, the absolute numbers have been relatively unchanged but the indications are quite different. The Canadian Apheresis Group indicated in 2010 that TTP/HUS is still the number 1 indication at 63% of the total plasma exchange activity for renal disease but P and C ANCA Vasculitis had risen to 14% followed by renal transplant at 10%, Goodpasture's Syndrome at 6% and transplant FSGS at 5% with Cryoglobulinemia 2% and Myeloma Nephropathy had dropped dramatically to less than 1% with no cases of SLE reported. This report describes the most common indications for plasma exchange in patient's with renal disease and the evidence that supports it's use in 2011.

Focal segmental glomerulosclerosis is a major cause of chronic kidney disease requiring transplantation in children. Recurrence rate in the renal allograft transplantation is as high as 50%. Recurrence of FSGS is associated with renal dysfunction and early graft loss. To date, there is no established therapy for recurrent FSGS after renal transplant. We have reviewed the current English literature in order to summarize current practices with emphasis on graft outcome. We conclude that despite multiple approaches to the post transplant management of recurrent FSGS, none have been shown to be consistently beneficial. Currently, pheresis combined with high dose anti-calcineurin with or without rituximab seems to be the most promising. Further controlled studies are needed to define the optimal therapeutic regimens to treat recurrent of FSGS.

Connective tissue growth factor (CTGF) belongs to the CCN family of proteins, which share a similar modular structure (1–3). Depending on the cell type, CTGF has key biologic functions ranging from regulation of cell growth to tissue remodeling (4). Expression of CTGF is observed in the mesenchyme during embryonic development, and studies involving disruption of the CTGF gene indicate that it is required for the coordination of chondrogenesis (5) and angiogenesis during development of the skeleton, and also lung development (4). There is little or no detectable CTGF in normal adult skin tissue; however, during normal wound healing, CTGF expression is activated at the wound site and then switched off once the repair process is complete (6). CTGF levels are increased in fibrotic tissue, and its levels have been shown to correlate with disease severity, e.g., in scleroderma (7). The precise mechanism by which CTGF activates cellular changes and the triggers that elicit CTGF expression in fibrotic lesions are poorly understood. Recently, activation of transforming growth factor β (TGFβ) signaling has been implicated as playing a major role in fibrosis (8). To directly assess the role of sustained TGFβ signaling, we have previously generated mice that specifically express genetically modified TGFβ receptors in fibroblasts, thus modulating TGFβ signaling (9,10). For example, expression of constitutively active TGFβ receptor I in fibroblasts postnatally recapitulated major clinical, biochemical, and histologic features of the fibrotic pathology in the skin and small blood vessels. Transgenic mouse fibroblasts displayed high levels of CTGF expression, suggesting that both TGFβ and CTGF may have an important role in a sustained chronic fibrotic outcome (9). A similar conclusion was reached from the analysis of different human fibroproliferative diseases. Interestingly, high levels of CTGF expression have been detected within fibrotic lesions in scleroderma patients even in the absence of elevated TGFβ levels (7). The purpose of this study was to investigate whether CTGF alone causes fibrosis in intact animals and whether the effects of CTGF are mediated through activation of TGFβ signaling or through other signaling pathways. For this purpose, we generated mice in which overexpression of CTGF was targeted to fibroblasts. We report that these mice spontaneously developed a multiorgan fibrotic phenotype affecting skin, lung, and kidney and including vascular remodeling of small blood vessels. The resulting phenotype, at least in the skin and lung, had features of tissue fibrosis similar to those observed in scleroderma. Molecular and cell biology studies of isolated primary mesenchymal connective tissue cells revealed that forced expression of CTGF in fibro-blasts did not involve the canonical TGFβ pathway, but promoted the activation of several other signaling pathways and downstream transcriptional programs, resulting in disruption of connective tissue architecture that is replaced by increased extracellular matrix (ECM). These results suggest that CTGF and its downstream pathways could be targets for antifibrotic therapy.

A lot of mutations of podocin, a key protein of podocyte slit diaphragm (SD), have been found both in hereditary and sporadic focal segmental glomeruloscleorosis (FSGS). Nevertheless, the mechanisms of podocyte injury induced by mutant podocins are still unclear. A compound heterozygous podocin mutation was identified in our FSGS patient, leading to a truncated (podocin (V165X)) and a missense mutant protein (podocin (R168H)), respectively. Here, it was explored whether and how both mutant podocins induce podocyte injury in the in vitro cultured podocyte cell line. Our results showed that podocin (R168H) induced more significant podocyte apoptosis and expression changes in more podocyte molecules than podocin (V165X). Podocyte injury caused by the normal localized podocin(V165X) was effectively inhibited by TRPC6 knockdown. The abnormal retention of podocin(R168H) in endoplasmic reticulum (ER) resulted in the mis-localizations of other critical SD molecules nephrin, CD2AP and TRPC6, and significantly up-regulated ER stress markers Bip/grp78, p-PERK and caspase-12. These results implicated that podocin (R168H) and podocin (V165X) induced different degrees of podocyte injury, which might be resulted from different molecular mechanisms. Our findings provided some possible clues for further exploring the pharmacological targets to the proteinuria induced by different mutant podocins.

SUMMARY: Aim: 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. Methods: 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 m2 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. Results: 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). Conclusion: Our study revealed no correlation between ACE I/D gene polymorphism and rapidity of progression of FSGS to ESRD in Iranian children.

Recurrence of FSGS following renal transplantation in pediatric patients is reported as 20-57%. Records of 37 pediatric patients transplanted for FSGS between 1990 and 2005 at a single center were reviewed. Recurrence of disease was assessed by nephrotic range proteinuria and/or FSGS on biopsy. Response to TPE was defined as urine protein to creatinine ratio

Similarities between atherosclerosis and glomerulosclerosis suggest that hyperlipidaemia may contribute to glomerular injury. Dietary supplementation with 4% cholesterol + 1% cholic acid was administered to rats 4 weeks after 1 1/3 nephrectomy and continued for 7 weeks. There was a significant increase in serum cholesterol (peak = 11.52 +/- 1.09 mmol l-1 vs. 4.73 +/- 0.31 on control diet, P less than 0.001) and triglyceride concentrations (peak = 2.31 +/- 0.27 mmol l-1 vs. 1.41 +/- 0.29, P less than 0.05) and a marked increase in beta-migrating lipoproteins. The severity of hypercholesterolaemia was significantly correlated with proteinuria (control diet: r = 0.600, cholesterol diet: r = 0.672, P less than 0.0001) as was hypertriglyceridaemia (control diet: r = 0.544, cholesterol diet: r = 0.678, P less than 0.0001). The percentage of glomeruli containing lipid deposits was increased from 21% to 60% (P less than 0.05). The kidney total cholesterol content was increased from 29.2 +/- 0.8 to 47.7 +/- 3.3 mumols g-1 dry weight (P less than 0.0001), with esterified cholesterol increasing from 7.5 +/- 0.4% to 14.5 +/- 2.1% of total (P less than 0.01). Serum cholesterol concentration was significantly correlated with both glomerular lipid deposition (rs = 0.7195, P less than 0.0001) and tissue total cholesterol content (rs = 0.6053, P less than 0.001). Lipid vacuolation was prominent in the paramesangium and within mesangial cells. Despite these changes hypertension, uraemia, proteinuria and glomerulosclerosis were not significantly increased on the cholesterol diet. Cholesterol deposition in the glomeruli occurs secondary to hyperlipidaemia in rats following subtotal nephrectomy but over 7 weeks no exacerbation of glomerulosclerosis is detectable.

SUMMARY: Aim: The ever-growing number and increasing survival of haematopoietic stem cell transplantation (HSCT) allow better recognition of its associated renal injuries. We aimed to study the clinicopathologic features of renal biopsies after HSCT by reviewing 13 percutaneous renal biopsies in our institute (Queen Mary Hospital). Methods: A retrospective clinicopathologic study of all renal biopsies archived to the Department of Pathology, Queen Mary Hospital during the period January 1999 to December 2006 was performed. Biopsies from patients with HSCT were selected. Clinical data on presentation and follow up were retrieved from hospital records and physicians. Results: In the 8-year period, a total of 2233 native renal biopsies were archived. Thirteen renal biopsies were selected from 12 patients with HSCT (11 allogeneic, one autologous). All but one patient were male. The age at renal biopsy ranged from 7 to 63 years (median: 32 years). The median interval of renal biopsy after HSCT was 24 months (range 1–134 months). Evidence of graft-versus-host disease was found in nine patients. The most common presentation was significant proteinuria (10 cases) and renal impairment (eight cases). The predominant histological changes were membranous glomerulonephritis (n = 4) and thrombotic microangiopathy (n = 4). One case of focal segmental glomerulosclerosis, IgA nephropathy, minimal change disease, acute tubular necrosis and hypertensive nephrosclerosis were also recorded. Four of our patients died at 0–11 months after renal biopsy. Of the remaining eight patients with a mean follow up of 43.6 months (range, 10–98 months), chronic renal impairment were found in three (37.5%) patients and significant proteinuria also persisted in three. One patient had cytogenetic evidence of relapse of underlying haematological malignancy after HSCT. Conclusion: Among the various renal lesions after HSCT, membranous glomerulonephritis and thrombotic microangiopathy were the most common. Mechanisms of renal injury varied from graft-versus-host disease-associated immune complex deposition to non-immune complex injury on endothelial cells, glomerular epithelial cells and tubular epithelium. Pathologists and clinicians should attend to the histological and temporal heterogeneity of renal injury when managing patients after HSCT.

Nephrotic syndrome represents a form of acquired thrombophilia thereby causing increased risk of thrombosis. In patients with nephrotic syndrome both venous and arterial thrombosis can occur; however, intracardiac thrombus is among the rarest reported in the literature. In this case report, we present a 10.5-yr-old boy with right atrial thrombosis and an acute rejection episode after renal transplantation due to end stage renal disease caused by focal segmental glomerulosclerosis manifested by nephrotic syndrome. The clinical course was successfully managed with surgical removal of thrombus, institution of anticoagulant as well as antirejection therapy. This report draws attention to the risks that could be associated with thrombosis in renal recipients with congenital or acquired thrombophilias and emphasizes the importance of identifying risk factors for thrombosis in these patients.

Minimal change nephrotic syndrome (MCNS) is the most common cause of the nephrotic syndrome in children, accounting for 90% of cases under the age of 10 years and more than 50% in older children. It has been proposed that MCNS reflects a disorder of T-lymphocytes. These T cells are thought to release a cytokine - so-called permeability factor - that injures the glomerular epithelial cells. The identity of this permeability factor is still uncertain. Epithelial cell damage may lead to albuminuria in MCNS by altering the metabolism of polyanions, such as heparan sulphates, that constitute most of the normal charge barrier to the glomerular filtration of macromolecules such as albumin. In contrast, in focal segmental glomerulosclerosis (FSGS) the proteinuria is primarily due to an increased number of large pores in the glomerular basement membrane, leading to an impairment in size selectivity. It has been documented by repeated renal biopsies that some patients with apparent MCNS at the initial biopsy progress to FSGS. Morphological signs which have been proposed to identify the high-risk subset of MCNS include widespread IgM deposits (IgM nephropathy) and diffuse mesangial hypercellularity. It has been also documented that the initial biopsy of paediatric patients who subsequently showed FSGS had larger glomeruli from children with MCNS and healthy controls. Therefore, the presence of glomerular hypertrophy in biopsies of apparent MCNS appeared to be a high specific indicator of increased risk for progression to FSGS. In comparison with MCNS, a higher proportion of patients with mild mesangial hypercellularity are initial non-responder. More severe degree of mesangial hypercellularity, as seen in patients with diffuse mesangial hypercellularity, was associated with an even poorer initial response to steroid. Accordingly, it appears that mesangial proliferative glomerulonephritis is a more severe form of MCNS in which the initial injury is greater, leading to mesangial dysfunction and a slower rate of recovery, and this disorder is a part of the MCNS-FSGS spectrum. In this viewpoint, it can also be said that FSGS is the most severe form of MCNS in which the initial injury is the greatest, so the majority of patients with FSGS are non-responders to steroid and progress to chronic renal failure. In summary, documents define the risk for progressive renal disease based on the presence of mesangial hypercellularity and glomerular hypertrophy in renal biopsies of patients with MCNS, thus directing vigilant follow up and more aggressive treatment of high-risk patients.

Aims: To analyse the expression of caveolin-1 in normal human kidney and during diseases leading to nephrotic syndrome in children and to compare its pattern with those observed in control samples, both human and animal. Methods and results: The study group was composed of 104 children diagnosed with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), lupus glomerulonephritis (LGN) and Schonlein–Henoch glomerulopathy (SH). The research protocol employed direct immunohistochemical assay with the use of mono- and polyclonal antibodies against caveolins. Kidney samples of Wistar rats, wild-type mice and caveolin-1-deficient mice were also analysed. In the control human samples, caveolin-1 was most abundant in the muscle layer of blood vessels and parietal epithelial cells (PECs). Its expression in PECs was significantly lower in children diagnosed with FSGS and LGN than in those with MCD, SH or in controls. In the control animal tissues, except for knock-out mice, caveolin-1 was present in distal convoluted tubules, PECs, endothelial cells and muscle. Conclusions: Caveolae are extremely stable elements of PECs and can be excluded from their cell membrane only in response to the dramatic cell reconstruction observed in FSGS and LGN.

To determine the outcomes of pediatric renal transplant recipients who received immunosuppression consisting of early withdrawal of corticosteroids at a single Northern California center. Protocols using minimal steroid exposure have been recently reported in adult transplant recipients with successful results. We examined the outcomes of pediatric renal transplant recipients who were managed at our center using a protocol with very early discontinuation of steroids after renal transplantation. We retrospectively studied the medical records of all renal transplant recipients followed at the Children’s Hospital at the University of California, Davis Medical Center from 01/2004 to 12/2005. All patients were less than 18 yr of age at the time of transplantation. The immunosuppressive protocol included three tapering daily doses of methylprednisolone, together with five doses of thymoglobulin followed by maintenance therapy with tacrolimus and MMF. Eight patients with equal numbers of males and females were transplanted during this time period. There were equal numbers of Caucasians, African-Americans, Hispanics, and Asians. A total of 37.5% (3/8) of the subjects received preemptive transplantation, 25% (2/8) received peritoneal, and 37.5% (3/8) received hemodialysis before transplantation. The median (range) age at transplantation was 12.3 (3.1–16.0) year with a follow-up of 1.7 (0.9–2.8) year. At one yr post-transplantation, 57% (4/7) of patients still required anti-hypertensives. Three children required erythropoietin supplementation after transplantation. The mean delta height standard deviation score at 12 months was 0.20 ± 0.56. There were no episodes of clinical acute rejection. One patient switched from tacrolimus to sirolimus due to biopsy-proven CAN. No patient became diabetic or required hypoglycemic agents. Surveillance biopsies showed no subclinical acute rejection in any patient. Steroid-free immunosuppression is safe in children after renal transplantation. Larger number of patients and longer follow-up are required to further confirm the effectiveness and safety of immunosuppression with rapid steroid discontinuation.

We describe a patient who presented with nephrotic syndrome and progressive renal failure with biopsy findings of focal segmental glomerulosclerosis (FSGS). He progressed rapidly to end-stage renal disease (ESRD) and remained hemodialysis dependent for five months despite high dose prednisone therapy. Initiation of plasmapheresis and low dose oral cyclophosphamide resulted in the prompt return of urine output and renal recovery. He remains off dialysis with stable renal function (creatinine clearance = 40 mL/min) two years later. This is the first report of late rescue from apparent ESRD due to FSGS with combined plasmapheresis and low dose oral cyclophosphamide.

SUMMARY: Aim: The aim of this analysis of renal biopsies in people with type 2 diabetes was to know the prevalence and nature of non-diabetic renal disease (NDRD) and to note its correlation with the duration of diabetes, extent of proteinuria and presence or absence of retinopathy. Methods: From January 2000 to December 2004, 160 people with type 2 diabetes with clinically suspected NDRD underwent renal biopsy reported by a single pathologist. The case records of these patients were retrospectively analysed. Based on the biopsy findings, patients were grouped as Group I, isolated NDRD; Group II, NDRD with underlying diabetic glomerulosclerosis; and Group III, isolated diabetic glomerulosclerosis. The relation of histology with clinical profile in each group was noted and statistically analysed using strata 6 software. Results: Of the 160 patients studied, 118 were males and 42 were females (2.8:1). The average age was 51.35 years (30–79). Indications for renal biopsy included: nephrotic syndrome in 55 (34.37%), acute renal failure (ARF) in 49 (30.62%), rapidly progressive renal failure (RPRF) in 24 (15%), absent retinopathy in 19 (11.87%), haematuria in 10 (6.25%) and acute on chronic renal failure (CRF) in three (1.87%) patients. Group I included 68 patients (42.50%), Group II included 48 patients (30%) and Group III included 44 patients (27.50%). The mean duration of diabetes was 5.37, 10.12 and 6.86 years in Groups I, II and III respectively. The duration of diabetes was significantly less in Group I compared with Group II and III combined (5.37 vs 8.53; P

Although normative values of post-transplant proteinuria have been reported in adults, data for pediatric renal transplant recipients have not been previously published. We hypothesized that pediatric renal transplant recipients achieve normal urinary protein to creatinine (UProt/UCr) ratios (0.2) by 60 days post-transplant in the absence of early recurrent disease. Retrospective chart review of 108 consecutive pediatric renal transplant recipients at Stanford University was performed. Thirty-two (30%) patients who were eligible hador = 1 UProt/UCr ratio obtained during the first 60 post-transplant days. Mean age at transplant was 13.9 +/- 4.2 yr. UProt/UCr ratios were grouped by week post-transplant for quantile analysis. Mean weekly UProt/UCr values were not lower than 0.2 until the ninth post-transplant week. No difference in post-transplant proteinuria existed between nephrectomized and non-nephrectomized transplant recipients. Experience with a single patient with proven focal segmental glomerulosclerosis (FSGS) recurrence suggests that normative UProt/UCr data may be useful in early identification of patients experiencing disease recurrence. Univariate correlations demonstrated that UProt/UCr negatively correlated with serum albumin levels (-0.415, p0.0001) and days post-transplant (-0.531, p0.0001). Independent of primary diagnosis, proteinuria persists throughout the first 60 days in most pediatric renal transplant patients, decreasing relative to time post-transplant.

Although recurrent diabetic nephropathy is common in patients with type I diabetes after kidney transplantation, the development of focal segmental glomerulosclerosis (FGS) is rare, and its development generally takes several years. We report here a case of type I diabetes mellitus with secondary FGS accompanied by proteinuria 10 months following kidney transplantation. Episode biopsy showed secondary FGS, evidenced by glomerular capillary collapse and large epithelial cells with ballooning degeneration. Exudative dense deposition of IgM in a diffuse global mesangial pattern and enlarged glomerular diameters were observed, suggestive of glomerular hyperfiltration which can lead to secondary FGS. An imbalance in body size between donor and recipient and/or uncontrolled diabetes are potential causes of glomerular hyperfiltration. We administered angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker to reduce hyperfiltration-induced renal damage; the combination therapy reduced proteinuria from 2346 to 258 mg/d. Secondary FGS should be a consideration after kidney transplantation in patients with type I diabetes mellitus.

We encountered two patients of recurrent nephrotic syndrome (NS) after renal transplantation that was resistant to plasma exchange (PEX). Case 1 was a 34-year-old man with a living-related renal transplant for type-I membranoproliferative glomerulonephritis (MPGN) related end-stage renal disease (ESRD). He developed overt proteinuria 7 months post-transplant and presented with NS 5 months later. Biopsy of the transplant kidney revealed recurrent type I MPGN, but no features of acute rejection (AR) or chronic allograft nephropathy (CAN). He was treated with cyclophosphamide (CP), oral prednisolone (40 mg/d), an anti-platelet agent, heparin sulfate, and PEX, but the nephrotic state persisted and renal function was deteriorated. He recommenced hemodialysis 3 yr and 9 months after renal transplant. Case 2 was a 47-year-old male who underwent living-related renal transplant for ESRD due to focal segmental glomerulosclerosis (FSGS). He presented with proteinuria shortly after renal transplantation. He also had frequent episodes of AR. Graft biopsy revealed recurrent FSGS. Treatment of pulse methylprednisolone and PEX was transiently effective, but NS relapsed shortly after PEX. Graft biopsy at our hospital showed features of CAN with moderate interstitial fibrosis and tubular atrophy, presence of intraglomerular foam cells but no segmental sclerosis. Treatment with 12 courses of low-density lipoprotein apheresis (LDL-A) reduced proteinuria from 9.6 to 2.0 g/d, and incomplete remission has been maintained for more than 1 yr after LDL-A with slowly progressive renal dysfunction. Despite recent therapeutic advances, including the use of immunosuppressants and PEX, treatment of recurrent disease remains difficult. The LDL-A might be useful in cases with recurrent FSGS resistant to PEX.

We reviewed the transplantation data and results of histopathological studies with additional angiotensin II (AII) immunostaining of renal graft biopsies of nine cases (10 grafts) with recurrent proteinuria and three controls without recurrent proteinuria that received renal transplantation for primary focal segmental glomerulosclerosis (FSGS) between 1986 and 2002. Recurrent FSGS was confirmed in six grafts from nine cases by light microscopy. In cases with recurrent proteinuria, loss of graft function was noted in all six renal grafts received between 1986 and early 1992 but in none of four grafts received between late 1992 and 2002. Two of four patients of the late group but none of those of the early group received angiotensin converting enzyme (ACEI) or angiotensin II receptor blocker (ARB) with plasma exchange (PE). In control cases without proteinuria, AII immunostaining was detected in tubules but not in glomeruli in 1-hour biopsies as well as later on. In cases with recurrent proteinuria, AII immunostaining was detected in both tubules and glomeruli, although glomerular AII staining was not observed in 1-hour biopsies. Our results suggest that effective treatment of post-transplantation recurrent FSGS requires ACEI or ARB with PE in the absence of another etiology.

Immunoadsorption is an adsorption technique for extracorporeal removal of circulating autoantibodies in autoimmune diseases. To prevent microbial growth during storage, the protein A columns are primed with thiomersal, which contains toxic ethyl mercury, which may be released during the procedure and potentially begin to accumulate and become toxic. To reduce the thiomersal-related mercury release during immunoadsorption treatment, we introduced a modified rinsing solution containing N-acetylcysteine, which is an avid mercury scavenger. Thirteen patients received 17 protein A immunoadsorption treatments and their venous blood samples were collected immediately before and after each session. The total blood mercury levels were measured by atomic absorption spectrometry, and the ethyl mercury levels by atomic fluorescence spectrometry. Following the manufacturer's recommendations, we used 600 mg of N-acetylcysteine to rinse the mercury from protein-loaded columns before each immunoadsorption treatment. After immunoadsorption, the ethyl mercury levels increased from 0.148 +/- 0.402 ng/g to 2.026 +/- 1.944 ng/g (P < 0.001), and the total blood mercury levels increased from 2.447 +/- 3.065 ng/g to 20.437 +/- 28.603 ng/g (P = 0.02). The post-treatment values of total blood mercury exceeded the upper safety level of 5 ng/g in all 17 immunoadsorption treatments, but no patient developed clinical signs of mercury toxicity. The results of our study showed an increase in total blood mercury and ethyl mercury levels during the immunoadsorption treatments, suggesting mercury release from thiomersal-primed columns despite the addition of N-acetylcysteine to the rinsing solution.