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Purpose: We aimed to evaluate therapeutic response and long-term renal outcomes of childhood idiopathic steroid-resistant nephrotic syndrome (iSRNS). Methods: We retrospectively reviewed treatment regimens, especially calcineurin inhibitor (CNI), pathologic diagnoses, and long-term renal outcomes of iSRNS patients for 30 years. Results: Of 516 patients with idiopathic NS, 52 (10.1%) had iSRNS. Renal biopsies from 48 patients showed minimal change disease (MCD) in 23 (47.9%), focal segmental glomerulosclerosis in 24 (50.0%), and mesangioproliferative glomerulonephritis in 1 (2.1%). The median follow-up period was 66.5 (range, 4–275) months, and 90.4% of them were treated with a CNI. CNI induced remission in 70.2% within 50.4 ± 43.5 days. Of the patients with MCD and focal segmental glomerular sclerosis (FSGS), 86.4% (19/22) and 45.0% (9/20) (p = 0.005) responded to CNI, respectively. Mean time until remission after using CNI was longer with FSGS (90.4 ± 54.0 days) than with MCD (29.6 ± 26.3 days) (p = 0.010). CNI-responsive patients with FSGS or MCD showed preserved renal function, and CNI nonresponsive MCD patients also showed preserved renal function during follow-up. However, end-stage renal disease (ESRD) progressed in 8 out of 11 patients with FSGS nonresponsive to the CNI for an average of 44.9 ± 18.4 months after diagnosis. Conclusion: Different response rates and times for remission were achieved with the CNI according to the pathology of iSRNS. All MCD patients regardless of CNI response and all CNI-responsive patients with FSGS showed excellent renal outcomes, while almost all FSGS patients nonresponsive to CNI eventually progressed to ESRD.

Background: Complement component 3 glomerulopathy (C3G) is a disease diagnosed based on the predominance of C3 immunostaining in glomeruli. The popular electron microscopic subtyping of C3G into dense deposit disease and C3 glomerulonephritis (GN) is not without limitations. We aimed to study the light microscopic (LM) patterns of C3G along with their clinicopathological correlation and treatment outcome. Methods: C3G biopsies were classified into 4 LM patterns (membranoproliferative GN [MPGN], mesangial proliferative GN [MesPGN], diffuse proliferative GN [DPGN], and crescentic GN [CrGN]). These patterns were compared for clinicopathological profile, treatment outcome, and renal survival. Further, predictors of end-stage renal disease (ESRD) were determined using the Cox proportional hazards model. Results: Of 162 biopsies, there were 83 MPGN, 36 DPGN, 22 MesPGN, and 21 CrGN. Majority of the patients were young, with males being more than females. About half (48%) of the patients received immunosuppression, steroids alone (29%) or steroids with other immunosuppressants (19%). The overall remission rate was 32.7% (median follow-up = 14 months). CKD developed in 46 patients and 31 patients progressed to ESRD. Predictors of progression to ESRD were older age (hazard ratio [HR] = 1.04, p < 0.01), advanced renal failure at presentation (HR = 3.73, p < 0.01), glomerulosclerosis (HR = 5.07, p < 0.01), and severity of interstitial fibrosis and tubular atrophy (HR = 8.25, p = 0.01). Conclusions: The LM patterns differed in their clinicopathological profiles, without any significant difference in their renal outcomes. Glomerulosclerosis and interstitial fibrosis portend a poor prognosis. Besides CrGN, MesPGN pattern of C3G presented as a severe form of disease.

Background: Focal segmental glomerulosclerosis (FSGS) is a clinicopathological syndrome characterized by nephrotic-range proteinuria with high incidence of progression to end-stage renal disease (ESRD). In primary FSGS, 40–60% of patients develop ESRD within 10–20 years. Summary: Recurrence of FSGS after kidney transplantation is frequent and is associated with poor allograft survival. The risk factors for recurrent FSGS include onset of FSGS during childhood, rapid progression of primary FSGS to ESRD, history of recurrent FSGS in previous allograft, and diffuse mesangial hypercellularity or collapsing variant of FSGS in the native kidney. The early histological findings of recurrent FSGS consist of unremarkable glomerular changes on light microscopy but significant podocyte effacement on electron microscopy; the loss of foot processes with eventual dropout of podocytes leads to the development of segmental lesions in the glomerulus. Experimental and clinical data suggest the existence of circulating permeability factors, such as soluble urokinase-type plasminogen activator receptor (suPAR), cardiotrophin-like cytokine factor-1 (CLCF-1), CD40 axis, and apolipoprotein A-Ib (ApoA-Ib), in the pathogenesis of recurrent FSGS. These biomarkers including circulating permeability factors may facilitate earlier diagnosis of FSGS posttransplant and may guide in the development of novel therapies that may be more effective and improve long-term outcomes in kidney transplantation. Key Messages: Several studies have suggested the possible circulating permeability factors, such as suPAR, CLCF-1, CD40 axis, and ApoA-Ib, in the pathogenesis and disease progression of FSGS and recurrent FSGS. Further studies should be performed to elucidate the true essential biomarker(s) associated with the onset and progression of FSGS as well as recurrent FSGS.

Background: Focal segmental glomerulosclerosis (FSGS) is a common histologic pattern of kidney injury, which may eventually lead to end-stage renal disease. Objectives: Salidroside (SAL, p-hydroxyphenyl-β-D-glucoside) is an active component isolated from Rhodiolarosea, which has various pharmacological properties including anti-inflammation and antioxidation. SAL may attenuate FSGS, but the underlying mechanism is not clear. Thus, in this study, we focus on the renoprotective role of SAL in FSGS using Adriamycin nephropathy (AN) mouse models. Methods: In C57 BL/6 mice, AN was induced by Adriamycin (10 mg/kg body weight, diluted in normal saline) via a tail vein on day 0. Then they were organized into 6 groups for the animal experiments: AN + saline group; AN + SAL group (40 mg/kg); AN + LY294002 (a selective phosphatidylinositol 3-kinase [PI3K] inhibitors, 50 mg/kg) group; AN + SAL + LY294002 group; AN + YC-1 (a selective hypoxia-inducible factor-1α [HIF-1α] inhibitors, 50 mg/kg) group; and AN + SAL + YC-1 group. All of the drugs were given on the day of Adriamycin injection and continued for 6 weeks, and the drugs were given by intraperitoneally. At 6 weeks, the mice were sacrificed; kidneys and blood samples were collected for further analysis. Results: In FSGS mouse models, SAL treatment could ameliorate proteinuria, renal function, and markers of Nephrotic Syndrome inhibit alpha-smooth muscle actin and fibronectin expression and downregulates the expression of HIF-1α. Besides, the levels of PI3K and p-protein kinase B (Akt) in renal tissues were significantly decreased after SAL injection. Eventually, SAL treatment results reduced inflammatory cytokines and reactive oxygen species production. Conclusions: In summary, SAL ameliorates FSGS mainly by inhibiting the expression of HIF-1α through PI3K/Akt pathway, which might offer an array of hope for ameliorating FSGS.

Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular injury, rather than a single disease, that is caused by diverse clinicopathological entities with different mechanisms of injury with the podocyte as the principal target of lesion, leading to the characteristic sclerotic lesions in parts (i.e., focal) of some (i.e., segmental) glomeruli. The lesion of FSGS has shown an increasing prevalence over the past few decades and is considered the most common glomerular cause leading to ESKD. Primary FSGS, which usually presents with nephrotic syndrome, is thought to be caused by circulating permeability factors that have a main role in podocyte foot process effacement. Secondary forms of FSGS include maladaptive FSGS secondary to glomerular hyperfiltration such as in obesity or in cases of loss in nephron mass, virus-associated FSGS, and drug-associated FSGS that can result in direct podocyte injury. Genetic FSGS is increasingly been recognized and a careful evaluation of patients with atypical primary or secondary FSGS should be performed to exclude genetic causes. Unlike primary FSGS, secondary and genetic forms of FSGS do not respond to immunosuppression and tend not to recur after kidney transplantation. Distinguishing primary FSGS from secondary and genetic causes has a prognostic significance and is crucial for an appropriate management. In this review, we examine the pathogenesis, clinical approach to distinguish between the different causes, and current recommendations in the management of FSGS.

Background: There is a paucity of data on the spectrum of renal diseases prevalent in the Jammu and Kashmir region. Objectives: To determine the spectrum of glomerulopathies in adult patients attending a tertiary care centre. Methods: Two hundred and twenty-one adequate biopsies from native kidneys of adult patients who presented with features suggestive of glomerular diseases at Sheri Kashmir Institute of medical sciences Srinagar Kashmir for the last 8 years were studied in a retrospective manner. Light and immunofluorescence (IF) microscopy were performed to evaluate these biopsies after obtaining well-informed consent from each patient. Results: Of the 221 biopsies carried out, 150 were performed on males and 71 on females with the mean age of 29 ± 13.5 years. The main presentation was the nephrotic syndrome in 177 (80%), hypertension in 60 (27%), renal insufficiency in 48 (21.7%), and abnormal urinary sediment in 42 (20.3%) of patients. The histopathology revealed minimal change disease (MCD) in 69 (31.2%), membranous glomerulonephritis (MGN) in 48 (21.7%), focal segmental glomerulsclerosis (FSG) in 49 (18%), and mesangioproliferative glomerulonephritis in 16 (7.2%). Patients with atypical presentation of diabetes mellitus showed diabetic nephropathy in 12 (5.4%) patients. Lupus nephritis was in 5 (2.2%) patients. Majority of the patients with MPGN had Immunoglobulin A deposits on IF. While evaluating the underlying cause of MGN, only 1 patient, a 62-year-old male, proved to have adenocarcinoma of the stomach. In the remaining patients, no secondary cause could be found. Thrombotic complications seen in our study were deep venous thrombosis, renal vein thrombosis and middle cerebral artery thrombosis. Conclusion: MCD and MGN were the most common primary glomerular diseases observed in our centre.

Focal segmental glomerulosclerosis (FSGS) is caused by various etiologies, with mitochondrial dysfunction being one of the causes. FSGS is known to be associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is a subclass of mitochondrial disease. However, it has rarely been reported in other mitochondrial disease subclasses. Here, we reported a 20-year-old man diagnosed with FSGS associated with chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) 3243A>G mutation. He presented with left ptosis, short stature, mild sensorineural deafness, and cardiac conduction block. A renal biopsy sample showed segmental sclerosis and adhesions between capillaries and Bowman’s capsule, indicating FSGS. Electron microscopy demonstrated abnormal aggregated mitochondria in podocytes, and the basement membrane and epithelial cells of Bowman’s capsule. Skeletal muscle biopsy also showed accumulation of abnormal mitochondria. mtDNA analysis identified heteroplasmic mtDNA 3243A>G mutation with no large-scale deletions. From these findings, we diagnosed the case as CPEO with multi-organ involvement including FSGS. Our report demonstrates that CPEO, as well as MELAS, can be associated with FSGS. Because mitochondrial disease presents with a variety of clinical symptoms, atypical cases with non-classical manifestations are observed. Thus, mitochondrial disease should be considered as an underlying cause of FSGS with systemic manifestations even with atypical phenotypes.

Obesity-related glomerulopathy (ORG) is characterized by glomerulomegaly accompanied in many patients by lesions of focal and segmental glomerulosclerosis. Slowly increasing subnephrotic proteinuria is the commonest presentation of ORG. Occasionally, massive proteinuria (>5-10 g/day) is detected, but the typical findings of nephrotic syndrome are characteristically absent even in patients with massive proteinuria. Superimposed obesity can fuel the progression of other renal diseases, and a reduced number of functioning nephrons (of congenital or acquired causes) synergizes with obesity to induce end-stage renal disease. Weight loss, either induced by diet or bariatric surgery, and renin-angiotensin blockers are effective treatments to slow progression, but a significant proportion of cases will develop end-stage renal disease.

Background/Aims: De novo expression of CD44 is considered as a marker of parietal epithelial cell (PEC) activation. The aim of our study was to explore CD74 expression, which can form a complex with CD44, in PECs during the progression of focal segmental glomerulosclerosis (FSGS). To clarify the role of CD74 expression and of its interaction with CD44, we generated a new mouse model with enhanced PEC activation through lipopolysaccharide (LPS) application to adriamycin (ADR)-induced nephropathy mice (LPS-treated ADR mice). Methods: As a new model, LPS was intraperitoneally injected into the mice 3 weeks after ADR injection. The mice were divided into 3 categories: control mice, ADR mice and LPS-treated ADR mice. Renal function parameters, histologic changes and immunohistochemical expression of CD74 and other PEC activation markers were analyzed after LPS application. Results: After LPS stimulation, the glomeruli were characterized by enlarged epithelial cells with strong CD74 expression, followed by pseudo-crescent formation. By double staining, CD74-positive enlarged cells showed co-expression of classical PEC markers, but not of Lotus tetragonolobus lectin (marker of proximal tubular cells), suggesting amplification of PEC activation. Time-course analysis displayed marked upregulation of CD74 expression during rapid PEC activation compared with CD44. Additionally, the time-dependent change in ERK phosphorylation showed a similar pattern to CD74. Conclusion: Our results indicate that CD74 can be a marker for PEC activation in FSGS. By modifying the ADR mouse model through LPS treatment, we found that CD74 upregulation better reflects a rapid amplification of PEC activation than CD44 expression.

Background: Focal segmental glomerulosclerosis (FSGS) is considered a subset of the podocytopathies. The molecular pathogenesis of podocytopathy is still unknown. There has not been an experimental animal model of isolated podocytopathy induced by antibody in C57BL/6 strain, which is widely used as the genetic background. Nephrin is closely associated with the slit diaphragm of the glomerular podocyte, and has recently received attention as a potential therapeutic target. The function of nephrin, especially its role in FSGS development via podocytopathy, is being elucidated. We report our experience with a C57BL/6 FSGS model induced by polyclonal rabbit anti-mouse nephrin antibody (α-mNep Ab). Methods: α-mNep Ab, which was generated by genetic immunization, was administered into C57BL/6 mice at once, intravenously. Urinary protein excretion, the development of glomerulosclerosis and the number of podocyte in mouse kidney were evaluated. Results: The α-mNep Ab-induced FSGS was associated with massive proteinuria and nephrotic syndrome. In periodic acid-Schiff staining, FSGS was observed from day 7 after antibody injection. Podocyte numbers and podocyte marker (anti-Wilms tumor 1 and anti-synaptopodin)-positive areas were clearly decreased. These results suggest that this FSGS mouse model reliably reproduces the human nephrotic syndrome and FSGS. Conclusion: We succeeded in making the nephrotic syndrome model mice induced by α-mNep Ab using C57BL/6. This model may be useful for studying the mechanisms of podocytopathy.

About 30% of children with nephrotic syndrome (NS) have inherited forms. Among them, mutations in Wilms tumor suppressor gene 1 (WT1) are a well characterized cause associated with steroid-resistant NS, Wilms tumor, and urogenital malformation in males. However, the role of WT1 mutations in adult-onset focal segmental glomerulosclerosis (FSGS) is unclear. We report the case of a 38-year-old female with FSGS. She had been diagnosed with streak ovaries during diagnostic workup for infertility. Mutational analysis identified the heterozygous mutation c.1372CT (p.Arg458*) in WT1 and the heterozygous non-neutral polymorphism c.868GA (p.Arg229Gln) in NPHS2. Chromosomal analysis revealed a normal 46,XX female karyotype. Our case highlights that WT1 mutations should be considered in XX females with adult-onset FSGS, especially if urogenital abnormalities are present.

Background: N-linked glycosylation, which is a post-translational modification process, plays an important role in protein folding, intracellular trafficking and membrane targeting, as well as in regulating the protein function. Recently, we identified a missense variant (p.T141L) in the short isoform 2 of the X-linked gene asparagine-linked glycosylation 13 (ALG13-is2), which segregated with focal segmental glomerulosclerosis and PCCD in a large Australian pedigree; however, any evidence of its pathogenicity was demonstrated. ALG13 gene encodes, through alternative splicing, 2 glycosyltransferase isoforms, which catalyse the second sugar addition of the highly conserved oligosaccharide precursor in the endoplasmic reticulum (ER). Mutations in the long isoform 1 were associated with epilepsy. Methods and Results: Here, we show a different expression of the 2 isoforms depending on the tissue. Specifically, the long isoform is highly expressed in lungs, ovaries, testes, cerebellum, cortex, retina, pituitary gland, and olfactory bulbs, while the short isoform is highly expressed in mouse podocytes and in human podocyte cell lines, at both mRNA and protein levels. The silencing of ALG13-is2 by specific siRNAs induces an altered N-linked glycosylation pattern of nephrin, as demonstrated by the presence of an additional immunostaining band of about 130 kD. In knock-down cells, immunofluorescence analysis shows perturbed organization of the cytoskeleton and altered localization of nephrin on the cellular membrane. We also demonstrated that the altered pattern of N-linked glycosylation induces an over-expression of binding immunoglobulin protein and calreticulin, suggesting ER stress. Conclusions: These results provide preliminary evidence that ALG13-is2 could be an important modifier of renal filtration defects.

Background/Aim: It has been shown that hypertension (HT) and prehypertension (Pre-HT) are associated with increased cardiovascular risk. However, the significance of secondary HT/Pre-HT in children with IgA nephropathy (IgAN) is uncertain. This study aimed to examine the clinical and histopathological features of pediatric patients with HT/Pre-HT. Methods: Data on children with IgAN from a single Chinese nephrology center were retrospectively reviewed. Morphological changes were evaluated using the Oxford classification, parameters including crescents, glomerular activity index, glomerular chronicity index (GCI), arterial lesions and Lee's grading. The clinical and pathological features were compared according to the occurrence of HT/Pre-HT. Results: One hundred and eight previously untreated children with IgAN were included. HT/Pre-HT was present in 19.44% of children. Children with HT/Pre-HT were older (14.67 ± 2.37 vs. 12.07 ± 2.94 years, p < 0.01) and had higher uric acid (380.62 vs. 301.68 μmol/l, p < 0.01) and lower estimated glomerular filtration rate (eGFR; 89.95 vs. 111.84 ml/min/1.73 m2, p < 0.01). These children also had a higher proportion of segmental glomerulosclerosis or adhesion, GCI, tubular atrophy/interstitial fibrosis and arteriole wall thickening (all p < 0.05). Blood pressure (BP) values were significantly correlated with eGFR, uric acid, segmental glomerulosclerosis or adhesion, tubular atrophy/interstitial fibrosis and arteriole wall thickening (all p < 0.05). In particular, serum uric acid levels had a stronger association with systolic BP (r = 0.434, p < 0.01). Conclusion: Our results show that elevated serum uric acid level might be a marker of HT/Pre-HT. In renal histology, chronic lesions were more severe and prevalent in patients with HT/Pre-HT than in those without HT/Pre-HT.

Aim: Primary focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic proteinuria in adults. Most studies on FSGS have combined pediatric and adult patients. This study aims at assessing the response to immunosuppression and its impact on renal survival in adults with primary FSGS. Methods: Patients with nephrotic proteinuria with primary FSGS seen from January 2010 to December 2014 were included. Clinical, laboratory and treatment details were recorded. Deterioration in renal function was defined as ≥50% decline in estimated glomerular filtration rate (eGFR) or progression to end-stage renal disease. Results: There were 116 patients with median follow-up of 23.6 (6-65.1) months. Baseline proteinuria was 5.1 ± 2.6 g/day and eGFR was 96.9 ± 35.1 ml/min/1.73 m2. One hundred one (94.4%) patients had received angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB). One hundred fourteen patients received steroids. Forty two of 114 patients (36.8%)were steroid resistant. Thirty eight received calcineurin inhibitors (CNI). Seventeen (44.7%) were CNI resistant of which 2 achieved remission with alternate immunosuppression. Eleven (9.5%) patients had worsening renal function - 9 had no remission, 2 had PR with none in CR (30 vs. 5.6% vs. 0, respectively, log-rank, p < 0.001). ACEi/ARBs use and remission of proteinuria were independently associated with better renal survival. Conclusion: Achieving remission, whether complete or partial, is the critical factor in predicting renal survival in nephrotic adults with primary FSGS. Steroid-resistant patients have reasonable renal survival, if proteinuria is reduced with timely use of alternate immunosuppression. CNI resistance is a major hurdle in management with limited treatment options.

Collagen IV nephropathies (COL4Ns) comprise benign familial microscopic hematuria, thin basement membrane nephropathy (TBMN), X-linked Alport syndrome (AS) and also autosomal recessive and dominant AS. Apart from the X-linked form of AS, which is caused by hemizygous mutations in the COL4A5 gene, the other entities are caused by mutations in the COL4A3 or COL4A4 genes. The diagnosis of these conditions used to be based on clinical and/or histological findings of renal biopsies, but it is the new molecular genetics approach that revolutionised their investigation and proved particularly instrumental, especially, in many not so clear-cut cases. More recently, the spectrum of COL4N has expanded to include late onset focal segmental glomerulosclerosis (FSGS) that develops on top of TBMN in later life. Also, other reports showed that some patients with a primary diagnosis of familial FSGS proved to have variants in COL4 genes. In the presence of a renal biopsy picture of FSGS and in the absence of either electron microscopy studies or molecular genetic studies that point to TBMN and COL4N, the patient and his family may be mistakenly diagnosed with hereditary FSGS leading to unnecessary further investigations, erroneous family counselling and improper corticosteroid treatment. TBMN is a frequent finding in the general population, and according to several recent reports, it may be the underlying cause and the explanation for many familial and sporadic cases of late-onset FSGS with non-nephrotic proteinuria. This is an important new finding that needs widespread recognition. It is anticipated that the molecular genetic analysis with next generation sequencing will certainly offer timely correct diagnosis.

Background/Aims: A subset of patients who present with proteinuria and are diagnosed with focal segmental glomerulosclerosis (FSGS) have inherited heterozygous COL4A3/A4 mutations and are also diagnosed with thin basement membrane nephropathy (TBMN-OMIM: 141200). Two studies showed that co-inheritance of NPHS2-p.Arg229Gln, a podocin variant, may increase the risk for proteinuria and renal function decline. Methods: We hypothesized that additional podocin variants may exert a similar effect. We studied genetically a well-characterized Cypriot TBMN patient cohort by re-sequencing the NPHS2 coding region. We also performed functional studies in cell culture experiments, investigating the interaction of podocin variants with itself and with nephrin. Results: Potentially disease-modifying podocin variants were searched for by analyzing NPHS2 in 35 ‘severe' TBMN patients. One non-synonymous variant, p.Glu237Gln, was detected. Both variants, p.Arg229Gln and p.Glu237Gln, were tested in a larger cohort of 122 TBMN patients, who were categorized as ‘mild' or ‘severe' based on the presence of microscopic hematuria alone or combined with chronic renal failure and/or proteinuria. Seven ‘severe' patients carried either of the 2 variants; none was present in the ‘mild' patients (p = 0.05, Pearson χ2). The 7 carriers belong in 2 families segregating mutation COL4A3-p.Gly1334Glu. Inheritance of the wild-type (WT) and mutant alleles correlated with the phenotype (combined concordance probability 0.003). Immunofluorescence (IF) experiments after dual co-transfection of WT and mutant podocin suggested altered co-localization of mutant homodimers. IF experiments after co-transfection of WT podocin and nephrin showed normal membrane localization, while both podocin variants interfered with normal trafficking, demonstrating perinuclear staining. Immunoprecipitation experiments showed stronger binding of mutant podocin to WT podocin or nephrin. Conclusion: The results support the hypothesis that certain hypomorphic podocin variants may act as adverse genetic modifiers when co-inherited with COL4A3/A4 mutations, thus predisposing to FSGS and severe kidney function decline.

Background/Aims: The pathophysiological pathways involved in the pathogenesis and evolution of renal fibrosis, have not been fully elucidated. Transforming growth factor-beta1 (TGF-β1) is involved in the development of renal scarring. Apoptosis is responsible for intrinsic cell deletion observed in end-stage kidney disease. Myofibroblasts are involved in the development of renal fibrosis. This study investigates whether there is a potential relationship between apoptosis, myofibroblast infiltration and TGF-β1 expression in the kidney of patients with glomerulonephritis (GN). Methods: Forty patients with various types of GN were included in the study. Myofibroblasts and TGF-β1 positive cells were detected in kidney biopsies by immunohistochemistry, while apoptotic cells were detected by the in situ end labelling of fragmented DNA. Results: Myofibroblasts were identified in the glomeruli of some patients with severe mesangioproliferative GN and glomerulosclerosis but a more intensive myofibroblast expression was found in the renal interstitium. TGF-β1 was expressed in the cytoplasm of tubular epithelial cells, in the renal interstitium and in the glomeruli of patients with GN. Apoptotic cells were mainly detected in the tubules and interstitium and were present in areas with intense myofibroblast infiltration. Positive correlations were observed between the intensity of myofibroblast expression in the interstitium and apoptosis in the tubulointerstitial area (r = 0.521, p < 0.01) as well as TGF-β1 expression (r = 0.462, p < 0.05) and degree of renal impairment (r = 0.430, p < 0.05). Conclusions: These observations suggest that myofibroblast infiltration and apoptosis along with TGF-β1 expression are associated with the development of interstitial fibrosis in patients with glomerular disease.

Background: Blockade of the renin-angiotensin system plays a key role in suppressing the progression of renal diseases. It has not been well established whether this therapy provides additional effects when combined with vitamin D or its analog in a model of adriamycin (ADR)-induced nephropathy. Methods: We evaluated the effect of an angiotensin II subtype 1 receptor blocker (telmisartan) combined with a vitamin D analog (oxacalcitriol) on mice ADR-induced nephropathy (9.5 mg/kg single intravenous injection). We also tested immortalized murine podocytes to examine the effects on podocyte apoptosis. Results: Mice with ADR-induced nephropathy developed progressive albuminuria and glomerulosclerosis within 30 days accompanied by decreased expression of slit diaphragm (SD)-associated proteins (nephrin and podocin), reduced numbers of podocytes, and increased systolic blood pressure. Treatment with telmisartan or oxacalcitriol alone moderately ameliorated kidney injury. The combined treatment most effectively reduced the albuminuria and glomerulosclerosis. These effects were accompanied by the restoration of SD-associated proteins, reduction of podocyte apoptosis, and prevention of podocyte depletion in the glomeruli. Treatment with telmisartan, oxacalcitriol, and the combination therapy resulted in similar reductions in systolic blood pressure. In cultured murine podocytes, ADR stimulated the expression of Bax/Bcl-2 and apoptosis as determined by Hoechst 33342 staining. These changes were effectively inhibited by telmisartan or oxacalcitriol, but the combination treatment most effectively reduced these effects. Conclusions: These data demonstrated that application of a renin-angiotensin system blocker plus a vitamin D analog effectively prevented renal injury in ADR-induced nephropathy. The observed amelioration of renal injury may be partly attributable to antiapoptotic effects in podocytes.

Age-related and disease-induced glomerulosclerosis (GS) in rats have both been well defined in a number of strains and experimental models, but the inter-relationship between the two is not clear. The present study was undertaken to compare the pattern of glomerular injury in these two types of GS. One- and two-shot Thy1 glomerulonephritis (GN) was induced at 2 months of age and followed for 12 months. At 12 months histological injury in proteinuric rats was characterized by segmental hyaline lesions. Two-shot Thy1 GN resulted in accelerated, but morphologically identical injury at 8 months. Histological lesions predictive of subsequent accelerated GS were evaluated at 1, 2, 4 and 6 months. In this regard, glomerular hypercellularity, rather than hypertrophy or matrix increase, was the most consistent histological index of later accelerated disease. The profibrotic cytokines transforming growth factor (TGF)-β1 and -β3 were localized distinctly to segmental hyaline lesions, but not to areas of matrix increase within the glomerular tuft. This study reveals that GS after Thy1 GN represents acceleration of an age-related disease, presents evidence for use of prolonged glomerular hypercellularity as the best histological index of future disease progression, and correlates the key lesion of GS in these animals, the segmental hyaline lesion, with the presence of TGF-β peptides.

Focal segmental glomerulosclerosis (FSGS) is the histologic expression of diverse processes affecting the renal glomeruli and occurring in primary and secondary forms. A number of pathogenic factors have been identified in primary FSGS, and multiple etiologies have been defined as contributing factors for the development of secondary FSGS. There is a complex interplay between etiologic and pathogenic factors, progression factors and intervention in the phenotypic expression of FSGS. Key components include genetic predisposition, environmental influences and the impact on phenotype of pharmacologic intervention. The phenotypic spectrum for FSGS ranges from mild proteinuria and slow progression to a devastating clinical syndrome characterized by heavy proteinuria and rapid loss of renal function over a period of months. While the pathogenesis is unknown, much is known about factors which are involved in the development and progression of both primary and secondary FSGS. The ultimate goal of understanding pathogenesis is to provide specific nontoxic therapy for those patients who have a definable form of FSGS. While this goal is not yet in sight, many types of intervention, not addressed in the current chapter, can influence the course of various diseases presenting as FSGS. Until specific therapy can be fashioned, it is necessary for the clinician caring for these patients to appreciate the complex interaction of pathogenetic factors involved in the development and pregression of FSGS, as a rationale for providing intervention to prevent development of the disease and to slow its course.

In children who exhibit a frequently relapsing course of minimal change disease (MCD), treatment is often difficult and frustrating to the physician and the family since the goal of a sustained remission remains elusive. The progression of the disease is often unpredictable from its clinical presentation since the lesion of MCD may evolve into a more severe form, such as mesangial IgM nephropathy or focal segmental glomerulosclerosis (FSGS), without alteration in signs and symptoms. Alkylating agents such as cyclophosphamide, or immunosuppressives such as cyclosporine can induce a more sustained remission, but are fraught with inherent toxicity, which makes difficult the decision to use these drugs in patients with MCD. Over a 10-year period we studied 49 patients who had more than one renal biopsy. Repeat biopsies were performed either to delineate the morphological lesion prior to change in therapy, or to confirm suspected drug toxicity, which would necessitate discontinuation of therapy. A total of 83 repeat biopsies were performed in these 49 patients. Of the 49 patients, 25 had MCD, and in 21 of these the lesion evolved into either IgM nephropathy (n = 7) or FSGS (n = 14). Of patients with IgM nephropathy (n = 12), 50% evolved into FSGS. The clinical diagnosis made prior to the repeat biopsy did not confirm with the histological diagnosis in 43% of cases, and a change in therapy or cessation of therapy was carried out in 43 of 83 repeat biopsy instances. Since the complications were mild and the ability of clinical findings to accurately predict the histological lesion limited, we conclude that repeat renal biopsies are a useful tool to fashion optimal therapy in children with frequently relapsing nephrotic syndrome.

To investigate how the interruption of the renin-angiotensin system (RAS) and reduction of blood pressure (BP) affect the lesions of chronic focal and segmental glomerulosclerosis (FGS), we studied the effects of high and low doses of angiotensin-converting enzyme inhibitors (temocapril – TEM) a newly developed ACE inhibitor with biliary tract excretion, on the hypertensive model of FGS. A high dose of TEM significantly lowered BP and suppressed both intense proteinuria and glomerular extracapillary lesions including macrophage infiltration. On the other hand, although a low dose of TEM did not significantly lower BP throughout the experimental period, it prevented renal lesions almost in the same manner as high-dose TEM with suppression of c-myc gene expression in glomeruli. These findings suggest that in PAN-induced chronic FGS, the systemic BP elevation could not be the major factor for the progression of renal damage which TEM could prevent without significant lowering of BP.

Background/Aim: Few prognostic markers have found general acceptance in IgA nephropathy (IgAN). The aim of the present study was to search for significant predictor(s) at the time of biopsy. Methods: Fifty-five patients with IgAN undergoing evaluation and treatment at our institution were examined regarding clinicopathologic features at the time of renal biopsy and, if possible, at follow-up. Factors predictive of outcome were evaluated. Renal histopathology was quantified using a glomerulosclerosis index (GSI), a tubulointerstitial index (TII), and a crescent index (CI). Results: The serum creatinine concentration (S-Cr) showed positive correlations with proteinuria and serum total cholesterol concentration, as well as with histopathologic findings. Heavy proteinuria (≧3.0 g/24 h) was associated with higher S-Cr and greater severity of pathologic abnormalities than with milder proteinuria. At follow-up, 6 patients progressed to chronic renal insufficiency, in whom the S-Cr increased by at least 50% to reach or exceed 1.5 mg/dl (132.6 µmol/l). By univariate analysis, elevated GSI, TII, and S-Cr, presence of nephrotic syndrome, elevated CI, and elevated total cholesterol were found to be negative predictors, in descending order of odds ratio. In multivariate analysis, however, only TII independently predicted unfavorable outcome. Conclusion: Renal biopsy in IgAN may be the most powerful predictor for renal outcome; an advanced tubulointerstitial lesion is unfavorable.

Background/Aim: There is increasing evidence that hypoalbuminemia and the inability of the renal distal tubule to excrete salt are not the only factors responsible for nephrotic edema. We tested the possibility that vascular hyperpermeability also plays a role in the pathophysiology of nephrotic edema in human primary glomerulonephritis. Methods: We investigated the capillary permeability by means of a standardized test using albumin labelled with technetium (99mTc-albumin) in 20 healthy adults and in 101 nephrotic adult patients comprising 60 patients with idiopathic nephrotic syndrome (INS; minimal-change nephropathy and segmental glomerulosclerosis), 32 with idiopathic membranous nephropathy (IMN) and 9 patients with idiopathic type I membranoproliferative glomerulonephritis (MPGN). The patients and healthy controls were also compared with a group of women (n = 25) with idiopathic cyclic edema, a disease in which an increase in capillary permeability plays a pivotal role. The capillary permeability measured by the Landis isotope test is normal in edematous patients with cardiac and renal impairment unrelated to glomerular disease, cirrhosis, hypothyroidism, lymphatic obstruction and diuretic abuse. As values were not normally distributed, nonparametric analysis of variance was used (Kruskal-Wallis test), and patient groups were compared with healthy controls and with women with idiopathic cyclic edema by means of the two-tailed nonparametric Mann-Whitney test. The effects of high-dose steroids and Ginkgo biloba extract (Tanakan®; an agent able to improve capillary permeability) were analyzed by means of the two-tailed nonparametric Wilcoxon test. Results: The capillary permeability was significantly increased (Mann-Whitney test) in each glomerular disease group compared with the healthy controls. 99mTc-albumin extravasation values (%; median and range in parentheses were the following: healthy controls 0 (0–8.4); idiopathic cyclic edema patients 11.5 (8–24), p < 0.001; INS 20 (0–50), p < 0.0001; IMN 12.5 (0–40), p < 0.001, and MPGN 10 (0–40), p < 0.05. An increase in capillary permeability exceeding the upper limit of control values ( >8% of 99mTc-albumin extravasation) was observed in 88% of INS, in 53% of IMN and in 44% of MPGN patients. The increase in capillary permeability (%) was greater in idiopathic nephrotic patients than in idiopathic cyclic edema patients (p < 0.005, Mann-Whitney test) and was markedly reduced in nephrotic patients receiving high-dose steroids (n = 8) [before 25 (8–40); after 0 (0–25), p < 0.005 (Wilcoxon’s test)] and high doses of G. biloba extract (n = 16) [before 30 (8–50); after 2.5 (0–20, p < 0.0005 (Wilcoxon’s test)]. Conclusions: We conclude that capillary permeability is severely altered in most of the nephrotic patients with primary glomerulonephritis. These results strongly suggest that the capillary hyperpermeability plays a role in the pathophysiology of nephrotic edema in primary glomerular disease, especially in INS. We postulate that this widespread abnormality in capillary permeability is related to the release of vascular permeability factor and other cytokines by immune cells.

This study describes the occurence of hepatitis C virus (HCV) infection in the setting of focal segmental glomerular sclerosis (FSGS). All patients with the pathologic diagnosis of idiopathic FSGS between 1992 and 1996 at the University of Washington Hospitals were examined using a retrospective cohort study design. FSGS was determined by renal biopsy in the absence of secondary causes. Demographic, laboratory, and outcome data were collected in a standardized fashion. Six patients (50%) were infected with HCV. Patients with HCV infection and FSGS were primarily Black (67%), hypertensive (100%), had a history of intravenous drug abuse (83%), and had normal liver enzymes. Those with HCV infection and a history of IVDA appeared clinically and histologically similar to previously described cases of ‘heroin nephropathy’. We demonstrate that there is a high prevalence of HCV infection in our population of patients with idiopathic FSGS. Although this may simply reflect an epiphenomenon, we propose that HCV infection may play a role in the development of FSGS in a predisposed host.

In primary minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), increased lymphocyte reactivity to renal antigens has been defined. Soluble HLA class I antigen (sHLA-I) is actively secreted by T and B lymphocytes when they are stimulated by mitogens, antigens and lymphokines. To determine if serum and urine sHLA-I levels could predict steroid response in patients with MCD and differentiate those from FSGS, we have investigated 45 healthy controls, biopsy-proven 17 patients with MCD (edema and 24-hour urine protein >3.5 g/day), 8 patients with FSGS (24-hour urine protein >1 g/day) and 10 patients with membranous nephropathy (MGN) (24-hour urine protein >1 g/day). Before and after prednisone therapy (1 mg/kg/day or 2 mg/kg/EOD for 8 weeks), the levels of serum and urinary sHLA-I were measured by ELISA (sHLA-STAT; Sangstat Co., Calif., USA). After 8 weeks of treatment, 10 patients with MCD were responders (MCD-CR) while the other 7 patients with MCD were nonresponders (MCD-NR). Three of 7 patients with MCD-NR were re-biopsied and finally diagnosed as FSGS. They were included in the data of patients with FSGS. In healthy controls, serum sHLA-I was detected (415 ± 256 ng/ml), but urinary sHLA-I was not. At entry, there were no differences in age, sex, serum Cr and 24-hour urine protein among the patients with MCD-CR, MCD-NR and FSGS, but serum albumin was significantly elevated in patients with FSGS and MGN (p < 0.05). Serum sHLA-I levels were notably elevated in MCD-CR (1,040 ± 1,066 ng/ml), in MCD-NR (668 ± 315 ng/ml) and in FSGS (713 ± 790 ng/ml), but not in patients with MGN (444 ± 86 ng/ml) when compared with controls (p < 0.05). On the other hand, urinary sHLA-I levels in MCD-NR (541 ± 239 ng/mg Cr) and in FSGS (457 ± 239 ng/mg Cr) were significantly higher than those in MGN (125 ± 28 ng/mg Cr) and in MCD-CR (100 ± 42 ng/mg Cr, p < 0.05) and these substantial differences were maintained for 8 weeks. In all patients, serum and urinary sHLA-I levels were not reduced during 8 weeks of steroid therapy. We conclude that elevated serum and urinary sHLA-I levels reflect increased cellular immune response and disease activity in patients with MCD and FSGS. In patients with MCD, urinary sHLA-I may be an easily measurable indicator of predicting steroid response, while MCD-NR with high urinary sHLA-I levels might be re-evaluated for the possibility of FSGS.

Although a lot of animal models of proteinuria have been established, proposals for the mechanisms of proteinuria are still controversial. In this work, during an 18-day trial, mice injected with a single dose of adriamycin (AD) rapidly showed combined glomerular albuminuria and immunoglobulinuria, progressively elevated levels of nitrite/nitrate in urine, hypercholesterolemia, abnormal renal function, segmentally or globally glomerular hyalinosis/sclerosis associated with tubular atrophy, enhanced glomerular deposition of immunoglobulins and fibrinogen, augmented expression of matrix components in the whole glomerular tuft, and loss of glomerular negative charge property. These laboratory and pathological features are comparatively similar to those of human focal segmental glomerulosclerosis in the advanced state. Juxtamedullary glomeruli appear to be more susceptible to the AD-related nephrotoxicity than those in the superficial renal cortex. A change in size-dependent glomerular permselectivity may precede a charge-dependent defect in glomeruli in this mouse model of proteinuria. Data in this study confirm the hypothesis of glomerular hyperfiltration involved in the pathogenesis of this chronic glomerulopathy associated with proteinuria in mice. In addition, nitric oxide may play a crucial role in the progression of the chronic glomerulopathy model.

Two patients, a 47-year-old woman suffering from chronic renal failure, hyper- uricemia and gout, and her 26-year-old son with hyperuricemia and chronic renal failure, are described. The father and two siblings of the woman had died of chronic renal failure. Both patients had a markedly reduced fractional excretion of urate, which was significantly increased by both benzbromarone and probenecid. A renal biopsy of the son revealed an unspecific chronic tubulointerstitial nephropathy. By light microscopy, many proximal tubular epithelial cells showed signs of apoptosis, which was confirmed with the specific TUNEL assay. We propose a hypothesis based on a gain-of-function mutation of the luminal anion exchanger of the proximal tubulus to explain reduced uric acid excretion, dominant inheritance and apoptosis of tubular epithelial cells in this rare disease. Treatment with a combination of allopurinol to reduce the renal urate load and benzbromarone to block the tubular anion exchanger and normalize fractional uric acid excretion is suggested.

In rats with five-sixth nephrectomy (remnant kidney), glomerulosclerosis was significantly reduced by dietary administration of vitamin E (alpha-tocopherol) during 11 and 16 weeks after reduction of nephron number. The activity of catalase and the production of H2O2 in remnant kidney cortex homogenate were not influenced by the vitamin E diet; however, the activities of glutathione peroxidase and superoxide dismutase were significantly increased (up to 140 and 180%, respectively, after 16 weeks). Lipid peroxidation, evaluated by malonaldehyde and 4-hydroxynonenal concentrations, was decreased in cortex homogenates and in urine. Though the extent of the effect of vitamin E on antioxidant enzyme levels and lipid peroxidation is small, the important reduction of glomerulosclerosis is in favor of dietary supplementation with vitamin E.

We have already reported an equally attenuating effect of castration or estrogen administration on the development of focal segmental glomerulosclerosis (FSGS) in the animal models of a short-term experimental period ended at 24 weeks. In the present study, to clarify the importance of the experimental period in studying the pathogenesis of the development of FSGS, we investigated a long-term effect of castration or estrogen administration on FSGS using an experimental model of uninephrectomized Sprague-Dawley (SD) rats ended at 54 weeks. Thirty male SD rats received unilaterally right nephrectomy at 6 weeks of age. They were divided into three groups: group 1 was control; group 2 was castrated at 6 weeks, and group 3 was administered 0.2 mg estrogen subcutaneously once a month from 6 weeks of age. Body weight, urinary protein, serum albumin and other serum constituents were investigated every 12 weeks from 18 to 54 weeks of age. Each group was studied morphologically at the end of the experiment. Castration attenuated glomerular injury to the same extent as seen in the study of a short-term experimental period, while estrogen administration failed to attenuate glomerular injury, although each treatment equally suppressed an urinary excretion of a sex-related low-molecular-weight (LMW) protein. Castration reduced significantly kidney weight (KW), glomerular volume (GV) and serum growth hormone (GH) levels, but estrogen treatment failed to reduce KW and GV, and conversely elevated GH levels. These results suggest that a sex-related LMW protein influenced by castration or estrogen treatment may not play an important role in the development of FSGS and that an increase in plasma GH levels may contribute to the failure of an attenuating effect of estrogen on glomerular injury.

To determine the contribution of the ovary to the development of glomerulo-sclerosis, we investigated the effect of ovariectomy on glomerulosclerosis, using the unilaterally nephrectomized (Nx) female Sprague-Dawley rat. At 6 weeks of age, groups 2 and 3 underwent unilateral right nephrectomy and group 3 was simultaneously ovariectomized, while group 1 underwent a sham operation. Body weight, blood pressure, urinary protein, serum albumin, cholesterol, blood urea nitrogen and serum creatinine were checked every 2 months from 2 to 12 months after right nephrectomy. Control group 1, the Nx group 2 and the ovariectomized (Nx + ovariectomized) group 3 were studied morphologically at 6 and 12 months after nephrectomy. Body weight significantly increased in ovariectomized rats as compared with control and Nx rats. Nx rats became proteinuric with age. Ovariectomy significantly reduced proteinuria to the same levels in the controls. The glomerulosclerosis index was significantly higher in Nx rats than in either controls or ovariectomized rats. Ovariectomy attenuated glomerular injury in Nx rats, though not to the same levels in the control rats. Three groups showed no significant differences in either blood pressure or plasma somatomedin C. Growth hormone (GH) was significantly decreased by ovariectomy. The severity of glomerular injury and the glomerular tuft volume correlated with GH levels. Our results suggested that a decrease in plasma GH may contribute to the attenuating effect of ovariectomy on the development of glomerular injury in aging unilaterally Nx female Sprague-Dawley rats.

Milan normotensive rats, which spontaneously develop marked proteinuria (PU) and glomerulosclerosis (GS), were either kept on a normal-protein diet, a normal-protein diet with additional low-dose captopril (CAP), which did not affect blood pressure, or on a low-protein diet. After 8 months PU (79 +/- 25 mg/day) GS (3 +/- 2%) and total glomerular volume (TGV; 27.9 +/- 2.9 mm3/kidney) were significantly lower (p0.05) in the low-protein diet group than in both the normal-protein group (PU 583 +/- 210 mg/day, GS 12 +/- 5%, TGV 34.6 +/- 8 mm3/kidney) and the low-CAP group (PU 611 +/- 224 mg/day, GS 16 +/- 6%, TGV 41.8 +/- 8.6 mm3/kidney). In conclusion, the development of glomerular hypertrophy and GS in Milan normotensive rats was reduced by the low-protein diet, but not by low-CAP treatment.

The effects of a high salt diet on glomerular hypertrophy and sclerosis were examined in a focal glomerular sclerosis rat model. Sprague-Dawley rats were injected twice with Adriamycin (ADR, 2.5 mg/kg body weight) and then divided into 3 groups: (1) ADR rats fed a 1% sodium chloride (NaCI) diet (control ADR rats); (2) ADR rats fed an 8% NaC1 diet (ADR-NaC1 group), and (3) ADR rats fed a 10% sodium bicarbonate (NaHCO3) diet (the ADR-NaHCO3 group), and were then observed for 8 weeks. There were no differences in the blood pressure levels between the control ADR and ADR-NaC1 groups. The urinary protein excretion was significantly less in the ADR-NaC1 and ADR-NaHCO3 groups than in the control ADR group. However, a progressive increase in the blood urea nitrogen and serum creatinine associated with extensive glomerular sclerosis and hypertrophy was only observed in the ADR-NaC1 group. An increase in the glomerular diameter preceded the development of glomerulosclerosis in this group. Furthermore, a daily administration of amiloride, a Na+/H+ exchanger inhibitor, to the ADR-NaC1 rats prevented the development of glomerular hypertrophy and sclerosis. These results therefore suggest that the aggravated effect of a high salt diet on glomerular sclerosis may be related to glomerular hypertrophy which is associated with the stimulation of the Na+/H+ exchanger.

The effect of d-alpha-tocopherol on the progression of renal dysfunction was investigated in rats injected with adriamycin (ADR), a model of progressive glomerulosclerosis associated with the nephrotic syndrome. Treatment with d-alpha-tocopherol was started 1 day before or 1 day after ADR injections (BE-TOC or AF-TOC rats). When compared to rats without d-alpha-tocopherol treatment (ADR-CON rats), the serum total cholesterol and triglyceride levels were significantly lower in the BE-TOC and AF-TOC groups. In week 16, the LDL cholesterol level and the atherogenic index were both significantly lower in BE-TOC and AF-TOC rats than in ADR-CON rats. The urinary protein, serum creatinine, blood urea nitrogen, malondialdehyde, and systolic blood pressure levels as well as the glomerulosclerosis score were high in ADR-CON rats, and reduced in BE-TOC or AF-TOC rats. There were no significant differences in body weight and serum albumin between the three groups in week 16. It is concluded that d-alpha-tocopherol can improve hyperlipidemia and ameliorate glomerulosclerosis in rats with ADR-induced progressive renal failure. Thus, d-alpha-tocopherol may have the potential for clinical application to treat focal glomerulosclerosis.

Hypercholesterolemic Imai rats, especially males, spontaneously develop proteinuria and glomerulosclerosis. We have shown that castration attenuated the progression of glomerular injury in male Imai rats. The present study was designed to investigate whether the attenuating effect of castration on glomerulosclerosis is eliminated by administration of testosterone. Testosterone propionate (TP) eliminated the attenuating effect of castration on the progression of glomerular injury by significantly and dose dependently increasing proteinuria and enhancing glomerular sclerosis. TP at 1 mg failed to reverse glomerulosclerosis to the control levels, despite a dose of TP sufficient to restore urinary protein excretion, serom testosterone level and glomerular growth. The results indicated that besides testosterone other sex-related hormones may be involved in the development of glomerulosclerosis in male Imai rats.

The association of a spondyloepiphyseal dysplasia and disproportionate short stature with focal glomerular sclerosis is reported in two girls. Renal disease manifested by proteinuria at the age of 2.5 and 11 years, leading to treatment-resistant nephrotic syndrome over 15 and 45 months, respectively. One patient went into end-stage renal failure shortly after nephrotic syndrome developed, the other died from sepsis. The association of spondyloepiphyseal dysplasia and focal glomerular sclerosis with nephrotic syndrome may represent a distinct disease entity.

Aim: The purpose of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C/T polymorphism and the prevalence and course of focal segmental glomerulosclerosis (FSGS) in our pediatric population. Methods: Genotypes for MTHFR were determined in 15 primary FSGS patients (male/female, 6/9) and 238 control subjects (male/female, 110/128) by the polymerase chain reaction and restriction fragment length polymorphism method. Results: For the whole group, the genotype frequencies (CC/CT/TT) of MTHFR in FSGS and control subjects were almost comparable. The TT genotype was associated with early onset of the disease as compared with the CC genotype. Furthermore, all the patients with the TT genotype had steroid-resistant FSGS and developed into end-stage renal failure, while those carrying either CC or CT genotype did not. Conclusion: We speculate that the TT genotype may be associated with early development and progression of childhood FSGS. Confirmatory studies using larger and ethnically distinct populations are needed to reveal the role of homocysteine in FSGS with consideration of medical interventions.

Adriamycin (ADR)-induced nephropathy is characterized by focal and segmental glomerulosclerosis and is supposed to be an ideal model of chronic progressive renal disease. The aim of our study was to investigate whether there might be an altered activity of glomerular proteinases in ADR nephropathy, thereby aggravating glomerular protein accumulation as an important initiating hallmark of glomerulosclerosis. In fact, we could demonstrate significantly enhanced levels of intraglomerular protein and DNA content in the experimental animals at week 7, 12 and 22 after administration of ADR. When relating intraglomerular proteinase activity, which was measured in ultrasonically destroyed isolated glomeruli, obtained by differential sieving techniques, to the intraglomerular protein and DNA content, this enzyme activity was significantly reduced throughout the observation period. Based on these data, we suggest that this relatively decreased proteinase activity in glomeruli exposed to ADR might play a pathogenetic role in the development of glomerular hypertrophy, an important harbinger of glomerulosclerosis.

Experimental evidence suggests a pathogenetic role for lipids in focal glomerulosclerosis (FGS) analogous to atherosclerosis. As foam cells (FC) are an important factor in atherosclerosis, a retrospective comparative study was done to evaluate the significance of intraglomerular FC in human FGS. Glomerular FC infiltration was evaluated in 115 biopsies of FGS, 120 biopsies of membranous glomerulonephritis (MGN) and 50 biopsies of minimal-change disease (MCD). Selected clinical and laboratory data collected at about the time of biopsy were reviewed. The proportion of biopsies showing glomerular FC was much higher in FGS (70%) than in either MGN (12%) or MCD (0%) p less than 0.001. The mean percent (+/- SD) of glomeruli with FC per biopsy was significantly greater in FGS (7.9 +/- 9.9) than in MGN (2.0 +/- 7.8; p less than 0.0001). Of the 14 MGN biopsies with FC, 13 showed superimposed FGS. Mean serum total cholesterol and triglyceride were not significantly higher in FGS than in either MGN or MCD. The results demonstrate a close association of glomerular FC infiltration with FGS.

To evaluate renal terminal complement activation in patients with glomerular diseases, we measured terminal complement complexes (TCCs) in plasma and urine with sandwich enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody against a C9 neoepitope expressed on TCC and a polyclonal antihuman C7 antibody. TCCs were detectable in plasma but not in urine in most of normal controls. In plasma, TCC levels were elevated in 4 of 22 patients with lupus nephritis and in 6 of 12 with membranoproliferative glomerulonephritis. However all patients with IgA nephritis, focal glomerulosclerosis, idiopathic membranous nephritis and idiopathic minimal change nephrotic syndrome (MC) showed normal values. In urine, TCCs were detectable in almost all patients with heavy proteinuria (greater than or equal to 100 mg/ml) except MC. The TCCs present in urine were partially purified by gel filtration using Sepharose 6B and were found to contain C5, C6, C7, C8, C9 and S protein by ELISA. Although the molecular weight of TCC is similar to that of IgM, the fractional excretion rate of TCC was about 100 times higher than that of IgM. These results suggest that TCCs detectable in urine contain SC5b-9 complexes and are mostly of renal origin.

Immunophenotyping of infiltrating glomerular and interstitial mononuclear leukocytes performed in renal tissues of 15 patients with focal segmental glomerulosclerosis (FSGS) was compared to 15 normal kidneys in order to investigate a possible role for cell-mediated immunity (CMI) in FSGS. In addition, distribution of HLA class II (-DQ, -DR, -DP and -DY) antigens and of the intercellular adhesion molecule 1 (ICAM-1) as well as the expression of well-defined renal antigens along the human nephron was analyzed. In comparison to normal kidneys, a reduction in HLA class II antigens of ICAM-1 and of renal antigens defined by the monoclonal antibodies TN8-TN10 was observed in sclerotic glomeruli. Furthermore, an increased number of T lymphocytes was found in glomeruli of FSGS with slight predominance of the CD8+ subset. Interstitial inflammation was present in all FSGS cases except 1 with T lymphocytes and monocytes/macrophages constituting the predominant infiltrating cell types. In contrast to the glomerular T cells, the number of interstitial CD4+ cells was greater than the number of CD8+ cells in almost all cases. As a sign of activation, most interstitial inflammatory cells carried HLA class II antigens and some of them also expressed ICAM-1. Proximal tubular epithelial cells often presented an abnormal expression of HLA-DQ and HLA-DP antigens associated with aberrant expression of ICAM-1 and TN8. The number of interstitial mononuclear leukocytes was correlated to serum creatinine levels at the time of renal biopsy. The present results provide further support for the involvement of CMI in the pathogenesis of FSGS.

Twenty-eight patients with an onset of nephrotic syndrome within 1 year were randomized to receive either ciclosporin and low-dose prednisone or high-dose prednisone alone. Both groups were treated for 8 weeks. Thirteen of 14 children receiving combined therapy underwent remission versus only 8 of 14 children receiving prednisone alone (p less than 0.05). However, there was no difference between the two groups as regards the duration of remission after discontinuation of therapy. In patients receiving combined therapy, immunological studies showed that high interleukin producers had a more sustained remission. There was no evidence of ciclosporin-induced nephrotoxicity in this short-term therapeutic trial.

BUF/Mna strain rats spontaneously develop renal glomerular sclerotic lesions (RSL) at a nearly 100% incidence, diagnosed by hyperalbuminuria (greater than 500 mg/dl) and glomerular lesions morphologically resembling one type of human focal glomerular sclerosis (FGS). Genetic segregation of RSL development was studied by crossing the BUF/Mna strain with two other rat strains, WKY/NCrj and ACI/NMs, which were free of RSL. Two autosomal recessive genes in the BUF/Mna rats were found to determine the susceptibility to RSL in both combinations of crosses.

Nine patients with biopsy-proven primary focal and segmental hyalinosis and sclerosis (FSHS) and steroid-resistant nephrotic syndrome were randomly allocated to either a period of 4-6 months of treatment (ciclosporin; (CS); 5-8 mg/kg/24 h and warfarin) or to a control period (warfarin alone) and then crossed over to the alternative for a further 4-6 months. Serum creatinine levels increased at a similar rate during treatment and control periods of observation. Serum albumin levels increased (p less than 0.05) and urinary protein excretion decreased (p less than 0.01) in association with the CS therapy compared to the control period of observation. No patient had complete resolution of the nephrotic syndrome. In primary FSHS, CS treatment is unlikely to produce complete resolution of nephrotic-range proteinuria but does significantly decrease urinary protein excretion.

Background: The reduction in nephrons in IgA nephropathy is critical to the prognosis of this disease. However, the immunopathological mechanism of the modifications seen in glomerular lesions is not clear. We thus investigated the influence of nephron reduction by heminephrectomy on renal lesions in a high immunoglobulin A inbred strain of ddY mouse (HIGA mouse), which shows progressive mesangial sclerosis with elevated renal expression of transforming growth factor (TGF)-β. Methods: Five-week-old HIGA mice were heminephrectomized (Nx), and were evaluated in comparison with a sham-operated group (S) at 40 weeks old. Histological findings, immunoglobulin depositions (IgG, IgA, and IgM), and expressions of cytokine and extracellular matrix proteins (TGF-β, fibronectin, collagen type I and IV) were analysed. PCNA and TUNEL stainings were performed with electron microscopic detection of apoptosis. Tissue renin-angiotensin systems (RAS) were also investigated by real-time quantitative RT-PCR. Results: In the Nx group, the glomerular tuft area and ratio of mesangial matrix area per tuft were significantly increased, and the glomerular cell count per tuft area was significantly decreased. Glomerular immunoglobulin deposits of IgG, IgA, and IgM in Nx were all significantly expanded in the paramesangium. The glomerular expressions of TGF-β and the extracellular matrix proteins were significantly increased in Nx mice. In contrast to the significant decrease of PCNA-positive cells, TUNEL-positive cells were significantly increased in Nx. Angiotensin-converting enzyme (ACE) was significantly increased in the renal cortex of Nx. Conclusion: Simple heminephrectomy, other than 5/6 renal ablation, of HIGA mice may be a potential model for research into the progressive glomerulosclerosis of human IgA nephropathy. The pathological role of apoptosis is apparently involved in these disease processes, possibly through upregulated RAS.

Frasier syndrome is a rare human developmental disorder classically affecting 46,XY females and leading to male pseudohermaphroditism and chronic renal failure. We describe a family with both 46,XX and 46,XY females affected by the syndrome due to WT1 splice site mutations. The diagnosis of Frasier syndrome in 1 of the children led to the discovery of the syndrome in 2 other siblings, of whom 1 is asymptomatic. Since the mutation was not found in either parents, gonadal mosaicism was suggested. The implication of family screening for WT1 gene mutation in asymptomatic members is also discussed.

Background: Idiopathic collapsing glomerulopathy (ICG) and HIV-associated nephropathy (HIV-AN) are characterized by severe nephrotic syndrome, collapse and sclerosis of the glomerular tuft with prominent podocyte alterations and extensive tubulointerstitial lesions. We previously showed phenotypic changes in podocytes from patients with diffuse mesangial sclerosis, a severe glomerulopathy sharing several morphological features with collapsing glomerulopathy. The aim of this study was to analyze the podocyte phenotype in ICG and HIV-AN. Methods: Using immunohistochemical techniques, we studied the podocyte expression of the transcription factor WT1 and its target PAX2, GLEPP1, synaptopodin and vimentin as markers of podocyte maturity and of proliferating cell nuclear antigen (PCNA) as a marker of proliferation. Apoptosis was analyzed by the TUNEL method. Results from renal biopsies of ICG and HIV-AN were compared with those obtained from normal kidney, minimal change nephrotic syndrome (MCNS), focal and segmental glomerulosclerosis (FSGS) and membranous glomerulonephritis (MGN). Results: Abnormal distribution of WT1 and PAX2 and extensive loss of podocyte markers were observed in ICG and HIV-AN; this dysregulation was associated with podocyte proliferation without detectable apoptosis. In contrast, no podocyte changes were detected in MCNS or MGN. In FSGS, phenotypic changes, without proliferation, were restricted to podocytes surrounding focal and segmental glomerular lesions. Increased PCNA expression and apoptosis were observed in ICG and HIV-AN tubular cells. Conclusion: Dysregulation of podocyte phenotype and proliferation are present in both ICG and HIV-AN. This suggests that, whatever their etiology, both types of collapsing glomerulopathy share a common pathogenic pathway. Upregulation of cell proliferation and apoptosis observed in tubular epithelial cells is probably involved in the occurrence of severe tubulointerstitial lesions in collapsing glomerulonephritis.

Background/Aims: In the rat Adriamycin model of chronic renal failure, the development of glomerulosclerosis and tubulointerstitial lesions is accompanied by decreased activities and mRNA levels of the antioxidant enzymes. In this study, we investigated the effect of oral vitamin E supplementation on antioxidant enzyme activities in both the cortex and isolated glomeruli from Adriamycin-treated rats. Methods: Glomerulosclerosis, tubulointerstitial lesions and ferric iron deposits were evaluated by histochemical staining methods, and antioxidant enzyme activities were measured by spectrophotometry. Results: Vitamin E supplementation of the normal diet attenuates Adriamycin-induced glomerulosclerosis and tubulointerstitial lesions, but not proteinuria and serum total cholesterol, low-density lipoprotein cholesterol, triglycerides and total protein concentrations. In the cortex, vitamin E completely prevented a decrease in enzyme activity for Cu/Zn superoxide dismutase and catalase, and partly for Mn superoxide dismutase and glutathione peroxidase. In the glomeruli, vitamin E completely prevented a decrease in activity for Cu/Zn superoxide dismutase, catalase and glutathione peroxidase, and partly for Mn superoxide dismutase. Conclusion: Dietary supplementation of vitamin E protects the activities of antioxidant enzymes in the kidney cortex and glomeruli, and attenuates the evolution towards terminal renal failure in rats treated with Adriamycin.

A patient developed relapsing inflammatory demyelinating polyradiculoneuropathy associated with nephrotic syndrome. Renal biopsy showed focal-segmental glomerulosclerosis. The review of the literature disclosed that glomerulonephritis with and without nephrotic syndrome seems to be not uncommon in inflammatory demyelinating polyradiculoneuropathy, such as Guillain-Barré syndrome. membranous glomerulonephritis is the most frequent histologic diagnosis while minimal change nephropathy, 'acute glomerulonephritis' and postinfectious type glomerulonephritis are not often present. This is the first case of inflammatory demyelinating polyradiculoneuropathy associated with nephrotic syndrome due to focal-segmental glomerulosclerosis. Larger prospective studies are necessary and may contribute to the understanding of the pathogenesis of both, glomerulonephritis and inflammatory demyelinating polyradiculoneuropathy.