Electron microscopic findings suggestive of focal and segmental glomerulosclerosis in patients with steroid-resistant nephrotic syndrome

Distinction between minimal change disease and unsampled Focal Segmental Glomerulosclerosis is a challenging concept in kidney biopsy of patients with nephrotic syndrome with minimal histopathological findings. This study was performed to compare electron microscopic findings in patients with steroid-resistant nephrotic syndrome with minimal histopathological abnormalities and cases with Focal Segmental Glomerulosclerosis. This Cohort study was conducted in Cancer Institute, Imam Khomeini Hospital Complex, Tehran, Iran. Twenty patients with steroid-resistant nephrotic syndrome and minimal changes on the light microscopic study were selected as case group. Similarly, 20 patients with Focal Segmental Glomerulosclerosis were selected as the control group. Ultrastructural findings were re-evaluated and scored qualitatively (0–3+). In patients with minimal changes on light microscopic evaluation, clinical course of the disease was followed after 5 years. Mean ages of the patients (8 women and 12 men) in case and control groups were 12.9 and 15.9 years, respectively (p > 0.05). There was no significant difference in number of examined glomeruli and sampling from cortico–medullary junction area between the groups. The mean percentage of sclerotic glomeruli in control group was 15.4%. Tubular atrophy and interstitial fibrosis were more frequent in control patients. Podocyte proliferation, GBM duplication (involving more than 10% of capillary walls), and moderate to severe multifocal expansion of mesangial matrix were significantly more obvious in FSGS patient samples (p < 0.05). No statistically significant difference was found in severity of cytoplasmic vacuolization, GBM wrinkling and splitting between the groups. Most of (80%) the patients with minimal changes improved during the 5-year follow-up. Generally, we concluded that Podocyte proliferation, GBM remodeling, and moderate to severe mesangial matrix expansion are the most reliable findings on electron microscopic examination in favor of FSGS.     

Effect of angiotensin converting enzyme gene I/D polymorphism in South Indian children with nephrotic syndrome

Nephrotic syndrome is one of the most common childhood kidney diseases. It is mostly found in the age group of 2 to 8 years. Around 10%–15% of nephrotic syndrome cases are non-responders of steroid treatment (SRNS). Angiotensin converting enzyme (ACE) (I/D) gene association studies are important for detecting kidney disease and herein we assessed the association of ACE (I/D) polymorphism with nephrotic syndrome in South Indian children. We recruited 260 nephrotic syndrome (162 boys and 98 girls) and 218 (140 boys and 78 girls) control subjects. ACE I/D polymorphism was analyzed by PCR using genotype allele specific primers. In ACE (I/D), we did not find significant association for the ungrouped data of nephrotic syndrome children and the control subjects. Kidney biopsies were done in 86 nephrotic syndrome cases (minimal change disease, n = 51; focal segmental glomerulosclerosis, n = 27; diffuse mesangial proliferation, n = 8). We segregated them into the minimal change disease / focal segmental glomerulosclerosis groups and observed that the ACE 'D' allele was identified with borderline significance in cases of focal segmental glomerulosclerosis and the 'Ⅰ' allele was assessed as having very weak association in cases of minimal change disease. 'Ⅱ' genotype was weakly associated with minimal change disease. Gender specific analysis revealed weak association of 'ID' genotype with female nephrotic syndrome in females. Dominant expression of DD genotype was observed in males with nephrotic syndrome. Our finding indicated that ACE (I/D) has moderate association with focal segmental glomerulosclerosis. However, due to the limited number of biopsy proven focal segmental glomerulosclerosis subjects enrolled, further studies are required to confirm these results.     

Glomerular morphometry I: nephrotic syndrome in childhood

Glomerular morphometry was performed on needle biopsy specimens from 53 children with the nephrotic syndrome with minimal change (MC), focal global glomerulosclerosis (FGS) and segmental glomerulosclerosis (SGS). There were significantly fewer epithelial cells and more mesangial cells in SGS compared with MC and FGS. The number of epithelial cells decreased with age in MC and FGS, but was constantly low at all ages in SGS. There were no significant differences in differential cellularity between MC, with or without focal glomerular obsolescence or focal tubular atrophy, and FGS. Glomerular diameter increased with age in MC and FGS, but not in SGS. These findings support the view that SGS is a distinct entity rather than a variant of MC.     

Mesangial alterations in steroid-responsive minimal change nephrotic syndrome

Summary Renal biopsies from 25 children with steroid-sensitive minimal change nephrotic syndrome were evaluated retrospectively to determine whether there is any relation between the morphological changes and the frequency of relapses. Biopsy material was examined by light-, immunofluorescence-, and electron microscopy, and by morphometric methods. The patients were divided in a group of 15 children with frequent relapses (FR) and another group of 10 children with an absence of, or only infrequent, relapses (NR/IR). Semiquantitative evaluation of biopsy specimens disclosed no significant differences between groups, but morphometric measurements performed on toluidine stained semithin sections showed a significant increase of mesangial nuclei in FR compared with NR/IR (P<0.01). Furthermore, the mean area of mesangial nuclei was decreased and the relative frequency of smaller nuclear profiles was higher in patients with FR compared to NR/IR (p<0.01). These findings suggest mesangial cell activation in FR which may be related to a longer course of the disease prior to renal biopsy (mean 4.0 years in FR vs. 1.4 years in NR/IR). In our opinion, morphometric assessment of discrete mesangial alterations is a promising method for exploring clinicopathological correlations in minimal change nephrotic syndrome.Presented in part at the 5th International Symposium of Pediatric Nephrology, Philadelphia, USA, October 6–10, 1980     

Circulating anti-actin and anti-ATP synthase antibodies identify a sub-set of patients with idiopathic nephrotic syndrome

Idiopathic nephrotic syndrome (iNS) with resistance or dependence to steroids is a common disease in children but in spite of an increasing clinical impact its pathogenesis is unknown. We screened for the presence of circulating antibodies against glomerular (podocytes, mesangium) and tubular cells (tubular epithelia) a cohort of 60 children with iNS including 8 patients with a familial trait of iNS or with proven mutation of NPHS1-NPHS2 and 12 with good sensitivity to steroids. Positive sera were found in 8 cases, all belonging to the category without familial trait/molecular defects. The targets of antibodies were characterized with Western blot and MALDI-Mass utilizing beta-hexyl cell extracts separated with two-dimensional electrophoresis. In all cases antibodies of the IgM class were directed against ATP synthase beta chain alone (4 cases) or in combination with actin (3 cases); one child presented IgG against aldose reductase. The clinical picture was nephrotic syndrome with steroid resistance or dependence and variable cyclosporin sensitivity; 3 patients developed end stage renal failure. The basic pathology picture was focal segmental glomerulosclerosis (FSGS) in 4 cases and mesangial proliferative glomerulonephrites with deposition of IgM in 2. Overall, patients with circulating auto-antibodies could not be readely differentiated on clinical grounds with the exception of 3 children who developed positivity for antinuclear antibodies during the follow-up. Affinity-purified IgM from one patient who underwent plasmapheresis for therapeutical pourposes (but not from a normal pool) induced proteinuria in Sprague-Dawley rats and concomitant human IgM deposition within glomeruli. This is the first report of circulating anti-actin/ATP synthase beta chain antibodies in a subset of patients with iNS. Both pathological significance and clinical impact given by the presence of these antibodies and the relationship with other conditions such as lupus-erythematosus, characterized by their presence, must be defined.     

The development of focal segmental glomerulosclerosis in Masugi nephritis is based on progressive podocyte damage

We analysed the sequence of structural changes leading to focal segmental glomerulosclerosis (FSGS) in chronic Masugi nephritis. The protocol resulted in an immediate onset of the disease and the development of segmental sclerosis in a considerable proportion of glomeruli within 28 days of serum injection. Throughout the study, the degree of structural damage was significantly correlated with protein excretion. Even 1 day after injection of the serum, the whole spectrum of early lesions was encountered involving all three cell types. Endothelial detachments, mesangiolysis and podocyte foot process effacement were most prominent. There was focal persistence of capillary microthrombosis but, generally, mesangial and endothelial injuries recovered. The development of podocyte lesions was different: on one hand recovery was seen leading to the re-establishment of an interdigitating foot process pattern, and on the other persistent podocyte detachments from peripheral capillaries allowed the attachment of parietal epithelial cells to naked portions of the glomerular basement membrane (GBM), and thus to the formation of a tuft adhesion to Bowman's capsule. Progressive podocyte degeneration at the flanks of an adhesion permitted expansion of the adhesion by encroachment of parietal cells onto the tuft along the denuded GBM. Inside an adhesion, capillaries and mesangial areas either collapse or become obstructed by hyalinosis or thrombosis. Resident cells disappear progressively from inside an adhesion; macrophages may invade. Segmental sclerosis in this model consists of collapsed tuft structures adhering broadly to the cortical interstitium. Proliferation of mesangial cells did not contribute to this development. Recovery of endothelial and mesangial lesions was associated with cell proliferation in early stages of the disease; podocyte proliferation was not encountered at any stage. We conclude that the inability to replace an outmatched podocyte crucially underlies the development of sclerosis. Severe podocyte damage cannot be repaired but leads to tuft adhesions to Bowman's capsule followed by progressive collapse of tuft structures inside an adhesion, resulting in segmental glomerulosclerosis.     

Focal segmental glomerulosclerosis and mild intellectual disability in a patient with a novel de novo truncating TRIM8 mutation

Mutations in the TRIM8 gene have been described in patients with severe developmental delay, intellectual disability and epilepsy. Only six patients have been described to date. All the previous mutations were truncating variants clustered in the C-terminus of the protein. A previous patient with TRIM8-related epileptic encephalopathy was reported to have nephrotic syndrome. Here we describe the clinical, radiological and histological features of an 8-year-old male patient with a TRIM8 mutation who, in contrast to previous patients, had only mild intellectual disability and well-controlled epilepsy. The patient was found to have proteinuria at 2 years of age. Renal biopsy findings were suggestive of focal segmental glomerulosclerosis. His kidney function declined and peritoneal dialysis was started at 5 years of age. He underwent renal transplant at 7 years of age. Trio-based whole genome sequencing identified a novel de novo heterozygous frameshift mutation in TRIM8 (NM_030912.2) c.1198_1220del, p.(Tyr400ArgfsTer2). This patient is further evidence that TRIM8 mutations cause a syndrome with both neurological and renal features. Our findings suggest the spectrum of TRIM8-related disease may be wider than previously thought with the possibility of milder neurodevelopmental problems and/or a more severe, progressive renal phenotype. We highlight the need for proteinuria screening in patients with TRIM8 mutations.     

Rituximab treatment for difficult-to-treat nephrotic syndrome in children:a multicenter,retrospective study

Background/aimThis study aimed to evaluate the efficacy of rituximab in children with difficult-to-treat nephrotic syndrome, considering the type of disease (steroid-sensitive or –resistant) and the dosing regimen.Materials and methodsThis multicenter retrospective study enrolled children with difficult-to-treat nephrotic syndrome on rituximab treatment from 13 centers. The patients were classified based on low (single dose of 375 mg/m²) or high (2-4 doses of 375 mg/m²) initial dose of rituximab and the steroid response. Clinical outcomes were compared.ResultsData from 42 children [20 steroid-sensitive (frequent relapsing / steroid-dependent) and 22 steroid-resistant nephrotic syndrome, aged 1.9–17.3 years] were analyzed. Eleven patients with steroid-sensitive nephrotic syndrome (55%) had a relapse following initial rituximab therapy, with the mean time to first relapse of 8.4 ± 5.2 months. Complete remission was achieved in 41% and 36% of steroid-resistant patients, with the median remission time of 3.65 months. At Year 2, eight patients in steroid-sensitive group (40%) and four in steroid-resistant group (18%) were drug-free. Total cumulative doses of rituximab were higher in steroid-resistant group (p = 001). Relapse rates and time to first relapse in steroid-sensitive group or remission rates in steroid-resistant group did not differ between the low and high initial dose groups. ConclusionThe current study reveals that rituximab therapy may provide a lower relapse rate and prolonged relapse-free survival in the steroid-sensitive group, increased remission rates in the steroid-resistant group, and a significant number of drug-free patients in both groups. The optimal regimen for initial treatment and maintenance needs to be determined.     

利妥昔单抗在难治性微小病变型肾病综合征中的疗效及分析

目的 回顾性分析利妥昔单抗(rituximab,RTX)治疗难治性微小病变型肾病综合征(minimal-change nephrotic syndrome,MCNS)的疗效和安全性,探讨影响其疗效的可能因素.方法 纳入2018年12月至2020年6月于我院肾内科接受RTX治疗的MCNS患者23例,根据发病年龄分为儿童组...     

HLA class II associations with idiopathic nephrotic syndrome in children

Abstract: The occasional familial occurrence of idiopathic nephrotic syndrome (NS) points to a genetic predisposition. Reports on associations with certain HLA class II antigens support this hypothesis. In order to define the immunogenetic background of NS more precisely, HLA class II allele frequencies in 161 children with NS were studied by restriction fragment length polymorphism (RFLP) typing. The patient cohorts consisted of 87 children from Southwest-France and 74 from Southwest-Germany. The control group consisted of 118 French and 101 German unrelated individuals from the same geographical areas. HLA alleles were defined in patients with steroid-sensitive (SS) and steroid-resistant (SR) NS and in controls. RFLP typing revealed that the previously reported association between SSNS and HLA-DR7 is confined to the RFLP split 7.1 (DRB1*07) with a combined relative risk (RRcomb) of 6.2. HLA-DQB typing showed an increased frequency of the allele DQB2b (DQB1*0201) (RRcomb = 7.8). HLA-DQA typing showed an association of SSNS with DQA3 (DQA1*0201,0301,0302) (RRcomb = 4.1). The highest RR (16.5) for SSNS was found in German patients who carried the two DRB1 specificities 17.1 (DRB1*0301) and 7.1 (DRB1*07). All associations were stronger in SS patients with frequent relapses or steroid dependency than in non- or infrequent relapsers. SR patients exhibited no significant associations with HLA class II alleles.     

Coincident idiopathic focal segmental glomerulosclerosis collapsing variant and diabetic nephropathy in an African American homozygous for MYH9 risk variants

Familial clustering of disparate kidney diseases including clinically diagnosed hypertensive and diabetic nephropathy, idiopathic focal segmental glomerulosclerosis, and HIV-associated nephropathy are often observed in African Americans. Admixture mapping recently identified the nonmuscle myosin heavy chain 9 gene (MYH9) as a susceptibility factor strongly associated with several nondiabetic etiologies of end-stage renal disease in African Americans, less strongly with diabetes-associated end-stage renal disease. MYH9-associated nephropathies reside in the spectrum of focal segmental glomerulosclerosis/focal global glomerulosclerosis. The renal histology in proteinuric African Americans homozygous for MYH9 risk variants with longstanding type 2 diabetes mellitus is unknown. We report a case of coincident idiopathic focal segmental glomerulosclerosis collapsing variant and diabetic nephropathy in an African American homozygous for the MYH9 E1 risk haplotype. This case demonstrates that diabetic African Americans with overt proteinuria can have mixed renal lesions, including those in the spectrum of MYH9-associated nephropathy. Careful interpretation of kidney biopsies in proteinuric African Americans with diabetes is necessary to exclude coincident nondiabetic forms of nephropathy, precisely define etiologies of kidney disease, and determine the natural history and treatment response in mixed lesions of diabetes-associated and MYH9-associated kidney disease.     

Thrombotic thrombocytopenic purpura and focal segmental glomerulosclerosis associated with the use of ecstasy

Ecstasy is a drug, which causes serious side effects and sometimes it can be lethal. These effects are due to idiosyncratic reactions as a result of various stimulations in adrenergic receptors. Here we present a case of a 36-year-old male patient who was diagnosed with thrombotic thrombocytopenic purpura associated with the use of ecstasy. Plasmapheresis along with methylprednisolone treatment restores patient condition to normal.     

Posterior reversible encephalopathy syndrome in a child with steroid-resistant nephrotic syndrome: a case report and review of literature

Posterior reversible encephalopathy syndrome (PRES) is a rare and serious syndrome of central nervous system that can develop in both adults and children. It is characterized by acute onset of headache, confusion, seizures or focal neurological deficits along with radiological findings of white matter abnormalities in the parietal and occipital lobes. In the past ten years, this syndrome has been described mainly in adults, rare in children. Here, we report a case of PRES presenting in a 12-year-old girl with steroid-resistant nephrotic syndrome. Her neurological symptom was rapidly recovered after control of hypertension without discontinuation of cyclosporine A.     

NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review.

Nephrotic syndrome, characterized by edema, proteinuria, hyperlipidemia and low serum albumin, is a manifestation of kidney disease involving the glomeruli. Nephrotic syndrome may be caused by primary kidney disease such as focal segmental glomerulosclerosis. Mutations in the podocin gene, NPHS2, have been shown in familial and sporadic forms of steroid-resistant nephrotic syndrome, including focal segmental glomerulosclerosis. Podocin is an integral membrane protein located at the slit diaphragm of the glomerular permeability barrier. Complete information is lacking for the population frequency of some NPHS2 variants for all racial and ethnic groups. The most frequently reported variant, R229Q, is more common among European-derived populations than African-derived populations. We calculated crude odds ratios and 95% confidence intervals of childhood nephrotic syndrome and focal segmental glomerulosclerosis associated with R229Q heterozygosity using data from five studies. The R229Q variant is not associated with focal segmental glomerulosclerosis in the US population of African descent. In contrast, the R229Q variant is associated with a trend toward increased focal segmental glomerulosclerosis risk in European-derived populations, with an estimated increased risk of 20-40%. Our insight into the association between NPHS2 variants and nephrotic disease is hampered by the limitations of the existing studies, including small numbers of affected individuals and suboptimal control groups. Nevertheless, the available data suggest that large epidemiological case-control studies to examine the association between NPHS2 variants and nephrotic syndrome are warranted.     

Second-hand smoke worsens allergies

Glomerular diseases with severe defects in glomerular permeability give rise to heavy proteinuria and can present as nephrotic syndrome. There are many different causes of the nephrotic syndrome and a renal biopsy is nearly always needed to elucidate the underlying disease. During the last decade, substantial advances have occurred in the understanding of the pathophysiological mechanisms involved in immune-mediated glomerular diseases. Here, we review the diagnostic and prognostic implications of recent progress on the understanding of membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, amyloidosis, IgA nephropathy and membranoproliferative glomerulonephritis.     

Disseminated cryptococcosis in a patient with nephrotic syndrome

Disseminated cryptococcosis mainly occurs in patients with impaired cell mediated immunity. We present a case of disseminated cryptococcosis in a non-HIV patient with nephrotic syndrome who never received immunosuppression. Cultures of bone marrow aspirate, cerebrospinal fluid analysis and histology of skin lesions were all consistent with Cryptococcus neoformans infection. Treatment with amphotericin B followed by fluconazole was successful and in the course of two months when, the skin nodules disappeared.     

小儿局灶节段性肾小球硬化53例临床病理分析

目的：探讨小儿局灶节段性肾小球硬化（FSGS）的病理特点及发病机制。方法：对53例肾穿标本进行光镜，电镜及免疫荧光检测，结果：肾小球局灶节段性透明变性及间质泡沫细胞浸润在小儿原发性FSGS中是一个较为特性的表现。原发性FSGS中，尖端病变一型预后良好，一部分轻微病变患者可能发展为FSGS。出现继发性FSGS则是预后不良的表示。结论：区别原发性还是继发性FSGS对临床治疗，估计预后意义重大。     

原发性肾病综合征患儿539例病理类型及随访

目的分析原发性肾病综合征（PNS）患儿的病理类型、治疗及随访情况。方法纳入2005年1月至2009年12月在湖南省儿童医院肾内科住院的诊断为PNS,进行肾脏病理学检查且随访时间≥6个月的患儿,根据年龄分为〈2岁组、～5岁组、～10岁组和〉10岁组,对不同年龄组肾脏病理类型、对糖皮质激素的反应、转归及随访资料进行分析。结果共纳入539例PNS患儿,男性402例,女性137例,男女比例为2.9∶1;〈2岁组159例（29.5%）,～5岁组269例（49.9%）,～10岁组84例（15.6%）,〉10岁组27例（5.0%）（P〈0.01）。①微小病变274例（50.8%）,局灶节段性肾小球硬化79例（14.6%）,系膜增生性肾小球肾炎173例（32.1%）,膜增生性肾小球肾炎6例（1.1%）,膜性肾病4例（0.74%）,增生硬化性肾小球肾炎2例（0.37%）,脂蛋白肾病1例（0.18%）。不同年龄组间肾脏病理类型的分布差异有统计学意义（P〈0.05）。②对糖皮质激素敏感和依赖的PNS患儿以微小病变为主（分别为62.4%和69.6%）,对糖皮质激素耐药的PNS患儿以系膜增生性肾小球肾炎为主（48.4%）。③539例中239例完全缓解,75例部分缓解,61例无效,158例症状控制,尿蛋白（-）,但仍在服用泼尼松。6例患儿分别因对糖皮质激素耐药,病情不能缓解,合并严重感染或进展至终末期肾病放弃治疗而死亡。结论儿童PNS的发病高峰年龄、肾脏病理类型以及对糖皮质激素耐药的发生率可能已发生改变,并且在不同年龄患儿间存在差异。