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.     

Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration

Mutations of the novel renal glomerular genes NPHS1 and NPHS2 encoding nephrin and podocin cause two types of severe nephrotic syndrome presenting in early life, Finnish type congenital nephrotic syndrome (CNF) and a form of autosomal recessive familial focal segmental glomerulosclerosis (SRN1), respectively. To investigate the mechanisms by which mutations might cause glomerular protein leak, we analysed NPHS1/NPHS2 genotype/phenotype relationships in 41 non-Finnish CNF patients, four patients with congenital (onset 0 to 3 months) focal segmental glomerulosclerosis and five patients with possible SRN1 (onset 6 months to 2 years). We clarify the range of NPHS1 mutations in CNF, detecting mutation 'hot-spots' within the NPHS1 coding sequence. In addition, we describe a novel discordant CNF phenotype characterized by variable clinical severity, apparently influenced by gender. Moreover, we provide evidence that CNF may be genetically heterogeneous by detection of NPHS2 mutations in some CNF patients in whom NPHS1 mutations were not found. We confirm an overlap in the NPHS1/NPHS2 mutation spectrum with the characterization of a unique di-genic inheritance of NPHS1 and NPHS2 mutations, which results in a 'tri-allelic' hit and appears to modify the phenotype from CNF to one of congenital focal segmental glomerulosclerosis (FSGS). This may result from an epistatic gene interaction, and provides a rare example of multiple allelic hits being able to modify an autosomal recessive disease phenotype in humans. Our findings provide the first evidence for a functional inter-relationship between NPHS1 and NPHS2 in human nephrotic disease, thus underscoring their critical role in the regulation of glomerular filtration.     

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.     

A case of acute polyneuropathy with nephrotic syndrome showing transient proximal sensory conduction defects

Acute sensorimotor polyneuropathy that resembles Guillain-Barré syndrome (GBS) is rarely accompanied with nephrotic syndrome, and its underlying immunological mechanisms are unclear. A 56-year-old man presented with simultaneous acute progressive symmetric sensorimotor polyneuropathy and proteinuria. A kidney biopsy revealed focal segmental glomerulosclerosis. Serial electrophysiologic studies showed only a transient proximal conduction block in the median nerve, stimulated somatosensory evoked potential and prolonged terminal latencies of the median and peroneal nerves. The patient's neurologic deficits and kidney dysfunction recovered with corticosteroid treatment. Our case showed that somatosensory evoked potential study can be an important objective tool in the diagnosis of acute polyneuropathy with normal distal nerve conduction and that corticosteroids should be considered in the initial treatment of GBS-resembling polyneuropathy associated with nephrotic syndrome.     

The Place of Cyclosporin in the Management of Primary Nephrotic Syndrome

The 3 main causes of primary nephrotic syndrome are minimal change nephropathy, focal segmental glomerulosclerosis and membranous nephropathy. Corticosteroids result in remission of proteinuria in most patients with minimal change nephropathy. Many patients, however, develop corticosteroid dependency. A course of cytotoxic drugs can also achieve remission but these agents cannot be administered for prolonged periods or in repeated cycles because their toxicity is cumulative. Review of the available literature indicates that cyclosporin may maintain remission of nephrotic syndrome in about 80% of patients with corticosteroid-sensitive disease, indicating an important role for this drug in patients with frequent relapses or corticosteroid dependency. Although cyclosporin is less effective in patients with focal segmental glomerulosclerosis, which is often corticosteroid-resistant, a number of studies indicate that it may be successful both in the few steroid-sensitive patients with frequent relapses and in some corticosteroid-resistant patients. In patients with membranous nephropathy, a 6-month course of corticosteroids and cytotoxic agents may favour remission of nephrotic syndrome and protect renal function. Several studies have shown that cyclosporin can improve proteinuria, and there is a tentative suggestion that it might also protect against renal function deterioration. The risk of nephrotoxicity can be minimised if cyclosporin is used at the correct doses and if renal function is carefully monitored during treatment. In summary, cyclosporin can be considered a useful tool for treating patients with nephrotic syndrome associated with primary glomerulonephritis.     

Acquired glomerular lesions in patients with Down syndrome

The long-term survival of persons with Down syndrome has dramatically increased over the past 50 years. There are no studies addressing the spectrum of glomerular lesions in these patients. We reviewed the clinical-pathologic characteristics of 17 patients with Down syndrome who underwent renal biopsy. The cohort consisted of 12 whites and 5 African Americans with mean age of 29 years (range, 6-45 years). History of hypothyroidism was present in 8 patients. Renal presentations included renal insufficiency (15 patients, mean serum creatinine 3.4 mg/dL), proteinuria (all patients, including 3 with nephrotic syndrome, mean 24-hour urine protein 4.2 g), and hematuria (14 patients, including 4 with gross hematuria). The glomerular diseases found on biopsy were IgA nephropathy (n = 5 patients), focal segmental glomerulosclerosis (n = 4), membranoproliferative glomerulonephritis (n = 2), acute postinfectious glomerulonephritis (n = 2), pauci-immune crescentic glomerulonephritis (n = 2), membranous glomerulonephritis (n = 1), and lupus nephritis (n = 1). Follow-up (mean, 47 months; range, 2-141 months) was available on 16 patients (94%). Two patients (1 with membranous glomerulonephritis and 1 with acute postinfectious glomerulonephritis) had complete remission; 8 patients (4 with IgA nephropathy, 2 with focal segmental glomerulosclerosis, 1 with lupus nephritis, and 1 with acute postinfectious glomerulonephritis) had chronic kidney disease; and 6 patients (2 with pauci-immune crescentic glomerulonephritis, 2 with membranoproliferative glomerulonephritis, 1 with IgA nephropathy, and 1 with focal segmental glomerulosclerosis) progressed to end-stage renal disease, 4 of whom died. In summary, a wide spectrum of glomerular diseases can be seen in patients with Down syndrome, with IgA nephropathy and focal segmental glomerulosclerosis being the most common. Renal biopsy is necessary to determine the type of glomerular lesion and appropriate treatment.     

Focal glomerular sclerosis and sarcoidosis

Idiopathic nephrotic syndrome occurred in a patient with sarcoidosis. Typical features of focal segmental glomerulosclerosis were present on kidney biopsy. A unique finding was the occurrence of IgA in blood vessels of the skin and lymph node. Whereas the sarcoid hilar adenopathy responded to steroid therapy, the nephrotic syndrome was resistant to steroids and immunosuppression. Evaluation of humoral and cellular immune responsiveness showed no abnormalities except cutaneous anergy. Glomerulonephritis is uncommon in sarcoidosis, and a brief outline of this association is included. This patient is of importance in view of the unexplained relationship between idiopathic nephrotic syndrome and T lymphocyte abnormalities.     

Novel homoplasmic mutation in the mitochondrial tRNATyr gene associated with atypical mitochondrial cytopathy presenting with focal segmental glomerulosclerosis

We report a 9-year-old girl with a mitochondrial cytopathy preceded by steroid-resistant focal segmental glomerulosclerosis (FSGS). The proband presented at the age of 2 years with steroid-resistant nephrotic syndrome caused by FSGS. Her renal function progressively deteriorated and a dilated cardiomyopathy developed at the age of 7 years. A skeletal muscle biopsy showed a combined respiratory chain (RC) defect and a partial deficiency of coenzyme Q(10). A novel mutation in the evolutionary highly conserved region of the mitochondrial tRNA(Tyr) gene was found in homoplasmic state in skeletal muscle, blood, and renal tissue. The mutation was also found in homoplasmic state in her mildly symptomatic mother. No other maternal family members were available for testing. The present case of mitochondrial cytopathy initially presenting with steroid-resistant nephrotic syndrome, unusual biochemical and renal findings associated with a novel tRNA point mutation suggests that steroid-resistant FSGS can predate other features of mitochondrial disease for a prolonged period of time and that the progressive glomerulopathy associated with combined mitochondrial RC defects is genetically heterogeneous.     

不同病理类型局灶节段性肾小球硬化症的临床病理分析

目的探讨不同病理类型局灶节段性肾小球硬化症（FSGS）的临床病理特征及其与临床表现的关系。方法对北京大学第一医院2000年1月—2005年12月收集的102例特发性FSGS进行回顾性病理阅片及分型,并对其活动性及慢性化病理改变进行定量评估,分析不同病理类型FSGS的病理变化及其临床表现的特征。结果102例FSGS中,非特殊型占55．9％,门部型占6．9％,细胞型占25．5％,顶端型占4．8％,塌陷型占6．9％。细胞型和顶端型FSGS的尿蛋白水平较非特殊型明显增高,塌陷型和顶端型FSGS的肾病综合征比例较其他三型明显升高（x^2=12．23,P＜0．05）,细胞型和塌陷型FSGS的病理活动性积分较其他3型明显增高（P＜0．05）;门部型FSGS的病程较其他4组患者明显增高,其病理慢性化积分较顶端型和非特殊型明显增高（P＜0．05）;顶端型FSGS的病理总积分最少,明显低于细胞型和塌陷型（P＜0．05）;其慢性化积分较非特殊型和门部型明显降低（P＜0．05）。结论非特殊型FSGS是特发性FSGS的主要病理类型;塌陷型和细胞型FSGS是病变处于活动性阶段的病理类型,门部型FSGS为病理改变呈慢性化的病理类型,顶端型FSGS是病理改变最轻的病理类型。     

A novel mutation of congenital nephrotic syndrome in a Slovenian child eventually receiving a renal transplant

Congenital nephrotic syndrome (CNS) is a rare disease defined as heavy proteinuria, hypoalbuminemia, hyperlipidemia, and edema presenting in the first three months of life. It is most commonly caused by mutations in the NPHS1 gene associated with nephrotic syndrome type 1, also known as Finnish-type CNS, which is inherited in an autosomal recessive manner. Symptomatic treatment with intravenous albumins, vitamins, minerals, nutritional, and hormonal supplementation and treatment of complications are mandatory. Children refractory to the symptomatic treatment are recommended to undergo nephrectomy and renal replacement therapy, preferably renal transplantation. We report on a child with Finnish type CNS with a NPHS1 mutation, which is the first case confirmed by genetic study in Slovenia. We showed for the first time that homozygous mutation c.2928-3del in the NPHS1 gene caused exon 22 skipping, leading to a truncated protein and Fin-minor phenotype.

Congenital nephrotic syndrome (CNS) is a rare form of nephrotic syndrome, presenting in the first three months of life. In most cases, it is caused by monogenic mutations of structural proteins that form the glomerular filtration barrier in the kidneys, such as gene NPHS1 (1).Pathogenic variants in the NPHS1 gene are associated with nephrotic syndrome type 1, also known as Finnish-type CNS, which is inherited in an autosomal recessive manner, with the mutations being homozygous or compound heterozygous. The syndrome is characterized by a severe steroid-resistant nephrotic syndrome apparent at birth, with rapid progression to end-stage renal failure (1,2).We report on a child with Finnish-type CNS with a NPHS1 mutation, which is the first case confirmed by a genetic study in Slovenia. The reported mutation was confirmed for the first time to be pathogenic.     

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.     

Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome

Of the 92 patients with the acquired immunodeficiency syndrome (AIDS) who were seen at our institution over a two-year period, 9 acquired the nephrotic syndrome (urinary protein greater than 3.5 g per 24 hours) and 2 had azotemia with lesser amounts of urinary protein. Five of these 11 patients had a history of intravenous-heroin addiction, but in the remaining six, there were no known predisposing factors for nephropathy. In nine patients (including the six non-addicts) the course of renal disease was marked by rapid progression to severe uremia. Renal tissue examined by biopsy in seven patients and at autopsy in three revealed focal and segmental glomerulosclerosis with intraglomerular deposition of IgM and C3. In the 11th patient, renal biopsy revealed an increase in mesangial matrix and cells, with deposition of IgG and C3 consistent with a mild immune-complex glomerulonephritis, and severe interstitial nephritis. We conclude that focal and segmental glomerulosclerosis may be associated with AIDS and suggest that rapid deterioration to uremia may characterize this renal disease.     

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.     

Cerebral infarction as a complication of nephrotic syndrome: a case report with a review of the literature

Arterial thrombosis is relatively rare compared with venous thrombosis in nephrotic syndrome. However, the assessment of its pathogenesis and risk factors in individual patient with nephrotic syndrome is necessary to allow appropriate prophylactic management because it is a potentially serious problem. Hereby, with review of the literature, we report a case of a 53 yr-old man with cerebral infarction associated with nephrotic syndrome due to focal segmental glomerulosclerosis during the course of treatments with diuretics and steroid. It reveals that the hypercoagulable state in nephrotic syndrome can be associated with cerebral infarction in adults. Prophylactic anticoagulants can be considered to reduce the risk of serious cerebral infarction in nephrotic patients with risk factors such as severe hypoalbuminemia and on diuretics or steroid treatment, even in young patients regardless of types of underlying glomerular diseases.     

Membranous glomerulopathy: emphasis on secondary forms and disease variants

Membranous glomerulopathy (MGN) is characterized by subepithelial immune complex deposits and glomerular basement membrane (GBM) thickening. The majority of patients present with nephrotic syndrome and outcomes are variable. Pathologically, deposits at sites other than the subepithelial aspect of the GBM favor the presence of secondary forms of MGN which are seen most commonly in the setting of autoimmune disease, infection, neoplasia, and with certain therapeutic agents. MGN is the most common form of de novo glomerular disease seen in the renal allograft and may be seen concurrently with other forms of glomerular disease including focal segmental glomerulosclerosis, IgA nephropathy, diabetic nephropathy, and anti-TBM nephritis. This review emphasizes the detection of secondary forms and variants of MGN.     

Rituximab in adult minimal change disease and focal segmental glomerulosclerosis - What is known and what is still unknown?

Primary forms of minimal change disease and focal segmental glomerulosclerosis are rare podocytopathies and clinically characterized by nephrotic syndrome. Glucocorticoids are the cornerstone of the initial immunosuppressive treatment in these two entities. Especially among adults with minimal change disease or focal segmental glomerulosclerosis, relapses, steroid dependence or resistance are common and necessitate re-initiation of steroids and other immunosuppressants. Effective steroid-sparing therapies and introduction of less toxic immunosuppressive agents are urgently needed to reduce undesirable side effects, in particular for patients whose disease course is complex. Rituximab, a B cell depleting monoclonal antibody, is increasingly used off-label in these circumstances, despite a low level of evidence for adult patients. Hence, critical questions concerning drug-safety, long-term efficacy and the optimal regimen for rituximab-treatment remain unanswered. Evidence in the form of large, multicenter studies and randomized controlled trials are urgently needed to overcome these limitations.     

A case of idiopathic nodular glomerulosclerosis mimicking diabetic glomerulosclerosis (Kimmelstiel-Wilson type)

A case of idiopathic nodular glomerulosclerosis mimicking diabetic Kimmelstiel-Wilson glomerulopathy is reported. The patient was a 45-year-old man suffering from nephrotic syndrome. Light and electron microscopy revealed diffuse and nodular glomerulosclerosis indistinguishable from diabetic nodular glomerulosclerosis. Diabetes mellitus, however, had been excluded both by extensive clinical and by laboratory investigation. The differential diagnosis also included amyloidotic and non-amyloidotic fibrillary glomerulopathy, light chain glomerulopathy, collagen type III disease, immunotactoid glomerulopathy, and the sclerosing variant of membranoproliferative glomerulonephritis. Immunohistochemistry and ultrastructural investigations, however, excluded these entities, and the diagnosis of idiopathic nodular glomerulosclerosis was made. This variant has to be included in the differential diagnosis of nodular glomerulopathy associated with nephrotic syndrome.     

NPHS2 Mutations in Steroid‐Resistant Nephrotic Syndrome: A Mutation Update and the Associated Phenotypic Spectrum

Mutations in the NPHS2 gene encoding podocin are implicated in an autosomal‐recessive form of nonsyndromic steroid‐resistant nephrotic syndrome in both pediatric and adult patients. Patients with homozygous or compound heterozygous mutations commonly present with steroid‐resistant nephrotic syndrome before the age of 6 years and rapidly progress to end‐stage kidney disease with a very low prevalence of recurrence after renal transplantation. Here, we reviewed all the NPHS2 mutations published between October 1999 and September 2013, and also all novel mutations identified in our personal cohort and in international genetic laboratories. We identified 25 novel pathogenic mutations in addition to the 101 already described. The mutations are distributed along the entire coding region and lead to all kinds of alterations including 53 missense, 17 nonsense, 11 small insertions, 26 small deletions, 16 splicing, two indel mutations, and one mutation in the stop codon. In addition, 43 variants were classified as variants of unknown significance, as these missense changes were exclusively described in the heterozygous state and/or considered benign by prediction software. Genotype–phenotype analyses established correlations between specific variants and age at onset, ethnicity, or clinical evolution. We created a Web database using the Leiden Open Variation Database ( www.lovd.nl/NPHS2 ) software that will allow the inclusion of future reports.     

Targeted next-generation sequencing in steroid-resistant nephrotic syndrome: mutations in multiple glomerular genes may influence disease severity

Genetic diagnosis of steroid-resistant nephrotic syndrome (SRNS) using Sanger sequencing is complicated by the high genetic heterogeneity and phenotypic variability of this disease. We aimed to improve the genetic diagnosis of SRNS by simultaneously sequencing 26 glomerular genes using massive parallel sequencing and to study whether mutations in multiple genes increase disease severity. High-throughput mutation analysis was performed in 50 SRNS and/or focal segmental glomerulosclerosis (FSGS) patients, a validation cohort of 25 patients with known pathogenic mutations, and a discovery cohort of 25 uncharacterized patients with probable genetic etiology. In the validation cohort, we identified the 42 previously known pathogenic mutations across NPHS1, NPHS2, WT1, TRPC6, and INF2 genes. In the discovery cohort, disease-causing mutations in SRNS/FSGS genes were found in nine patients. We detected three patients with mutations in an SRNS/FSGS gene and COL4A3. Two of them were familial cases and presented a more severe phenotype than family members with mutation in only one gene. In conclusion, our results show that massive parallel sequencing is feasible and robust for genetic diagnosis of SRNS/FSGS. Our results indicate that patients carrying mutations in an SRNS/FSGS gene and also in COL4A3 gene have increased disease severity.