Frequent COL4 mutations in familial microhematuria accompanied by later‐onset Alport nephropathy due to focal segmental glomerulosclerosis

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

肾小球微小病变与局灶节段性肾小球硬化症足细胞中线粒体形态的定量研究(英文)

目的探索肾小球微小病变(MCD)与局灶节段性肾小球硬化症(FSGS)两种肾小球病中足细胞内线粒体的形态学差异。方法选择5例MCD和5例FSGS病例,在透射电镜放大30000倍的情况下,根据等距离曲线移动原则对每个病例拍照40张。根据Merz曲线和Gunderson测试系统选择线粒体和足细胞,测算并获得包括线粒体截面面积(A)、周长(C)、体积密度(VV)及面数密度(NA)等指标进行分析。结果 MCD和FSGS足细胞中线粒体相关参数的变异度及P值如下:A:0.47vs1.73,P=0.970;C:4.89vs24.71,P=0.590;VV:0.49vs1.74,P=0.946;NA:0.26vs0.58,P=0.602。结论 FSGS和MCD足细胞中线粒体的A、C、VV和NA等参数无统计学差异(所有P>0.05),但FSGS中所有参数的变异度均比MCD中的更明显,仍需进一步进行体视学研究。     

Urinary excretion of IGFBP-1 and -3 correlates with disease activity and differentiates focal segmental glomerulosclerosis and minimal change disease

The glomerular microenvironment is influenced by circulating growth factors that are filtered from the blood stream and pass the glomerular filtration barrier. In this study, we wanted to explore the role of IGF-binding proteins (IGFBPs) in two diseases that concern podocytes. We analyzed glomerular expression and urinary excretion of IGFBP-1, -2, and -3 in patients with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD). We found that patients with active FSGS excrete high amounts of podocalyxin positive cells as well as IGFBP-1 and -3. In human podocytes, we can induce mRNA expression of IGFBP-3 in response to TGF-β and in human microvascular endothelial cells expression of IGFBP-1 and -3 in response to TGF-β and Bradykinin. We conclude that the local expression of IGFBPs in podocytes and endothelial cells might contribute to the pathogenesis of glomerular disease and that IGFBP-1 and -3 are potential non-invasive markers of FSGS.     

Lessons from studies on focal segmental glomerulosclerosis: an important role for parietal epithelial cells?

Glomerular diseases are caused by multiple mechanisms. Progressive glomerular injury is characterized by the development of segmental or global glomerulosclerosis independent of the nature of the underlying renal disease. Most studies on glomerular disease focus on the constituents of the filtration barrier (podocytes, glomerular basement membrane (GBM), endothelial cells) or the mesangial cells. Little attention is given to the epithelial cells lining Bowman's capsule, the so called parietal epithelial cells (PECs). This 'lack of attention' is partly explained by the presumed 'passive' function of PECs, which are large, flattened cells that cover Bowman's capsule in a single cell layer and form a barrier between the ultrafiltrate and the periglomerular interstitium, in normal glomerular physiology. A more important reason has been the lack of an established primary role for the parietal epithelium in glomerular diseases. However, in recent years, several studies have demonstrated that PECs are involved in extracapillary proliferation. In addition, PECs can become highly active, proliferating cells, expressing many growth factors, chemokines, cytokines, and their receptors. It was recently demonstrated that PECs also play a part in the development of focal segmental glomerulosclerosis (FSGS). This review summarises current knowledge of the PEC, with emphasis on the role of PECs in the development of FSGS.     

Recurrence of nephrotic syndrome/focal segmental glomerulosclerosis following renal transplantation in children

The incidence of recurrence of nephrotic syndrome/focal segmental glomerulosclerosis (NS/FSGS) is variable (~30%). The incidence of recurrence is less in African-Americans than in whites and Hispanics. Graft survival rates are decreased in recipients with FSGS, especially if remission of the NS is not achieved in those with recurrence. Although controversial, the use of living donor (LD) transplants are not contraindicated; however, obligatory heterozygote parental grafts with a podocin mutation should be used with caution. Optimal treatment to induce a remission post-transplant has not been delineated. Pre-transplant and/or prophylactic post-transplant pre-operative plasmapheresis (PP) for high-risk patients--especially those with recurrence in a previous graft--may be promising. An international multicenter controlled study is required to delineate the optimal approach to prevent and/or treat the recurrence of NS/FSGS.     

Bone mineral content and mineral metabolism during cyclosporine treatment of nephrotic Syndrome

OBJECTIVE: Although cyclosporine (Cy) has been associated with bone loss following transplantation, its effects on bone in growing children are largely unknown. STUDY DESIGN: Thirty-seven patients (2-16 years of age) with remitting nephrotic syndrome (NS), n = 16 receiving Cy for 39 +/- 27 months and n = 21 without Cy, underwent mineral metabolism and bone turnover assessment. In 28 of 37 patients, bone mineral density (BMD) was obtained while off corticosteroid therapy (Rx). RESULTS: Urinary calcium (Ca), phosphate (PO(4)), and magnesium (Mg) excretion was normal, but serum Mg was lower in patients receiving Cy (1.8 +/- 0.1 v 1.95 +/- 0.2 mg/dL, P < .05). BMD Z scores were similar at the spine (-0.45 +/- 0.74 v 0.04 +/- 0.9) and femur (-0.17 +/- 0.52 v 0.38 +/- 1.28) with no Z score <-2. Serum bone-specific alkaline phosphatase was normal, and N-telopeptide of type I collagen also normal, was higher on Cy (P < .05). Cumulative prednisone exposure was similar and had no significant effect on height and BMD Z scores. Length of Cy-Rx and time elapsed from onset of NS did not correlate with BMD, height Z score, or markers of bone turnover. CONCLUSIONS: In growing children with NS, during long-term Cy-Rx urinary wasting of Ca and Mg was absent and bone density was preserved.     

X-linked Alport syndrome in Hellenic families: phenotypic heterogeneity and mutations near interruptions of the collagen domain in COL4A5

The X-linked Alport syndrome (ATS) is caused by mutations in COL4A5 and exhibits a widely variable expression. Usually ATS is heralded with continuous microhematuria which rapidly progresses to proteinuria, hypertension and chronic or end-stage renal disease (ESRD) by adolescence, frequently accompanied by sensorineural deafness and ocular complications. Milder forms of ATS also exist. We studied 42 patients (19M, 23F) of nine Hellenic families suspected clinically of X-linked ATS who presented with marked phenotypic heterogeneity. We identified mutations in COL4A5 in six families. Two males with nonsense mutation E228X reached ESRD by ages 14 and 18. Frameshift mutation 2946delT followed the same course with early onset renal involvement and deafness. However, two males with the milder missense mutation G624D, reached ESRD after 39 years and one patient showed thin basement membrane nephropathy (TBMN). Another 5/8 affected males with missense mutation P628L also developed ESRD between 30 and 57 years, while three exhibit only mild chronic renal failure (CRF). The data support previous findings that certain mutations are associated with milder phenotypes and confirm that mutation G624D may be expressed as TBMN with familial hematuria. Similar conclusions apply for missense mutation P628L. Interestingly, mutations G624D and P628L are near the 12th natural interruption of COL4A5 triple helical domain, which may explain the milder phenotype.