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Tubulointerstitial kidney disease is an important cause of progressive renal failure whose aetiology is incompletely understood. We analysed a large pedigree with maternally inherited tubulointerstitial kidney disease and identified a homoplasmic substitution in the control region of the mitochondrial genome (m.547A>T). While mutations in mtDNA coding sequence are a well recognised cause of disease affecting multiple organs, mutations in the control region have never been shown to cause disease. Strikingly, our patients did not have classical features of mitochondrial disease. Patient fibroblasts showed reduced levels of mitochondrial tRNAPhe, tRNALeu1 and reduced mitochondrial protein translation and respiration. Mitochondrial transfer demonstrated mitochondrial transmission of the defect and in vitro assays showed reduced activity of the heavy strand promoter. We also identified further kindreds with the same phenotype carrying a homoplasmic mutation in mitochondrial tRNAPhe (m.616T>C). Thus mutations in mitochondrial DNA can cause maternally inherited renal disease, likely mediated through reduced function of mitochondrial tRNAPhe.

Hepcidin is a critical inhibitor of iron export from macrophages, enterocytes, and hepatocytes. Given that it is filtered and degraded by the kidney, its elevated levels in renal failure have been suggested to play a role in the disordered iron metabolism of uremia, including erythropoietin resistance. Here, we used a novel radioimmunoassay for hepcidin-25, the active form of the hormone, to measure its levels in renal disease. There was a significant diurnal variation of hepcidin and a strong correlation to ferritin levels in normal volunteers. In 44 patients with mild to moderate kidney disease, hepcidin levels were significantly elevated, positively correlated with ferritin but inversely correlated with the estimated glomerular filtration rate. In 94 stable hemodialysis patients, hepcidin levels were also significantly elevated, but this did not correlate with interleukin-6 levels, suggesting that increased hepcidin was not due to a general inflammatory state. Elevated hepcidin was associated with anemia, but, intriguingly, the erythropoietin dose was negatively correlated with hepcidin, suggesting that erythropoietin suppresses hepcidin levels. This was confirmed in 7 patients when hepcidin levels significantly decreased after initiation of erythropoietin treatment. Our results show that hepcidin is elevated in renal disease and suggest that higher hepcidin levels do not predict increased erythropoietin requirements.

During embryonic development, the kidney epithelium originates from cells that undergo a mesenchymal to epithelial transition (MET). The reverse process, epithelium to mesenchyme transition (EMT), has been implicated in epithelial tumor progression and in the fibrosis that leads to end-stage kidney failure. Snail transcription factors induce both natural and pathological EMT, but their implication in renal development and disease is still unclear. We show that Snail genes are downregulated during the MET that occurs during renal development and that this is correlated with Cadherin-16 expression. Snail suppresses Cadherin-16 via the direct repression of the kidney differentiation factor HNF-1beta, a novel route by which Snail disrupts epithelial homeostasis. Indeed, Snail activation is sufficient to induce EMT and kidney fibrosis in adult transgenic mice. Significantly, Snail is also activated in patients with renal fibrosis. Thus, Snail expression is suppressed during renal development and it must remain silent in the mature kidney where its aberrant activation leads to fibrosis.

Background. Hereditary microscopic haematuria often segregates with mutations of COL4A3, COL4A4 or COL4A5 but in half of families a gene is not identified. We investigated a Cypriot family with autosomal dominant microscopic haematuria with renal failure and kidney cysts. Methods. We used genome-wide linkage analysis, whole exome sequencing and cosegregation analyses. Results. We identified a novel frameshift mutation, c.4611_ 4612insG:p.T1537fs, in exon 49 of COL4A1. This mutation predicts truncation of the protein with disruption of the Cterminal part of the NC1 domain. We confirmed its presence in 20 family members, 17 with confirmed haematuria, 5 of whom also had stage 4 or 5 chronic kidney disease. Eleven family members exhibited kidney cysts (55% of those with the mutation), but muscle cramps or cerebral aneurysms were not observed and serum creatine kinase was normal in all individuals tested. Conclusions. Missense mutations of COL4A1 that encode the CB3 [IV] segment of the triple helical domain (exons 24 and 25) are associated withHANAC syndrome (hereditary angiopathy, nephropathy, aneurysms and cramps). Missense mutations of COL4A1 that disrupt the NC1 domain are associated with antenatal cerebral haemorrhage and porencephaly, but not kidney disease. Our findings extend the spectrum of COL4A1 mutations linked with renal disease and demonstrate that the highly conserved C-terminal part of the NC1 domain of the a1 chain of type IV collagen is important in the integrity of glomerular basement membrane in humans. [ABSTRACT FROM AUTHOR]

Small-molecule stabilizers of hypoxia inducible factor (HIF) are being developed for the treatment of renal anaemia. These molecules inhibit prolyl hydroxylase domain-containing (PHD) enzymes, resulting in HIF activation and increased production of erythropoietin. Currently, renal anaemia is treated with recombinant human erythropoietin or related analogues, referred to as conventional erythropoiesis stimulating agents (ESAs). Advantages of PHD enzyme inhibitors over conventional ESAs include their oral administration and their simpler - and potentially cheaper - production. Importantly, inhibition of PHD enzymes is likely to have a range of consequences other than increasing levels of erythropoietin, and these effects could be beneficial - for instance by reducing the need for parenteral iron - but might in some instances be harmful. Several companies are currently testing PHD enzyme inhibitors in patients with renal anaemia and have reported clear evidence of efficacy without serious safety concerns. A central question that current studies are beginning to address is whether using PHD enzyme inhibitors will influence hard end points, including mortality and the rate of cardiovascular events. In terms of approaches to therapy, the exquisite specificity of conventional ESAs is a striking contrast to the pleiotropic effects of activating HIF. Excitingly, PHD inhibitors could also be useful for conditions besides renal anaemia, such as protection from ischaemic injury. [ABSTRACT FROM AUTHOR]

Familial hematuria (FH) is explained by at least four different genes (see below). About 50% of patients develop late proteinuria and chronic kidney disease (CKD). We hypothesized that MYH9/APOL1, two closely linked genes associated with CKD, may be associated with adverse progression in FH. Our study included 102 thin basement membrane nephropathy (TBMN) patients with three known COL4A3/COL4A4 mutations (cohort A), 83 CFHR5/C3 glomerulopathy patients (cohort B) with a single CFHR5 mutation and 15 Alport syndrome patients (cohort C) with two known COL4A5 mild mutations, who were categorized as “Mild” (controls) or “Severe” (cases), based on renal manifestations. E1 and S1 MYH9 haplotypes and variant rs11089788 were analyzed for association with disease phenotype. Evidence for association with “Severe” progression in CFHR5 nephropathy was found with MYH9 variant rs11089788 and was confirmed in an independent FH cohort, D (cumulative p value = 0.001, odds ratio = 3.06, recessive model). No association was found with APOL1 gene. Quantitative Real time PCR did not reveal any functional significance for the rs11089788 risk allele. Our results derive additional evidence supporting previous reports according to which MYH9 is an important gene per se, predisposing to CKD, suggesting its usefulness as a prognostic marker for young hematuric patients. [ABSTRACT FROM AUTHOR]

Complement is an important aspect of defence against infection and its activation and regulation are finely balanced. Disordered complement regulation can lead to C3 glomerulonephritis (C3GN), which is characterized by complement (but not immunoglobulin) deposition in the glomerulus of the kidney. Although only recently recognized as a clinical entity, C3GN is important and elucidation of its molecular causes, by studies of single cases and families, has identified key proteins that protect the kidney from complement-mediated damage. The commonest cause of C3GN is complement factor H-related 5 (CFHR5) nephropathy, which is endemic in Greek Cypriots. Genetic evidence implicates some of the same complement regulators in the aetiology of common immune complex glomerular disorders such as IgA nephropathy and lupus nephritis. Importantly, therapeutic manipulation of the complement pathway is now feasible. An exciting challenge is to determine whether this can be applied to kidney diseases that are caused by complement dysregulation, and also whether they might be used to intervene in other kidney diseases. [ABSTRACT FROM AUTHOR]

Background. IgA nephropathy is a major cause of end-stage renal disease worldwide. Its aetiology is poorly understood but there is good evidence for a major genetic component, although to date, no gene has been conclusively identified. We describe a new UK multicentre DNA collection assembled to investigate this. A Japanese genome-wide analysis recently reported that common genetic variation in immunoglobulin mu-binding protein 2 (IGHMBP2) was associated with IgA nephropathy. We sought to replicate this using the new UK collection, and through an independent parallel analysis of a Han Chinese population. [ABSTRACT FROM PUBLISHER]

IgA nephropathy is the commonest form of glomerulonephritis worldwide, but we still know relatively little about its pathogenesis. Potentially, genetic studies might provide new insights and suggest novel therapeutic approaches to this important cause of chronic kidney disease. Two approaches that are likely to yield new information are analysis of multiply affected pedigrees and large-scale, well-controlled association studies. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Erythropoiesis-stimulating agents (ESAs) are widely used to treat anaemia in patients with kidney disease. A potential alternative approach is to increase erythropoietin production using small-molecule inhibitors of prolyl hydroxylase domain (PHD) enzymes. Recent phase III trials of the PHD inhibitor roxadustat demonstrate similar efficacy and safety to ESAs. [ABSTRACT FROM AUTHOR]

The article focuses on a study which attempted to establish the genetic basis for a familial disorder of complement regulation associated with persistent microscopic haematuria, recurrent macroscopic haematuria, glomerulonephritis and progressive renal failure. Through a genome-wide linkage study and candidate gene analysis, a mutation was identified. The cosegregation of the occurrence of familial disease with the same mutation in the complement factor H-related protein gene is also observed.

A response by Damien R. Ashby and colleagues to a letter to the editor about their article "Hepcidin Levels in Patients With Renal Disease," in a previous 2009 issue is presented.

A response by Damien R. Ashby, Daniel P. Gale and colleagues to a letter to the editor on their article "Plasma Hepcidin Levels are Elevated But Responsive to Erythropoietin Therapy in Renal Disease" published in a previous issue of the journal is presented.