Alleles of the α1 immunoglobulin gene 3′ enhancer control evolution of IgA nephropathy toward renal failure

Alleles of the α1 immunoglobulin gene 3′ enhancer control evolution of IgA nephropathy toward renal failure.BackgroundIgA nephropathy is the most common glomerular disease. Mechanisms leading to its occurrence and controlling the evolution of the disease remain largely unknown. Various genetic factors have been found, mostly implicating immunologically relevant genes (IgH, TCR, human lymphocyte antigen, and complement loci). A regulatory region recently identified downstream, the α1 gene of the IgH locus, was a likely candidate for the control of IgA1 production in patients. Alleles of this region, differing by size, sequence, and orientation of the α1 hs1,2 transcriptional enhancer, were first identified through Southern blot hybridization.MethodsWe established a polymerase chain reaction (PCR) method suitable for routine testing that amplifies minisatellites within the α1 hs1,2 enhancer, with variable numbers of tandem repeats (VNTR) defining the two alleles. This assay allowed the typing of 104 patients with IgAN and 83 healthy volunteers. Results from typing of α1 hs1,2 alleles were compared with long-term clinical outcome in patients. Enhancer alleles were compared in a luciferase reporter gene assay.ResultsThe α1 hs1,2 alleles do not constitute a predictive factor for IgA nephropathy, since similar allelic frequencies were observed in healthy individuals and in unrelated European patients. In contrast, among patients, homozygosity for the weakest enhancer allele (AA genotype) was significantly correlated with a milder form of the disease, whereas the allele B was associated with severe evolution. The minisatellite region within the α1 hs1,2 enhancer carried potential transcription factor-binding sites, and its duplication increased the transcriptional strength of the α1 hs1,2 allele B over that of allele A.ConclusionAltogether, these alleles may constitute a risk factor for the prognosis of IgA nephropathy

C3 glomerulopathy in adults: monoclonal gammopathy should be considered.

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Renal impairment in multiple myeloma: time is of the essence.

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Optimizing treatment strategies in myeloma cast nephropathy: rationale for a randomized prospective trial.

International audienceRenal failure is a frequent complication of multiple myeloma (MM) that strongly affects patient survival. Although a variety of renal diseases may be observed in MM, myeloma cast nephropathy (MCN), a tubulo-interstitial disorder related to precipitation of a monoclonal light chain (LC) within tubular distal lumens, is the main cause of severe and persistent renal failure. To date, the respective frequency and initial evolution of renal disorders associated with monoclonal LC in MM remain poorly defined. Treatment of MCN relies on urgent symptomatic measures and rapid introduction of chemotherapy to reduce the production of monoclonal LC. The introduction of novel chemotherapy regimens based on the association of bortezomib with dexamethasone is likely to have improved the prognosis of MM patients with renal failure. In addition, the combination of novel agents with efficient removal of circulating LC through high cut-off hemodialysis membrane may further increase renal response rate. However, the impact on patient and renal outcomes of these potential therapeutic advances has not been evaluated in prospective studies. The randomized trials EuLITE in the UK and Germany and MYRE in France should help to answer these issues. MYRE is a randomized controlled phase III trial (NCT01208818) that aims to better define the epidemiology and typology of inaugural renal failure in MM and to optimize therapy of MCN patients with and without dialysis-dependent renal failure

Renal improvement in myeloma with plasma exchange.

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A monoclonal V kappa l light chain responsible for incomplete proximal tubulopathy.

Calcium and phosphate metabolism abnormalities are frequent in myeloma patients and the role of renal lesions in such ionic perturbations may have been overlooked. The authors herein report the complete primary structure of a Bence Jones Vkappal light chain responsible for myeloma-associated proximal tubulopathy with increased phosphaturia. Plasma and serum biochemical evaluations indicated a proximal tubular dysfunction mainly manifested as tubular acidosis and phosphate loss. The study of a kidney biopsy showed interstitial and tubular lesions with numerous myeloma casts and peculiar features of the proximal tubular cells, which carried numerous phagolysosomal inclusions with occasional crystalline periodic striation. The nephrotoxic light chain primary structure was deduced from the bone marrow monoclonal plasma cells RNA. The kappal sequence was highly homologous to kappa chains previously characterized in patients with Fanconi syndrome. It was related to the Vkappal subgroup and was composed of a variable segment encoded by the O8/O18 germline gene rearranged to Jkappa4. The primary sequence presented unusual features restricted to the variable region, including substitutions of residues 28 and 31 in the complementary determining region 1 (CDR1) by amino acids of different charge. An unusual conformation of the kappal domain, likely resulting from somatic hypermutation, could alter the catabolism of the protein after its internalization and result in the tubular cell dysfunction. Comparison with Fanconi syndrome studies suggests that Vkappal Bence Jones proteins may damage proximal tubular cells to an extent varying according to light chain (LC) sequence and structure, either leading to crystal formation and Fanconi syndrome or inducing partial inhibition of proximal tubule function

Renal transplantation in light chain amyloidosis: coming out of the cupboard.

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Toward understanding renal Fanconi syndrome: step by step advances through experimental models.

International audienceRenal Fanconi syndrome (FS) is a generalized dysfunction of proximal tubular epithelial cells leading to the urinary leak of essential metabolites like phosphate, uric acid, glucose, amino acids and low molecular weight proteins. From inherited forms involving mutations on apparently unrelated genes to acquired forms induced by drugs, heavy metals or monoclonal immunoglobulin (Ig) light chains (LC), heterogeneous causalities of FS have complicated the understanding of this pathology for a long time. Experimental models of FS have allowed researchers to face the challenge and have helped unravel the main mechanisms disturbing proximal tubule reabsorption. Administration of cadmium to animals first demonstrated an inhibition of Na/K/ATPase activity, highlighting how a single toxic component could induce the general sodium-linked transport defect observed in FS. Today, genetically modified mice allow the development of reliable and reproducible experimental models for inherited or acquired forms of FS. One of the most exciting advances offered by these models is the unexpected major role of endocytosis in the function of the proximal tubule revealed by megalin and ClC-5 knockout mice. Using gene-targeted insertion, a transgenic mouse for LC-associated FS, the most frequent adult form of FS, has also been recently developed and represents a major step in the development of models of this pathology. Beyond deciphering molecular and cellular events at the origin of FS, these models also represent essential tools for the development of therapeutic strategies