Early increase in blood pressure and diastolic left ventricular malfunction in patients with glomerulonephritis

Early increase in blood pressure and diastolic left ventricular malfunction in patients with glomerulonephritis. In patients with diabetic nephropathy blood pressure increases progressively before the conventional threshold of normal blood pressure (140/90mm Hg) is transgressed. In patients with glomerulonephritis, no information on this point is available. To clarify this issue we sequentially examined 20 untreated patients with biopsy-proven primary chronic glomerulonephritis (GN) who had casual blood pressure below 140/90mm Hg and normal GFR by inulin clearance. Patients were compared with normotensive healthy controls who were matched for BMI, gender and age. We measured ambulatory 24-hour blood pressure (SpaceLab system), echocardiography (ASE criteria, Acuson 128 XP 10), CIn and CPAH, urinary Na excretion, PRA and insulin concentration. In patients with GN, the median 24 hour (P < 0.0005), daytime (P < 0.001) and nocturnal sleeping time (P < 0.0001) MAP values were significantly higher than in matched controls (daytime, mean 97mm Hg, 85 to 106 GN vs. 89 controls range 82 to 102; nocturnal sleeping time, mean 80.3mm Hg, 71 to 89.5 GN vs. 73 controls, range 63 to 84). Echocardiographic examination showed significantly greater posterior wall thickness (P < 0.01) and ventricular septal thickness (P < 0.003). In addition the early diastolic to late diastolic (E/A) ratio of mitral valve peak inflow velocity was significantly (P < 0.0008) lower in patients. The data point to left ventricular wall thickening accompanied by LV diastolic malfunction. The study documents elevated ambulatory blood pressure in patients with primary chronic glomerulonephritis despite normal body weight and normal GFR. This is associated with evidence of target organ damage in the heart. The findings suggest that in patients with glomerulonephritis blood pressure increases initially within the normotensive range. This observation in conjunction with evidence of early target organ changes provides an argument for early antihypertensive intervention, but controlled trials to test efficacy and safety of this proposal are necessary

Functional rescue of the glomerulosclerosis phenotype in Mpv17 mice by transgenesis with the human Mpv17 homologue

The germ line insertion of a defective retrovirus into the Mpv17 gene of mice is associated with a recessive phenotype. Mice homozygous for the integration develop glomerulosclerosis at a young age. The phenotype resembles human glomerulosclerosis in its physiological parameters as well as in histology. A human homologue of the Mpv17 gene has been identified, isolated and analyzed. We here show that this gene, which has a role in the production of reactive oxygen species, can rescue the phenotype of Mpv17 deficient mice when introduced by transgenesis. This provides formal proof for the hypothesis that the phenotype is caused by the loss of function of the Mpv17 gene. It also provides evidence for the functional conservation of the Mpv17 gene in mammals and points to a potential role of this gene in human kidney disease

PDGF and TGF-β contribute to the natural course of human IgA glomerulonephritis

PDGF and TGF-β contribute to the natural course of human Ig-A glomerulonephritis. PDGF and TGF-β are known mediators of mesangial cell proliferation and matrix expansion. The presence of these regulatory factors was examined in 30 renal biopsies from patients with IgA glomerulonephritis (IgA-GN) at the mRNA and protein level. Normal renal tissue served as control. The mRNA expression of PDGF A/B chains, PDGF-βR and TGF-β1 was evaluated by means of RT/PCR with subsequent Southern blot hybridization and/or non-radiactive in situ hybridization. In addition, PDGF-AB/BB, PDGF-βR, TGF-β isoforms (β1, β1+2, β2+3), the small TGF-β1 latency associated peptide (TGF-β1 LAP) and the extracellular matrix proteins tenascin and decorin were analyzed by immunocytochemistry. The expression of growth factors was correlated with light microscopic and clinical features. Compared to normal control kidneys, an increased expression of PDGF-BB/PDGF-βR mRNAs and the corresponding proteins was observed in all biopsies with IgA-GN. Up-regulation was related to the degree of glomerular proliferation and the extent of fibrosing interstitial lesions. In contrast, there was a discordance between TGF-β1 mRNA and protein expression (evaluated by immunocytochemistry). In all biopsies, irrespective of the stage of the disease, abundant TGF-β1 transcripts were detected, whereas TGF-β1 immunoreactivity was expressed to a lesser degree and disclosed a more variable staining pattern. In patients with significant proliferative glomerular lesions and minor tubulointerstitial alterations, TGF-β1 positivity was confined to areas of glomerular proliferation, whereas in cases with more severe histology including sclerosing lesions TGF-β1 immunoreactivity was less prominent. The distribution and the intensity of TGF-β1 LAP staining commonly exceeded the positivity noted for TGF-β1, indicating only limited TGF-β1 activation. A decreased reactivity for tenascin accompanied the morphological features of glomerular sclerosis. The staining patterns and the fact that only very few inflammatory cells, particularly CD68 positive monocytes/macrophages, were detected in glomeruli confirm that predominantly resident glomerular cells (mesangial and endothelial cells) are the major source of up-regulated growth factor production in IgA-GN. Since the expression of PDGF-AB/BB paralleled the severity of proliferative glomerular changes, PDGF seems to represent a potential indicator of activity in this condition. It is suggested that an imbalance between PDGF and TGF-β (by restricted translation and/or activation) production contribute to the progressive nature of IgA-GN

ANCA-Associated Glomerulonephritis: Risk Factors for Renal Relapse.

Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild-moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray's regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8-14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray's model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different

Urinary matrix calculi consisting of microfibrillar protein in patients on maintenance hemodialysis

Urinary matrix calculi consisting of microfibrillar protein in patients on maintenance hemodialysis. In seven patients on maintenance hemodialysis,de novo recurrent renal stone formation was observed. In all patients, the underlying disease was glomerulonephritis, with or without the nephrotic syndrome. All patients had considerable persistent proteinuria. The stones consisted predominantly of protein, as revealed by amino acid analysis, and had a negligible carbohydrate and lipid content. Only in some specimens, X-ray diffraction and scanning electron microscopy revealed the presence of small amounts of whewellit (calcium oxalate monohydrate) and/or uric acid. In semithin sections, the stones had a laminated texture and exhibited structural anisotropy under polarized light. With transmission electron microscopy, they were found to consist of peculiar microfibrils. The proteinaceous material differed from fibrin or Tamm-Horsfall-protein, as indicated by ultrastructure, carbohydrate analysis, and amino acid analysis. Symptomaticde novo matrix stone formation constitutes another complication of dialyzed patients which has not been reported so far.Calculs urinaires constitués de protéines microfibrillaires chez des malades en hémodialyse chronique. Chez sept malades en hémodialyse chronique, la formation récidivante de calculs urinaires a été observée. Chez tous les malades, la maladie initiale était une glomérulonéphrite avec ou sans syndrome néphrotique. Tous les malades avaient une protéinurie importante. Les calculs étaient essentiellement constitués de protéine, comme l'indiquait l'analyse des acides aminés, et avaient un contenu négligeable en hydrates de carbone et lipides. Dans quelques échantillons seulement la diffraction X et la microscopie électronique à balayage ont révélé la présence de faibles quantités d'oxalate de calcium monohydrate et/ou d'acide urique. Sur les coupes semifines les calculs avaient un aspect laminé et étaient anisotropiés en lumière polarisée. En microscopie électronique à transmission il a été observé des microfibrilles particulières. La substance protéique diffère de la fibrine ou de la protéine de Tamm-Horsfall d'après l'étude ultrastructurale, l'analyse des hydrates de carbone, et l'analyse des acides aminés. La formation de novo de calculs, accompagnée de syndromes de lithiase, constitue une complication non encore rapportée à ce jour au cours de la dialyse chronique

Association of non-HLA antibodies against endothelial targets and donor-specific HLA antibodies with antibody-mediated rejection and graft function in pediatric kidney transplant recipients

Background!#!Non-HLA antibodies against endothelial targets have been implicated in the pathogenesis of antibody-mediated rejection (ABMR), but data in pediatric patients are scarce.!##!Methods!#!We retrospectively analyzed a carefully phenotyped single-center (University Children's Hospital Heidelberg, Germany) cohort of 62 pediatric kidney transplant recipients (mean age at transplantation, 8.6 ± 5.0 years) at increased risk of graft function deterioration. Patients had received their transplant between January 1, 1999, and January 31, 2010. We examined at time of late index biopsies (more than 1-year post-transplant, occurring after January 2004) the association of antibodies against the angiotensin II type 1 receptor (AT!##!Results!#!We observed a high prevalence (62.9%) of non-HLA antibody positivity. Seventy-two percent of HLA-DSA positive patients showed additional positivity for at least one non-HLA antibody. Antibodies against AT!##!Conclusions!#!Our data indicate that the combined detection of antibodies to HLA and non-HLA targets may allow a more comprehensive assessment of the patients' immune responses against the kidney allograft and facilitates immunological risk stratification

Identification of a New Gene Locus for Adolescent Nephronophthisis, on Chromosome 3q22 in a Large Venezuelan Pedigree

Nephronophthisis, an autosomal-recessive cystic kidney disease, is the most frequent monogenic cause for renal failure in childhood. Infantile and juvenile forms of nephronophthisis are known to originate from separate gene loci. We describe here a new disease form, adolescent nephronophthisis, that is clearly distinct by clinical and genetic findings. In a large, 340-member consanguineous Venezuelan kindred, clinical symptoms and renal pathology were evaluated. Onset of terminal renal failure was compared with that in a historical sample of juvenile nephronophthisis. Onset of terminal renal failure in adolescent nephronophthisis occurred significantly later (median age 19 years, quartile borders 16.0 and 25.0 years) than in juvenile nephronophthisis (median age 13.1 years, quartile borders 11.3 and 17.3 years; Wilcoxon test P=.0069). A total-genome scan of linkage analysis was conducted and evaluated by LOD score and total-genome haplotype analyses. A gene locus for adolescent nephronophthisis was localized to a region of homozygosity by descent, on chromosome 3q22, within a critical genetic interval of 2.4 cM between flanking markers D3S1292 and D3S1238. The maximum LOD score for D3S1273 was 5.90 (maximum recombination fraction .035). This locus is different than that identified for juvenile nephronophthisis. These findings will have implications for diagnosis and genetic counseling in hereditary chronic renal failure and provide the basis for identification of the responsible gene