BACKGROUND: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. METHODS: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2-5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. RESULTS: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. CONCLUSIONS: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.
- MeSH
- biopsie MeSH
- dítě MeSH
- dospělí MeSH
- hodnoty glomerulární filtrace MeSH
- IgA nefropatie * komplikace farmakoterapie patologie MeSH
- IgA vaskulitida * komplikace farmakoterapie patologie MeSH
- ledviny patologie MeSH
- lidé MeSH
- mladiství MeSH
- nefritida * komplikace MeSH
- proteinurie etiologie MeSH
- retrospektivní studie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.
- MeSH
- celogenomová asociační studie MeSH
- IgA nefropatie * farmakoterapie genetika diagnóza MeSH
- imunoglobulin A genetika MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.
- MeSH
- alely MeSH
- Asijci genetika MeSH
- běloši genetika MeSH
- celogenomová asociační studie * MeSH
- interferonové regulační faktory genetika MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- membranózní glomerulonefritida diagnóza genetika imunologie MeSH
- molekulární modely MeSH
- NF-kappa B - podjednotka p50 genetika MeSH
- receptory pro fosfolipasy A2 genetika MeSH
- sekvence aminokyselin MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.
- MeSH
- antigeny CD11b genetika MeSH
- celogenomová asociační studie MeSH
- genetická pleiotropie genetika MeSH
- genetické lokusy genetika MeSH
- HLA-D antigeny genetika MeSH
- IgA nefropatie genetika MeSH
- imunita genetika MeSH
- interakce hostitele a patogenu genetika MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- protoonkogenní proteiny c-vav genetika MeSH
- signální adaptorové proteiny CARD genetika MeSH
- střeva imunologie parazitologie MeSH
- věk při počátku nemoci MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Chronic kidney disease (CKD) is estimated in about 7- 11% of the general population, and the prevalence of CKD has doubled in about 10 years. In addition, an increasing number of elderly patients affected of end stage renal di- sease (ESRD) requires dialysis treatment or kidney trans- plantation. The perception of chronic pain, especially in el- derly patients in dialysis treatment is often underestimated. There are numerous painful syndromes unique to ESRD such as calciphylaxis and renal osteodystrophy that may depend on age on dialysis. Such pain include also most types of symptoms that are typical seen in cancer patients. Chronic pain, as well as depression, often are not adequa- tely treated. A common complication of uremia is periphe- ral polyneuropathy (PNP) which affects more than 50% of CKD patients. The PNP is responsible of a common painful disease called restless leg syndrome. The control of pain in renal disease represents a very big problem, considering the relationship between clearance of drugs and renal func- tion. In this group of patients many drugs can undergo to over treatment of pain and consequently there is an higher risk of side effects or complications. A new application for treating pain in uremic patients is the High Tone Muscle Electrostimulation therapy (HTEMS). It represents a form of electrostimulation for external muscle used as an alterna- tive treatment for symptomatic diabetic PPN. This type of therapy could be a valuable supplement in the treatment of pain and neuropathic discomfort in ESRD patients.
Cíle: Hladina fosfátů u uremických pacientů je významným problémem, který přispívá k jejich vyšší nemocnosti i úmrtnosti. Dokázali jsme, že sekrece fosfátů slinami je zvýšená jak u dialyzovaných (HD), tak u pacientů s chronickým onemocněním ledvin (CKD) ve srovnání se zdravými, a že úzce souvisí s hladinou fosfátů v séru a může přispívat k jejich vyšší celkové hladině. Existence určitého denního rytmu sekrece fosfátů u zdravých, s maximem brzy večer, a prokázání zvýšené sekrece fosfátů u HD i CKD pacientu byla podnětem k prozkoumání možných abnormalit v denním rytmu sekrece fosfátů u uremických pacientů. Metody: U padesáti šesti hemodialyzovaných pacientů bez reziduální diurézy byla hodnocena sekrece fosfátů v 8:00,12:00,17:00 a 22:00 hodin. Jako kontrolní skupina sloužil soubor devatenácti zdravých dobrovolníků odpovídajícího věku a pohlaví. Výsledky: U HD paaentu byla prokázána zvýšená sekrece fosfátů ve srovnáni se zdravými dobrovolníky: 43,77 mg/dl ± 20,61 V den dialýzy a 44,75 ± 23,04 mimo den dialýzy, oproti 19,63 ± 2,94, p < 0,0001. Na rozdíl od situace u zdravých dobrovolníků byla fosfátová sekrece slinami u dialyzovaných pacientů zvýšena během celého dne a nepodléhala žádnému dennímu rytmu. Závěry: Výsledky této studie přinášejí podněty pro nové možnosti terapeutického ovlivnění hyperfosfatémie u uremických pacientů, založené na redukci sekrece fosfátů slinami.
Aims: Phosphate balance in uremic patients represents a dramatic problem, which contributes to their increased morbidity and mortality. We have shown that salivary phosphate secretion is higher both in dialysis (HD) and in chronic renal failure patient s (CRF) compared with healthy subjects, closely related with serum phosphorous and may contribute to their increased phosphate balance. The presence of a circadian rhythm of salivary phosphate secretion with early evening acrophases in healthy subjects and our demonstration of increased salivary phosphate secretion both in HD and CRF have prompted us to check for possible abnormalities of the circadian rhythm of salivary phosphate secretion in uremic patients. Methods: Salivary phosphate secretion at 8.00, 12.00 a.m. and at 05.00 pm and 10.00 p.m. was evaluated in 56 HD patients without residual diuresis. 19 healthy subjects age and sex matched were used as control group. Results: Higher salivary phosphate secretion was confirmed in HD patients compared to healthy subjects: 43.77 mg/dl ± 20.61 at the day of dialysis and 44.75 ± 23.04 at the dialysis free day vs 19.63 ± 2.94, p < 0.0001. Contrary to healthy subjects, HD patients’ salivary phosphate secretion was higher throughout the day without any circadian rhythm. Conclusion: The results of this study add new considerations for a possible therapeutic approach to hyperphosphatemia in uremic patients based on the reduction of salivary phosphate secretion.
