Focal segmental glomerulosclerosis (FSGS), an important cause of end-stage kidney disease (ESKD), covers a spectrum of clinicopathological syndromes sharing a common glomerular lesion, based on an ...injury of podocytes caused by diverse insults to glomeruli. Although it is well expressed in many reports that the term FSGS is not useful and applicable to a single disease, particularly in genetic studies, FSGS continues to be used as a single clinical diagnosis. Distinguishing genetic forms of FSGS is important for the treatment and overall prognosis because secondary forms of FSGS, produced by rare pathogenic variations in podocyte genes, are not good candidates for immunosuppressive treatment. Over the past decade, several next generation sequencing (NGS) methods have been used to investigate the patients with steroid resistance nephrotic syndrome (SRNS) or FSGS. Pathogenic variants in
COL4A3
,
COL4A4
, or
COL4A5
genes have been frequently identified in patients with histologic diagnosis of FSGS. The contribution of these mostly heterozygous genetic variations in FSGS pathogenesis and the clinical course of patients with these variations have not been well characterized. This review emphasizes the importance of appropriate approach in selection and diagnosis of cases and interpretation of the genetic data in these studies and suggests a detailed review of existing clinical variant databases using newly available population genetic data.
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.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The complement system causes kidney injury in a variety of different diseases, and clinical evaluation of the complement system is an important part of the diagnostic workup of patients with ...glomerulonephritis. In cases of ongoing, uncontrolled complement activation, the kidney is susceptible to complement hyperactivation, and thrombotic microangiopathy associated kidney injury can occur. Two principle modes of complement-mediated kidney injury have been proposed: classical pathway mediated injury in immune complex diseases and/or alternative pathway mediated renal injury causing atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathy in patients with abnormalities in alternative pathway regulation. Recent advances have also provided new insights into the pathogenesis of glomerular and tubulointerstitial injury associated with aberrant complement activation. Complement inhibition is effective for treatment of aHUS, and there is growing evidence of the favourable effect of the anti-C5 monoclonal antibody eculizumab. Measurement of ex vivo serum-induced endothelial C5b-9 deposits is supposed to be a sensitive tool to monitor complement activation and eculizumab effectiveness. Although understanding the role of the complement system in the pathogenesis of many kidney diseases is improved, there is not a simple algorithm for identifying which patients should be treated with complement inhibitors or for how long complement inhibition should be continued.
Background: Homozygosity for LIMS1 rs893403-GG genotype is linked to an increased risk of allograft rejection after kidney transplantation. Ischemia-reperfusion of the kidney allograft leads to long ...term infiltration of activated and effector-memory T lymphocytes and resulting in rejection and long-term fibrosis. However, the genotype, LIMS1 expression under ischemic conditions and the long-term histopathological relationships remain ill-defined. Methods: We examined the impact of the recipient’s LIMS1-rs893403 genotype with transplant kidney histopathology. The association of the LIMS1-rs893403 genotype and LIMS1 and GCC2 mRNA expression in ischemic donor kidneys were also examined. Recipients who underwent transplant kidney biopsy were genotyped for the LIMS1-rs893403 variant and associated deletion. Histopathological findings were compared between recipients with LIMS1 risk and non-risk genotypes. Real-time PCR and immunofluorescence staining for LIMS1 and GCC2 expression were performed in non-utilized donor kidneys. Results: Demographic, clinical, and treatment characteristics and the histopathological diagnosis were similar between recipients with rs893403 GG and AA/AG genotype. The Banff tubulitis score was higher in GG recipients (n = 24) compared to AA/AG (n = 86) recipients (1.42 ± 0.65 vs. 1.12 ± 0.66, p = 0.03). Ischemic kidneys with GG showed higher LIMS1 and GCC2 mRNA expression than kidneys with AG. Kidneys with rs893403-GG had higher tubular LIMS1 and GCC2 immunohistochemical staining compared to kidneys with rs893403-AG. Conclusions: Our data supports the role of the LIMS1 locus in kidney transplant rejection, particularly in lymphocyte infiltration into the internal aspect of the tubular basement membranes. Increased LIMS1 and GCC2 expression in ischemic donor kidneys with the GG genotype require further studies.
Background/Aims: The aim of this study is to investigate the utility of clinical age, gender, mean arterial pressure (MAP) and laboratory parameters eGFR, hemoglobin (Hgb), serum levels of ...creatinine, uric acid, albumin, proteinuria, hematuria and also histopathological lesions (Oxford classification parameters, crescents, intensity and pattern of staining for C3, C1Q, IgA, IgG, IgM) as progression markers in patients with IgA Nephropathy (IgAN). Methods: A total of 111 IgAN patients with a follow-up period >1 year or who reached kidney failure GFR category G5 chronic kidney disease (CKD) <1 year were investigated. Primary endpoint was the development of kidney failure or eGFR decline ≥50% from the baseline. Kaplan-Meier and Cox proportional hazards analyses were performed. Results: Mean follow-up period was 33±29 months. Thirty-seven (33.3%) patients progressed to kidney failure and 4 (3.6%) patients developed eGFR decline ≥50% from the baseline after a median of 23 and 65 months, respectively. In multivariate Cox regression analysis, baseline levels of Hgb (HR:0.782, 95% CI 0.559-0.973, p=0.037), serum uric acid (HR:1.293, 95% CI 1.023-1.621, p=0.046), eGFR (HR:0.966, 95% CI 0.947-0.984, p=0.004) and intensity of C3 staining (HR:1.550, 95% CI 1.198-1.976, p=0.049) predicted primary endpoint. Serum uric acid level was associated independently with T score (β=0.303, p=0.005) in patients with eGFR>30 ml/min/m 2 . Conclusions: Hyperuricemia and the deposition of C3 are independent risk factors for IgAN progression.
Vascular calcification is associated with increased cardiovascular mortality in chronic hemodialysis patients. This prospective study investigated the relationship between serum osteoprotegerin, ...receptor activator of NF-κB ligand, inflammatory markers, and progression of coronary artery calcification score.
Seventy-eight hemodialysis patients were enrolled. Serum IL-1β, IL-6, TNF-α, osteoprotegerin, receptor activator of NF-κB, fetuin A, and bone alkaline phosphatase were measured by ELISA. Coronary artery calcification score was measured two times with 1-year intervals, and patients were classified as progressive or nonprogressive.
Baseline and first-year serum osteoprotegerin levels were significantly higher in the progressive than nonprogressive group (17.39±9.67 versus 12.90±6.59 pmol/L, P=0.02; 35.17±18.35 versus 24±11.65 pmol/L, P=0.002, respectively). The ratio of serum osteoprotegerin to receptor activator of NF-κB ligand at 1 year was significantly higher in the progressive group (0.26 0.15-0.46 versus 0.18 0.12-0.28, P=0.004). Serum osteoprotegerin levels were significantly correlated with coronary artery calcification score at both baseline (r=0.36, P=0.001) and 1 year (r=0.36, P=0.001). Importantly, progression in coronary artery calcification score significantly correlated with change in serum osteoprotegerin levels (r=0.39, P=0.001). In addition, serum receptor activator of NF-κB ligand levels were significantly inversely correlated with coronary artery calcification scores at both baseline (r=-0.29, P=0.01) and 1 year (r=-0.29, P=0.001). In linear regression analysis for predicting coronary artery calcification score progression, only baseline coronary artery calcification score and change in osteoprotegerin were retained as significant factors in the model.
Baseline coronary artery calcification score and serum osteoprotegerin levels were significantly associated with progression of coronary artery calcification score in hemodialysis patients.
Background
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease. The course and progression of the disease is highly variable. In this study, we aimed to ...investigate the impact of clinical characteristics and basic biochemical parameters on progression of chronic kidney disease (CKD) in ADPKD patients.
Materials and methods
A total of 323 consecutive patients with ADPKD were enrolled into the study and followed with a mean duration of 100 ± 38 months. Patients were grouped as rapid progressors (RP) and slow progressors (SP) according to median rates of decline in glomerular filtration rate (ΔGFR) per year, namely 1 ml/min/year.
Results
History of macroscopic hematuria, urinary stone and smoking were more common in male patients; hepatic and other organ cysts were more common in female patients. ∆GFR/year was similar between males and females 0.95 (0–3.02) vs. 1.11 (0.10–2.74) ml/min/year,
p
= 0.21. History of smoking and pack-year of cigarettes smoked were significantly higher in the RP compared to the SP group (36 vs. 18 %,
p
= 0.01 and 5.24 ± 1.20 vs. 3 ± 1.32 pack-year,
p
= 0.02, respectively). Baseline 24 h-proteinuria was found to be significantly correlated with the percent decline of GFR (∆%GFR) per year (
r
= 0.303, 0.001). In Cox regression analysis for predicting the progression of CKD, age, hypertension, urinary stone and proteinuria were retained as the significant independent factors predicting progression of CKD in the model.
Conclusion
Baseline proteinuria was significantly correlated with ∆%GFR per year. Hypertension and proteinuria were found to be the major treatable risk factors for the progression of CKD in ADPKD patients.
PDF
