Assessment of Matrix Gla Protein,Klotho Gene Polymorphisms,and Oxidative Stress in Chronic Kidney Disease

Abstract

Increased vascular calcification and oxidative stress are considered as extra renal risk factors at the pathogenesis cardiovascular events in chronic kidney disease (CKD). We investigated matrix Gla protein (MGP) (T-138C, Glu60X, Thr83Ala) and Klotho (Cys370Ser) gene polymorphisms, serum MGP levels, and oxidative stress status of 84 CKD patients and 37 healthy controls. The MGP gene Glu60X and Thr83Ala polymorphisms were significantly associated with CKD. The correlation between T-138C genotype of MGP gene, Cys370Ser genotype of Klotho gene, and CKD was not significant (p > 0.05). At the haplotype analysis, the combination of the X allele of Glu60X and the Thr allele of Thr83Ala showed a significantly increased risk of CKD (p < 0.05). X allele, Thr allele, and C allele of T-138C were associated with diabetes mellitus and CKD phenotypes occurring concurrently (p < 0.01). Serum zinc levels were significantly low in end-stage renal disease (ESRD) patients (p = 0.0001). The total comet score frequency of ESRD patients was higher than that of control group (p < 0.05). The urinary 8-hydroxy-2′-deoxyguanosine levels were significantly high in CKD patients (p < 0.05). According to this study, analyzing the distribution of MGP gene and oxidative stress status would be very informative in order to detect their role at CKD.     

Dendritic Cells in Kidney Transplant Biopsy Samples Are Associated with T Cell Infiltration and Poor Allograft Survival

Progress in long-term renal allograft survival continues to lag behind the progress in short-term transplant outcomes. Dendritic cells are the most efficient antigen-presenting cells, but surprisingly little attention has been paid to their presence in transplanted kidneys. We used dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin as a marker of dendritic cells in 105 allograft biopsy samples from 105 kidney transplant recipients. High dendritic cell density was associated with poor allograft survival independent of clinical variables. Moreover, high dendritic cell density correlated with greater T cell proliferation and poor outcomes in patients with high total inflammation scores, including inflammation in areas of tubular atrophy. We then explored the association between dendritic cells and histologic variables associated with poor prognosis. Multivariate analysis revealed an independent association between the densities of dendritic cells and T cells. In biopsy samples with high dendritic cell density, electron microscopy showed direct physical contact between infiltrating lymphocytes and cells that have the ultrastructural morphologic characteristics of dendritic cells. The origin of graft dendritic cells was sought in nine sex-mismatched recipients using XY fluorescence in situ hybridization. Whereas donor dendritic cells predominated initially, the majority of dendritic cells in late allograft biopsy samples were of recipient origin. Our data highlight the prognostic value of dendritic cell density in allograft biopsy samples, suggest a new role for these cells in shaping graft inflammation, and provide a rationale for targeting dendritic cell recruitment to promote long-term allograft survival.     

Diagnosis,Education, and Care of Patients with APOL1-Associated Nephropathy: A Delphi Consensus and Systematic Review

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Blood Kidney Injury Molecule-1 Is a Biomarker of Acute and Chronic Kidney Injury and Predicts Progression to ESRD in Type I Diabetes

Currently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (P<0.01). Blood KIM-1 levels were also elevated in patients with CKD of varous etiologies. In a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted rate of eGFR loss and risk of ESRD during 5–15 years of follow-up, after adjustment for baseline urinary albumin-to-creatinine ratio, eGFR, and Hb1Ac. These results identify KIM-1 as a blood biomarker that specifically reflects acute and chronic kidney injury.     

Chronic Kidney Disease in Cuba: Epidemiological Studies,Integral Medical Care,and Strategies for Prevention

The experience of the Republic of Cuba regarding epidemiological studies, integral medical care, and strategies for the prevention of chronic kidney disease is summarized in this report. Cuba has a National Program for Chronic Renal Disease, Dialysis, and Renal Transplantation. There is a national nephrology net, integrated by the Institute of Nephrology as the coordinator center, that has 47 nephrology services with a hemodialysis unit (24 of them with peritoneal dialysis unit), 9 transplantation centers, 33 organ procurement hospitals, and 5 histocompatibility laboratories.

In 2004, the incidence rate in dialysis patients was 111 pmp, and the prevalence rate was 149 pmp, demonstrating an increasing mean of 17.0% and 10.0% per year, respectively. Renal transplantation rate was 16.6 pmp. The detection, registration, and follow-up of patients with chronic kidney disease (serum creatinine ≥1.5 mg/dL or glomerular filtration rate <60 mL/min) by family doctors was 9,761 patients, 0.87 patients per 1,000 inhabitants.

In the 1980s, three population-based screening studies were performed to define the burden of chronic renal failure in different regions of Cuba. The prevalence rate was 1.1, 3.3, and 3.5 per 1,000 inhabitants, respectively. At present, another three population-based screening studies are ongoing in order to detect the chronic kidney disease in earliest stages.

The continuing medical education activities have been very useful in raising the awareness of medical doctors and the basic health staff about the threats posed by and the strategies to prevent, diagnose, and treat chronic kidney disease.     

Potential Advantages and Limitations of Applying the Chronic Kidney Disease Classification to Kidney Transplant Recipients

The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) classification of Chronic Kidney Disease (CKD) characterizes patients by their level of kidney function and includes kidney transplant recipients (KTRs). Most KTRs have stage > or = 3 CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2) and may benefit from aggressive CKD care. Recent modifications to the K/DOQI CKD classification reflect the recognition of KTRs as a unique subset of CKD patients in whom the presentation, progression and implications of CKD may vary from those in nontransplant CKD populations. Currently, there is limited information about how adopting the CKD classification in KTRs will influence clinical management and outcomes. Appropriately designed studies are needed to develop transplant-specific CKD treatment recommendations, and to ensure patient, health provider and payer acceptance of the continued need for aggressive CKD care after transplantation. Education and implementation strategies will be required to ensure appropriate integration of the CKD classification and treatment guidelines into existing posttransplant care programs. The CKD classification thus represents an exciting potential strategy to improve clinical outcomes that should be adopted, further studied and modified to incorporate considerations unique to KTRs.     

Kidney Transplant Rejection and Tissue Injury by Gene Profiling of Biopsies and Peripheral Blood Lymphocytes

A major challenge for kidney transplantation is balancing the need for immunosuppression to prevent rejection, while minimizing drug-induced toxicities. We used DNA microarrays (HG-U95Av2 GeneChips, Affymetrix) to determine gene expression profiles for kidney biopsies and peripheral blood lymphocytes (PBLs) in transplant patients including normal donor kidneys, well-functioning transplants without rejection, kidneys undergoing acute rejection, and transplants with renal dysfunction without rejection. We developed a data analysis schema based on expression signal determination, class comparison and prediction, hierarchical clustering, statistical power analysis and real-time quantitative PCR validation. We identified distinct gene expression signatures for both biopsies and PBLs that correlated significantly with each of the different classes of transplant patients. This is the most complete report to date using commercial arrays to identify unique expression signatures in transplant biopsies distinguishing acute rejection, acute dysfunction without rejection and well-functioning transplants with no rejection history. We demonstrate for the first time the successful application of high density DNA chip analysis of PBL as a diagnostic tool for transplantation. The significance of these results, if validated in a multicenter prospective trial, would be the establishment of a metric based on gene expression signatures for monitoring the immune status and immunosuppression of transplanted patients.     

上皮膜蛋白-1在人椎间盘髓核细胞中的表达

目的观察上皮膜蛋白-1(epithelia membrane protein-1,EMP-1)在人椎间盘髓核细胞中存在的表达。方法利用我们已建成的人胚椎间盘髓核细胞和退变椎间盘细胞培养体系,采用半定量反转录PCR和免疫组化方法检测EMP-1在这两种细胞中的表达情况。结果人胚及退变椎间盘髓核细胞中EMP-1均有表达,分布在不同部位,且具有一定的丰度。结论 EMP-1在正常和退变椎间盘细胞中的存在和生物学特性改变,提示EMP-1可能在椎间盘退变中担当重要角色。     

Kidney Function and Risk of Cardiovascular Disease and Mortality in Kidney Transplant Recipients: The FAVORIT Trial

In kidney transplant recipients, cardiovascular disease (CVD) is the leading cause of death. The relationship of kidney function with CVD outcomes in transplant recipients remains uncertain. We performed a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial to assess risk factors for CVD and mortality in kidney transplant recipients. Following adjustment for demographic, clinical and transplant characteristics, and traditional CVD risk factors, proportional hazards models were used to explore the association of estimated GFR with incident CVD and all‐cause mortality. In 4016 participants, mean age was 52 years and 20% had prior CVD. Mean eGFR was 49±18 mL/min/1.73 m². In 3676 participants with complete data, there were 527 CVD events over a median of 3.8 years. Following adjustment, each 5 mL/min/1.73 m² higher eGFR at levels below 45 mL/min/1.73 m² was associated with a 15% lower risk of both CVD [HR = 0.85 (0.80, 0.90)] and death [HR = 0.85 (0.79, 0.90)], while there was no association between eGFR and outcomes at levels above 45 mL/min/1.73 m². In conclusion, in stable kidney transplant recipients, lower eGFR is independently associated with adverse events, suggesting that reduced kidney function itself rather than preexisting comorbidity may lead to CVD.