Summary Patients with chronic kidney failure—defined as a glomerular filtration rate persistently below 15 mL/min per 1·73 m2 —have an unacceptably high mortality rate. In developing countries, ...mortality results primarily from an absence of access to renal replacement therapy. Additionally, cardiovascular and non-cardiovascular mortality are several times higher in patients on dialysis or post-renal transplantation than in the general population. Mortality of patients on renal replacement therapy is affected by a combination of socioeconomic factors, pre-existing medical disorders, renal replacement treatment modalities, and kidney failure itself. Characterisation of the key pathophysiological contributors to increased mortality and cardiorenal risk staging systems are needed for the rational design of clinical trials aimed at decreasing mortality. Policy changes to improve access to renal replacement therapy should be combined with research into low-cost renal replacement therapy and optimum clinical care, which should include multifaceted approaches simultaneously targeting several of the putative contributors to increased mortality.
Background Chronic subclinical volume overload happens very frequently in hemodialysis patients and is associated directly with hypertension, increased arterial stiffness, left ventricular ...hypertrophy, and ultimately higher mortality. Study Design Randomized controlled parallel-group trial. Setting & Participants 131 patients from one hemodialysis center, randomly assigned into 2 groups. Intervention Dry weight prescription using results derived from repeated 3-month bioimpedance measurements to guide ultrafiltration for strict volume control (bioimpedance group; n = 62) compared with clinical judgment without bioimpedance measures (clinical-methods group; n = 69) for 2.5 years. Outcomes The primary outcome was all-cause mortality over 2.5 years (the duration of the intervention). Secondary outcomes were change in relative arterial stiffness, fluid overload, and blood pressure (BP) over 2.5 years. Measurements Bioimpedance measurements were performed using a Body Composition Monitor device. Pulse wave velocity analysis was performed at baseline, 2.5 years (end of intervention), and 3.5 years (end of study). Relative fluid overload and BP were assessed at 3-month intervals. Results The unadjusted HR for all-cause death in the bioimpedance group (vs the clinical-methods group) was 0.100 (95% CI, 0.013-0.805; P = 0.03). After 2.5 years, we found a greater decline in arterial stiffness, relative fluid overload, and systolic BP in the bioimpedance group than the clinical-methods group. Between-group differences in change from baseline to the end of intervention were −2.78 (95% CI, −3.75 to 1.80) m/s for pulse wave velocity ( P < 0.001), −2.99% (95% CI, −5.00% to −0.89%) for relative fluid overload ( P = 0.05), and −2.43 (95% CI, −7.70 to 2.84) mm Hg for systolic BP ( P = 0.4). Limitations Echocardiography was not performed as cardiovascular assessment and the caregivers were not masked to the intervention. Conclusions Our study showed improvement in both surrogate and hard end points after strict volume control using bioimpedance to guide dry weight adjustment. These findings need to be confirmed in a larger trial.
Background Convective dialysis therapies (hemofiltration or hemodiafiltration) are associated with lower mortality compared to hemodialysis in observational studies. A previous meta-analysis of ...randomized trials comparing convective modalities with hemodialysis in 2006 was inconclusive due to insufficient data. Additional randomized trials recently have reported conflicting results. Study Design Systematic review and meta-analysis of randomized trials to February 27, 2013. Setting & Population Patients with chronic kidney failure treated by hemodialysis, hemodiafiltration, hemofiltration, or biofiltration. Selection Criteria for Studies Randomized controlled trials. Intervention Convective therapies (hemodiafiltration, hemofiltration, and acetate-free biofiltration) compared with hemodialysis. Outcomes All-cause and cardiovascular mortality, nonfatal cardiovascular events, hospitalization, change in dialysis modality, health-related quality of life, adverse events, blood pressure, and clearances of urea and β2 -microglobulin. Results 35 trials (4,039 participants) were included. In low-quality evidence, convective dialysis had little or no effect on all-cause mortality (relative risk RR, 0.87; 95% CI, 0.70-1.07) and may reduce cardiovascular mortality (RR, 0.75; 95% CI, 0.58-0.97) and hypotension (RR, 0.72; 95% CI, 0.66-0.80) during dialysis, but had uncertain effects on nonfatal cardiovascular events (RR, 1.14; 95% CI, 0.85-1.52) and hospitalization (RR, 1.21; 95% CI, 0.12-12.05). Adverse events were not reported systematically and health-related quality-of-life outcomes were sparse. Convective therapies reduced predialysis levels of β2 -microglobulin (mean difference, −5.77 95% CI, −10.97 to −0.56 mg/dL) and increased dialysis dose (Kt/Vurea mean difference, 0.10; 95% CI, 0.02-0.19), but these effects were very heterogeneous. Sensitivity analyses limited to trials comparing hemodiafiltration with hemodialysis showed similar results. Limitations Studies had important risks of bias leading to low confidence in the summary estimates and generally were limited to patients who had adequate dialysis vascular access. Conclusions Treatment effects of convective dialysis are unreliable due to limitations in trial methods and reporting. Convective dialysis may reduce cardiovascular but not all-cause mortality, and effects on nonfatal cardiovascular events and hospitalization are inconclusive.
Diabetic nephropathy (DN), a major cause of ESRD, is undoubtedly multifactorial and is caused by environmental and genetic factors. To identify a genetic basis for DN susceptibility, we are ...collecting multiplex DN families in the Caucasian (CA) and African-American (AA) populations for whole genome scanning and candidate gene analysis. A candidate gene search of diabetic sibs discordantly affected, concordantly affected and concordantly unaffected for DN was performed with microsatellite markers in genomic regions suspected to harbor nephropathy susceptibility loci. Regions examined were at human chromosome 10p,10q (orthologous to the rat renal susceptibility Rf-1 locus), and at NPHS1 (nephrin), CD2AP, Wilms tumor (WT1), and NPHS2 (podocin) loci. Linkage analyses were conducted using model-free methods (SIBPAL, S.A.G.E.) for AA, CA, and the combined sample. Allele frequencies and the identity by descent sharing were estimated separately for AA and CA, and race was included as a covariate in the final linkage analysis. To date, we have collected 212 sib pairs from 46 CA and 50 AA families. The average age of diabetes onset was 46.8 yr versus 36.2 yr for CA and 39.5 yr versus 40.2 yr for AA, in males versus females respectively. Genotyping data were available for 106 sib pairs (43 CA, 63 AA) from 27 CA (44% male probands) and 38 AA families (43% male probands). Average AA and CA sibship size was 2.73. Singlepoint and multipoint linkage analyses indicate that marker D10S1654 on chromosome 10p is potentially linked to DN (CA only multipoint P = 4 x 10(-3)). Interestingly, the majority of the linkage evidence derives from the CA sib pairs. We are now adding sib pairs and increasing marker density on chromosome 10. We have excluded linkage with candidate regions for nephrin, CD2AP, WT1, and podocin in this sample. In conjunction with previous reports, our data support evidence for a DN susceptibility locus on chromosome 10.
Serum C-peptide concentrations poorly phenotype type 2 diabetic end-stage renal disease patients.
A homogeneous patient population is necessary to identify genetic factors that regulate complex ...disease pathogenesis. In this study, we evaluated clinical and biochemical phenotyping criteria for type 2 diabetes in end-stage renal disease (ESRD) probands of families in which nephropathy is clustered. C-peptide concentrations accurately discriminate type 1 from type 2 diabetic patients with normal renal function, but have not been extensively evaluated in ESRD patients. We hypothesized that C-peptide concentrations may not accurately reflect insulin synthesis in ESRD subjects, since the kidney is the major site of C-peptide catabolism and would poorly correlate with accepted clinical criteria used to classify diabetics as types 1 and 2.
Consenting diabetic ESRD patients (N = 341) from northeastern Ohio were enrolled. Clinical history was obtained by questionnaire, and predialysis blood samples were collected for C-peptide levels from subjects with at least one living diabetic sibling (N = 127, 48% males, 59% African Americans).
Using clinical criteria, 79% of the study population were categorized as type 1 (10%) or type 2 diabetics (69%), while 21% of diabetic ESRD patients could not be classified. In contrast, 98% of the patients were classified as type 2 diabetics when stratified by C-peptide concentrations using criteria derived from the Diabetes Control and Complications Trial Research Group (DCCT) and UREMIDIAB studies. Categorization was concordant in only 70% of ESRD probands when C-peptide concentration and clinical classification algorithms were compared. Using clinical phenotyping criteria as the standard for comparison, C-peptide concentrations classified diabetic ESRD patients with 100% sensitivity, but only 5% specificity. The mean C-peptide concentrations were similar in diabetic ESRD patients (3.2 ± 1.9 nmol/L) and nondiabetic ESRD subjects (3.5 ± 1.7 nmol/L, N = 30, P = NS), but were 2.5-fold higher compared with diabetic siblings (1.3 ± 0.7 nmol/L, N = 30, P < 0.05) with normal renal function and were indistinguishable between type 1 and type 2 diabetics. Although 10% of the diabetic ESRD study population was classified as type 1 diabetics using clinical criteria, only 1.5% of these patients had C-peptide levels less than 0.20 nmol/L, the standard cut-off used to discriminate type 1 from type 2 diabetes in patients with normal renal function. However, the criteria of C-peptide concentrations> 0.50 nmol/L and diabetes onset in patients who are more than 38 years old identify type 2 diabetes with a 97% positive predictive value in our ESRD population.
Accepted clinical criteria, used to discriminate type 1 and type 2 diabetes, failed to classify a significant proportion of diabetic ESRD patients. In contrast to previous reports, C-peptide levels were elevated in the majority of type 1 ESRD diabetic patients and did not improve the power of clinical parameters to separate them from type 2 diabetic or nondiabetic ESRD subjects. Accurate classification of diabetic ESRD patients for genetic epidemiological studies requires both clinical and biochemical criteria, which may differ from norms used in diabetic populations with normal renal function.
Background Chronic kidney disease (CKD) is associated with such complications as fractures and the need for parathyroidectomy. Mineral metabolism control in patients with CKD has been poor. Studies ...have assessed fractures and parathyroidectomy risk with mineral disturbances, but with considerable diversity in methods. Thus, a systematic review was conducted to assess method or clinical heterogeneity by comparing the design, analytical techniques, and results of studies. Study Design Systematic review of the MEDLINE, EMBASE, and Cochrane databases between 1980 and December 2007. Setting & Population Patients with CKD or dialysis patients. Selection Criteria for Studies Observational and clinical trials investigating the risk of fractures or parathyroidectomy with mineral disturbances. Predictor Mineral metabolism variables (phosphorus, calcium, and parathyroid hormone PTH levels). Outcomes Fractures, need for parathyroidectomy. Results 9 studies were identified that assessed fractures (n = 6) or need for parathyroidectomy (n = 3). Data for fractures or parathyroidectomy risk in predialysis patients are absent. Diversity across studies was observed in populations, methods of exposure assessment, adjusted covariates, and reference mineral levels used in risk estimation. A significant fracture risk was observed with increasing PTH levels. However, additional data are required to understand fracture risk with changes in phosphorus or calcium levels. Data supported greater parathyroidectomy risk with increasing PTH, phosphorus, or calcium levels. Limitations Clinical and method heterogeneity across studies precluding the quantitative synthesis of data. Conclusions Serious limitations were observed in the number, quality, and method rigor of studies. Despite heterogeneity across studies, data suggest a significant parathyroidectomy risk with mineral disturbances and a fracture risk with increasing PTH levels in dialysis patients. Additional high-quality data for risk of fractures or parathyroidectomy with changes in phosphorus, calcium, or PTH levels is required to highlight the importance of managing such common, but subclinical, conditions as mineral metabolism disturbances.
Antibody-based therapeutics and vaccines are essential to combat COVID-19 morbidity and mortality after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple mutations in ...SARS-CoV-2 that could impair antibody defenses propagated in human-to-human transmission and spillover or spillback events between humans and animals. To develop prevention and therapeutic strategies, we formed an international consortium to map the epitope landscape on the SARS-CoV-2 spike protein, defining and structurally illustrating seven receptor binding domain (RBD)–directed antibody communities with distinct footprints and competition profiles. Pseudovirion-based neutralization assays reveal spike mutations, individually and clustered together in variants, that affect antibody function among the communities. Key classes of RBD-targeted antibodies maintain neutralization activity against these emerging SARS-CoV-2 variants. These results provide a framework for selecting antibody treatment cocktails and understanding how viral variants might affect antibody therapeutic efficacy.
The impressive cardiovascular morbidity and mortality of chronic kidney disease (CKD) patients is attributable in a significant proportion to endothelial dysfunction (ED), arterial stiffness, and ...vascular calcifications. Abnormal vascular reactivity in these patients is more pronounced compared with other high-risk populations, but remains undiagnosed in the usual clinical setting. We briefly review the most important causes and risk factors of ED, oxidative stress, and inflammation related to arterial stiffness. We describe the main methods of ED investigation and the importance of using potential biomarkers together with classic techniques for a more comprehensive assessment of this condition. These methods include evaluation of: forearm blood flow by plethysmography, skin microcirculation by laser Doppler, and flow-mediated vasodilation by Doppler ultrasound imaging. Applanation tonometry is an easy-to-handle tool that allows a clinically reliable assessment of arterial stiffness and is also useful in quantifying endothelium-dependent and -independent vascular reactivity. We also discuss the diagnostic and therapeutic impact of new markers of ED in the CKD population. Improvement of endothelial function is an important challenge for clinical practice, and there are relatively few therapeutical strategies available. Therefore, a combined biomarker and bedside investigational approach could be a starting point for developing optimal therapeutic tools.
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