A Paradigm to Discover Biomarkers Associated With Chronic Kidney Disease Progression.

Biomarker discovery in the field of risk prediction in chronic kidney disease (CKD) embraces the prospect of improving our ability to risk stratify future adverse outcomes and thereby guide patient care in a new era of personalised medicine. However, many studies that report biomarkers predictive of CKD progression share a key methodological limitation: failure to characterise patients' renal progression precisely. This weakens any observable association between a biomarker and an outcome poorly defined by a patient's change in renal function over time. In this commentary, we discuss the need for a better approach in this research arena and describe a compelling strategy that has the advantage of offering robust and meaningful biomarker exploration relevant to CKD progression.

Coffee Consumption and Kidney Function: A Mendelian Randomization Study.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) is a leading cause of morbidity and mortality worldwide, with limited strategies for prevention and treatment. Coffee is a complex mixture of chemicals, and consumption has been associated with mostly beneficial health outcomes. This work aimed to determine the impact of coffee consumption on kidney function. STUDY DESIGN: Genome-wide association study (GWAS) and Mendelian randomization. SETTING & PARTICIPANTS: UK Biobank baseline data were used for a coffee consumption GWAS and included 227,666 participants. CKDGen Consortium data were used for kidney outcomes and included 133,814 participants (12,385 cases of CKD) of mostly European ancestry across various countries. EXPOSURE: Coffee consumption. OUTCOMES: Estimated glomerular filtration rate (eGFR), CKD GFR categories 3 to 5 (G3-G5; eGFR<60mL/min/1.73m2), and albuminuria. ANALYTICAL APPROACH: GWAS to identify single-nucleotide polymorphisms (SNPs) associated with coffee consumption in UK Biobank and use of those SNPs in Mendelian randomization analyses of coffee consumption and kidney outcomes in CKDGen. RESULTS: 2,126 SNPs were associated with coffee consumption (P<5×10-8), 25 of which were independent and available in CKDGen. Drinking an extra cup of coffee per day conferred a protective effect against CKD G3-G5 (OR, 0.84; 95% CI, 0.72-0.98; P=0.03) and albuminuria (OR, 0.81; 95% CI, 0.67-0.97; P=0.02). An extra cup was also associated with higher eGFR (ß=0.022; P=1.6×10-6) after removal of 3 SNPs responsible for significant heterogeneity (Cochran Q P = 3.5×10-15). LIMITATIONS: Assays used to measure creatinine and albumin varied between studies that contributed data and a sex-specific definition was used for albuminuria rather than KDIGO guideline recommendations. CONCLUSIONS: This study provides evidence of a beneficial effect of coffee on kidney function. Given widespread coffee consumption and limited interventions to prevent CKD incidence and progression, this could have significant implications for global public health in view of the increasing burden of CKD worldwide.

Regional Variation in Acute Kidney Injury Requiring Dialysis in the English National Health Service from 2000 to 2015 - A National Epidemiological Study.

BACKGROUND: The absence of effective interventions in presence of increasing national incidence and case-fatality in acute kidney injury requiring dialysis (AKI-D) warrants a study of regional variation to explore any potential for improvement. We therefore studied regional variation in the epidemiology of AKI-D in English National Health Service over a period of 15 years. METHOD: We analysed Hospital Episode Statistics data for all patients with a diagnosis of AKI-D, using ICD-10-CM codes, in English regions between 2000 and 2015 to study temporal changes in regional incidence and case-fatality. RESULTS: Of 203,758,879 completed discharges between 1st April 2000 and 31st March 2015, we identified 54,252 patients who had AKI-D in the nine regions of England. The population incidence of AKI-D increased variably in all regions over 15 years; however, the regional variation decreased from 3·3-fold to 1·3-fold (p<0·01). In a multivariable adjusted model, using London as the reference, in the period of 2000-2005, the North East (odd ratio (OR) 1·38; 95%CI 1·01, 1·90), East Midlands (OR 1·38; 95%CI 1·01, 1·90) and West Midlands (OR 1·38; 95%CI 1·01, 1·90) had higher odds for death, while East of England had lower odds for death (OR 0·66; 95% CI 0·49, 0·90). The North East had higher OR in all three five-year periods as compared to the other eight regions. Adjusted case-fatality showed significant variability with temporary improvement in some regions but overall there was no significant improvement in any region over 15 years. CONCLUSIONS: We observed considerable regional variation in the epidemiology of AKI-D that was not entirely attributable to variations in demographic or other identifiable clinical factors. These observations make a compelling case for further research to elucidate the reasons and identify interventions to reduce the incidence and case-fatality in all regions.

Comparison of progressive conductivity reduction with diacontrol and standard dialysis.

We examined whether progressive reduction of dialysate sodium with Diacontrol (DC, plasma conductivity targeted feedback system) confers any clinical benefit over a similar strategy using dialysis with fixed dialysate conductivity (HD). Ten stable patients entered a randomized crossover study conducted over 360 dialysis sessions. Sodium balance, blood pressure (BP), intradialytic hypotension rates (IDH), thirst score, and extracellular water (ECW) were recorded. Interdialytic ambulatory BP was measured at the highest and lowest conductivities. BP, interdialytic weight gains and thirst scores were low at the outset and were not altered significantly by conductivity reduction. The lowest fixed dialysate setting of 13.2 mS/cm resulted in greater sodium depuration than the lowest conductivity setting allowable with DC, as reflected by lower post dialysis plasma conductivity (13.4 +/- 0.14 mS/cm versus 13.5 +/- 0.04 mS/cm, p < 0.001). Predialysis ECW fell from 0.22 +/- 0.04 l/kg to 0.21 +/- 0.09 l/kg as conductivity reduced with HD (p < 0.05), but did not change significantly with DC. When HD and DC were matched for end-dialysis plasma conductivity, there were no differences in BP, IDH frequency, or dialysis tolerability even at the lowest conductivity settings. In a setting of dialysate sodium reduction, DC did not appear to have any short-term clinical advantage over standard dialysis, and its range is limited at the lower conductivity settings.

Length of interdialytic interval influences serum calcium and phosphorus concentrations.

BACKGROUND: Higher levels of serum phosphorus and calcium are associated with increased haemodialysis (HD) patient mortality. Both of these factors act synergistically to promote vascular smooth muscle differentiation to an osteoblast-like phenotype and subsequent vascular calcification. The aim of this study was to investigate the influence of interdialytic interval on serum levels, as well as the influence of oral calcium-based phosphate binder load on the magnitude of the observed differences. METHODS: We studied 100 patients undergoing HD three times per week, over a 2 week period. Haemoglobin, albumin, calcium and phosphate were measured pre-dialysis before each HD session. Oral phosphate binder usage was recorded. All patients were treated with dialysate containing 1.25 mEq/l calcium. RESULTS: Both mean serum phosphate and calcium were higher after the long interdialytic interval (1.59+/-0.05 vs 1.45+/-0.04 mmol/l, P = 0.0005, and 2.46+/-0.03 vs 2.4+/-0.02 mmol/l, P = 0.001, for serum phosphate and uncorrected calcium, respectively). There were no significant differences in haemoglobin or serum albumin, indicating that variable dilution from an increased hydration status in the long interdialytic interval was unlikely to contribute to these observed differences. A total of 74 patients were treated with calcium-containing binders and 26 patients with sevelamer. Patients on sevelamer did not exhibit the observed cyclical increase in serum calcium seen in patients on calcium-containing binders (mean difference in serum calcium 0.09+/-0.01 mmol/l in the calcium-treated group vs 0.01+/-0.01 mmol/l in the sevelamer-treated patients, P = 0.0004). The increase in serum calcium after the long interval as compared with the short interval was proportional to the daily amount of the oral calcium-containing binder load ingested (r = 0.63, P<0.0001). CONCLUSION: Cyclical differences in interdialytic interval and overall exposure to both dietary phosphate and oral calcium load influence serum levels. This may have consequences for registry reporting, therapy modulation and potentially the pathogenesis of accelerated vascular calcification seen in HD patients.