Background Recent cardiovascular outcome trials have shown that sodium–glucose co-transporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease (CKD) in patients with type 2 diabetes at high cardiovascular risk. Whether these benefits extend to CKD patients without type 2 diabetes or cardiovascular disease is unknown. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) will assess the effect of the SGLT2 inhibitor dapagliflozin on renal and cardiovascular events in a broad range of patients with CKD with and without diabetes. Methods DAPA-CKD is a randomized, double-blind, placebo-controlled, trial in which ∼4300 patients with CKD Stages 2–4 and elevated urinary albumin excretion will be enrolled. The vast majority will be receiving a maximum tolerated dose of a renin–angiotensin system inhibitor at enrolment. Results After a screening assessment, eligible patients with a urinary albumin:creatinine ratio ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 are randomly assigned to placebo or dapagliflozin 10 mg/day. Enrolment is monitored to ensure that at least 30% of patients do not have diabetes and that no more than 10% have an eGFR >60 mL/min/1.73 m2. The primary endpoint is a composite of a sustained decline in eGFR of ≥50%, end-stage renal disease, renal death or cardiovascular death. The trial will conclude when 681 primary renal events have occurred, providing 90% power to detect a 22% relative risk reduction (α level of 0.05). Conclusion DAPA-CKD will determine whether the SGLT2 inhibitor dapagliflozin, added to guideline-recommended therapies, safely reduces the rate of renal and cardiovascular events in patients across multiple CKD stages with and without diabetes.

Uridine kinase (UK) and uracil phosphoribosyltransferase (UPRT) are enzymes catalyzing the formation of uridine 5'-monophosphate (UMP) from uridine and adenine 5'-triphosphate (ATP) and from uracil and phosphoribosyl-alpha-l-pyrophosphate (PRPP), respectively, in the pyrimidine salvage pathway. Here, we report the characterization and functional analysis of a gene AtUK/UPRT1 from Arabidopsis thaliana. Sequencing of an expressed sequence tag clone of this gene revealed that it contains a full-length open reading frame of 1461 nucleotides and encodes a protein with a molecular mass of approximately 53 kDa. The sequence analysis revealed that the N-terminal region of AtUK/UPRT1 contains a UK domain and the C-terminal region consists of a UPRT domain. Expression of AtUK/UPRT1 in upp and upp-udk mutants of Escherichia coli supplied with 5-fluorouracil (5-FU) and 5-fluorouridine (5-FD) led to growth inhibition. Identical results were obtained with 5-FD and 5-FU treatments when the UK and UPRT domains were separated by the introduction of translation initiation and stop codons prior to complementation into the upp-udk and upp mutants. These results suggest that the AtUK/UPRT1 product can use uracil and uridine as substrates for the production of UMP. We also investigated the function of AtUK/UPRT1 in an Arabidopsis mutant. The wild-type Arabidopsis plants showed drastic growth retardation when they were treated with 5-FU and 5-FD while the growth of atuk/uprtl mutant plants was not significantly affected. These findings confirm that AtUK/UPRT1 has a dual role in coding for both uridine kinase and uracil phosphoribosyltransferase that form UMP through the pyrimidine salvage pathway in Arabidopsis.

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PurposeContinuous renal replacement therapy (CRRT) has been established for critically ill acute kidney injury (AKI) patients. In addition, some centers consist of a specialized CRRT team (SCT) with physicians and nurses. To our best knowledge, however, ona a few studies have yet been carried out on the superiority of SCT management.Materials and MethodsA total of 551 patients, who received CRRT between January 2008 and March 2009, were divided into two groups based on the controller of CRRT. The impact of the CRRT management on 28-day mortality was compared between two groups by Kaplan-Meier curve and Cox analysis.ResultsDuring the study period, the number of filters used, down-time per day, and intensive care unit length of day were significantly higher in non-SCT group than in SCT group (6.2 hrs vs. 5.0 hrs, p=0.042; 5.0 hrs vs. 3.8 hrs, p<0.001; 27.5 days vs. 21.1 days, p=0.027, respectively), while net ultrafiltration rate was significantly lower in non-SCT group than SCT group (28.0 mL/kg/hr vs. 29.5 mL/kg/hr, p=0.043, respectively). In addition, 28-day mortality rate was significantly lower in SCT group than with non-SCT group (p=0.031). Moreover, Cox regression analysis showed that 28-day mortality rate was significantly lower in SCT control group, even after adjusting for age, gender, severity scores, biomarkers, risk, injury, failure, loss, and end-stage renal disease, and contributing factors (hazard ratio 0.91, p=0.046).ConclusionA well-trained CRRT team could be beneficial for mortality improvement of AKI patients requiring CRRT.

BackgroundThe role of mineral metabolism in mortality among dialysis patients has received increased attention, but some aspects remain unclear. The aim of the present study was to investigate the prognostic value of serum calcium and phosphate levels for all-cause mortality and cause-specific mortality in dialysis patients.MethodsPatients on hemodialysis and peritoneal dialysis were enrolled from a multicenter prospective cohort study in Korea (NCT00931970). The patients were divided into low, normal, and high groups according to their baseline serum calcium or phosphate levels. Cox proportional analysis and a proportional hazards model for the subdistribution of a competing risk were used to calculate hazard ratios (HRs) for the association of serum calcium and phosphate levels with all-cause and cause-specific mortality. Time-dependent values of calcium and phosphate were also evaluated to assess the effect of longitudinal change in mineral metabolism parameters on mortality types.ResultsA total of 3,226 dialysis patients were followed up for a mean of 19.8 ± 8.2 months. Infection was the most common cause of death. Low serum phosphate was significantly associated with all-cause and infection-related death using time-dependent values (HR, 1.43 [95% confidence interval (CI), 1.06–1.93], P = 0.02, and HR, 1.66 [95% CI, 1.02–2.70], P = 0.04, respectively). Low serum phosphate was associated with significantly higher infection-related mortality, especially in patients older than 65 years or on dialysis more than one year or with serum albumin lower than 3.9 g/dL (HR, 2.06 [95% CI, 1.13–3.75], P = 0.02, HR, 2.19 [95% CI, 1.20–4.01], P = 0.01, and HR, 1.77 [95% CI, 1.00–3.13], P = 0.05, respectively). Multinomial logistic regression analysis results suggested that low serum albumin, creatinine, and body mass index correlated with low serum phosphate.ConclusionsLow serum phosphate in dialysis patients was an independent risk factor for infection-related death, especially in elderly patients. Persistently low serum phosphate might be a nutritional biomarker to predict increased susceptibility to infection and in turn worse outcomes in dialysis patients.

BackgroundThe nature of cost-saving effects of early referral to a nephrologist in patients with chronic kidney disease (CKD) is not fully evaluated. We evaluated the health care costs before and after dialysis according to the referral time.MethodsA total of 879 patients who were newly diagnosed as having end-stage renal disease from August 2008 to June 2011 were prospectively enrolled. The early referral (ER) group was defined as patients who were referred to a nephrologist more than a year before dialysis and had visited a nephrology clinic 2 or more times. Patients whose referral time was less than a year were considered the late referral (LR) group. Information about medical costs was acquired from the claim data of the Korea Health Insurance Review and Assessment Service.ResultsThe total medical costs during the first 12 months after the initiation of dialysis were not different between the 526 ER patients and the 353 LR patients. However, the costs of the ER patients during the first month were significantly lower than those of the LR patients (ER vs. LR: 3029±2219 vs. 3438±2821 US dollars [USD], P = 0.025). The total 12-month health care costs before the initiation of dialysis were significantly lower in the ER group (ER vs. LR: 6206±5873 vs. 8610±7820 USD, P<0.001). In the multivariate analysis, ER significantly lowered the health care costs during the 12 months before (2534.0±436.2 USD, P<0.001) and the first month (428.5±172.3 USD, P = 0.013) after the initiation of dialysis.ConclusionsThe ER of patients with CKD to a nephrologist is associated with decreased medical costs during the pretreatment period of renal replacement therapy and the early period of dialysis initiation.

BackgroundThe association of a higher body mass index (BMI) with better survival is a well-known “obesity paradox” in patients on hemodialysis (HD). However, men and women have different body compositions, which could impact the effect of BMI on mortality. We investigated the effect of gender on the obesity-mortality relationship in Korean patients on HD.MethodsThis study included 2,833 maintenance patients on HD from a multicenter prospective cohort study in Korea (NCT00931970). The relationship between categorized BMI and gender-specific mortality was evaluated by an adjusted Cox proportional hazard model with restricted cubic spline analyses and the Competing risk analysis. We also investigated the effect of changes in BMI over 12 months and serum creatinine level on survival in male and female patients on HD.ResultsThe mean BMI was 22.6 ± 3.3 kg/m2 and the mean follow up duration was 24.2 ± 3.4 months. The patients with the highest quintile of BMI (≥25.1 kg/m2) showed lower mortality (subdistributional hazard ratio [SHR] = 0.63, 95% confidence interval [CI] = 0.43–0.93, P = 0.019) compared with those with the reference BMI quintile. When analyzed by gender, male patients with a BMI over 25.1 kg/m2 had lower mortality risk (HR = 0.43, 95% CI = 0.25–0.75, P = 0.003); however, no significant difference was found in female patients. Increased BMI after 12 months and high serum creatinine were associated with better survival only in male patients on HD.ConclusionsBMI could be used as a risk factor for mortality in male patients on HD. However, the mortality of female patients on HD was not related with baseline and follow-up BMI. This suggests that BMI is a good surrogate marker of lean body composition, especially in male patients on HD.

Background Complement activation has been highlighted in immunoglobulin (Ig) A nephropathy pathogenesis. However, whether the complement system can affect the downstream phenotype of IgA nephropathy remains unknown. Herein, we investigated the association of mesangial C3 deposition with the Oxford classification and their joint effects on worsening kidney function. Methods We investigated 453 patients with biopsy-proven IgA nephropathy. C3 deposition was defined as an immunofluorescence intensity of C3 ≥2+ within the mesangium. The subjects were classified according to the combination of C3 deposition and Oxford classification lesions. The primary endpoint was a composite of ≥30% decline in the estimated glomerular filtration rate or an increase in proteinuria ≥3.5 g/g during follow-up. Results Among the Oxford classification lesions, mesangial hypercellularity (M1), segmental glomerulosclerosis (S1) and tubulointerstitial fibrosis (T1–2) and crescentic lesion significantly correlated with C3 deposition. During a median follow-up of 33.0 months, the primary endpoint occurred more in patients with M1, S1, T1–2 and mesangial C3 deposition than in those without. In individual multivariable-adjusted Cox analyses, the presence of M1, S1, T1–2 and C3 deposition was significantly associated with higher risk of reaching primary endpoint. In the combined analyses of C3 deposition and the Oxford classification lesions, the hazard ratios for the composite outcome were significantly higher in the presence of C3/M1, C3/S1 and C3/crescent than in the presence of each lesion alone. Conclusions Complement deposition can strengthen the significance of the Oxford classification, and the presence of both components portends a poorer prognosis in IgA nephropathy.