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Recent studies suggest that correcting low serum bicarbonate levels may reduce the progression of kidney disease; however, few patients with chronic kidney disease have low serum bicarbonate. Therefore, we examined whether higher levels of serum bicarbonate within the normal range (20–30mmol/l) were associated with better kidney outcomes in the African American Study of Kidney Disease and Hypertension (AASK) trial. At baseline and during follow-up of 1094 patients, the glomerular filtration rates (GFR) were measured by iothalamate clearances and events were adjudicated by the outcomes committee. Mean baseline serum bicarbonate, measured GFR, and proteinuria were 25.1mmol/l, 46ml/min per 1.73m2, and 326mg/g of creatinine, respectively. Each 1mmol/l increase in serum bicarbonate within the normal range was associated with reduced risk of death, dialysis, or GFR event and with dialysis or GFR event (hazard ratios of 0.942 and 0.932, respectively) in separate multivariable Cox regression models that included errors-in-variables calibration. Cubic spline regression showed that the lowest risk of GFR event or dialysis was found at serum bicarbonate levels near 28–30mmol/l. Thus, our study suggests that serum bicarbonate is an independent predictor of CKD progression. Whether increasing serum bicarbonate into the high-normal range will improve kidney outcomes during interventional studies will need to be considered.

Frequent hemodialysis can alter volume status, blood pressure, and the concentration of osmotically active solutes, each of which might affect residual kidney function (RKF). In the Frequent Hemodialysis Network Daily and Nocturnal Trials, we examined the effects of assignment to six compared with three-times-per-week hemodialysis on follow-up RKF. In both trials, baseline RKF was inversely correlated with number of years since onset of ESRD. In the Nocturnal Trial, 63 participants had non-zero RKF at baseline (mean urine volume 0.76 liter/day, urea clearance 2.3ml/min, and creatinine clearance 4.7ml/min). In those assigned to frequent nocturnal dialysis, these indices were all significantly lower at month 4 and were mostly so at month 12 compared with controls. In the frequent dialysis group, urine volume had declined to zero in 52% and 67% of patients at months 4 and 12, respectively, compared with 18% and 36% in controls. In the Daily Trial, 83 patients had non-zero RKF at baseline (mean urine volume 0.43 liter/day, urea clearance 1.2ml/min, and creatinine clearance 2.7ml/min). Here, treatment assignment did not significantly influence follow-up levels of the measured indices, although the range in baseline RKF was narrower, potentially limiting power to detect differences. Thus, frequent nocturnal hemodialysis appears to promote a more rapid loss of RKF, the mechanism of which remains to be determined. Whether RKF also declines with frequent daily treatment could not be determined.

Patients with type 2 diabetes at high risk for cardiovascular disease who were already taking a renin–angiotensin system blocker were randomly assigned to the direct renin inhibitor aliskiren or placebo. The study was discontinued early for no benefit, or even possible harm. Mortality associated with type 2 diabetes remains nearly twice that when diabetes is absent. 1 Complications of diabetes, particularly renal and cardiovascular disease, substantially increase the risk of subsequent severe illness and death. When a patient has both renal and cardiovascular disease, the risk is magnified further. 2 , 3 Blood-pressure lowering is beneficial in slowing renal-disease progression, reducing cardiovascular disease events, and preventing premature death. 4 Renin–angiotensin–aldosterone system (RAAS) blockers are highly effective, with apparent benefits extending beyond simple blood-pressure lowering 5 – 8 ; such agents have become the preferred first-line interventions in high-risk persons with diabetes. Theoretically, dual RAAS blockade should be more . . .

Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-α. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-α were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-α was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.

The guidelines proposed by the Kidney Disease Outcomes Quality Initiative (K/DOQI) suggested that intact parathyroid hormone (iPTH) should be maintained in a target range between 150 and 300 pg ml−1 for patients with stage 5 chronic kidney disease. Our study sought to verify the effectiveness of that range in preventing bone remodeling problems in hemodialysis patients. We measured serum ionized calcium and phosphorus while iPTH was measured by a second-generation assay. Transiliac bone biopsies were performed at the onset of the study and after completing 1 year follow-up. The PTH levels decreased within the target range in about one-fourth of the patients at baseline and at the end of the study. The bone biopsies of two-thirds of the patients were classified as showing low turnover and a one-fourth showed high turnover, the remainder having normal turnover. In the group achieving the target levels of iPTH 88% had low turnover. Intact PTH levels less than 150 pg ml−1 for identifying low turnover and greater than 300 pg ml−1 for high turnover presented a positive predictive value of 83 and 62%, respectively. Our study suggests that the iPTH target recommended by the K/DOQI guidelines was associated with a high incidence of low-turnover bone disease, suggesting that other biochemical markers may be required to accurately measure bone-remodeling status in hemodialysis patients.

Chronic kidney disease is an emerging health problem worldwide. The eye shares striking structural, developmental, and genetic pathways with the kidney, suggesting that kidney disease and ocular disease may be closely linked. A growing number of studies have found associations of chronic kidney disease with age-related macular degeneration, diabetic retinopathy, glaucoma, and cataract. In addition, retinal microvascular parameters have been shown to be predictive of chronic kidney disease. Chronic kidney disease shares common vascular risk factors including diabetes, hypertension, smoking, and obesity, and pathogenetic mechanisms including inflammation, oxidative stress, endothelial dysfunction, and microvascular dysfunction, with ocular diseases supporting the ‘Common Soil Hypothesis.’ In this review, we present major epidemiological evidence for these associations and explore underlying pathogenic mechanisms and common risk factors for kidney and ocular disease. Understanding the link between kidney and ocular disease can lead to the development of new treatment and screening strategies for both diseases.

Over 10% of the global population suffers from kidney disease. However, only kidney replacement therapies, which burden medical expenses, are currently effective in treating kidney disease. Therefore, elucidating the complicated molecular pathology of kidney disease is an urgent priority for developing innovative therapeutics for kidney disease. Recent studies demonstrated that intertwined renal vasculature often causes ischemia-reperfusion injury (IRI), which generates oxidative stress, and that the accumulation of oxidative stress is a common pathway underlying various types of kidney disease. We reported that activating the antioxidative transcription factor Nrf2 in renal tubules in mice with renal IRI effectively mitigates tubular damage and interstitial fibrosis by inducing the expression of genes related to cytoprotection against oxidative stress. Additionally, since the kidney performs multiple functions beyond blood purification, renoprotection by Nrf2 activation is anticipated to lead to various benefits. Indeed, our experiments indicated the possibility that Nrf2 activation mitigates anemia, which is caused by impaired production of the erythroid growth factor erythropoietin from injured kidneys, and moderates organ damage worsened by anemic hypoxia. Clinical trials investigating Nrf2-activating compounds in kidney disease patients are ongoing, and beneficial effects are being obtained. Thus, Nrf2 activators are expected to emerge as first-in-class innovative medicine for kidney disease treatment.

In this report of two randomized trials, patients with type 2 diabetes at risk for cardiovascular disease received the sodium–glucose cotransporter 2 inhibitor canagliflozin or placebo and were followed for 188 weeks. Canagliflozin reduced the risk of cardiovascular events.

In most patients with hypertensive nephropathy and low glomerular filtration rate (GFR), the kidney function progressively declines despite the adequate control of the hypertension with angiotensin-converting enzyme inhibition. Previously we found that 2 years of oral sodium citrate slowed GFR decline in patients whose estimated GFR (eGFR) was very low (mean 33ml/min). This treatment also slowed GFR decline in an animal model of surgically reduced nephron mass. Here, we tested if daily oral sodium bicarbonate slowed GFR decline in patients with hypertensive nephropathy with reduced but relatively preserved eGFR (mean 75ml/min) in a 5-year, prospective, randomized, placebo-controlled, and blinded interventional study. Patients matched for age, ethnicity, albuminuria, and eGFR received daily placebo or equimolar sodium chloride or bicarbonate while maintaining antihypertensive regimens (including angiotensin-converting enzyme inhibition) aiming for their recommended blood pressure targets. After 5 years, the rate of eGFR decline, estimated using plasma cystatin C, was slower and eGFR was higher in patients given sodium bicarbonate than in those given placebo or sodium chloride. Thus, our study shows that in hypertensive nephropathy, daily sodium bicarbonate is an effective kidney protective adjunct to blood pressure control along with angiotensin-converting enzyme inhibition.

Calcium balance in chronic kidney disease is poorly understood as calcium deficiency is a stimulus for secondary hyperparathyroidism and consequent bone loss while calcium excess promotes extraosseous calcifications. To help resolve this, we evaluated calcium balance in normal individuals and in patients with chronic kidney disease (CKD) on daily diets containing 800 and 2000mg elemental calcium. Both normal individuals and patients with late stage 3 and stage 4 CKD were in slightly negative to neutral calcium balance on the 800-mg calcium diet. Normal individuals were in modest positive calcium balance on the 2000-mg diet, while patients with CKD on the same diet were in marked positive calcium balance at least over the 9 days of study; and significantly greater than the normal individuals. Increased calcium intake significantly decreased 1,25-dihydroxy-vitamin D and intact parathyroid hormone levels but did not alter the serum calcium concentration. Thus, our findings have important implications for both preventing calcium deficiency and loading in individuals with late stage 3 and stage 4 CKD.