In recent years, the imbalance in phosphate homeostasis in patients with end-stage renal disease (ESRD) has been the subject of much research. It appears that, while hyperphosphatemia may be a tangible indicator of deteriorating kidney function, lack of phosphate homeostasis may also be associated with the increased risk of cardiovascular events and mortality that has become a hallmark of ESRD. The need to maintain phosphorus concentrations within a recommended range is reflected in evidence-based guidelines. However, these do not reflect serum phosphorus concentrations achieved by most patients in clinical practice. Given this discrepancy, it is important to consider ways in which dietary restriction of phosphorus intake and, in particular, use of phosphate binders in patients with ESRD can be made more effective. Poor adherence is common in patients with ESRD and has been associated with inadequate control of serum phosphorus concentrations. Studies indicate that, among other factors, major reasons for poor adherence to phosphate binder therapy include high pill burden and patients’ lack of understanding of their condition and its treatment. This review examines available evidence, seeking to understand fully the reasons underlying poor adherence in patients with ESRD and consider possible strategies for improving adherence in clinical practice.

Endothelial dysfunction underlies multiple cardiovascular consequences of chronic kidney disease (CKD) and antecedent diabetes or hypertension. Endothelial insults in CKD or end-stage renal disease (ESRD) patients include uremic toxins, serum uric acid, hyperphosphatemia, reactive oxygen species, and advanced glycation endproducts (AGEs). Sevelamer carbonate, a calcium-free intestinally nonabsorbed polymer, is approved for hyperphosphatemic dialysis patients in the US and hyperphosphatemic stage 3–5 CKD patients in many other countries. Sevelamer has been observed investigationally to reduce absorption of AGEs, bacterial toxins, and bile acids, suggesting that it may reduce inflammatory, oxidative, and atherogenic stimuli in addition to its on-label action of lowering serum phosphate. Some studies also suggest that noncalcium binders may contribute less to vascular calcification than calcium-based binders. Exploratory sevelamer carbonate use in patients with stages 2–4 diabetic CKD significantly reduced HbA1c, AGEs, fibroblast growth factor (FGF)-23, and total and low-density lipoprotein (LDL) cholesterol versus calcium carbonate; inflammatory markers decreased and defenses against AGEs increased. Sevelamer has also been observed to reduce circulating FGF-23, potentially reducing risk of left ventricular hypertrophy. Sevelamer but not calcium-based binders in exploratory studies increases flow-mediated vasodilation, a marker of improved endothelial function, in patients with CKD. In contrast, lanthanum carbonate and calcium carbonate effects on FMV did not differ in hemodialysis recipients. The recent INDEPENDENT-CKD randomized trial compared sevelamer versus calcium carbonate in predialysis CKD patients (investigational in the US, on-label in European participants); sevelamer reduced 36-month mortality and the composite endpoint of mortality or dialysis inception. Similarly, INDEPENDENT-HD in incident dialysis patients showed improved survival with 24 months of sevelamer versus calcium-based binders. This review discusses recent exploratory evidence for pleiotropic effects of sevelamer on endothelial function in CKD or ESRD. Endothelial effects of sevelamer may contribute mechanistically to the improved survival observed in some studies of CKD and ESRD patients.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to improve cardiovascular and renal outcomes in patients with established cardiovascular disease, chronic kidney disease (CKD), and heart failure (HF) with reduced or preserved ejection fraction. Clinical benefit has been substantiated in patients with and without type 2 diabetes (T2D). Consequently, SGLT2is have an increasingly important role in HF and CKD management that extends beyond T2D treatment. Their pleiotropic pharmacological effects underlying their cardiovascular and renal benefits are not completely understood but include significant effects beyond blood glucose reduction. SGLT2is inhibit the reabsorption of glucose and sodium in the proximal tubule which, in addition to lowering blood glucose, activates tubuloglomerular feedback, leading to reduced glomerular hydrostatic pressure and the mitigation of glomerular filtration rate loss. SGLT2is have diuretic and natriuretic effects, leading to decreased blood pressure, preload, and left ventricular (LV) filling pressure, and improvements in other surrogates of afterload. In HF, SGLT2is mitigate the risks of hyperkalemia and ventricular arrhythmia and improve LV dysfunction. SGLT2is also reduce sympathetic tone and uric acid levels, increase hemoglobin levels, and are postulated to have anti-inflammatory properties. This narrative review discusses the multifactorial and interrelated pharmacological mechanisms underlying the cardiovascular and renal benefits of SGLT2is.

This observational cohort study compared the likelihood of maintained (stabilized/up-titrated) renin–angiotensin–aldosterone system inhibitor (RAASi) therapy at 6 months following hyperkalaemia in patients with chronic kidney disease (CKD) and/or heart failure (HF) from the USA, Japan and Spain who received sodium zirconium cyclosilicate (SZC) for at least 120 days, relative to those with no prescription for a potassium (K⁺) binder. Using health registers and hospital medical records, patients with CKD and/or HF receiving RAASi therapy who experienced a hyperkalaemia episode were identified. Propensity score (PS) matching (1:4) was applied to balance the SZC cohort to the no K⁺ binder cohort on baseline characteristics. Logistic regression analysis was performed to compare the odds of maintained RAASi therapy at 6 months in the SZC versus no K⁺ binder cohorts. The PS-matched SZC cohort included 565 (USA), 776 (Japan) and 56 (Spain) patients; the no K⁺ binder cohort included 2068, 2629 and 203 patients, respectively. At 6 months, 68.9% (USA), 79.9% (Japan) and 69.6% (Spain) in the SZC cohorts versus 53.1% (USA), 56.0% (Japan) and 48.3% (Spain) in the no K⁺ binder cohorts had maintained RAASi therapy. Meta-analysed across countries, the odds ratio of maintained RAASi therapy in the SZC cohort versus no K⁺ binder cohort was 2.56 (95% confidence interval 1.92–3.41; P < .0001). In routine clinical practice across three countries, patients treated with SZC were substantially more likely to maintain guideline-concordant RAASi therapy at 6 months following hyperkalaemia relative to patients with no K⁺ binder treatment.

Background: Intensive BP lowering in the Systolic Blood Pressure Intervention Trial (SPRINT) produced acute decreases in kidney function and higher risk for AKI. We evaluated the effect of intensive BP lowering on long-term changes in kidney function using trial and outpatient electronic health record (EHR) creatinine values. Methods: SPRINT data were linked with EHR data from 49 (of 102) study sites. The primary outcome was the total slope of decline in eGFR for the intervention phase and the post-trial slope of decline during the observation phase using trial and outpatient EHR values. Secondary outcomes included a ≥30% decline in eGFR to <60 ml/min per 1.73 m² and a ≥50% decline in eGFR or kidney failure among participants with baseline eGFR ≥60 and <60 ml/min per 1.73 m², respectively. Results: EHR creatinine values were available for a median of 8.3 years for 3041 participants. The total slope of decline in eGFR during the intervention phase was −0.67 ml/min per 1.73 m² per year (95% confidence interval [CI], −0.79 to −0.56) in the standard treatment group and −0.96 ml/min per 1.73 m² per year (95% CI, −1.08 to −0.85) in the intensive treatment group (P < 0.001). The slopes were not significantly different during the observation phase: −1.02 ml/min per 1.73 m² per year (95% CI, −1.24 to −0.81) in the standard group and −0.85 ml/min per 1.73 m² per year (95% CI, −1.07 to −0.64) in the intensive group. Among participants without CKD at baseline, intensive treatment was associated with higher risk of a ≥30% decline in eGFR during the intervention (hazard ratio, 3.27; 95% CI, 2.43 to 4.40), but not during the postintervention observation phase. In those with CKD at baseline, intensive treatment was associated with a higher hazard of eGFR decline only during the intervention phase (hazard ratio, 1.95; 95% CI, 1.03 to 3.70). Conclusions: Intensive BP lowering was associated with a steeper total slope of decline in eGFR and higher risk for kidney events during the intervention phase of the trial, but not during the postintervention observation phase.

The worldwide epidemic of chronic kidney disease shows no signs of abating in the near future. Current dialysis forms of renal replacement therapy (RRT), even though successful in sustaining life and improving quality of life somewhat for patients with ESRD, have many limitations that result in still unacceptably high morbidity and mortality. Transplantation is an excellent option but is limited by the scarcity of organs. An ideal form of RRT would mimic the functions of natural kidneys and be transparent to the patient, as well as affordable to society. Recent advances in technology, although generally in early stages of development, might achieve these goals. The application of nanotechnology, microfluidics, bioreactors with kidney cells, and miniaturized sorbent systems to regenerate dialysate makes clinical reality seem closer than ever before. Finally, stem cells hold much promise, both for kidney disease and as a source of tissues and organs. In summary, nephrology is at an exciting crossroad with the application of innovative and novel technologies to RRT that hold considerable promise for the near future.