Background Hyperkalemia is common among hemodialysis (HD) patients and has been associated with adverse clinical outcomes. Previous studies considered a single serum potassium (K) measurement or time-averaged values, but serum K excursions out of the target range may be more reflective of true hyperkalemia events. We assessed whether hyperkalemia excursions lead to an elevated risk of adverse clinical outcomes. Methods Using data from 21 countries in Phases 4–6 (2009–18) of the Dialysis Outcomes and Practice Patterns Study (DOPPS), we investigated the associations between peak serum K level, measured monthly predialysis, over a 4-month period (‘peak K’) and clinical outcomes over the subsequent 4 months using Cox regression, adjusted for potential confounders. Results The analysis included 62 070 patients contributing a median of 3 (interquartile range 2–6) 4-month periods. The prevalence of hyperkalemia based on peak K was 58% for >5.0, 30% for >5.5 and 12% for >6.0 mEq/L. The all-cause mortality hazard ratio for peak K (reference ≤5.0 mEq/L) was 1.15 [95% confidence interval (CI) 1.09, 1.21] for 5.1–5.5 mEq/L, 1.19 (1.12, 1.26) for 5.6–6.0 mEq/L and 1.33 (1.23, 1.43) for >6.0 mEq/L. Results were qualitatively consistent when analyzing hospitalizations and a cardiovascular composite outcome. Conclusions Among HD patients, we identified a lower K threshold (peak K 5.1–5.5 mEq/L) than previously reported for increased risk of hospitalization and mortality, with the implication that a greater proportion (>50%) of the HD population may be at risk. A reassessment of hyperkalemia severity ranges is needed, as well as an exploration of new strategies for effective management of chronic hyperkalemia.

Diabetic nephropathy (DN) remains an unmet medical challenge as its prevalence is projected to continue to increase and specific medicines for treatment remain undeveloped. Activation of the immune system, in particular T-cells, is emerging as a possible mechanism underlying DN disease progression in humans and animal models. We hypothesized that inhibition of T-cell activation will ameliorate DN. Interaction of B7-1 (CD80) on the surface of antigen presenting cells with its binding partners, CTLA4 (CD152) and CD28 on T-cells, is essential for T-cell activation. In this study we used the soluble CTLA4-Fc fusion protein Abatacept to block cell surface B7-1, preventing the cellular interaction and inhibiting T-cell activation. When Abatacept was dosed in an animal model of diabetes-induced albuminuria, it reduced albuminuria in both prevention and intervention modes. The number of T-cells infiltrating the kidneys of DN animals correlated with the degree of albuminuria, and treatment with Abatacept reduced the number of renal T-cells. As B7-1 induction has been recently proposed to underlie podocyte damage in DN, Abatacept could be efficacious in DN by protecting podocytes. However, this does not appear to be the case as B7-1 was not expressed in 1) kidneys of DN animals; 2) stimulated human podocytes in culture; or 3) glomeruli of DN patients. We conclude that Abatacept ameliorates DN by blocking systemic T-cell activation and not by interacting with podocytes.

In patients with current or a history of hyperkalaemia, treatment with renin-angiotensin-aldosterone system inhibitors (RAASi) is often compromised. Patiromer, a novel potassium (K + ) binder, may improve serum K + levels and adherence to RAASi.

Background Sodium zirconium cyclosilicate (SZC) binds potassium and ammonium in the gastrointestinal tract. In addition to serum potassium reduction, Phase 2 trial data have shown increased serum bicarbonate with SZC, which may be clinically beneficial because maintaining serum bicarbonate ≥22 mmol/L preserves kidney function. This exploratory analysis examined serum bicarbonate and urea, and urine pH data from three SZC randomized, placebo-controlled Phase 3 studies among patients with hyperkalaemia [ZS-003 (n = 753), HARMONIZE (n = 258) and HARMONIZE-Global (n = 267)]. Methods In all studies, patients received ≤10 g SZC 3 times daily (TID) for 48 h to correct hyperkalaemia, followed by randomization to maintenance therapy with SZC once daily (QD) versus placebo for ≤29 days among those achieving normokalaemia. Results Significant dose-dependent mean serum bicarbonate increases from baseline of 0.3 to 1.5 mmol/L occurred within 48 h of SZC TID in ZS-003 (all P < 0.05), which occurred regardless of chronic kidney disease (CKD) stage. Similar acute increases in HARMONIZE and HARMONIZE-Global were maintained over 29 days. With highest SZC maintenance doses, patient proportions with serum bicarbonate <22 mmol/L fell from 39.4% at baseline to 4.9% at 29 days (P = 0.005) in HARMONIZE and from 87.9% to 70.1%, (P = 0.006) in HARMONIZE-Global. Path analyses demonstrated that serum urea decreases (but not serum potassium or urine pH changes) were associated with SZC effects on serum bicarbonate. Conclusions SZC increased serum bicarbonate concentrations and reduced patient proportions with serum bicarbonate <22 mmol/L, likely due to SZC-binding of gastrointestinal ammonium. These SZC-induced serum bicarbonate increases occurred regardless of CKD stage and were sustained during ongoing maintenance therapy.

Background Chronic kidney disease (CKD) is a major global health burden, and is associated with increased adverse outcomes, poor quality of life, and substantial health care costs. While there is an increasing need to build patient-centered pathways for improving CKD management in clinical care, data in this field are scarce. Objective The aim of this study was to understand patient-reported experiences, symptoms, outcomes, and treatment journeys among patients with CKD through a retrospective and qualitative approach based on data available through PatientsLikeMe (PLM), an online community where patients can connect and share experiences. Methods Adult members (aged ≥18 years) with self-reported CKD within 30 days of enrollment, who were not on dialysis, and registered between 2011 and 2018 in the PLM community were eligible for the retrospective study. Patient demographics and disease characteristics/symptoms were collected from this retrospective data set. Qualitative data were collected prospectively through semistructured phone interviews in a subset of patients, and questions were oriented to better understand patients’ experiences with CKD and its management. Results The retrospective data set included 1848 eligible patients with CKD, and median age was 56 years. The majority of patients were female (1217/1841, 66.11%) and most were US residents (1450/1661, 87.30%). Of the patients who reported comorbidities (n=1374), the most common were type 2 diabetes (783/1374, 56.99%), hypertension (664/1374, 48.33%), hypercholesterolemia (439/1374, 31.95%), and diabetic neuropathy (376/1374, 27.37%). The most commonly reported severe or moderate symptoms in patients reporting these symptoms were fatigue (347/484, 71.7%) and pain (278/476, 58.4%). In the qualitative study, 18 eligible patients (13 females) with a median age of 60 years and who were mainly US residents were interviewed. Three key concepts were identified by patients to be important to optimal care and management: listening to patient needs, coordinating health care across providers, and managing clinical care. Conclusions This study provides a unique source of real-world information on the patient experience of CKD and its management by utilizing the PLM network. The results reveal the challenges these patients face living with an array of symptoms, and report key concepts identified by patients that can be used to further improve clinical care and management and inform future CKD studies.

Background and ObjectiveHyperkalaemia can be a life-threatening condition, particularly in patients with advanced chronic kidney disease with and without heart failure. Renin-angiotensin-aldosterone system inhibitor therapy offers cardiorenal protection in chronic kidney disease and heart failure; however, it may also cause hyperkalaemia subsequently resulting in down-titration or discontinuation of treatment. Hence, there is an unmet need for hyperkalaemia treatment in patients with chronic kidney disease with and without heart failure to enable renin-angiotensin-aldosterone system inhibitor use in this patient population. In this study, we develop a de novo disease progression and cost-effectiveness model to evaluate the clinical and economic outcomes associated with the use of patiromer for the treatment of hyperkalaemia in patients with chronic kidney disease with and without heart failure. Methods A Markov model was developed using data from the OPAL-HK trial to assess the health economic impact of patiromer therapy in comparison to standard of care in controlling hyperkalaemia in patients with advanced chronic kidney disease with and without heart failure in the Irish setting. The model was designed to predict the natural history of chronic kidney disease and heart failure and quantify the costs and benefits associated with the use of patiromer for hyperkalaemia management over a lifetime horizon from a payer perspective. Results Treatment with patiromer was associated with an increase in discounted life-years (8.62 vs 8.37) and an increase in discounted quality-adjusted life-years (6.15 vs 5.95). Incremental discounted costs were predicted at €4979 per patient, with an incremental cost-effectiveness ratio of €25,719 per quality-adjusted life-year gained. Patients remained taking patiromer treatment for an average of 7.7 months, with treatment associated with reductions in the overall clinical event incidence and a delay in chronic kidney disease progression. Furthermore, patiromer was associated with lower overall rates of hospitalisation, major adverse cardiovascular events, dialysis, renin-angiotensin-aldosterone system inhibitor discontinuation episodes and renin-angiotensin-aldosterone system inhibitor down-titration episodes. At a willingness-to-pay threshold of €45,000 per quality-adjusted life-year in Ireland, treatment with patiromer was estimated to have a 100% chance of cost effectiveness compared with standard of care. Conclusions This study has demonstrated an economic case for the reimbursement of patiromer for the treatment of hyperkalaemia in patients with chronic kidney disease with and without heart failure in Ireland. Patiromer was estimated to improve life expectancy and quality-adjusted life expectancy, whilst incurring marginal additional costs when compared with current standard of care. Results are predominantly attributed to the ability of patiromer to enable the continuation of renin-angiotensin-aldosterone system inhibitor treatment whilst also reducing potassium levels.

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BACKGROUND AND AIMS Renal fibrosis is a central feature of chronic kidney disease (CKD), and the severity of CKD correlates with the magnitude of renal fibrosis. Despite the causative role attributed to fibrosis in CKD progression, there is still no treatment available that directly targets renal fibrosis. Upon kidney injury, embryonic signalling pathways are activated, promoting the repair and regeneration of injured tissue. Maladaptive repair mechanisms have been associated with the development of renal fibrosis and sustained activation of Wnt/β-catenin signalling contributes to CKD progression. GPR124 (ADGRA2 gene), has been identified as a potential fibrotic mediator through its upregulation in pericytes during pericyte to myofibroblast transition. GPR124 has been identified to function as a co-receptor for Wnt7 mediating canonical Wnt signaling in endothelial cells. We observed elevated GPR124 expression in mouse kidneys after chronic ischaemia reperfusion injury (cIRI). To further explore the role of GPR124 in CKD progression, we have studied its correlation with disease severity in human NURTuRE kidney biopsies [1]. We have also looked at GPR124 therapeutic potential in mouse cIRI. Given its potential disease relevance, we set out to develop inhibitory GPR124 antibodies as novel therapeutics to treat renal fibrosis. METHOD Diagnostic FFPE kidney cortex biopsy samples from 497 NURTuRE patients were subjected to bulk RNA-Seq. Library preparation with Illumina Enrichment Tagmentation technology was followed by sequencing and alignment of paired-end reads to the reference genome GRCh38/ENSEMBL 97 and quantification. Monoclonal Anti-GPR124 antibodies were generated against the extracellular domain of human GPR124. Top candidates were selected by FACS binding and further characterized in a TCF/LEF luciferase assay for the inhibition of Wnt7 signaling. One hu/ms cross-reactive candidate was studied in a 14-day IRI mouse model to assess its anti-fibrotic effect in vivo. Mice were exposed to 30-min unilateral renal ischaemia, followed by 14 days recovery. Kidneys were studied for gene expression by RT-PCR. Animals were divided into sham (n = 5), control IRI (no antibody, n = 12) and treated groups (each n = 12). The antibody was administered before ischemia and during the recovery phase in two doses [50 mg/kg and 150 mg/kg]. RESULTS CONCLUSION NURTuRE provides us with a unique opportunity to assess relevance of a potential target candidate gene in kidney disease patients. The potential of GPR124 as a therapeutic target was highlighted by the upregulation of expression levels along disease severity and biological pathway analysis, where our data supports a potential role in extracellular matrix reorganization. The administration of GPR124 antibodies and inhibition of the GPR124-mediated Wnt signaling in vivo inhibited the development of ischaemia-induced fibrosis in the mouse kidney. The results strongly support a role for GPR124 in human kidney disease progression, through inhibition of fibrosis, and its potential as a future clinical target.