Capacity for the management of kidney failure in the International Society of Nephrology Oceania and South East Asia (OSEA) region:Report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)

The International Society of Nephrology (ISN) region of Oceania and South East Asia (OSEA) is a mix of high and low-income countries, with diversity in population demographics and densities. There have been three iterations of the ISN-Global Kidney Health Atlas (GKHA) which have aimed to deliver in-depth assessments of global kidney care across the spectrum from early detection of CKD to treatment of kidney failure. This paper reports the findings of the latest ISN-GKHA in relation to kidney care capacity in OSEA. Among the 30 countries/territories in OSEA, 19 (63%) participated in the ISN-GKHA, representing over 97% of the region’s population. The overall prevalence of treated kidney failure in OSEA was 1,203 per million population (pmp), 45% higher than the global median of 823 pmp. In contrast, kidney replacement therapy (KRT) in OSEA was less available than the global median (chronic hemodialysis 89% OSEA vs 98% globally, peritoneal dialysis 72% vs 79%, kidney transplantation 61% vs 70%). Only 56% of countries could provide access to dialysis to at least half of people with incident kidney failure, lower than the global median of 74% of countries with available dialysis services. There were inequalities in access to KRT across OSEA, with widespread availability and low out-of-pocket costs in high-income countries and limited availability, often coupled with large out-of-pocket costs, in middle-and low-income countries. Workforce limitations were observed across OSEA, especially in lower middle-income countries. Extensive collaborative work within OSEA and globally will help close the noted gaps in kidney care provision

EFFECTS OF THE MEDITERRANEAN DIET ON CARDIOVASCULAR OUTCOMES: A SYSTEMATIC REVIEW AND META-ANALYSIS

BACKGROUND: A Mediterranean dietary pattern is widely recommended for the prevention of chronic disease. We sought to define the most likely effects of the Mediterranean diet on vascular disease and mortality. METHODS: We searched MEDLINE, EMBASE and the Cochrane Central Register without language restriction for randomized controlled trials comparing Mediterranean to control diets. Data on study design, patient characteristics, interventions, follow-up duration, outcomes and adverse events were sought. Individual study relative risks (RR) were pooled to create summary estimates. RESULTS: Six studies with a total of 10950 participants were included. Effects on major vascular events (n = 477), death (n = 693) and vascular deaths (n = 315) were reported for 3, 5 and 4 studies respectively. For one large study (n = 1000) there were serious concerns about the integrity of the data. When data for all studies were combined there was evidence of protection against major vascular events (RR 0.63, 95% confidence interval 0.53-0.75), coronary events (0.65, 0.50-0.85), stroke (0.65, 0.48-0.88) and heart failure (0.30, 0.17-0.56) but not for all-cause mortality (1.00, 0.86-1.15) or cardiovascular mortality (0.90, 0.72-1.11). After the study of concern was excluded the benefit for vascular events (0.69, 0.55-0.86) and stroke (0.66, 0.48-0.92) persisted but apparently positive findings for coronary events (0.73, 0.51-1.05) and heart failure (0.25, 0.05-1.17) disappeared. CONCLUSION: The Mediterranean diet may protect against vascular disease. However, both the quantity and quality of the available evidence is limited and highly variable. Results must be interpreted with caution

Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non -diabetic patients with chronic kidney disease (DIAMOND):a randomised, double-blind, crossover trial

Background: SGLT2 inhibition decreases albuminuria and reduces the risk of kidney disease progression in patients with type 2 diabetes. These benefits are unlikely to be mediated by improvements in glycaemic control alone. Therefore, we aimed to examine the kidney effects of the SGLT2 inhibitor dapagliflozin in patients with proteinuric kidney disease without diabetes. Methods: DIAMOND was a randomised, double-blind, placebo-controlled crossover trial done at six hospitals in Canada, Malaysia, and the Netherlands. Eligible participants were adult patients (aged 18–75 years) with chronic kidney disease, without a diagnosis of diabetes, with a 24-h urinary protein excretion greater than 500 mg and less than or equal to 3500 mg and an estimated glomerular filtration rate (eGFR) of at least 25 mL/min per 1·73 m2, and who were on stable renin–angiotensin system blockade. Participants were randomly assigned (1:1) to receive placebo and then dapagliflozin 10 mg per day or vice versa. Each treatment period lasted 6 weeks with a 6-week washout period in between. Participants, investigators, and study personnel were masked to assignment throughout the trial and analysis. The primary outcome was percentage change from baseline in 24-h proteinuria during dapagliflozin treatment relative to placebo. Secondary outcomes were changes in measured GFR (mGFR; via iohexol clearance), bodyweight, blood pressure, and concentrations of neurohormonal biomarkers. Analyses were done in accordance with the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT03190694. Findings: Between Nov 22, 2017, and April 5, 2019, 58 patients were screened, of whom 53 (mean age 51 years [SD 13]; 32% women) were randomly assigned (27 received dapagliflozin then placebo and 26 received placebo then dapagliflozin). One patient discontinued during the first treatment period. All patients were included in the analysis. Mean baseline mGFR was 58·3 mL/min per 1·73 m2 (SD 23), median proteinuria was 1110 mg per 24 h (IQR 730–1560), and mean HbA1c was 5·6% (SD 0·4). The difference in mean proteinuria change from baseline between dapagliflozin and placebo was 0·9% (95% CI −16·6 to 22·1; p=0·93). Compared with placebo, mGFR was changed with dapagliflozin treatment by −6·6 mL/min per 1·73 m2 (–9·0 to −4·2; p<0·0001) at week 6. This reduction was fully reversible within 6 weeks after dapagliflozin discontinuation. Compared with placebo, bodyweight was reduced by 1·5 kg (0·03–3·0; p=0·046) with dapagliflozin; changes in systolic and diastolic blood pressure and concentrations of neurohormonal biomarkers did not differ significantly between dapagliflozin and placebo treatment. The numbers of patients who had one or more adverse events during dapagliflozin treatment (17 [32%] of 53) and during placebo treatment (13 [25%] of 52) were similar. No hypoglycaemic events were reported and no deaths occurred. Interpretation: 6-week treatment with dapagliflozin did not affect proteinuria in patients with chronic kidney disease without diabetes, but did induce an acute and reversible decline in mGFR and a reduction in bodyweight. Long-term clinical trials are underway to determine whether SGLT2 inhibitors can safely reduce the rate of major clinical kidney outcomes in patients with chronic kidney disease with and without diabetes. Funding: AstraZeneca

Novel therapeutic options in models of nephropathy

Despite a better understanding of the pathogenesis and progression of chronic kidney disease (CKD), the functional decline of kidney function in patients with any form of nephropathy remains the greatest challenge to clinicians. Renal fibrosis is considered the ‘point of no return’ for any form of chronic kidney disease, including diabetic nephropathy, and renal dysfunction induced by inflammation, hypoxia, reactive oxygen species, and lipotoxicity. However, there are limited therapeutic options to mitigate against kidney fibrosis, and therefore novel agents are required to add to the armamentarium of therapies for slowing the progression of CKD. In this thesis HK-2 cells were used as an in vitro model to study the cellular response to known mediators of renal injury. HK-2 cells are derived from proximal tubular cells (PTCs) from normal adult human renal cortex. They retain phenotypic and functional characteristics indicative of well-differentiated PTCs. These cells were cultured in conditions inherent in diabetes mellitus (DM) mimicking the microenvironment of CKD. The functional relationship between transforming growth factor-Bl (TGF—Bl), bone morphogenetic protein-7 (BMP-7) and Kriippel-like factor—6 (KLF-6) in epithelial mesenchymal transition (EMT) was studied using recombinant human TGF-B] and BMP- 7. The BMP receptors and markers of EMT were assessed in HK-2 cells after exposure to 0.5 ng/ml of TGF-Bl for 48 hours. Overexpression of BMP-7 was induced and BMP receptor expression was assessed in KLF-6 overexpressing and silenced cells. TGF-Bl significantly down-regulated bone morphogenetic protein receptor-IA (BMPR-IA) expression. Cells overexpressing KLF-6 showed decreased expression of BMPR-IA and other type I BMP receptors, and silencing of KLF-6 increased BMPR—IA expression. Cells overexpressing BMP-7 had significantly higher E-cadherin and phosphorylated Smadl/5/8, which was not observed with concurrent TGF-Bl exposure. In vivo studies confirmed a reduction in BMP-7 and BMPR-IA but an increase in KLF-6 expression in established diabetic nephropathy. TGF-Bl and KLF-6 synergistically induced suppression of BMPRIA and downstream reduction of BMP-7 signalling. These findings suggest that the presence of TGF-Bl in multiple forms of nephropathy mitigates against the use of thMP- 7 as an antifibrotic therapeutic agent

Corticosteroid therapy in IgA Nephropathy: A friend or foe?

Background: The administration of corticosteroids in addition to supportive care to delay progressive Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis worldwide, remains controversial. This is partly due to the paucity of well-designed randomized controlled trials and well-known corticosteroid-related side effects. As a result, clinical equipoise in corticosteroid therapy exists depending on geographical regions and the clinician’s preference. Summary: Better understanding around the pathogenesis of IgAN has prompted several clinical trials exploring the effects of immunosuppressive agents including corticosteroids. Earlier studies of corticosteroids were limited by suboptimal study designs, inadequate implementation of standard of care and inconsistent adverse events data collection. Two well designed, adequately powered, multi-centre randomized controlled trials, the STOP-IgAN and TESTING studies, have reported contrasting kidney outcomes that have further fuelled the clinical conundrum regarding the efficacy of corticosteroids. Both studies independently reported greater adverse events with corticosteroids. A novel targeted release formulation of budesonide, which has been hypothesised to reduce the adverse events associated with systemic corticosteroids, has shown promising results in the Phase 3 NefigaRD trial. Studies of treatments targeting B-cells and the complement cascade are currently underway and early data appear encouraging. This review provides an overview of the current literature around the understanding of the pathomechanisms, and benefits and harm of corticosteroid use in IgAN. Key Messages: Recent evidence suggests the use of corticosteroids in a selected cohort of people with IgAN at high risk of disease progression can improve kidney outcomes but comes with an associated risk of treatment-related adverse events particularly with higher doses. Management decisions should therefore follow an informed patient-clinician discussion

Endothelin receptor antagonists in kidney protection for diabetic kidney disease and beyond?

The burden of chronic kidney disease is increasing worldwide, largely due to the increasing global prevalence of diabetes mellitus and hypertension. While renin angiotensin system inhibitors and sodium-glucose cotransporter two inhibitors are the management cornerstone for reducing kidney and cardiovascular complications in patients with diabetic and non-diabetic kidney disease (DKD), they are partially effective and further treatments are needed to prevent the progression to kidney failure. Endothelin receptor antagonism represent a potential additional therapeutic option due to its beneficial effect on pathophysiological processes involved in progressive kidney disease including proteinuria, which are independently associated with progression of kidney disease. This review discusses the biological mechanisms of endothelin receptor antagonists (ERA) in kidney protection, the efficacy and safety of ERA in randomised controlled trials reporting on kidney outcomes, and its potential future use in both diabetic and non-DKDs