ISN Academy: Dialysis
Teamwork matters: educational sessions conducted by clinical pharmacist enhanced adherence to treatment among hemodialysis patients
The role of clinical pharmacist in enhancing hemodialysis patients’ adherence and clinical outcomes: a randomized-controlled study
Alshogran et al. Int J Clin Pharm (2022).
Summary:The study randomised 120 haemodialysis (HD) patients from three different centres in Jordan to receive an education program with a clinical pharmacist, or to continue standard medical care. The intervention involved a 30-minute individual session and provision of an educational booklet, and then, where needed, further face-to-face or telephone sessions monthly. The educational booklet, which was reviewed by two nephrologists, included a wide range of topics such as disease management principles, life-style changes and the importance of treatment adherence. Overall adherence was assessed by self-report using the End‑stage Renal Disease Adherence Questionnaire (ESRD-AQ), with domains including the adherence to lifestyle changes, medications, fluid restriction, dietary recommendations and dialysis attendance. According to this tool, higher scores indicate greater adherence. Overall adherence at baseline was similar between the two groups, although a greater number of intervention participants were participating in regular physical activity at baseline (35% vs 14% with control p=0.009). After 3 months, the total adherence score was higher in the intervention group (1170.6±44.1 vs 665.8±220.7, p<0.001). This group also demonstrated a superior change from baseline (174.6 ± 151.7 higher than baseline compared to −260.1 ± 258.6 in the control group, p<0.001). The two groups showed no difference in dialysis attendance or in interdialytic weight gain, although there were fewer episodes of shortening dialysis in the intervention group, improvements in urea and creatinine levels, fewer hospitalisations, and improvements in several quality-of-life metrics.
Comment: Patients on chronic haemodialysis are given many health and lifestyle recommendations with significant impacts upon quality of life, while at the same time managing comorbidities, disease complications and life beyond their health problems. A clinical pharmacist education service, as demonstrated in this trial, could make an important difference for such patients, by helping them to better understand and manage the complexity of their disease, including practical strategies to optimise adherence. Further studies with a larger sample size and longer follow-up would help to further substantiate the merits of such an approach and to reinforce the key role clinical pharmacists can play in patient care.
ISN Academy: Cardiorenal
Early initiation of empagliflozin in acute decompensated heart failure does not worsen kidney function and improves diuresis
Effects of early empagliflozin initiation on diuresis and kidney function in patients with acute decompensated heart failure (EMPAG-HF)
Schulze et al. Circulation (2022).
Summary: In this single-center and double-blind trial, 60 patients with acute decompensated heart failure (ADHF) were randomized to receive either empagliflozin 25mg/d or placebo, added to standard treatment, given within 12 hours of hospitalization, and continued for 5 days. The eligibility criteria allowed for adults with or without diabetes, and with eGFR down to 30ml/min/1.73m2 and an AKI no worse than AKIN stage 2. The mean age was 75±10 years, 38% were women, the mean eGFR at baseline was 60.2±18.7 mL/min/1.73m2 and all patients were on loop diuretics. The primary outcome of the total urine output over 5 days was 25% greater (p=0.003) in the empagliflozin group, compared with the placebo group. Patients in the empagliflozin group showed no significant difference in body weight reduction, however, needed less loop diuretic and had a greater reduction in NT-proBNP compared with patients in the placebo group after 5 days (p<0.001), and also demonstrated greater improvement in NYHA heart failure class. There were no differences between groups in adverse kidney outcomes, mean eGFR, or urinary biomarkers of kidney injury. The empagliflozin group had a higher mean eGFR at 30-day follow-up. The mortality rate was comparable between the two groups (one patient in experimental arm and two in control group).
Comment: SGLT2 inhibitors have established benefits in patients with chronic stable heart failure, however, have not been proven for use in patients with ADHF. Typically, an intermittent reversible reduction of eGFR is seen during the first 2 to 4 weeks of treatment with SGLT2 inhibitors due to the hemodynamic effect of the drug reducing intraglomerular pressure, which protects the kidney over time. This finding has led to concerns about the very early use of SGLT2 inhibitors in patients with ADHF, especially in those with more advanced CKD and those using higher doses of diuretic therapy. In this study, the initial decrease of eGFR was similar in the empagliflozin group compared with placebo on a group level, while the mean eGFR was higher in the empagliflozin group at 30 days. The reason for the less-than-expected acute dip in eGFR in the empagliflozin group was not elucidated, however, it may in part be due to the empagliflozin group only having baseline mild CKD, then requiring lower doses of loop diuretics, and achieving more rapid systemic decongestion than the placebo group. Unfortunately, due to the relatively short follow-up period, this trial was underpowered for analysis of clinical endpoints of interest such as cardiovascular mortality and re-hospitalization, however, the study suggests SGLT2 inhibitors may be an encouraging pharmacologic alternative to augment diuresis in the treatment of ADHF.
ISN Academy: Glomerular Diseases
“To me, fair friend, you never can be old”: leflunomide is a promising option for maintenance therapy of lupus nephritis
Leflunomide versus azathioprine for maintenance therapy of lupus nephritis: a prospective, multicentre, randomised trial and long-term follow-up
Fu et al. Ann Rheum Dis (2022).
Summary: In this multicenter open-label non-inferiority trial, 270 adult patients with lupus nephritis class III, IV, and/or V, proteinuria of ≥1 g/24 h, and SLEDAI score of ≥8, were enrolled in the induction phase and received intravenous cyclophosphamide and oral glucocorticoids. After this phase, the 215 patients who achieved complete or partial response were randomized to receive low-dose prednisone in combination with either leflunomide (LEF) 20mg/day or azathioprine (AZA; 50mg, then up-titrated to 100mg/day) for 36 months. Median time to kidney flare, the primary endpoint of the study, was similar in the LEF group (16 months, 17/108 patients) and in the AZA group (14 months, 19/107 patients, p=0.676). Secondary endpoints, including 24h proteinuria, serum creatinine, eGFR, C3 levels, and SLEDAI scores, were also comparable in both groups during the 36-months follow-up. No cases of kidney failure or death were reported during the study. The incidence of adverse events was similar in the LEF and the AZA treatment arms (56.5% and 58.9%, respectively), among them the most common were hematological abnormalities and elevated liver enzymes.
Comment: Despite several treatment options available for maintenance therapy, sustaining long-term remission of lupus nephritis is still challenging in real-life practice. The new and widely discussed agents like iptacopan, obinutuzumab, anifrolumab are still under study and it will likely be some time before such agents are integrated into routine management, so it’s important to give careful consideration to “old” immunosuppressive therapies. This is the first RCT to demonstrate the non-inferiority of leflunomide to azathioprine in terms of efficacy and safety for remission maintenance of LN. However, it should be taken into account that it was an open-label trial on patients of Chinese ancestry with a relatively short follow-up of 36 months. The use of leflunomide may also be limited by its contraindication in pregnancy, with a long washout period requiring careful pregnancy planning. Nevertheless, the results of the trial demonstrate that LEF is a promising option for maintenance therapy of LN, that should be studied further in larger, double-blind RCTs with ethnically diverse participants.
ISN Academy: Glomerular Diseases
Mizoribine is a potential future option for maintenance therapy in patients with myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis
The efficacy and safety of mizoribine for maintenance therapy in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) associated: the usefulness of serum mizoribine monitoring
Mase et al. Clin Exp Nephrol (2022).
Summary: Adults with rapidly progressing glomerulonephritis secondary to myeloperoxidase-associated vasculitis (MPO-AAV) who reached complete or incomplete remission after induction therapy were randomised to receive mizoribine (MZR; n=25) as a maintenance agent or standard care (n=28). During the induction phase of treatment, 7 patients in the experimental arm and 3 in the control arm received cyclophosphamide, while the remaining patients received steroid monotherapy. At baseline, complete remission (BVAS 0-1) was achieved in 15 patients in the MZR group and 18 patients in the control group; others were in partial remission (BVAS > 1, but without new clinical symptoms). The dose of MZR was titrated according to serum drug concentrations 3h post-dose (from 25mg300mg daily dose). There was no significant difference in relapse rate between two groups during 12 months of follow-up (MZR group, n = 6; control group, n = 4; p = 0.422). The mean dose of corticosteroids decreased from 12.1 mg to 7.5 mg in the MZR group and from 13.9 mg to 8.6 mg in the control group. Only ten patients achieved the target level of MZR in serum, although 4 patients were excluded from this analysis due to sample errors. There was no significant difference in the number of patients with adverse events between groups, which were predominantly infectious by nature (p=0.339).
Comment: Mizoribine, a purine metabolism antagonist, was developed in Japan in 1971 and has been investigated and used in the management of a number of renal and rheumatic diseases. In the present small study, it did not demonstrate improvements in the management of MPO-AAV when added to steroid therapy, although its potential as steroid-sparing alternative to prednisolone-based care, or to other steroid-sparing therapies, was not tested. Further studies are needed to better establish its potential role, including its optimal and safe dosing and long-term outcomes.
ISN Academy: Transplant
An interesting new avenue for research in the rapidly evolving field of diabetic kidney disease management
Efficacy and safety of cotadutide, a dual glucagon-like peptide-1 and glucagon receptor agonist, in a randomized phase 2a study of patients with type 2 diabetes and chronic kidney disease
Parker et al. Diabetes Obes Metab (2022).
Summary: Forty-one individuals with type 2 diabetes and chronic kidney disease (eGFR 30-59mL/min/1.73m2 ), and with a BMI in the overweight or obese range, were randomised to daily subcutaneous cotadutide or placebo. Cotadutide was titrated from 50μg daily to 300 μg over 2.5 weeks and the total treatment period was 32 days. Treatment resulted in a significant improvement in the glycaemic outcomes of area under the glucose concentration-time curve during a mixed meal tolerance test at 32 days compared to baseline (–26.71% vs. +3.68% for placebo, p<0.001), and greater amount of time with glycaemia on-target during continuous monitoring (+14.79% vs. –21.23%, p=0.001). There were marked improvements in weight with active treatment at 3.41kg average weight loss compared to 0.13kg weight loss with placebo (p<0.001). Among 18 patients with micro- or macro-albuminuria, the albumin-to-creatinine ratio was reduced by 51% compared to placebo, with results not achieving statistical significance (p=0.0504). There was no significant difference in eGFR. Adverse events with cotadutide were double those with placebo, predominantly involving mild gastrointestinal upset
Comment: Cotadutide targets two receptors, GLP1 receptors and glucagon receptors, at a ratio of approximately 5:1. GLP-RA agonism is of established benefit in reducing proteinuria, and a large trial is underway to establish whether the GLP1-RA semaglutide can prevent end-stage kidney disease (FLOW trial, NCT03819153). In animal studies, the addition of glucagon receptor agonism helps to offset stimulation of hepatic gluconeogenesis, which may provide particular benefits for fatty liver disease. Glucagon receptors are also found in the renal tubules, specifically the thick ascending limb, distal tubule, and collecting duct, and agonism may have impacts for kidney function and electrolyte management. Further research is necessary to understand whether there are true benefits to dual GLP1 and glucagon agonism compared to GLP1-RA agonism alone, as well as to evaluate the safety and efficacy for short- and long-term kidney outcomes, including electrolyte handling.
ISN Academy: Transplant
Everolimus transplant regimen may significantly boost COVID-19 vaccination response in those over 65
Enhanced Humoral Immune Response After COVID-19 Vaccination in Elderly Kidney Transplant Recipients on Everolimus Versus Mycophenolate Mofetil–containing Immunosuppressive Regimens
de Boer et al. Transplantation (2022).
Summary: Forty-one individuals with type 2 diabetes and chronic kidney disease (eGFR 30-59mL/min/1.73m2 ), and with a BMI in the overweight or obese range, were randomised to daily subcutaneous cotadutide or placebo. Cotadutide was titrated from 50μg daily to 300 μg over 2.5 weeks and the total treatment period was 32 days. Treatment resulted in a significant improvement in the glycaemic outcomes of area under the glucose concentration-time curve during a mixed meal tolerance test at 32 days compared to baseline (–26.71% vs. +3.68% for placebo, p<0.001), and greater amount of time with glycaemia on-target during continuous monitoring (+14.79% vs. –21.23%, p=0.001). There were marked improvements in weight with active treatment at 3.41kg average weight loss compared to 0.13kg weight loss with placebo (p<0.001). Among 18 patients with micro- or macro-albuminuria, the albumin-to-creatinine ratio was reduced by 51% compared to placebo, with results not achieving statistical significance (p=0.0504). There was no significant difference in eGFR. Adverse events with cotadutide were double those with placebo, predominantly involving mild gastrointestinal upset
Comment: Cotadutide targets two receptors, GLP1 receptors and glucagon receptors, at a ratio of approximately 5:1. GLP-RA agonism is of established benefit in reducing proteinuria, and a large trial is underway to establish whether the GLP1-RA semaglutide can prevent end-stage kidney disease (FLOW trial, NCT03819153). In animal studies, the addition of glucagon receptor agonism helps to offset stimulation of hepatic gluconeogenesis, which may provide particular benefits for fatty liver disease. Glucagon receptors are also found in the renal tubules, specifically the thick ascending limb, distal tubule, and collecting duct, and agonism may have impacts for kidney function and electrolyte management. Further research is necessary to understand whether there are true benefits to dual GLP1 and glucagon agonism compared to GLP1-RA agonism alone, as well as to evaluate the safety and efficacy for short- and long-term kidney outcomes, including electrolyte handling.
ISN Academy: Chronic Kidney Disease
Pushing the resource limits in Bangladesh: coordinated nephrologists and community health workers patient educational program has some beneficial effect
Chronic kidney disease awareness campaign and mobile health education to improve knowledge, quality of life, and motivation for a healthy lifestyle among patients with chronic kidney disease in Bangladesh: randomized controlled trial
Sarket et al J Med Internet Res (2022).
Summary: Forty-one individuals with type 2 diabetes and chronic kidney disease (eGFR 30-59mL/min/1.73m2 ), and with a BMI in the overweight or obese range, were randomised to daily subcutaneous cotadutide or placebo. Cotadutide was titrated from 50μg daily to 300 μg over 2.5 weeks and the total treatment period was 32 days. Treatment resulted in a significant improvement in the glycaemic outcomes of area under the glucose concentration-time curve during a mixed meal tolerance test at 32 days compared to baseline (–26.71% vs. +3.68% for placebo, p<0.001), and greater amount of time with glycaemia on-target during continuous monitoring (+14.79% vs. –21.23%, p=0.001). There were marked improvements in weight with active treatment at 3.41kg average weight loss compared to 0.13kg weight loss with placebo (p<0.001). Among 18 patients with micro- or macro-albuminuria, the albumin-to-creatinine ratio was reduced by 51% compared to placebo, with results not achieving statistical significance (p=0.0504). There was no significant difference in eGFR. Adverse events with cotadutide were double those with placebo, predominantly involving mild gastrointestinal upset
Comment: Cotadutide targets two receptors, GLP1 receptors and glucagon receptors, at a ratio of approximately 5:1. GLP-RA agonism is of established benefit in reducing proteinuria, and a large trial is underway to establish whether the GLP1-RA semaglutide can prevent end-stage kidney disease (FLOW trial, NCT03819153). In animal studies, the addition of glucagon receptor agonism helps to offset stimulation of hepatic gluconeogenesis, which may provide particular benefits for fatty liver disease. Glucagon receptors are also found in the renal tubules, specifically the thick ascending limb, distal tubule, and collecting duct, and agonism may have impacts for kidney function and electrolyte management. Further research is necessary to understand whether there are true benefits to dual GLP1 and glucagon agonism compared to GLP1-RA agonism alone, as well as to evaluate the safety and efficacy for short- and long-term kidney outcomes, including electrolyte handling.