[Semaglutide in Chronic Kidney Disease: Great Enthusiasm. But How Does It Work?] / La Semaglutide nella Malattia Renale Cronica: tanto entusiasmo. Ma come funziona?

Chronic Kidney Disease (CKD) is a clinical condition characterized by the progressive loss of kidney function. 10% of the world's population is affected by this condition, which represents the fifth leading cause of death globally. Furthermore, CKD is associated with increased risk of fatal and non-fatal cardiovascular events, and progression to end-stage renal disease. Over the last twenty years, an exponential growth in its prevalence and incidence has been observed. For this reason, various drugs have been developed and implemented in clinical practice, with various mechanisms, with the aim of reducing and minimizing this dramatic "cardio-renal" risk. These include SGLT2 inhibitors, mineralocorticoid receptor antagonists, and endothelin receptor antagonists. However, a large proportion of CKD patients do not respond sufficiently to these treatments. GLP-1 receptor agonists represent a class of antidiabetic and nephroprotective drugs that are very promising in improving the prognosis of patients with CKD, especially if associated with one of the above-mentioned classes. In this article, we discuss the direct and indirect mechanisms through which one of the GLP-1 agonists, semaglutide, ensures nephro- and cardioprotection in patients with CKD and type 2 diabetes.

Current evidence on the use of anti-RAAS agents in congenital or acquired solitary kidney.

RATIONAL: The inhibition of renin-angiotensin-aldosterone system (RAAS) is a major strategy for slowing the progression of chronic kidney disease (CKD). The utility of anti-RAAS agents in patients with congenital or acquired solitary kidney is still controversial. OBJECTIVE: A systematic literature review was conducted. MAIN FINDINGS: The conclusions of the few available studies on the topic are homogeneously in agreement with a long-term reno-protective activity of anti-RAAS drugs in patients with solitary kidney, especially if patients are hypertensive or proteinuric. However, angiotensin 2 (ANG2) levels permit a functional adaptation to a reduced renal mass in adults and is crucial for sustaining complete kidney development and maturation in children. A hormonal interference on ANG2 levels has been supposed in women. Consequently, at least in children and women, the use of ARBs appears more appropriate. Principle conclusions: Available data on this topic are limited; however, by their overall assessment, it would appear that anti-RAAS drugs might also be reno-protective in patients with solitary kidney. The use of ARBs, especially in children and in women, seems to be more appropriate. However, more experimental data would be strictly necessary to confirm this hypothesis.

Exercise in Patients on Dialysis: A Multicenter, Randomized Clinical Trial.

Previous studies have suggested the benefits of physical exercise for patients on dialysis. We conducted the Exercise Introduction to Enhance Performance in Dialysis trial, a 6-month randomized, multicenter trial to test whether a simple, personalized walking exercise program at home, managed by dialysis staff, improves functional status in adult patients on dialysis. The main study outcomes included change in physical performance at 6 months, assessed by the 6-minute walking test and the five times sit-to-stand test, and in quality of life, assessed by the Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire. We randomized 296 patients to normal physical activity (control; n=145) or walking exercise (n=151); 227 patients (exercise n=104; control n=123) repeated the 6-month evaluations. The distance covered during the 6-minute walking test improved in the exercise group (mean distance±SD: baseline, 328±96 m; 6 months, 367±113 m) but not in the control group (baseline, 321±107 m; 6 months, 324±116 m; P<0.001 between groups). Similarly, the five times sit-to-stand test time improved in the exercise group (mean time±SD: baseline, 20.5±6.0 seconds; 6 months, 18.2±5.7 seconds) but not in the control group (baseline, 20.9±5.8 seconds; 6 months, 20.2±6.4 seconds; P=0.001 between groups). The cognitive function score (P=0.04) and quality of social interaction score (P=0.01) in the kidney disease component of the KDQOL-SF improved significantly in the exercise arm compared with the control arm. Hence, a simple, personalized, home-based, low-intensity exercise program managed by dialysis staff may improve physical performance and quality of life in patients on dialysis.

The case of chronic hepatitis B treatment with tenofovir: an update for nephrologists.

Tenofovir is a nucleotide acting both as an inhibitor of human immunodeficiency (HIV) reverse transcriptase and as a competitor for hepatitis B virus (HBV) RNA-directed DNA polymerase. Approved worldwide in 2001, tenofovir is used as a component of highly active antiretroviral therapy (HAART) in patients with HIV infection. Since 2008, it has also been indicated for treatment of chronic HBV infection or HIV/HBV co-infection. The aim of the treatment consists in suppressing viral replication, thus reducing hepatic complications and improving patient survival. Furthermore, tenofovir could represent an effective therapeutic option in lamivudine-resistant HBV patients. Tenofovir is eliminated unchanged through urine via glomerular filtration (80%) and proximal tubular secretion (20%). Thus, alterations in renal clearance may interfere with tenofovir pharmacokinetics and systemic drug concentrations, modifying the therapeutic response. Hence, a renal overload of tenofovir in patients with a pre-existing kidney impairment could result in a worsening of renal function. Following a brief introduction on HBV infection and its therapeutic options, we review the latest evidence, to our knowledge, on renal toxicity of tenofovir in HBV patients and on drug management.

Fitness for entering a simple exercise program and mortality: a study corollary to the exercise introduction to enhance performance in dialysis (EXCITE) trial.

BACKGROUND/AIMS: In this corollary analysis of the EXCITE study, we looked at possible differences in baseline risk factors and mortality between subjects excluded from the trial because non-eligible (n=216) or because eligible but refusing to participate (n=116). METHODS: Baseline characteristics and mortality data were recorded. Survival and independent predictors of mortality were assessed by Kaplan-Meier and Cox regression analyses. RESULTS: The incidence rate of mortality was higher in non-eligible vs. eligible non-randomized patients (21.0 vs. 10.9 deaths/100 persons-year; P<0.001). The crude excess risk of death in non-eligible patients (HR 1.96; 95% CI 1.36 to 2.77; P<0.001) was reduced after adjustment for risk factors which differed in the two cohorts including age, blood pressure, phosphate, CRP, smoking, diabetes, triglycerides, cardiovascular comorbidities and history of neoplasia (HR 1.60; 95% CI 1.10 to 2.35; P=0.017) and almost nullified after including in the same model also information on deambulation impairment (HR 1.16; 95% CI 0.75 to 1.80; P=0.513). CONCLUSIONS: Deambulation ability mostly explains the difference in survival rate in non-eligible and eligible non-randomized patients in the EXCITE trial. Extending data analyses and outcome reporting also to subjects not taking part in a trial may be helpful to assess the representability of the study population.

Physical performance and clinical outcomes in dialysis patients: a secondary analysis of the EXCITE trial.

BACKGROUND/AIMS: Scarce physical activity predicts shorter survival in dialysis patients. However, the relationship between physical (motor) fitness and clinical outcomes has never been tested in these patients. METHODS: We tested the predictive power of an established metric of motor fitness, the Six-Minute Walking Test (6MWT), for death, cardiovascular events and hospitalization in 296 dialysis patients who took part in the trial EXCITE (ClinicalTrials.gov Identifier: NCT01255969). RESULTS: During follow up 69 patients died, 90 had fatal and non-fatal cardiovascular events, 159 were hospitalized and 182 patients had the composite outcome. In multivariate Cox models - including the study allocation arm and classical and non-classical risk factors - an increase of 20 walked metres during the 6MWT was associated to a 6% reduction of the risk for the composite end-point (P=0.001) and a similar relationship existed between the 6MWT, mortality (P<0.001) and hospitalizations (P=0.03). A similar trend was observed for cardiovascular events but this relationship did not reach statistical significance (P=0.09). CONCLUSIONS: Poor physical performance predicts a high risk of mortality, cardiovascular events and hospitalizations in dialysis patients. Future studies, including phase-2 EXCITE, will assess whether improving motor fitness may translate into better clinical outcomes in this high risk population.