Safety of empagliflozin treatment in four clinical studies: a plain language summary

The renal benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2) are now well established, and these agents are recommended by the American Diabetes Association and Kidney Disease: Improving Global Outcomes guidelines for patients with type 2 diabetes and chronic kidney disease. However, the safety profile of SGLT2 inhibitors in chronic kidney disease is not as clear. We describe the adverse event rates of SGLT2 inhibitors, primarily empagliflozin, in Kaiser Permanente Southern California members with diabetic kidney disease. This study was a multicenter retrospective descriptive analysis evaluating Kaiser Permanente Southern California members with type 2 diabetes and chronic kidney disease 1, 2, or 3 who first filled an SGLT2 inhibitor prescription in 2018, with follow-up through 2019. Primary outcomes were event rates of diabetic ketoacidosis, bone fracture, amputation, urinary tract infection, genital mycotic infection, hyperkalemia, and acute kidney injury. Secondary outcomes were mean changes in estimated glomerular filtration rates, serum creatine levels, urine albumin-to-creatinine ratios, and hemoglobin A1c percentages during the follow-up period. Of 213 patients, 39 experienced at least 1 adverse event, for a total of 50 adverse events. Urinary tract infection had the highest incidence (62.1 events/1000 person-years), followed by genital mycotic infection (58.0 events/1000 person-years). Favorable changes were observed during the follow-up period for urine albumin-to-creatinine ratios and hemoglobin A1c percentages, with mean decreases of 81.8 mg/g and 0.7%, respectively. SGLT2 inhibitors were discontinued in 47.4% of patients, with the top reasons including increase in serum creatinine (8%) and urinary or genital side effects (5.6%). Although most patients did not experience adverse events, urinary tract infections and genital mycotic infections were more common. Our detection of rates and types of adverse effects replicated most results reported in clinical trials. Discontinuations were largely attributed to reasons other than adverse events.

Generalizability of FIGARO-DKD and FIDELIO-DKD Trial Criteria to the US Population Eligible for Finerenone.

Management of Hypertension in Patients With Diabetic Kidney Disease: Summary of the Joint Association of British Clinical Diabetologists and UK Kidney Association (ABCD-UKKA) Guideline 2021

Background and Aims Pregnant women with chronic kidney disease (CKD) are at risk of developing/exacerbating urinary tract infection (UTI) due to the presence of additional (“specific”) risk factors. The aim of our study was estimation the features of UTI in women with CKD during pregnancy. Method The study included 139 women with CKD G1-G3 who had UTI during pregnancy. Most women (63) had chronic glomerulonephritis, 47 had with chronic pyelonephritis, and the rest had diabetic nephropathy (11), chronic tubulointerstitial nephritis (9), renal transplant (7) and lupus nephritis (2). An analysis of the bacteriological examination of urine, the sensitivity of pathogens to antibiotics, clinical manifestations and perinatal complications was performed. Results The following forms UTI are diagnosed: asymptomatic bacteriuria (50.4%), exacerbation of chronic pyelonephritis, including renal transplant (33.1%), acute pyelonephritis (16.5%). The true bacteriuria is determined identically at all stages of CKD, in those with chronic pyelonephritis in 70%, chronic glomerulonephritis in 45% of cases (p = 0.02). Gram-negative microorganisms become apparent in 73.6% of pregnant women with CKD, less often in patients with glomerular pathology than with chronic pyelonephritis (66% versus 81%). Escherichia coli among gram-negative microorganisms was 74.4%, a high frequency of detection of strains with the production of extended-spectrum β-lactamases was established. The course of asymptomatic bacteriuria in pregnant women with non-diabetic glomerulopathy was characterized by a moderate tendency to relapse and moderate release of resistant pathogens. The course of asymptomatic bacteriuria in patients with diabetic nephropathy and after kidney transplantation, on the contrary, had a pronounced tendency to relapse and the frequent release of resistant pathogens. Exacerbation of chronic pyelonephritis proceeded with minimal clinical manifestations, a vivid clinical picture of exacerbation of the disease was determined in one third of pregnant women. It was characterized by a high tendency to relapse and the development of systemic infection, a high frequency of release of resistant pathogens. Pregnant women with CKD who underwent UTI had a high risk of giving birth to premature babies (23% versus 11% p=0.01) who were required to carry out artificial lung ventilation and transfer to stage nursing (34% versus 16%, p=0.01). Conclusion The course of UTI in pregnant women with CKD is characterized by a high prevalence, dependence on primary renal disease, the release of resistant pathogens, and a high probability of an atypical clinical picture.

Rationale and Strategies for Early Detection and Management of Diabetic Kidney Disease

Renin-Angiotensin System Blockade in Advanced Kidney Disease: Stop or Continue?

BackgroundPatients with diabetic mellitus (DM) and chronic kidney disease (CKD) are at an increased risk of urinary tract infection (UTI) due to their altered immunological integrity. These patients are similarly prone to developing frailty, a state of cumulative health deficits involving multiple domains and leading to adverse outcomes. Whether frailty predisposes affected individuals to UTI among patients with DM and CKD remains unclear.MethodsA population-based cohort of patients with DM and CKD (n = 79,887) were assembled from the Longitudinal Cohort of Diabetes Patients, with their baseline frailty status measured by a modified FRAIL scale. We analyzed their risk of developing UTI depending on their severity of frailty, after accounting demographic profiles, lifestyle factors, comorbidities, concurrent medications, and major interventions. A secondary analysis focused on the risk of urosepsis related to frailty.ResultsAmong all participants, 36.1 %, 50.3 %, 12.8 %, and 0.8 % did not have or had 1, 2, and ≥ 3 FRAIL items, respectively, at baseline. After 3.51 years, 11,175 UTI events occurred. Kaplan-Meier analysis showed that participants with DM, CKD and an increasing number of FRAIL items had successively higher incidence of UTI than those without any FRAIL items (log rank p < 0.001). Cox proportional hazard modeling revealed that after accounting for all confounders, those with more severe frailty exhibited a significantly higher risk of incident UTI (for groups of 1, 2, and ≥ 3 FRAIL items, hazard ratio 1.19, 1.24, and 1.43, respectively; all p < 0.001) than those without. An 11 % risk elevation for UTI could be observed for every FRAIL item increase. Participants with more severe frailty exhibited a trend of having higher risk of urosepsis as well.ConclusionsHaving frailty predicted a higher risk of developing UTI in the future in patients with DM and CKD. It would be prudent to screen for frailty in these patients and provide optimal frailty-directed management to attenuate their risk of UTI and improve their outcomes.

Effect of Pay for Performance on Hypertension in the United Kingdom

How well do we care for patients with hypertension?

Introduction: Heart Failure (HF) is a major public health burden, but population-based estimates of incidence rates of clinical outcomes by HF category are scarce. We calculated adjusted incidence rates of type 2 diabetes (T2D) and chronic kidney disease (CKD) in patients with HF with preserved (HFpEF) or reduced ejection fraction (HFrEF). Methods: We identified adult patients with a HF diagnosis from 2005-2017 in the electronic medical record of Kaiser Permanent Northwest and calculated age/sex adjusted incidence or progression rates per 1,000 person-years using generalized estimating equations over 15 years of follow-up (2005-2019). Patients with their first diagnosis of T2D or with two eGFR values &lt;60ml/min/1.73m 2 per the CKD-EPI equation recorded after a HF diagnosis were counted as incident cases. Progression of CKD was calculated among those with CKD at baseline defined as deteriorating to a lower eGFR category (category 3a, 45-59 ml/min/1.73m 2 ; 3b, 30-44; 4, 15-29; 5, &lt;15 or ESKD). Progression to insulin was calculated among those with T2D at baseline not already on insulin. Results: Of the 37,773 patients with a HF diagnosis, 36% had no EF available. 46.4% were categorized as HFpEF, 6.7% HFmrEF and 10.9% HFrEF. Compared with HFrEF patients, those with HFpEF were older (72.1 vs. 68.6 years) and more likely to be female (55% vs. 33%). Patients with HFrEF were more likely than HFpEF to develop CKD or have CKD deterioration (Table). However, due to the much larger size of the HFpEF group, HFpEF generated higher absolute numbers of events. Incidence rates and progression of T2D were smaller for both HFrEF and HFpEF. Conclusions: In a large real-world dataset of HF patients, rates of CKD progression were very high in both HFrEF and HFpEF, affecting approximately half of patients with CKD at baseline. Although progression and new incidence of CKD were relatively lower in HFpEF vs. HFrEF, the greater prevalence of HFpEF was driving the majority of heart failure-associated CKD.

The burden of adverse cardiorenal outcomes among patients with the trifecta of diabetes, heart failure (HF) and chronic kidney disease (CKD) remains high. Steroidal mineralocorticoid receptor antagonists (MRAs) have been shown to improve clinical outcomes in patients with HF, however, there is significant underutilization of these agents, especially in patients with advanced CKD. Non-steroidal MRAs are an emerging therapeutic option for patients with diabetic kidney disease and are now guideline-supported in this population. Non-steroidal MRAs have a unique pharmacological profile distinct from their steroidal counterparts that retains the class-specific cardiorenal benefits but may help mitigate adverse effects, especially hyperkalaemia, in patients with CKD. In this review we summarize the current evidence on the use of non-steroidal MRAs for improving cardiorenal outcomes in patients with CKD and diabetes, as well as for combination use alongside other foundational medical therapies used in HF and CKD.

Relation of Baseline Systolic Blood Pressure and Long-Term Outcomes in Ambulatory Patients With Chronic Mild to Moderate Heart Failure

Insulin and glucose-lowering agents for treating people with diabetes and chronic kidney disease.

Chronic kidney disease and type 2 diabetes are independently associated with heart failure (HF), a leading cause of morbidity and mortality. In the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trials, finerenone (a selective, nonsteroidal mineralocorticoid receptor antagonist) improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type 2 diabetes. These prespecified analyses from FIGARO-DKD assessed the effect of finerenone on clinically important HF outcomes. Patients with type 2 diabetes and albuminuric chronic kidney disease (urine albumin-to-creatinine ratio ≥30 to <300 mg/g and estimated glomerular filtration rate ≥25 to ≤90 mL per min per 1.73 m2, or urine albumin-to-creatinine ratio ≥300 to ≤5000 mg/g and estimated glomerular filtration rate ≥60 mL per min per 1.73 m2), without symptomatic HF with reduced ejection fraction, were randomized to finerenone or placebo. Time-to-first-event outcomes included new-onset HF (first hospitalization for HF [HHF] in patients without a history of HF at baseline); cardiovascular death or first HHF; HF-related death or first HHF; first HHF; cardiovascular death or total (first or recurrent) HHF; HF-related death or total HHF; and total HHF. Outcomes were evaluated in the overall population and in prespecified subgroups categorized by baseline HF history (as reported by the investigators). Overall, 7352 patients were included in these analyses; 571 (7.8%) had a history of HF at baseline. New-onset HF was significantly reduced with finerenone versus placebo (1.9% versus 2.8%; hazard ratio [HR], 0.68 [95% CI, 0.50-0.93]; P=0.0162). In the overall population, the incidences of all HF outcomes analyzed were significantly lower with finerenone than placebo, including an 18% lower risk of cardiovascular death or first HHF (HR, 0.82 [95% CI, 0.70-0.95]; P=0.011), a 29% lower risk of first HHF (HR, 0.71 [95% CI, 0.56-0.90]; P=0.0043) and a 30% lower rate of total HHF (rate ratio, 0.70 [95% CI, 0.52-0.94]). The effects of finerenone on improving HF outcomes were not modified by a history of HF. The incidence of treatment-emergent adverse events was balanced between treatment groups. The results from these FIGARO-DKD analyses demonstrate that finerenone reduces new-onset HF and improves other HF outcomes in patients with chronic kidney disease and type 2 diabetes, irrespective of a history of HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02545049.

The Impact of APOL1 on Chronic Kidney Disease and Hypertension.