Kidney Disease In Individuals Research Articles

#208 Obesity is associated with incident chronic kidney disease in individuals with normal renal function

Abstract Background and Aims Obesity is a representative modifiable risk factor for chronic kidney disease (CKD). This study aimed to investigate whether both body mass index (BMI), waist-to-hip ratio (WHR) and changes of WHR during follow-up are risk factors for development of incident CKD. Method A total of 2 711 participants from a community-based cohort with normal renal function were prospectively analyzed. Among participants with obesity, we analyzed the change in WHR to evaluate the association of obesity reduction with CKD development. Results During a mean follow-up of 11.03 ± 4.22 years, incident CKD occurred in 190 (7.0%) participants. In the fully adjusted multivariable Cox proportional hazard models, the risk of incident CKD increased with higher BMI (hazard ratio, 1.06; 95% confidence interval, 1.00–1.11; p = 0.033) and higher WHR (hazard ratio, 1.33; 95% confidence interval, 1.07–1.66; p = 0.009). In the Kaplan–Meier analysis, cumulative adverse renal events were significantly more common in the maintained obesity group than in the reduced obesity group (p = 0.001). Conclusion Both higher BMI and WHR were associated with development of CKD, but the magnitude of the effect of WHR was higher than that of BMI. Moreover, reducing obesity would be beneficial for renal prognosis.

The correlation between heart failure and diabetic kidney disease in individuals diagnosed with type 2 diabetes mellitus

The correlation between heart failure and diabetic kidney disease in individuals diagnosed with type 2 diabetes mellitus

Inhibition of SGL2 Prevents Albumin Induced Proximal Tubule Inflammation

Albuminuria is an independent risk factor for cardiovascular disease and renal damage in hypertension. It is associated with a higher risk of cardiovascular morbidity and mortality, and with declining kidney function. The Na+-glucose cotransporter-2 (SGLT2) plays a crucial role in glucose and sodium reabsorption in the proximal tubule. Clinical trials have shown that SGLT2 inhibitors can reduce cardiovascular events, lower blood pressure, and decrease the risk of end-stage kidney disease in individuals with type 2 diabetes mellitus. These trials have also demonstrated the potential of SGLT2 inhibitors to provide additional benefits beyond their glucose control, including decreased albuminuria. In this study, we hypothesized that exposure to elevated albumin causes proximal tubule injury and the release of cytokines from the basolateral membrane. We propose that by reducing transport in the proximal tubule, SGLT2 inhibitors may alleviate kidney damage by reducing cytokine production and subsequently renal inflammation. To test our hypothesis, we conducted experiments using Dahl salt-sensitive (SS) rats and immortalized human proximal tubule cells (RPTEC-TERT1). To determine how early albuminuria and proximal injury occur in the development of salt-sensitive hypertension, 24-hour urine was collected from SS rats fed either a control salt (CS, 0.4% NaCl, n=10) or a high salt (HS, 4.0% NaCl, n=11) diet for 7 days. Significant increases in albuminuria were observed after 1 day of HS (CS: 25±7 vs. HS: 59±13 mg/day p=0.016). This was followed by significant increases in urinary kidney injury molecule-1 (Kim-1) after 2 days of HS (CS: 13±2 vs. HS: 23±3 pg/day p=0.021). Preliminary analysis found substantial increases in urinary CCL2 after 4 days of HS (CS: 58±7 vs. HS: 135±25 pg/mg, n=5). To investigate whether the renoprotective effects of SGLT2 inhibitors are in part due to their ability to reduce inflammation in the proximal tubule, we exposed the apical membrane of RPTEC-TERT1 cells to human serum albumin (HSA, 10mg/ml, n=6) with and without Dapagliflozin (Dapa, 15ng/ml, n=5) for 24-hours and measured the levels of CCL2 in the basolateral media. HSA caused a significant increase in CCL2 levels relative to control cells (Control: 42.5±5.6 vs. HSA: 84.1±8.7 pg/mg, p=0.00). This increase was prevented by co-treatment with Dapa and CCL2 levels were equivalent to those in the control cells (HSA+Dapa: 44.0±4.5 pg/mg, p=0.988). In conclusion, our findings support the hypothesis that albuminuria precedes proximal tubule injury and may contribute to the development of renal inflammation in salt-sensitive hypertension. The ability of Dapa to reduce prevent albumin induced CCL2 production in RPTEC-TERT1 cells suggests that SGLT2 inhibitors may reduce renal inflammation in salt-sensitive hypertension and is an area of ongoing studies. Studies funded by R01HL152166 to LE. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Predictors of chronic kidney disease survival in type 2 diabetes: a 12-year retrospective cohort study utilizing estimated glomerular filtration rate

Predicting the course of kidney disease in individuals with both type 1 and type 2 diabetes mellitus (DM) is a significant clinical and policy challenge. In several regions, DM is now the leading cause of end-stage renal disease. The aim of this study to identify both modifiable and non-modifiable risk factors, along with clinical markers and coexisting conditions, that increase the likelihood of stage 3–5 chronic kidney disease (CKD) development in individuals with type 2 DM in the United Arab Emirates (UAE). This was a single-center retrospective cohort study based on data derived from electronic medical records of UAE patients with DM who were registered at outpatient clinics at Tawam Hospital in Al Ain, UAE, between January 2011 and December 2021. Type 2 DM patients aged ≥ 18 years who had serum HbA1c levels ≥ 6.5% were included in the study. Patients with type 1 DM, who had undergone permanent renal replacement therapy, who had under 1 year of follow-up, or who had missing or incomplete data were excluded from the study. Factors associated with diabetic patients developing stage 3–5 CKD were identified through Cox regression analysis and a fine and gray competing risk model to account for competing events that could potentially hinder the development of CKD. A total of 1003 patients were recruited for the study. The mean age of the study cohort at baseline was 70.6 ± 28.2 years. Several factors were found to increase the risk of developing stage 3–5 CKD: advancing age (HR 1.005, 95% CI 1.002–1.009, p = 0.026), a history of hypertension (HR 1.69, 95% CI 1.032–2.8, p = 0.037), a history of heart disease (HR 1.49, 95% CI 1.16–1.92, p = 0.002), elevated levels of serum creatinine (HR 1.006, 95% CI 1.002–1.010, p = 0.003), decreased levels of estimated glomerular filtration rate (eGFR) (HR 0.943, 95% CI, 0.938–0.947; p < 0.001), and the use of beta-blockers (HR 139, 95% CI 112–173, p = 0.003). Implementing preventative measures, initiating early interventions, and developing personalized care plans tailored to address specific risk factors are imperative for reducing the impact of CKD. Additionally, the unforeseen findings related to eGFR highlight the ongoing need for research to deepen our understanding of the complexities of kidney disease.

APOL1 nephropathy - a population genetics success story.

More than a decade ago, apolipoprotein L1 (APOL1) risk alleles designated G1 and G2, were discovered to be causally associated with markedly increased risk for progressive kidney disease in individuals of recent African ancestry. Gratifying progress has been made during the intervening years, extending to the development and clinical testing of genomically precise small molecule therapy accompanied by emergence of RNA medicine platforms and clinical testing within just over a decade. Given the plethora of excellent prior review articles, we will focus on new findings regarding unresolved questions relating mechanism of cell injury with mode of inheritance, regulation and modulation of APOL1 activity, modifiers and triggers for APOL1 kidney risk penetrance, the pleiotropic spectrum of APOL1 related disease beyond the kidney - all within the context of relevance to therapeutic advances. Notwithstanding remaining controversies and uncertainties, promising genomically precise therapies targeted at APOL1 mRNA using antisense oligonucleotides (ASO), inhibitors of APOL1 expression, and small molecules that specifically bind and inhibit APOL1 cation flux are emerging, many already at the clinical trial stage. These therapies hold great promise for mitigating APOL1 kidney injury and possibly other systemic phenotypes as well. A challenge will be to develop guidelines for appropriate use in susceptible individuals who will derive the greatest benefit.

Resting Heart Rate Independent of Cardiovascular Disease Risk Factors Is Associated With End-Stage Renal Disease: A Cohort Study Based on 476 347 Adults.

The relationship between resting heart rate (RHR) and the risk of end-stage renal disease (ESRD) among those without cardiovascular disease remains unclear. We aim to establish temporal consistency and elucidate the independent relationship between RHR and the risk of ESRD. This cohort enrolled participants from 476 347 individuals who had taken part in a screening program from 1996 to 2017. We identified 2504 participants who had ESRD, and the median follow-up was 13 years. RHR was extracted from electrocardiography results, and the study assessed the relationship between RHR and the risk of ESRD using the Cox proportional hazards model. Of the participants, 32.6% had an RHR of 60 to 69 beats per minute (bpm), and 22.2% had an RHR of ≥80 bpm. Participants with an RHR of ≥80 bpm had a higher stage of chronic kidney disease, lower estimated glomerular filtration rate, and more proteinuria than those with an RHR of 60 to 69 bpm. Participants with an RHR of 80 to 89 and ≥90 bpm had a 24% (hazard ratio [HR], 1.24 [95% CI, 1.09-1.42]) and 64% (HR, 1.64 [95% CI, 1.42-1.90]) higher risk of ESRD, respectively. The risk of ESRD remained significantly elevated (HR, 1.32 [95% CI, 1.10-1.58] per 10-beat increase from 60 bpm) after excluding participants who smoked; had hypertension, diabetes, or hyperlipidemia; or were overweight. An RHR of ≥80 bpm is significantly associated with an increased risk of ESRD. These results suggest that RHR may serve as a risk factor for kidney disease in individuals without established cardiovascular disease risk factors.

Retinol intake is associated with the risk of chronic kidney disease in individuals with type 2 diabetes mellitus: results from NHANES

The aim of this study was to investigate the potential association between retinol intake and the risk of chronic kidney disease (CKD) in individuals with type 2 diabetes mellitus (T2DM). The study included individuals diagnosed with T2DM between 2009 and 2018 from the NHANES database. Demographic and laboratory test data were collected for these individuals, as well as information on CKD diagnosis. Logistic regression models were utilized to estimate the relationship between different retinol intakes and the risk of CKD in patients with T2DM. A total of 3988 patients were included in the study. The mean prevalence of CKD in the T2DM population in the United States from 2009 to 2018 was 36.98 (0.02)%. Multivariate logistic regression analysis revealed a 26% decrease in the incidence of CKD in individuals with higher retinol intake compared to those with lower retinol intake in T2DM (OR = 0.74; 95% CI 0.56–0.98). Furthermore, an increase in retinol intake per 1-standard deviation (SD) was associated with a 16% decreased risk of the incidence of CKD (OR = 0.84; 95% CI 0.72–0.97). Lower retinol intake is an independent risk factor for the onset of CKD in patients with T2DM, and augmenting moderate quantities of retinol confers potential nephroprotective advantages.

Editing of APOL1 mRNA reduces APOL1 expression and activation of innate immunity

The APOL1 gene encodes Apoliprotein L1, an innate immune response protein that confers protection against Trypanosomal diseases and likely other infectious diseases. 1 Thomson R. Genovese G. Canon C. et al. Evolution of the primate trypanolytic factor APOL1. Proc Natl Acad Sci U S A. 2014; 111: E2130-2139 Crossref PubMed Scopus (160) Google Scholar ,2 Limou S. Dummer P.D. Nelson G.W. et al. APOL1 toxin, innate immunity, and kidney injury. Kidney Int. 2015; 88: 28-34 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar The G1 and G2 variants of APOL1, which are enriched in persons of West African ancestry, provide enhanced protection against Trypanosome infection, but persons with APOL1 high risk (HR) genotypes (two risk alleles) have markedly increased risk of progressive CKD. 2 Limou S. Dummer P.D. Nelson G.W. et al. APOL1 toxin, innate immunity, and kidney injury. Kidney Int. 2015; 88: 28-34 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Because most individuals with HR genotypes do not develop kidney disease, it is likely that a “second hit” may be necessary to unmask the HR genotype-associated risk. APOL1 HR genotype is most strongly associated with severe kidney disease occurring in the setting of high interferon levels due to infection (HIV or COVID-19), 3 Kopp J.B. Nelson G.W. Sampath K. et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011; 22: 2129-2137 Crossref PubMed Scopus (602) Google Scholar ,4 Kudose S. Batal I. Santoriello D. et al. Kidney Biopsy Findings in Patients with COVID-19. J Am Soc Nephrol. 2020; 31: 1959-1968 Crossref PubMed Scopus (245) Google Scholar lupus nephritis, 5 Freedman B.I. Langefeld C.D. Andringa K.K. et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol. 2014; 66: 390-396 Crossref PubMed Scopus (203) Google Scholar interferon treatment, 6 Nichols B. Jog P. Lee J.H. et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015; 87: 332-342 Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar and kidney transplantation. 7 Santoriello D. Husain S.A. De Serres S.A. et al. Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts. Kidney Int. 2018; 94: 1189-1198 Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar As APOL1 expression is strongly induced by interferons, 6 Nichols B. Jog P. Lee J.H. et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015; 87: 332-342 Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar upregulation of toxic G1 and G2 variants in the setting of high interferon is hypothesized to be an important contributor to kidney injury. Thus, improved understanding of the factors that regulate APOL1 expression may provide new strategies to prevent or treat kidney disease in individuals with HR genotypes.

Differential Methylation of Telomere-Related Genes Is Associated with Kidney Disease in Individuals with Type 1 Diabetes.

Diabetic kidney disease (DKD) represents a major global health problem. Accelerated ageing is a key feature of DKD and, therefore, characteristics of accelerated ageing may provide useful biomarkers or therapeutic targets. Harnessing multi-omics, features affecting telomere biology and any associated methylome dysregulation in DKD were explored. Genotype data for nuclear genome polymorphisms in telomere-related genes were extracted from genome-wide case-control association data (n = 823 DKD/903 controls; n = 247 end-stage kidney disease (ESKD)/1479 controls). Telomere length was established using quantitative polymerase chain reaction. Quantitative methylation values for 1091 CpG sites in telomere-related genes were extracted from epigenome-wide case-control association data (n = 150 DKD/100 controls). Telomere length was significantly shorter in older age groups (p = 7.6 × 10-6). Telomere length was also significantly reduced (p = 6.6 × 10-5) in DKD versus control individuals, with significance remaining after covariate adjustment (p = 0.028). DKD and ESKD were nominally associated with telomere-related genetic variation, with Mendelian randomisation highlighting no significant association between genetically predicted telomere length and kidney disease. A total of 496 CpG sites in 212 genes reached epigenome-wide significance (p ≤ 10-8) for DKD association, and 412 CpG sites in 193 genes for ESKD. Functional prediction revealed differentially methylated genes were enriched for Wnt signalling involvement. Harnessing previously published RNA-sequencing datasets, potential targets where epigenetic dysregulation may result in altered gene expression were revealed, useful as potential diagnostic and therapeutic targets for intervention.

The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization study.

Observational studies have investigated the effect of serum lipids on kidney function, but these findings are limited by confounding, reverse causation and have reported conflicting results. Mendelian randomization (MR) studies address this confounding problem. However, they have been conducted mostly in European ancestry individuals. We, therefore, set out to investigate the effect of lipid traits on the estimated glomerular filtration rate (eGFR) based on serum creatinine in individuals of African ancestry. We used the two-sample and multivariable Mendelian randomization (MVMR) approaches; in which instrument variables (IV's) for the predictor (lipid traits) were derived from summary-level data of a meta-analyzed African lipid GWAS (MALG, n=24,215) from the African Partnership for Chronic Disease Research (APCDR) (n=13,612) & the Africa Wits-IN-DEPTH partnership for Genomics studies (AWI-Gen) dataset (n=10,603). The outcome IV's were computed from the eGFR summary-level data of African-ancestry individuals within the Million Veteran Program (n=57,336). A random-effects inverse variance method was used in our primary analysis, and pleiotropy was adjusted for using robust and penalized sensitivity testing. The lipid predictors for the MVMR were high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG). We found a significant causal association between genetically predicted low-density lipoprotein (LDL) cholesterol and eGFR in African ancestry individuals β=1.1 (95% CI [0.411-1.788]; p=0.002). Similarly, total cholesterol (TC) showed a significant causal effect on eGFR β=1.619 (95% CI [0.412-2.826]; p=0.009). However, the IVW estimate showed that genetically predicted HDL-C β=-0.164, (95% CI=[-1.329 to 1.00]; p=0.782), and TG β=-0.934 (CI=[-2.815 to 0.947]; p=0.33) were not significantly causally associated with the risk of eGFR. In the multivariable analysis inverse-variance weighted (MVIVW) method, there was evidence for a causal association between LDL and eGFR β=1.228 (CI=[0.477-1.979]; p=0.001). A significant causal effect of Triglycerides (TG) on eGFR in the MVIVW analysis β=-1.3 ([-2.533 to-0.067]; p=0.039) was observed as well. All the causal estimates reported reflect a unit change in the outcome per a 1 SD increase in the exposure. HDL showed no evidence of a significant causal association with eGFR in the MVIVW method (β=-0.117 (95% CI [-1.252 to 0.018]; p=0.840)). We found no evidence of a reverse causal impact of eGFR on serum lipids. All our sensitivity analyses indicated no strong evidence of pleiotropy or heterogeneity between our instrumental variables for both the forward and reverse MR analysis. In this African ancestry population, genetically predicted higher LDL-C and TC are causally associated with higher eGFR levels, which may suggest that the relationship between LDL, TC and kidney function may be U-shaped. And as such, lowering LDL_C does not necessarily improve risk of kidney disease. This may also imply the reason why LDL_C is seen to be a poorer predictor of kidney function compared to HDL. In addition, this further supports that more work is warranted to confirm the potential association between lipid traits and risk of kidney disease in individuals of African Ancestry. Wellcome (220740/Z/20/Z).

Machine learning-based warning model for chronic kidney disease in individuals over 40 years old in underprivileged areas, Shanxi Province.

Chronic kidney disease (CKD) is a progressive disease with high incidence but early imperceptible symptoms. Since China's rural areas are subject to inadequate medical check-ups and single disease screening programme, it could easily translate into end-stage renal failure. This study aimed to construct an early warning model for CKD tailored to impoverished areas by employing machine learning (ML) algorithms with easily accessible parameters from ten rural areas in Shanxi Province, thereby, promoting a forward shift of treatment time and improving patients' quality of life. From April to November 2019, CKD opportunistic screening was carried out in 10 rural areas in Shanxi Province. First, general information, physical examination data, blood and urine specimens were collected from 13,550 subjects. Afterward, feature selection of explanatory variables was performed using LASSO regression, and target datasets were balanced using the SMOTE (synthetic minority over-sampling technique) algorithm, i.e., albuminuria-to-creatinine ratio (ACR) and α1-microglobulin-to-creatinine ratio (MCR). Next, Bagging, Random Forest (RF) and eXtreme Gradient Boosting (XGBoost) were employed for classification of ACR outcomes and MCR outcomes, respectively. 12,330 rural residents were included in this study, with 20 explanatory variables. The cases with increased ACR and increased MCR represented 1,587 (12.8%) and 1,456 (11.8%), respectively. After conducting LASSO, 14 and 15 explanatory variables remained in these two datasets, respectively. Bagging, RF, and XGBoost performed well in classification, with the AUC reaching 0.74, 0.87, 0.87, 0.89 for ACR outcomes and 0.75, 0.88, 0.89, 0.90 for MCR outcomes. The five variables contributing most to the classification of ACR outcomes and MCR outcomes constituted SBP, TG, TC, and Hcy, DBP and age, TG, SBP, Hcy and FPG, respectively. Overall, the machine learning algorithms could emerge as a warning model for CKD. ML algorithms in conjunction with rural accessible indexes boast good performance in classification, which allows for an early warning model for CKD. This model could help achieve large-scale population screening for CKD in poverty-stricken areas and should be promoted to improve the quality of life and reduce the mortality rate.

Level of education is associated with coronary heart disease and chronic kidney disease in individuals with type 2 diabetes: a population-based study

IntroductionTo study the relationship between education level and vascular complications in individuals with type 2 diabetes in Norway.Research design and methodsMultiregional population-based cross-sectional study of individuals with type 2 diabetes...

Exercise reduces the risk of chronic kidney disease in individuals with nonalcoholic fatty liver disease: A nationwide cohort study

AimsRecent studies of individuals with nonalcoholic fatty liver disease (NAFLD) have indicated benefits of exercise in improving outcomes. We investigated whether exercise reduces the risk of chronic kidney disease (CKD) in individuals with NAFLD. MethodsA total of 7275 participants from the Korea National Health and Nutrition Examination Survey (KNHANES) cohort, and 40,418 participants with NAFLD from the National Health Insurance Service (NHIS) cohort were included for the cross-sectional and longitudinal analyses, respectively. For the cross-sectional analysis, the primary outcome was prevalent CKD, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. For the longitudinal analysis, the primary outcome was incident CKD, defined as the occurrence of eGFR <60 mL/min/1.73m2 or proteinuria (≥ trace) on two consecutive measurements during follow-up. ResultsIn the KNHANES cohort, prevalent CKD was observed in 229 (6.1%), 48 (2.6%), and 36 (2.1%) participants in the 0, 1-2, and ≥ 3 exercise sessions/week groups, respectively. The likelihood of prevalent CKD was lowest in participants allocated to the ≥ 3 sessions/week group (adjusted OR 0.49; 95% CI, 0.33-0.71; P < 0.001). During a median follow-up of 5.0 years in the NHIS cohort, incident CKD occurred in 1,047 (9.7/1,000 person-years), 188 (7.3/1,000 person-years), and 478 (7.4/1,000 person-years) participants in the 0, 1-2, and ≥ 3 sessions/week groups, respectively. The risk of incident CKD was lowest in participants allocated to the ≥ 3 sessions/week group (adjusted HR 0.85; 95% CI, 0.76-0.95; P = 0.004). ConclusionsExercise was significantly associated with a reduced risk of both prevalent and incident CKD in individuals with NAFLD.

GSTM1 Copy Number and Kidney Disease in People With HIV

GSTM1 Copy Number and Kidney Disease in People With HIV

Association of SGLT2 inhibitors with cardiovascular, kidney, and safety outcomes among patients with diabetic kidney disease: a meta-analysis

BackgroundWe conducted a systematic review and meta-analysis of the cardiovascular, kidney, and safety outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) among patients with diabetic kidney disease (DKD).MethodsWe searched electronic databases for major randomized placebo-controlled clinical trials published up to September 30, 2021 and reporting on cardiovascular and kidney outcomes of SGLT2i in patients with DKD. DKD was defined as chronic kidney disease in individuals with type 2 diabetes. Random-effects meta-analysis models were used to estimate pooled hazard ratios (HR) and 95% confidence intervals (CI) for clinical outcomes including major adverse cardiovascular events (MACE: myocardial infarction [MI], stroke, and cardiovascular death), kidney composite outcomes (a combination of worsening kidney function, end-stage kidney disease, or death from renal or cardiovascular causes), hospitalizations for heart failure (HHF), deaths and safety events (mycotic infections, diabetic ketoacidosis [DKA], volume depletion, amputations, fractures, urinary tract infections [UTI], acute kidney injury [AKI], and hyperkalemia).ResultsA total of 26,106 participants with DKD from 8 large-scale trials were included (median age: 65.2 years, 29.7–41.8% women, 53.2–93.2% White, median follow-up: 2.5 years). SGLT2i were associated with reduced risks of MACE (HR 0.83, 95% CI 0.75–0.93), kidney composite outcomes (HR 0.66, 95% CI 0.58–0.75), HHF (HR 0.62, 95% CI 0.55–0.71), cardiovascular death (HR 0.84, 95% CI 0.74–0.96), MI (HR 0.78, 95% CI 0.67–0.92), stroke (HR 0.76, 95% CI 0.59–0.97), and all-cause death (HR 0.86, 95% CI 0.77–0.96), with no significant heterogeneity detected. Similar results were observed among participants with reduced estimated glomerular filtration rate (eGFR: < 60 mL/min/1.73m2). The relative risks (95% CI) for adverse events were 3.89 (1.42–10.62) and 2.50 (1.32–4.72) for mycotic infections in men and women respectively, 3.54 (0.82–15.39) for DKA, and 1.29 (1.13–1.48) for volume depletion.ConclusionsAmong adults with DKD, SGLT2i were associated with reduced risks of MACE, kidney outcomes, HHF, and death. With a few exceptions of more clear safety signals, we found overall limited data on the associations between SGLT2i and safety outcomes. More research is needed on the safety profile of SGLT2i in this population.

Endoplasmic reticulum-translocation is essential for APOL1 cellular toxicity

SummaryTwo variants at the APOL1 gene, encoding apolipoprotein L1, account for more than 70% of the increased risk for chronic kidney disease in individuals of African ancestry. While the initiating event for APOL1 risk variant cell injury remains to be clarified, we explored the possibility of blocking APOL1 toxicity at a more upstream level. We demonstrate that deletion of the first six amino acids of exon 4 abrogates APOL1 cytotoxicity by impairing APOL1 translocation to the lumen of ER and splicing of the signal peptide. Likewise, in orthologous systems, APOL1 lethality was partially abrogated in yeast strains and flies with reduced dosage of genes encoding ER translocon proteins. An inhibitor of ER to Golgi trafficking reduced lethality as well. We suggest that targeting the MSALFL sequence or exon 4 skipping may serve as potential therapeutic approaches to mitigate the risk of CKD caused by APOL1 renal risk variants.

Mechanisms of Cardiorenal Protection of Glucagon-Like Peptide-1 Receptor Agonists.

The worldwide prevalence of type 2 diabetes (T2D) is steadily increasing, and it remains a challenging public health problem for populations in both developing and developed countries around the world. Despite the recent advances in novel antidiabetic agents, diabetic kidney disease and cardiovascular disease remain the leading causes of morbidity and mortality in T2D. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), incretin hormones that stimulate postprandial insulin secretion, serve as a promising avenue for treatment of T2D as they result in a variety of antihyperglycemic effects including increased endogenous insulin secretion, decreased gluconeogenesis, inhibition of pancreatic α-cell glucagon production, decreased pancreatic β-cell apoptosis, and increased β-cell proliferation. GLP-1RAs have also been found to delay gastric emptying, promote weight loss, increase satiety, decrease hypertension, improve dyslipidemia, reduce inflammation, improve albuminuria, induce natriuresis, improve cardiovascular function, and prevent thrombogenesis. In this review, we will present risk factors for the development of cardiac and kidney disease in individuals with T2D and discuss possible mechanisms for the cardiorenal protective effects seen with GLP-1RAs. We will also present the possibility of dual- and tri-receptor agonist therapies with GLP-1, gastric inhibitory peptide, and glucagon RAs as an area of possible mechanistic synergy in the treatment of T2D and the prevention of cardiorenal complications.

400-P: Skin Autofluorescence Is Associated with Progression of Kidney Disease in Individuals with Type 2 Diabetes: Results from the Hong Kong Diabetes Biobank

Skin autofluorescence (SAF), a non-invasive measure of the accumulation of advanced glycation end products (AGEs) in skin collagen, is associated with baseline estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). We aimed to investigate whether SAF can identify individuals with type 2 diabetes (T2D) at high-risk of renal function decline. A total of 3,806 Chinese with T2D had SAF measured between 2016 to 2019. The primary endpoint was incident end-stage kidney disease (ESKD) or ≥40% decline in eGFR relative to baseline. The secondary endpoint was the annual change in eGFR during follow-up. A Cox proportional hazard model was used for the primary endpoint, and linear mixed-effects model with random intercept and slope for eGFR slope and the association between SAF and rate of eGFR change. People with prevalent ESKD were excluded. Mean ± SD age was 60.4 ± 10.4 years, with mean ± SD eGFR 81.5 ± 22.9 ml/min/1.73 m2; median (interquartile range [IQR]) UACR was 2.2 (0.8-9.6) mg/mmol; and median eGFR slope was -2.18 ml/min/1.73 m2/year. During a median (IQR) 1.76 (1.13-3.13) years of follow-up, 219 experienced the primary endpoint. SAF was associated with increased risk of progression of kidney disease (adjusted hazard ratio 1.16 per SD, 95% CI [1.01, 1.33]), even after adjustment for established risk factors including eGFR and UACR. SAF was identified as an independent determinant of rate of eGFR decline (adjusted Beta coefficient -2.85 per SD, 95% CI [-3.82, -1.87]). Using the median eGFR slope as the cut-off, higher SAF was associated with faster eGFR decline (adjusted odds ratio 1.12 per SD, 95% CI [1.03, 1.22]) on multivariate logistic regression. This study demonstrates for the first time in a prospective setting that higher SAF is independently associated with increased risk of progression of kidney disease in individuals with T2D. Disclosure Q. Jin: None. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. A. Jenkins: Advisory Panel; Self; Abbott Diabetes, Sanofi-Aventis, Other Relationship; Self; Amgen Inc., Research Support; Self; Abbott, International Diabetes Federation, JDRF, Medtronic, Mylan N. V. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. E. S. Lau: None. A. Luk: None. R. Ozaki: None. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. T. So: None. H. Yeung: None. K. Loo: n/a. C. K. Lim: Stock/Shareholder; Self; GemVCare Ltd. Funding Research Grants Council of Hong Kong (R4012-18)

APOL1 in an ethnically diverse pediatric population with nephrotic syndrome: implications in focal segmental glomerulosclerosis and other diagnoses.

APOL1 high-risk genotypes (HRG) are associated with increased risk of kidney disease in individuals of African ancestry. We analyzed the effects of APOL1 risk variants on an ethnically diverse Brazilian pediatric nephrotic syndrome (NS) cohort. Multicenter study including 318 NS patients, categorized as progressors to advanced CKD [estimated glomerular filtration rate (eGFR)] < 30 mL/min/1.73 m2] and slow/non-progressors (eGFR > 30 mL/min/1.73 m2 through the study). We employed Cox regression with progression time as the outcome and APOL1 genotype as the independent variable. We tested this association in the entire cohort and three subgroups; (1) focal segmental glomerulosclerosis (FSGS), (2) steroid-resistant NS (SRNS), and (3) those who underwent kidney biopsy. Nineteen patients (6%) had an HRG. Of these, 47% were self-reported White. Patients with HRG manifested NS at older ages and presented higher frequencies of FSGS and SRNS. HRG patients progressed to advanced CKD more often than low-risk-genotype (LRG) children in the whole NS cohort (p = 0.001) and the three subgroups. In SRNS and biopsied patients, a single risk variant was associated with trends of higher CKD progression risk. Novel discoveries include a substantial prevalence of HRG among patients self-reported White, worse kidney outcomes in HRG versus LRG children in the FSGS subgroup, and a trend of higher CKD progression risk associated with a single risk variant in the SRNS cohort. These findings suggest APOL1-associated NS extends beyond patients self-reported non-White, the HRG effect is independent of FSGS, and a single risk variant may have a detrimental impact in children with NS.

Predictors associated with sickle cell nephropathy: a systematic review.

Sickle cell anemia affects more than 30 million people worldwide. Chronic kidney disease develops in 40% of individuals. The death rate of patients with sickle nephropathy is still high, with little known predictors related to its development. To answer the question "What predictors are associated with the onset of chronic kidney disease in patients with sickle cell anemia?", this article seeks to contribute to a better understanding of sickle nephropathy, making possible a new look at the sickle cell anemia and its kidney complications. A systematic review was developed, using the PRISMA recommendation, for cohort studies on predictors related to the outcome of sickle nephropathy in patients with sickle cell anemia. Initially 321 studies were identified in Pubmed, of which six were selected to compose this systematic review. Lower hemoglobin levels, increased ages and albuminuria were the most pointed predictors associated with chronic kidney disease. The main predictors associated with the development of chronic kidney disease in individuals with sickle cell anemia were lower hemoglobin levels, increased ages, and albuminuria. New studies evaluating predictors for the development of chronic kidney disease in sickle cell anemia are needed to better understand its installation and prevent its progression.