Increased Risk Of Chronic Kidney Disease Research Articles

Protein-truncating variant in APOL3 increases chronic kidney disease risk in epistasis with APOL1 risk alleles.

BACKGROUNDTwo coding alleles within the APOL1 gene, G1 and G2, found almost exclusively in individuals genetically similar to West African populations, contribute substantially to the pathogenesis of chronic kidney disease (CKD). The APOL gene cluster on chromosome 22 contains a total of 6 APOL genes that have arisen as a result of gene duplication.METHODSUsing a genome-first approach in the Penn Medicine BioBank, we identified 62 protein-altering variants in the 6 APOL genes with a minor allele frequency of >0.1% in a population of participants genetically similar to African reference populations and performed population-specific phenome-wide association studies.RESULTSWe identified rs1108978, a stop-gain variant in APOL3 (p.Q58*), to be significantly associated with increased CKD risk, even after conditioning on APOL1 G1/G2 carrier status. These findings were replicated in the Veterans Affairs Million Veteran Program and the All of Us Research Program. APOL3 p.Q58* was also significantly associated with a number of quantitative traits linked to CKD, including decreased kidney volume. This truncating variant contributed the most risk for CKD in patients monoallelic for APOL1 G1/G2, suggesting an epistatic interaction and a potential protective effect of wild-type APOL3 against APOL1-induced kidney disease.CONCLUSIONThis study demonstrates the utility of targeting population-specific variants in a genome-first approach, even in the context of well-studied gene-disease relationships.FUNDINGNational Heart, Lung, and Blood Institute (F30HL172382, R01HL169378, R01HL169458), Doris Duke Foundation (grant 2023-2024), National Institute of Biomedical Imaging and Bioengineering (P41EB029460), and National Center for Advancing Translational Sciences (UL1-TR-001878).

Impact of hyperuricemia on CKD risk beyond genetic predisposition in a population-based cohort study

The bidirectional effect of hyperuricemia on chronic kidney disease (CKD) underscores the importance of hyperuricemia as a risk factor for CKD. We evaluated the effect of hyperuricemia on the presence and development of CKD after considering genetic background by calculating polygenic risk scores (PRSs). We employed genome-wide association study summary statistics—excluding the United Kingdom Biobank (UKB) datasets among published CKD Gen Consortium papers—to calculate the PRSs for CKD in white background subjects. To validate PRS performance, we divided the UKB into two datasets to validate and test the data. We used logistic regression analysis to evaluate the association between hyperuricemia and CKD, and performed Kaplan–Meier survival analysis exclusively for subjects with available follow-up data. In total, 438,253 clinical data and 4,307,940 single nucleotide polymorphisms from 459,155 samples were included. We observed a significant positive association between PRS and CKD and the presence and development of CKD. Hyperuricemia significantly increased CKD risk (adjusted odds ratio 1.55, 95% confidence interval 1.48–1.61). The impact of hyperuricemia on CKD was maintained irrespective of PRS range. In addition, negative interaction between hyperuricemia and PRS for CKD was found. Survival analysis indicates that the presence of hyperuricemia significantly increased the risk of CKD development. The PRS for CKD thoroughly reflects the risk of CKD development. Hyperuricemia is a significant indicator of CKD risk, even after incorporating the genetic risk score for CKD. Irrespective of genetic risk, patients with a prospective risk of developing CKD require uric acid monitoring and management.

Genetic association analyses highlight apolipoprotein B as a determinant of chronic kidney disease in patients with type 2 diabetes

Blood lipid levels were associated with chronic kidney disease (CKD) in patients with type 2 diabetes (T2D), but the genetic basis and causal nature remains unclear. This study aimed to investigate the relationships of lipids and their fractions with CKD in patients with T2D. Our prospective analysis involved 8,607 White participants with T2D but no CKD at baseline from the UK Biobank. Five common lipid traits were included as exposures. Weighted genetic risk scores (GRSs) for these lipid traits were developed. The causal associations between lipid traits, as well as lipid fractions, and CKD were explored using linear or nonlinear Mendelian randomization (MR). The 10-year predicted probabilities of CKD were evaluated via integrating MR and Cox models. Higher GRS of apolipoprotein B (ApoB) was associated with an increased CKD risk (HR[95 % CI]:1.07[1.02,1.13] per SD;P = 0.008) after adjusting for potential confounders. Linear MR indicated a positive association between genetically predicted ApoB levels and CKD (HR[95 % CI]:1.53[1.12,2.09];P = 0.008), but no evidence of associations was found between other lipid traits and CKD in T2D. Regarding 12 ApoB-contained lipid fractions, a significant causal association was found between medium very-low-density lipoprotein particles and CKD (HR[95 % CI]:1.16[1.02,1.32];P = 0.020). Nonlinear MR did not support nonlinearity in these causal associations. The 10-year probability curve showed that ApoB levels was positively associated with the risk of CKD in patients with T2D. Lower ApoB levels were causally associated with a reduced risk of CKD in patients with T2D, positioning ApoB as a potential therapeutic target for CKD prevention in this population.

Urine cotinine versus self-reported smoking and the risk of chronic kidney disease.

Evidence on the role of smoking in the development of chronic kidney disease (CKD) has mostly relied on self-reported smoking status. We aimed to compare the associations of smoking status as assessed by self-reports and urine cotinine with CKD risk. Using the PREVEND prospective study, smoking status was assessed at baseline using self-reports and urine cotinine in 4333 participants (mean age, 52 years) without a history of CKD at baseline. Participants were classified as never, former, light current, and heavy current smokers according to self-reports and comparable cutoffs for urine cotinine. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated for CKD. The percentages of self-reported and cotinine-assessed current smokers were 27.5% and 24.0%, respectively. During a median follow-up of 7.0 years, 593 cases of CKD were recorded. In analyses adjusted for established risk factors, the HRs (95% CI) of CKD for self-reported former, light current, and heavy current smokers compared with never smokers were 1.17 (0.95-1.44), 1.48 (1.10-2.00), and 1.48 (1.14-1.93), respectively. On further adjustment for urinary albumin excretion (UAE), the HRs (95% CI) were 1.07 (0.87-1.32), 1.26 (0.93-1.70), and 1.20 (0.93-1.57), respectively. For urine cotinine-assessed smoking status, the corresponding HRs (95% CI) were 0.81 (0.52-1.25), 1.17 (0.92-1.49), and 1.32 (1.02-1.71), respectively, in analyses adjusted for established risk factors plus UAE. Self-reported current smoking is associated with increased CKD risk, but dependent on UAE. The association between urine cotinine-assessed current smoking and increased CKD risk is independent of UAE. Urine cotinine-assessed smoking status may be a more reliable risk indicator for CKD incidence than self-reported smoking status.

Associations of long-term exposure to ambient sulfur dioxide, carbon monoxide, ozone, and benzene with risk of incident chronic kidney disease in the UK

Limited studies have examined associations of gaseous air pollutants exposure with chronic kidney disease (CKD) in Europe. This study aimed to calculate the relationships between long-term exposure to ambient sulfur dioxide (SO2), carbon monoxide (CO), ozone (O3), and benzene and CKD in the UK. We included 502 369 participants from the UK biobank cohort. Associations of SO2, CO, O3, and benzene with CKD were estimated using Cox proportional hazards model. The shape of the exposure-response association between each air pollutant and CKD was then depicted using the shape constrained health impact function. We finally estimated the incidence of CKD attributable to each air pollutant by linking the constructed exposure-response association to the 2019 Global Burden of Disease data. Our results suggested SO2, high O3 days (daily max 8 hr O3 concentration > 120 µg m−3), CO, and benzene were positively associated with the risk of incident CKD. The hazard ratios (HRs) of CKD for SO2, CO, and benzene were 1.058 (95% CI: 1.039–1.078), 1.003 (95% CI: 1.001–1.005), and 1.619 (1.433–1.829) for every 1 μg m−3 increase in the concentration, respectively. For high O3 days, the HR of CKD was 1.044 (95% CI: 1.032–1.056) for every 1 d increase, but correlation to O3 concentration did not reach the statistical significance in the time-varying model. The risk of CKD increased non-linearly with increasing SO2, high O3 days, and CO, and linearly with increasing benzene. We estimated that 7.9%, 16.0%, 8.0% of incident CKD cases in the UK in 2021 could be attributed to exposure to SO2, O3, and benzene, respectively. We concluded that exposure to SO2, CO, O3, and benzene were all positively associated with increased CKD risk. Our findings highlight the importance of considering air pollution while making strategies targeting on CKD management.

Ambient PM2.5 components and prevalence of chronic kidney disease: a nationwide cross-sectional survey in China.

Chronic kidney disease (CKD) is a global public health concern, and accumulating evidence has indicated that air pollution increases the odds of CKD. However, a limited number of studies have examined the long-term effects of ambient fine particulate matter (PM2.5) components on the risk of CKD among general population; thus, major knowledge gaps remain. Using data from a nationwide representative cross-sectional survey in China and a validated PM2.5 composition dataset, we established generalized linear models to quantify the association between five major components of PM2.5 and CKD prevalence. There were significant associations between long-term exposure to three PM2.5 components [including black carbon (BC), sulfate (SO42-), organic matter (OM)] and increased odds of CKD prevalence. Along with an interquartile range (IQR) increment in BC (3.3 μg/m3), SO42- (9.7 μg/m3), and OM (16.2 μg/m3) at a 4-year moving average, the odds ratios (ORs) for CKD prevalence were 1.28 (95% CI 1.07, 1.54), 1.23 (95% CI 1.03, 1.45), and 1.23 (95% CI 1.02, 1.47), respectively. We did not detect any significant association of the other two PM2.5 components [nitrate (NO3-) or ammonium (NH4+)] with CKD prevalence. Stratified analyses revealed no differences (P ≥ 0.05) in the effect estimates of subgroups based on administrative region, sex, age, and other demographic characteristics. For instance, along with an IQR increment in BC at a 4-year moving average, the ORs of CKD prevalence among males and females were 1.30 (95% CI 0.98, 1.73) and 1.29 (95% CI 1.01, 1.65), respectively. The odds of CKD were generally higher with increasing PM2.5 composition concentration. Our study demonstrated that long-term exposure to specific PM2.5 components including BC, SO42-, and OM increased CKD risk in the general population. This study could provide new insights into source-directed PM2.5 control and CKD prevention.

The effect of hyperuricemia and its interaction with hypertension towards chronic kidney disease in patients with type 2 diabetes: evidence from a cross- sectional study in Eastern China.

This study aimed to explore the synergistic interaction effect between hyperuricemia and hypertension towards chronic kidney disease in patients with type 2 diabetes. This research originates from a cross-sectional study performed in Zhejiang Province, Eastern China, between March and November 2018. The correlation between serum uric acid levels and the risk of chronic kidney disease was assessed using a restricted cubic spline model. An unconditional multivariable logistic regression model, along with an interaction table, was utilized to explore the potential interaction effect of hyperuricemia and hypertension towards chronic kidney disease. 1,756 patients with type 2 diabetes were included in this study, the prevalence of chronic kidney disease (CKD) was 27.62% in this population. A U-shaped non-linear pattern emerged correlating serum uric acid (SUA) levels and CKD risk, indicating that both low and high SUA levels were linked to an increased CKD risk. This risk achieved its lowest point (nadir) at SUA approximately equals to 285μmol/L (p for trend <0.05). Once adjustments for age, gender, education level, abnormal fasting plasma glucose (FPG), abnormal hemoglobin A1c (HbA1c), abnormal total cholesterol (TC), abnormal high-density lipoprotein cholesterol (HDL-C), alcohol consumption and duration of diabetes were factored in, it was found that patients with both hyperuricemia and hypertension demonstrated a 5.42-fold (95% CI: 3.72-7.90) increased CKD risk compared to the reference group. The additive interaction between hyperuricemia and hypertension was statistically significant, as manifested by the following values: a relative excess risk due to interaction (RERI) of 2.57 (95% CI: 0.71-4.71), an attributable proportion due to interaction (AP) of 0.47 (95% CI: 0.14-0.64), and a synergy index (SI) of 2.39 (95% CI: 1.24-4.58). In contrast, there was no significant interaction effect in multiplicative scale. Hyperuricemia and hypertension may contribute additively to CKD, beyond their isolated impacts. Evaluating the risk of CKD in type 2 diabetes patients necessitates considering this potential interaction.

Proton pump inhibitors and chronic kidney disease risk: a comparative study with histamine-2 receptor antagonists

This observational study explored the association between proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H2RA) use and the risk of chronic kidney disease (CKD). Using the National Health Insurance Service-National Sample Cohort (NHIS-NSC) and six-hospital electronic health record (EHR) databases, CKD incidence was analyzed among PPI and H2RA users. Propensity score matching was used to balance baseline characteristics, with 1,869 subjects each in the PPI and H2RA groups from the NHIS-NSC, and 5,967 in EHR databases. CKD incidence was similar for both groups (5.72/1000 person-years vs. 7.57/1000 person-years; HR = 0.68; 95% CI, 0.35–1.30). A meta-analysis of the EHR databases showed no significant increased CKD risk associated with PPI use (HR = 1.03, 95% CI: 0.87–1.23). These results suggest PPI use may not increase CKD risk compared to H2RA use, but the potential role of PPI-induced CKD needs further research. Clinicians should consider this when prescribing long-term PPI therapy.

Depressive symptoms and sleep duration in relation to chronic kidney disease: Evidence from the China health and retirement longitudinal study

ObjectiveNowadays, the joint effects of depressive symptoms and sleep duration on the risk of chronic kidney disease (CKD) are still unclear. We aimed to prospectively assess the combined effect of depressive symptoms and sleep duration on the incidence of CKD in middle-aged and elderly Chinese population. MethodsA total of 10,953 participants from the China Health and Retirement Longitudinal Study (CHARLS) were included. Depressive symptoms were measured using the 10-item Center for Epidemiological Studies Depression scale (CESD-10). Sleep duration was evaluated by self-reported. CKD events were based on self-reported physicians' diagnosis or personal estimate glomerular filtration rate level (eGFR <60 mL/min/1.73 m2). Cox regression models were established to analyze the correlation between depressive symptoms, sleep duration and the risk of CKD. ResultsOver a mean follow-up time was 6.76 ± 0.98 years, 851 (7.8%) participants had reported CKD events during the follow-up. Elevated depressive symptoms (HR = 1.65, 95% CI = 1.43–1.90) and short sleep duration (HR = 1.48, 95% CI = 1.27–1.72) were independently associated with an increased CKD risk after adjusting for potential confounding factors. Participants with short sleep duration (< 6 h)/elevated depressive symptoms (HR = 2.24, 95% CI = 1.89–2.65) were associated with the highest risk of CKD than those with normal sleep duration/low depressive symptoms. ConclusionsElevated depressive symptoms and short sleep duration were independent risk factors for CKD. There was a combined effect between depressive symptoms and sleep duration in increasing the risk of CKD.

Associations and mitigations: an analysis of the changing risk factor landscape for chronic kidney disease in primary care using national general practice level data

ObjectivesEarly recognition of chronic kidney disease (CKD) should be achieved by every modern healthcare system. The objective of this study was to investigate CKD risk factor trends in England using...

Coding Variants of the FMO3 Gene Are Associated with the Risk of Chronic Kidney Disease: A Case-Control Study.

Chronic kidney disease (CKD) is a global health concern involving roughly one-tenth of developed countries' populations. The flavin-containing dimethylaniline monooxygenase 3 (FMO3) gene encodes an enzyme that catalyzes trimethylamine N-oxide (TMAO), a toxin in CKD sufferers. This preliminary study aims to evaluate the association between coding region variations of FMO3, rs2266782G/A (E158K), rs2266780A/G (E308G), and rs1736557G/A (V257M), and the susceptibility to CKD. A total of 356 participants were enrolled, including 157 patients diagnosed with CKD and 199 age-matched healthy individuals. Genotyping of FMO3 gene variations was performed via PCR-RFLP and ARMS-PCR methods. Our findings revealed a significant association between rs2266780A/G and rs1736557G/A and CKD under different genetic models. Compared to the GGG haplotype of rs2266782/rs1736557/rs2266780, the GAG, GAA, AAG, and AAA haplotype combinations conferred an increased risk of CKD in our population. Interaction analysis revealed that some genotype combinations, including GA/AA/AA, AA/AA/AA, GA/AA/GA, and GG/AG/AA, dramatically increased CKD risk in the Iranian population. No correlation was found between FMO3 polymorphisms and CKD stages. These observations highlight the potential impact of coding variants of the FMO3 gene on the onset of CKD. Further investigations into expanded populations and diverse races are needed to confirm our findings.

Associations of multiple plasma metals with chronic kidney disease in patients with diabetes

As common contaminants, metals are non-negligible risk factors for diabetes and chronic kidney disease. However, whether there is an association between multiple metals exposure and incident chronic kidney disease (CKD) risk in patients with diabetes is unclear. We conducted a prospective study to evaluate these associations. In total, 3071 diabetics with baseline estimated glomerular filtration rate (eGFR)≥60mL/min/1.73m2 from the Dongfeng-Tongji cohort were included. We measured baseline plasma concentrations of 23 metals and investigated the associations between plasma metal concentrations and CKD in diabetics using logistic regression, the least absolute shrinkage and selection operator (LASSO), and the Bayesian Kernel Machine Regression (BKMR) models. During average 4.6 years of follow-up, 457 diabetics developed CKD (14.9%). The three models consistently found plasma levels of zinc, arsenic, and rubidium had a positive association with incident CKD risk in patients with diabetes, while titanium, cadmium, and lead had an inverse correlation. The results of BKMR showed a significant and positive overall effect of 23 metals on the risk of CKD, when all of the metals were above the 50th percentile as compared to the median value. In addition, potential interactions of zinc and arsenic, zinc and cadmium, zinc and lead, titanium and arsenic, and cadmium and lead on CKD risk were observed. In summary, we found significant associations of plasma titanium, zinc, arsenic, rubidium, cadmium, and lead with CKD in diabetes and interactions between these metals except for rubidium. Co-exposure to multiple metals was associated with increased CKD risk in diabetics.

Higher Neutrophil-To-Lymphocyte Ratio Was Associated with Increased Risk of Chronic Kidney Disease in Overweight/Obese but Not Normal-Weight Individuals.

Background: Inflammation has been proposed to play potential roles in the development and progression of chronic kidney disease (CKD). We evaluated the relationship of neutrophil-to-lymphocyte ratio (NLR), a systemic inflammation marker, with CKD in normal-weight and overweight/obese adults. Methods: This cross-sectional study included 2846 apparently healthy adults who underwent a health examination between August 2000 and April 2002. Normal-weight was defined as a body mass index (BMI, kg/m2) of 18.5–24, while overweight/obesity was defined as a BMI of ≥24. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2. Logistic and linear regression analysis was performed to explore the NLR–CKD relationship. Results: Of the 2846 participants (1777 men and 1069 women), there were 348 CKD individuals (12.3%), with 262 (14.7%) men and 86 (8%) women. A total of 1011 men (56.9%) and 408 women (38.2%) were overweight or obese. Compared with the normal-weight participants, CKD prevalence was higher in the overweight/obese women (6.1% vs. 11.3%, p = 0.002), but not in the overweight/obese men (14.5% vs. 14.9%, p = 0.793). CKD percentages in the NLR quartile groups were 9.4%, 11.5%, 15.4%, and 22.7% in men (p < 0.0001) and 6.4%, 7.1%, 10.5%, and 8.2% in women (p = 0.2291). After adjustment for confounders, each increment of one unit of NLR was associated with a higher CKD risk in the overweight/obese men (adjusted odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.03–1.82, p = 0.03) and women (adjusted OR = 1.77, 95% CI = 1.08–2.90, p = 0.023), whereas NLR was not associated with CKD in normal-weight men or women. Further, in the overweight/obese participants with an eGFR of 50–70 mL/min/1.73 m2, univariable linear regression analysis revealed a significant negative correlation between NLR and eGFR for men (p = 0.004) and women (p = 0.009). Conclusions: It was found that higher NLR was associated with an increased CKD risk in overweight/obese but not in normal-weight men and women in an adult health examination dataset. Our study suggests a role of NLR for CKD prediction in overweight/obese individuals.

The role of serum testosterone and dehydroepiandrosterone sulfate in kidney function and clinical outcomes in chronic kidney disease: a systematic review and meta-analysis.

Objective/designTestosterone might mediate sex differences in kidney function and chronic kidney disease (CKD). However, few studies analyzing the association between testosterone and kidney function showed conflicting results. Therefore, we performed a systematic review and meta-analysis.MethodsSix electronic databases were searched from inception to March 4, 2020, for studies that investigated the association of (i) testosterone status with kidney function in the general population or (ii) testosterone status with clinical outcomes (kidney function decline, kidney failure, cardiovascular (CV) events, and cardiovascular and all-cause mortality) in CKD patients. We used random and fixed-effect models to obtain pooled effect estimates with 95% confidence intervals (CIs).ResultsNo randomized–controlled trials that met the inclusion criteria were identified. One study was conducted in the general population and reported an increased risk of incident CKD with low vs normal testosterone (hazard ratio (HR): 1.38, 95% CI: 1.05;1.80). Seven studies were conducted in men with CKD and included testosterone as determinant, of which six could be meta-analyzed. Low testosterone was associated with an increased risk of all-cause mortality and CV events (pooled HR: 1.98, 95% CI: 1.36;2.89; pooled HR of 2.40, 95% CI: 1.22;4.71, respectively). Two studies showed an increased risk of all-cause mortality with decreased dehydroepiandrosterone sulfate (DHEAS) in men with CKD; results regarding CV events were conflicting.ConclusionsAlthough literature is scarce, evidence suggests that lower testosterone may increase CKD risk in the general population and risk of all-cause mortality and CV events in men with CKD. Whether testosterone supplementation could prevent these potential detrimental outcomes should be determined in future intervention studies.

Management of Psychiatric Disorders in Patients with Chronic Kidney Diseases.

Management of Psychiatric Disorders in Patients with Chronic Kidney Diseases.

Higher aldosterone is associated with increased renal impairment risk in patients with hypertension and abnormal glucose metabolism: a longitudinal study.

Objective:The aim of this study was to evaluate the association between plasma aldosterone concentration (PAC) and renal impairment in patients with both hypertension and abnormal glucose metabolism (AGM).Methods:The longitudinal observational study included 2033 hypertensive individuals with AGM who did not have chronic kidney disease (CKD) at baseline. CKD was defined as estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m2 and/or positive proteinuria. Directed acyclic graphs and LASSO regression analyses were applied to identify adjusted sets. Cox proportional hazard models and linear regression were used to evaluate the association of PAC with CKD and its components including decreased renal function (DRF) and proteinuria. Mediation analysis was used to examine the role of blood pressure (BP) in the association between the two.Results:During total follow-up of 5951 person-years with a median follow-up of 31 months, 291 participants developed CKD. The incidence of CKD was increased with the elevation in tertile PAC. Multivariable Cox model showed that PAC was positively associated with increased CKD risk (hazard ratio = 1.76 for natural log-transformed PAC, P < 0.001), and with increased risk of DRF and proteinuria. SBP mediated 7.5–17.9% of the association between PAC and renal impairment. Overall results remained consistent and significant in sensitivity analysis by excluding those with suspicious primary aldosteronism, too short follow-up time and mineralocorticoid receptor antagonists use.Conclusion:Higher PAC was associated with increased CKD risk in patients with hypertension and AGM, even in the absence of suspicious primary aldosteronism. The results indicate PAC may serve as a potential therapeutic target in this population.

HIV Viremia Is Associated With APOL1 Variants and Reduced JC-Viruria.

Variants in the Apolipoprotein L1 (APOL1) gene (G1-rs60910145, rs73885319, G2-rs71785313) are common in Africans and in individuals of recent African ancestry and are associated with an increased risk of non-diabetic chronic kidney disease (CKD) and in particular of HIV associated nephropathy (HIVAN). In light of the significantly increased risk of HIVAN in carriers of two APOL1 risk alleles, a role in HIV infectivity has been postulated in the mechanism of APOL1 associated kidney disease. Herein, we aim to explore the association between HIV viremia and APOL1 genotype. In addition, we investigated interaction between BK and JC viruria, CKD and HIV viremia. A total of 199 persons living with HIV/AIDS (comprising 82 CKD cases and 117 controls) from among the participants in the ongoing Human Heredity and Health in Africa (H3Africa) Kidney Disease Research Network case control study have been recruited. The two APOL1 renal risk alleles (RRA) genotypes were associated with a higher risk of CKD (OR 12.6, 95% CI 3.89–40.8, p < 0.0001). Even a single APOL1 RRA was associated with CKD risk (OR 4.42, 95% CI 1.49–13.15, p = 0.007). The 2 APOL1 RRA genotypes were associated with an increased probability of having HIV viremia (OR 2.37 95% CI 1.0–5.63, p = 0.05). HIV viremia was associated with increased CKD risk (OR 7.45, 95% CI 1.66–33.35, P = 0.009) and with a significant reduction of JC virus urine shedding (OR 0.35, 95% CI 0.12–0.98, p = 0.046). In contrast to prior studies, JC viruria was not associated with CKD but was restricted in patients with HIV viremia, regardless of CKD status. These findings suggest a role of APOL1 variants in HIV infectivity and emphasize that JC viruria can serve as biomarker for innate immune system activation.

RNA-Sequencing of Isolated Cell Populations Expressing Human APOL1 Risk Variants Reveals Molecular Correlates of Sickle Cell Nephropathy in Zebrafish Podocytes

Background: Kidney failure occurs in 5-13% of individuals with sickle cell disease (SCD), and is associated with early mortality. We have shown previously that genetic variation in apolipoprotein L1 (APOL1) is associated with increased risk for developing SCD nephropathy (Ashley-Koch et al, 2011). Two APOL1 alleles (G1 and G2) have been identified as risk factors for SCD nephropathy, as well as chronic kidney disease (CKD) in African Americans without SCD (Limou et al, 2014). Both risk alleles are highly prevalent in individuals of African descent. Despite the strong association of G1 and G2 with kidney dysfunction, the mechanisms by which these variants contribute to increased CKD risk remain poorly understood. However, the observation of podocyte effacement in CKD patients suggests that podocytes and/or endothelial cells are likely implicated in pathogenesis. We established zebrafish models of these human risk alleles previously for the purpose of better understanding the underlying pathology contributing to SCD nephropathy (Anderson et al, 2015). Here, we have utilized these models to explore further the cell-type specific transcriptomic perturbations contributing to nephropathy.Methods: To investigate the effects of the APOL1 G2 risk variant on cell-type specific transcriptomes, we injected human APOL1 mRNA into embryos from 3 different zebrafish lines expressing cell-type specific reporters to permit the isolation of podocytes (pod:NTR-mCherry), endothelial cells (fli1:egfp), or peripheral neurons (hb9:gfp; control). Three populations from each line were utilized: (1) uninjected controls; (2) embryos injected with canonical human APOL1 (G0); and (3) embryos injected with human APOL1 (G2) mRNA. Larvae were dissociated at 4 days post-fertilization (4 dpf), and fluorescent cell types were isolated via fluorescence activated cell-sorting (FACS). Messenger RNA was extracted from sorted cell populations (n=3 FACS sorted cell populations per condition) and subsequently amplified to obtain a sufficient amount of RNA for sequencing. The amplified RNA was prepared into cDNA libraries, and sequenced on an Illumina HiSeq 2500. We performed pairwise comparisons between uninjected and G0 injected larvae in each cell type to ascertain the effects of canonical human APOL1 on the zebrafish kidney transcriptome. Additionally, to measure the effects of APOL1 G2 expression on the transcriptome, we compared APOL1 G0 and APOL1 G2 samples. Transcripts were considered to be differentially expressed if they achieved an FDR-adjusted q-value of less than 0.05. To understand better the biological processes altered by injection condition, we conducted gene ontology enrichment analyses (GOEA) on sets of differentially expressed genes.Results: Our analysis of uninjected and APOL1 G0 libraries identified 38, 154, and 204 differentially expressed (DE) genes in endothelial cells, podocytes, and motor neurons, respectively. No significant enrichment of gene ontology terms was detected, suggesting that canonical G0 APOL1 did not have a substantial impact on the zebrafish transcriptome. In contrast, the comparison of APOL1 G0 and APOL1 G2 samples found 95, 7400 (Figure below), and 652 DE genes in endothelial cells, podocytes, and motor neurons, respectively. GOEA of the podocyte DE gene list showed enrichment for several autophagy-associated terms, including “Lysosome” and “Phagosome”. Close inspection of these autophagy-associated genes revealed that the majority are up-regulated in G2 relative to G0 (68/75 genes for “Lysosome” and 52/78 genes for “Phagosome”). Thus, the G2 allele appears to induce transcription of genes involved in autophagy in podocytes.Summary: Taken together, these data suggest that podocytes are the predominant cell type affected by the expression of APOL1 G2. The comparison of podocytes injected with APOL1 G0 or APOL1 G2 yielded an order of magnitude more DE transcripts than any other comparison. The GOEA results of the podocyte comparison are consistent with a recent study of transgenic mice expressing the G1 or G2 APOL1 high risk variants, which showed alterations in endocytic vesicle content and autophagic flux (Beckerman et al 2017). Ongoing work includes molecular analysis to characterize the effects of the APOL1 G1 allele. This work will continue to shed light on the molecular pathology of SCD nephropathy and provide insight into new therapeutic strategies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Independent and interactive effects of kidney stone formation and conventional risk factors for chronic kidney disease: a follow-up study of Japanese men.

To assess the impact of interactions between kidney stone formation and conventional risk factors on incident chronic kidney disease (CKD). A total of 11,402 subjects (men 30-69years of age, Japanese) without CKD at baseline were observed over an average period of 4 years. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) to determine the association between incident CKD, kidney stone formation, and conventional risk factors (diabetes mellitus, hypertension, overweight/obesity, dyslipidemia, and hyperuricemia/gout). We also examined the interactions of renal stones and the conventional risk factors for CKD. In total, 2301 men (20.2%) developed incident CKD during the follow-up period. After multivariable adjustment, kidney stones were found to increase the risk of incident CKD (HR 1.16; 95% CI 1.03-1.32). Kidney stone formers with hypertension, dyslipidemia, or hyperuricemia/gout presented a greater risk for incident CKD than those who had either kidney stones or other risk factors. However, no significant interactions between kidney stones and other risk factors were found to increase CKD risk. On the other hand, a negative interactive effect between kidney stones and overweight/obesity was observed, leading to reversed risk of incident CKD in coexistence of both factors. Kidney stones were linked to a higher risk for the development of CKD. However, no positive interactive effects were identified between renal stones and conventional risk factors on the risk of incident CKD.

Screening of Chronic Kidney Disease in Primary Health: Comparison of the Urine Dipstick Albumin-to-Creatinine Ratio and Dipstick Proteinuria

Abstract Background: Chronic kidney disease (CKD) needs to be detected early in order to prevent a poor outcome in the general population. A semiquantitative evaluation based on a dipstick has become available to detect the urinary albumin-to-creatinine ratio (ACR) and proteinuria simultaneously in spot urine samples. The aim of this study was to compare dipstick ACR with proteinuria for CKD screening in a primary healthcare setting. Methods: This cross-sectional study analyzed 88,479 subjects who underwent a health check up at 16 health promotion centers in 13 Korean cities. Dipstick ACR and proteinuria was measured using the automated urine test strip analyzer UC-3500 (Sysmex, Kobe, Japan). CKD definition and risk categories according to the 2012 Kidney Disease: Improving Global Outcomes guidelines were created using a combination of eGFR and albuminuria. Albuminuria was defined using dipstick ACR ≥ 30 mg/g and dipstick proteinuria as ≥ trace or protein-to-creatinine ratio (PCR) ≥ 150 mg/g. Results: The prevalence of CKD using dipstick ACR, proteinuria, and PCR were 16.3%, 12.7%, and 11.9%, respectively. The concordance rates between the dipstick ACR- and proteinuria- or PCR-based CKD risk categories were 88.76% (κ = 0.567) and 92.06% (κ = 0.683), respectively. On being grouped according to dipstick proteinuria, CKD risk categories would be underestimated than be overestimated. 37.2% and 37.6% of the subjects with ≥ moderately increased CKD risk using ACR-based category were reclassified into lower risk CKD using dipstick proteinuria (≥ trace) and PCR, respectively. Conclusion: The CKD risk category using dipstick proteinuria was underestimated compared to the ACR-based CKD risk category. These data suggest that screening of CKD using dipstick ACR is recommended in primary healthcare settings.