Risk Of Kidney Disease Research Articles

#832 Sickle cell trait and APOL1 high risk genotype increase the risk of ESKD similar to diabetes in British Africans

Abstract Background and Aims Little is known of the risk of end-stage kidney disease (ESKD) in British Africans with Sickle Cell Trait or APOL1 High-risk genotypes. We aim to determine the prevalence of the APOL1 high-risk genotype and genetically defined Sickle Cell Trait in British Africans and their association with ESKD. Method We analysed 7380 British Africans from a UK population cohort, UK Biobank. It contains deep phenotypes, biomarkers, and DNA sequence data. We used whole exome sequencing data to identify carriers of known APOL1 high risk genotypes (G1G1, G1G2, G2G2) and SCT (heterozygous carriers of p.Glu7Lys in HBB). We identified individuals with ESKD (in receipt of renal replacement therapy including kidney transplant) using self-report, hospital admissions records, and general practice records. We used a cox proportional hazard model to determine the risk of ESKD with these genotypes adjusted for age, sex, hypertension, smoking and diabetes. Results 1131/7380 (17.9%) British Africans carry the APOL1 High risk genotype whereas 860/7380 (14.3%) had genetically defined SCT. Both risk states were found in 216/7380 individuals. Together, 32.2% carry one or both of these variants and 36/2207 (1.6%) developed ESKD. Of those with neither SCT nor APOL1 HR genotype 32/5173 (0.67%) developed ESKD. The multivariable cox-proportional hazard model showed that APOL1 high risk genotype increased the risk of ESKD by two-fold (HR 2.12-95% CI 1.19-3.79), p = 0.011. Surprisingly, the risk of ESKD was also two-fold higher in SCT carriers (HR 2.59 95% CI 1.44-4.68), p = 0.002 independent of APOL1 genotype. This risk was of ESKD for people with either SCT or the APOL1 high risk genotype was similar to that associated with diabetes (HR 2.75 95% 1.58-4.80), p < 0.001. The polygenic score for eGFR did not change the risk of ESKD in these carriers. Conclusion We show for the first time that 1 in 3 British Africans carry either two APOL1 high-risk variants or sickle cell trait, both of which double the risk of ESKD. These genetic risk factors increase the risk of developing ESKD to a level similar to that resulting from diabetes. A sensible starting point would be a trial of screening and aggressive management of conventional risk factors for ESKD.

#804 The nonlinear association between body mass index and chronic kidney disease: a prospective cohort study and Mendelian randomization analysis

Abstract Background and Aims Previous studies mainly focused on linear association between body mass index (BMI) and the risk of chronic kidney disease (CKD). In the current research, we conducted a prospective cohort observational study and Mendelian Randomization analysis to explore whether non-linear relationship exists between BMI and CKD. Method In the prospective cohort study, 495,465 participants from the UK biobank were included. The Cox proportional hazards model with fractional polynomial transformation was used to estimate the hazard ratio of BMI for incident CKD. In addition, nonlinear Mendelian Randomization analysis was performed using the fractional polynomial method to verify the causality of the association. Results In the observational analysis, a J-shaped association was observed between BMI and the risk of CKD. The risk of CKD was lowest when the BMI was around 18-20 kg/m2, and the hazard of developing CKD increased in participants with lower or higher BMI (Fig. 1). When assessing the causal relationship, in Mendelian Randomization analysis, despite that a nonlinear relationship still held true (P-value for non-linearity = 0.008), the odds ratio for CKD monotonically rised with increasing BMI (Fig. 2). Conclusion The J-shape association between BMI and CKD revealed by the observational cohort study was not supported by the Mendelian Randomization, which indicated a monotonically causal relationship that the risk of CKD rised with increasing BMI.

#1048 Why are felids at such a high risk of chronic kidney disease?

Abstract Background and Aims Felids are obligatory hyper-carnivorous mammals, representing the utmost manifestation of a carnivorous dietary adaptation. Chronic kidney disease (CKD) could be characterized as an epidemic amongst domestic and captive wild felids, affecting up to 87%. However, its aetiology remains yet unknown. The aim of the study was to assess how various diets influence the development of CKD in felids. Method Ninety adult, captive non-domestic felids (tigers, leopards, cheetahs, and lions) from zoological parks were examined under anaesthesia. Their examination and sampling were part of planned annual health evaluations, not related to experiments. Husbandry and dietary information, as well as medical history were collected through a questionnaire. Blood serum and urine were taken. For the staging of CKD, symmetric dimethylarginine (SDMA), the level of azotaemia (serum creatinine) and the level of proteinuria with the urinary protein creatinine ratio were evaluated and correlated to dietary, biological and management factors. Results Sixty percent of the felids were diagnosed with CKD. The risk for developing CKD was much higher in animals fed primarily with skeletal muscle meat only compared to animals being fed with meat containing bones or whole pray carcasses. Furthermore, the incorporation of fasting days was significantly linked to a lower CKD prevalence. In addition, feeding a combination of white and red meat showed a lesser association with CKD presence compared to exclusively feeding red meat. Conclusion Non-domestic felids in captivity are exposed to different feeding practices. Diets closer to natural, wild diets resulted in lower risks of developing CKD. Feeding strategies such as whole-body prey, the inclusion of white meat and the implementation of fasting days were associated to significantly lower risks of developing CKD in captive wild felids. Future studies on investigating the benefits of dietary supplements, the impact of the Calcium:Phosphorus ratio, the composition of meat and the structure of fasting days is needed. In addition, the role of chronic low-grade inflammation (inflammatory biomarker analysis) as well as the impact of various dietary regimes on the microbiota composition should be explored further.

#2228 Hypocitraturia is the main factor associated with proteinuria in patients with kidney stones

Abstract Background and Aims Patients with kidney stones (KS) are at increased risk for chronic kidney disease. Research published so far has focused on factors associated with low glomerular filtration rate in KS patients, however, factors associated with proteinuria have not been fully described. The aim of this retrospective study was to assess the presence of proteinuria in our cohort of patients with known or presumed calcium KS and to analyze which common clinical and metabolic variables might be associated with proteinuria. Method We performed a retrospective cross-sectional study in patients (pts) treated at our stone clinic at the University Medical Centre Ljubljana in the ten-year period from January 1st 2010 to December 31st 2019. We excluded patients who did not have 24-hour proteinuria determined and patients with known urate, struvite or cystine stones. We noted the presence of arterial hypertension (AH), diabetes mellitus, a family history of kidney stones, age, sex, eGFR, body mass index, history of renal colic events and urological procedures for kidney stones, and 24-hour urine measurements (calcium, urate, oxalate, citrate, sodium, and proteinuria). Categorical variables were analyzed with Chi-Square test, normally distributed numerical values with Student's t-test and non-normally distributed with Mann-Whitney U test. P-values < 0.05 were considered statistically significant. Associations with p-values < 0.1 were included into a binary logistic regression analysis to determine the probability of predicting the presence of 24-hour proteinuria, defined as > 0.25 g/day in our laboratory. Results In the allocated time period 335 pts were examined. After exclusion, 251 pts were included into the analysis (mean age 49.5 ± 14.2 years, 116 (46.2%) males, 135 (53.8%) females). Complete 24-hour urine metabolic analysis was available for 238 pts. Proteinuria was present in 40 pts (15.9%) and was significantly more common in pts with AH compared to normotensive pts (18/77 (23.4%) vs. 22/174 (12.6%), p 0.027) and more common in males compared to females (23/116 (19.8%) vs. 17/135 (12.6%), p 0.083). Numerical variables with a p-value < 0.1 regarding the association with the presence of proteinuria are presented in Table 1. In regression analysis the model significantly predicted the presence of proteinuria (χ2 20.738, p 0.014, R2 0.343) and was able to predict the result overall in 85.2% of cases. Of all the variables included only citrate significantly predicted the presence of proteinuria (OR 1.732; 95% CI 1.009, 2.972; p 0.046). Proteinuria was significantly more common in pts with hypocitraturia (<1.67 mmol/day) compared to pts with normal urinary citrate (29/116 (25%) vs. 9/122 (7.4%), p < 0.001) and in pts with immeasurably low urinary citrate (<0.2 mmol/day) compared to higher citrate (15/27 (55.6%) vs. 23/211 (10.9%), p < 0.001). Conclusion Proteinuria was relatively common in our cohort. The main factor associated with proteinuria was urinary citrate. Proteinuria was significantly more common in pts with hypocitraturia compared to pts with normal urinary citrate and was present in the majority of pts with immeasurably low urinary citrate. Further studies are warranted to clarify the clinical relevance and implications of this findings.

#1964 Diagnosis performance of urine oxalate/creatinine ratio for hyperoxaluria screening

Abstract Background and Aims Primary and secondary hyperoxaluria is characterized by significantly elevated urinary oxalate levels, increased risk of kidney stones, nephrocalcinosis, and chronic kidney disease. Patients with enteric hyperoxaluria are especially at high-risk populations. However, identifying hyperoxaluric individuals within these populations remains challenging due to difficulties in obtaining complete urine collections. This study aims to evaluate the diagnostic performance of the urine oxalate/creatinine ratio to improve the screening of hyperoxaluria. Method We pooled data from an adult tertiary renal exploration center, including living donors, short bowel syndrome patients, bariatric surgery patients, and individuals with nephrolithiasis or other nephrological issues undergoing 24-hour urine analysis. We assessed the relationship between the urine oxalate/creatinine ratio and 24-hour oxalate excretion. The diagnostic performance of the ratio was analyzed using ROC curves, and an optimal diagnostic threshold was established. Results Of the 1485 initially included adult patients reported in Table 1, 37% lacked complete urine collections, resulting in a study population of 974 individuals (453 females, 521 males, median age 48 years, median renal function 97 ml/min/1.73 m²). Nineteen percent had hyperoxaluria, with a higher prevalence in females (25% vs. 13% in males). Median 24-hour oxaluria was 548 (432,740) µmol/d in the diseased group and 244 (188,309) µmol/d in the healthy group. A strong correlation (Spearman's rank correlation rho= 0.8, p < 0.001) was found between the urine oxalate/creatinine ratio and 24-hour oxalate excretion. ROC curves for both genders exhibited similar performance, with an optimal threshold for the entire population yielding an AUC of 0.97 (0.962-0.981). The diagnostic threshold for maximum sensitivity was an oxalate/creatinine ratio of 0.025 mmol/mmol (Sensitivity = 1, Specificity = 0.65, PPV = 0.4, NPV = 1), while for maximum specificity, it was an oxalate/creatinine 0.074 mmol/mmol (Sensitivity= 0.31, Specificity = 1, PPV = 1, NPV = 0.862). The optimal diagnostic threshold chosen by the minimum distance from the left-upper corner was an oxalate/creatinine 0.034 mmol/mmol (Sensitivity= 0.92, Specificity = 0.91, PPV = 0.69, NPV = 0.98) (Fig. 1). Conclusion The urine oxalate/creatinine ratio demonstrates excellent diagnostic performance and is efficient in screening hyperoxaluric patients within high-risk populations. However, the positive predictive value is insufficient to be a standalone reliable diagnostic test. Therefore, 24-hour urine oxalate measurement remains necessary for diagnosis.

#2061 Perirenal fat thickness as a potential marker for cardiovascular risk in chronic kidney disease: the influence of vitamin D analogs

Abstract Background and Aims Patients with CKD show high cardiovascular complication rates. There are classical cardiovascular risk factors, such as obesity, dyslipidemia, and diabetes; however, other cardiovascular disease risk factors are associated with mineral metabolism disorders (phosphorus, hyperparathyroidism, etc.) typically appear in CKD. Due to their pleiotropic effects, vitamin D analogs, such as cholecalciferol, calcitriol, or paricalcitol, have proven effective in controlling bone mineral disease secondary to CKD and cardiovascular pathologies. On the other hand, visceral adiposity has been shown as a risk factor in the general population and in patients with CKD. Specifically, the fat deposited in regions such as the epicardium generates a complex autocrine and paracrine hormonal mechanism that has been associated with cardiovascular complications. Although it has not been widely evaluated, the adipose tissue surrounding the kidneys (perirenal fat [PRF]) could provide additional information of interest in the CKD population. The aim of the study is to assess the relationship between cardiovascular disease, PRF, and the effect of therapeutic interventions for bone and mineral metabolism in patients with CKD. Method This prospective observational and cross-sectional study was designed to evaluate the usage of vitamin D analogs in patients with CKD, focusing on cardiovascular history and PRF accumulation. All the patients were evaluated at the outpatient clinic in Consuelo Hospital in Valencia Spain (January-November 2022). Eighty-three patients with different grades of CKD (G1A1 to G5A3 not on dialysis) were included and follow-up for 24 months. All the patient's data from electronic medical and analytical records were entered into a protocol sheet. The patients that meet the inclusion criteria (eGFR ≤90 or>15 ml/min/1.73 m2; age ≥18 years at the time of signing informed consent, and a life expectancy higher than 1 year) were eligible to participate in the study. As exclusion criteria, patients with an active inflammatory process such as infection, active cancer, or other inflammatory states were excluded beyond those mentioned in inclusion. Patients with an AKI, ADPKD, or CKD requiring RRT were also excluded. Patients were discriminated according to their history of cardiovascular disease (coronary artery disease, stroke, and peripheral vascular disease) and the use of Vitamin D analogs (Cholecalciferol, Calcitriol, and Paricalcitol). The thickness of the PRF was measured in centimeters (cm) through a B-mode ultrasound with a 3.5-MHz convex transductor (Alpinion®; Alpinion Medical Systems, Korea). Patients underwent a bilateral renal ultrasound, and the kidneys were measured anteroposteriorly, transversally, and longitudinally. PRF was measured in the distal third between the cortex and the hepatic border and/or spleen. Results The mean age of the patients was 58.3 ± 16 years. Patients with a cardiovascular disease history showed significantly higher levels of urea (62.0 vs 45.2 mg/dl, p < 0.05), uric acid (5.5 vs 4.3 mg/dl; p < 0.03), intact parathyroid hormone (iPTH) (186.2 vs 65.2 pcg/dl; p0.05) and decreased eGFR (53.55 vs 89.00 ml/min/1.73 mts2). The mean PRF thickness (0.99 vs 0.80 cm; SD ± 0.30; p0.05) was also observed to be elevated with respect to the group who had no previous cardiovascular events (Fig. 1). Moreover, this group showers higher levels (1.2 vs 7.1; p < 0.005) of CRP. Those patients on oral treatment with Paricalcitol (1 mcg/day) had lesser PRF accumulation than those treated with Cholecalciferol (1000 IU/day) or Calcitriol (0.5 mcg/day) (p < 0.05) (Fig. 2). It was not adjusted for confounding factors such as weight, height, or BMI. Conclusion These results show a close relationship between the presence of cardiovascular disease history and a higher accumulation of PRF. The mechanisms by which paricalcitol could influence the decrease in PRF are so far unknown, however, some studies have shown an association between PTH elevation and obesity. Finally, achieving a decrease in the latter could reduce visceral adipose tissue, thus reducing the cardiovascular risk in CKD-affected patients.

#1450 Polygenic risk score of native IgA nephropathy predicts risk of post-transplant disease recurrence

Abstract Background and Aims IgA nephropathy (IgAN) is a polygenic immune-mediated progressive glomerular disease. Recent GWAS reported that high genome-wide polygenic risk score (IgAN GPS), including 1 249 077 variants mapping to systemic immune pathways, was associated with risk of end stage kidney disease (ESKD). Post transplant (KTx) IgAN recurrence occurs in 30% of cases and it is a major cause of graft loss. Pathogenesis and predictors of IgAN recurrence are still not well defined. Herein, we studied the role of native IgAN GPS and clinical factors in predicting post-KTx IgAN recurrence and graft failure in a large cohort of KTx recipients. Method Four thousand one hundred eighty six KTx recipients from 6 sites were genome wide genotyped and imputed against multi-ancestry reference panels, retrieving >10 million variants. In each recipient, native IgAN GPS was computed and standard-normalized (i.e. expressed in units of standard deviations from the mean distribution in matched controls). Native kidney disease diagnosis, clinical parameters, and post-KTx outcome data were retrieved retrospectively from clinical charts. The IgAN GPS was tested as predictor of native IgAN in the entire KTx cohort in a logistic regression model adjusted for sex, age, recruitment site, and first 5 PCs. IgAN GPS was tested as predictor of age at transplantation (proxy for age at ESKD) among KTx recipients with native IgAN in a linear regression model adjusted for sex, recruitment site, and first 5 PCs. In recipients with native IgAN, recipient and donor parameters were individually tested as predictors for time to IgAN recurrence and time to graft failure in Cox proportional hazards models adjusted for recruitment site and first 5 PCs. Predictors with P-value < .1 were included in the multivariable models. Recipient IgAN GPS was added to the clinical models and tested for prediction of time-to IgAN recurrence, and, among KTx recipients with IgAN recurrence, of time-to subsequent graft failure. Results Three hundred sixty nine KTx recipients were affected by native IgAN, 271 were of male sex, median age at transplantation was 45 years, and 149 received a living donor KTx. Over a median follow-up time of 46 months, 96 IgAN recurrence events occurred, and, among KTx recipients with recurrent IgAN, 27 subsequent graft failure events occurred after 100 months post KTx. IgAN GPS significantly predicted native IgAN cases among all KTx recipients (OR [95% CI]: 1.95 [1.76,2.16], p = 5.60E-07, AUROC 0.73), and lower age at transplantation among recipients with native IgAN (beta [s.e.]: −1.11[0.55], p = 0.04). Clinical model for IgAN recurrence included age, sex, year of transplant, HLA mismatch, recruitment site, and first 5 PCs; clinical model for graft failure included age, sex, year of transplant, HLA mismatch, type of donation, donor age, sex, rejection events, recruitment site, and first 5 PCs. At the multivariable analysis, IgAN GPS, lower age at transplantation, lower HLA mismatch, and higher year of transplant were independently associated with time to IgAN recurrence (Fig. 1a). Among KTx recipients with recurrent IgAN, higher IgAN GPS predicted time-to graft failure independently from clinical factors (Fig. 1b), but not in non-recurrent cases. Conclusion In the KTx setting, IgAN GPS was an independent predictor of IgAN recurrence, suggesting shared genetic susceptibility between native and recurrent IgAN. In addition, associations of IgAN GPS with lower age at transplantation, and with graft failure among recurrent IgAN cases, suggest that IgAN GPS may be predictive of a more aggressive native as well as recurrent disease. Associations with lower HLA mismatch advocate donor-recipient genetic similarities as potential additional predictors of IgAN recurrence. These data, which need external validation, may provide potential new insights into the pathobiology and prediction of recurrent IgAN.

#2348 Paradoxical association of pre-donation estimated glomerular filtration rate with kidney function decline in living kidney donors

Abstract Background and Aims Living kidney donors (LKD) are at risk for chronic kidney disease (CKD). Whether differences in pre-donation estimated glomerular filtration rates (eGFR) are associated with differences in the rate of post-donation eGFR decline is unclear. We aim to examine the association between pre-donation eGFR and the risk of kidney function decline post-donation. Method A retrospective cohort study using the Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR) database included LKD with pre- and early post-donation eGFR as well as eGFR at 6, 12, and 24 months after donation. The association between the quartile (Q) of pre-donation eGFR and time to ≥35% decline in post-donation eGFR compared to pre-donation eGFR was examined by competing-risks survival regression with death serving as a competing risk variable. Results Of 129,943 LKD ≥18 years old undergoing donation between October 1987 and September 2022, mean ± SD age was 42 ± 12 years and 61% were female. Mean overall pre-donation eGFR was 95.76 ± 29.80 mL/min/1.732 and mean pre-donation eGFR of LKD in Q1, 2, 3, and 4 were 63.50 ± 8.86, 83.05 ± 4.53, 100.30 ± 5.72, and 136.22 ± 23.69 mL/min.1.73 m2, respectively (Ptrend <0.001). Compared to pre-donation eGFR, the mean eGFR at early post-donation was significantly decreased to 53.56 ± 39.81 mL/min.1.73 m2 (mean eGFRpost-pre −43.38 mL/min.1.73 m2; P < 0.001), but mean post-donation eGFR at 6, 12, and 24 months continued trending up to 57.58 ± 45.37, 59.28 ± 43.25, and 61.05 ± 42.51 mL/min.1.73 m2, respectively which were significantly greater than early post-donation eGFR (mean eGFR 6mo-post 4.28, eGFR12mo-post 6.01, and eGFR24mo-post 7.82 mL/min.1.73 m2; P < 0.001; Fig. 1). Median survival for ≥35% decline in post-donation eGFR was 6.43 months (5.50, 11.30) with an incidence rate of 0.08 person-months. Among 75,220 LKD with follow-up data, 58,985 (78%) had the event and 15 (0.02%) died. Compared to LKD with pre-donation eGFR in Q1, LKD in other Q had a significantly higher risk for ≥35% decline in post-donation eGFR with a positively graded association (HR (95% CI)Q2 1.28 (1.23, 1.32); HRQ3 1.41 (1.36, 1.46); and HRQ4 1.60 (1.55, 1.65)). After adjusting for age, gender, race, body mass index, history of hypertension, diabetes, U.S. citizen status, education, and the interaction term between the quartile pre-donation eGFR and race, the magnitude of the association increased but the direction remained (HR (95%C I)Q2 1.41 (1.36, 1.47) HRQ3 1.72 (1.65, 1.79), and HRQ4 2.11 (2.02, 2.20). In addition, race was identified as an effect modifier with an increased risk for ≥35% decline in post-donation eGFR observed in Hispanic/Latino LKD (Pinteraction Q 2, Q3, Q4 0.025, 0.005, and <0.001). Conclusion Higher pre-donation eGFR is associated with a greater risk for post-donation eGFR decline especially among Hispanic/Latino LKD. Candidacy for living kidney donation should not be declined based only on eGFR; while some racial-ethnic minorities may be at greater risk even having higher pre-donation eGFR.

#2171 The impact of preoperative hypertension and blood pressure control on kidney outcomes after surgery for localized kidney cancer: a prospective study

Abstract Background and Aims Kidney surgery represents the treatment of choice for localized renal cell carcinomas (RCC). Postoperative acute kidney injury (AKI) is reported in 40% of the patients undergoing partial nephrectomy [1]. A nephron-sparing approach is not always feasible for anatomical as well as oncological reasons and total nephrectomy is associated with an even higher risk of both acute and chronic impairment of renal function. Recently, interest has risen in the development of prediction models able to preoperatively identify patients at higher risk of AKI and chronic kidney disease (CKD) development after kidney surgery, but the role of hypertension in this field is yet underexplored. The aim of the present study was therefore to assess the impact of hypertension and blood pressure control on kidney outcomes after surgery for RCC. Method We prospectively enrolled 45 patients with an estimated glomerular-filtration-rate (eGFR) > 45 ml/min per 1.73 m2 who underwent kidney surgery for RCC at our institution between May 1, 2022, and September 30, 2023. Clinical characteristics of the study cohort are reported in Table 1. In-hospital AKI was defined as an increase of serum creatinine > 0.3 mg/dl from baseline and CKD development (defined as eGFR <60 ml/min/1.73 m2) was evaluated at 3 months. Ambulatory blood pressure monitoring (24h-ABPM) was assessed at baseline. Comparisons between groups were made by analysis of variance. Comparisons of proportions among groups were made using the χ2 test. Multivariate logistic regression analysis was used to describe the relationship between clinical variables and the presence of in-hospital AKI. Results Among the 45 patients enrolled, 42% (n = 19) developed postoperative AKI, of whom 32% (n = 6) had a complete kidney function recovery, whereas 68% (n = 13) developed CKD. Of the 39 patients with a basal ABPM evaluation, 87% (n = 34) had a diagnosis of hypertension. For 35% (n = 12) of these patients a first diagnosis of hypertension was made. AKI patients had higher median SBP (143 ± 9 vs 133 ± 12 mmHg, p = 0.008) and SBP variability (24 ± 4 vs 20 ± 5 mmHg, p = 0.01) compared with non-AKI patients. Preoperative 24h-SBP >130 mmHg was independently associated with in-hospital AKI (p = 0.05), regardless of age, gender, hypertension, diabetes and antihypertensive treatment. Considering the 3-month eGFR, we observed that compared with non-AKI patients, baseline 24h-SBP was higher, as a trend, in AKI patients who did not develop CKD or in those developing CKD on previous normal kidney function (de novo CKD), while no difference in 24h-SBP was observed between AKI and non-AKI patients in the subgroup of patients with preoperative CKD (CKD on CKD) (Fig. 1). Conclusion Preoperative hypertension, a potentially modifiable risk factor, is associated with an increased risk of AKI after kidney surgery. Moreover, an early identification of hypertension is of utmost importance taking into account that a strict blood pressure control, regardless of renal function at baseline, may be crucial to counteract the development or the progression of CKD.

#1117 Skipping breakfast and progression of chronic kidney disease in a general Japanese population

Abstract Background and Aims Unhealthy eating habits such as skipping breakfast are associated with adverse health outcomes including coronary heart disease, metabolic syndrome and diabetes mellitus. However, it remains uncertain whether skipping breakfast affects chronic kidney disease (CKD) risk. The aim of this study was to investigate the association between skipping breakfast and progression of CKD. Method Between 2008 and 2019, we conducted a retrospective cohort study using annual health check data in Iki City, Nagasaki, Japan. A total of 922 participants aged 30 years or older who had CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 and/or proteinuria) at baseline were included in the present analysis. The breakfast-skipping group was defined as participants who skipped breakfast more than 3 times per week. The outcome was CKD progression defined as a decline of at least 30% in the eGFR from the baseline status. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for CKD progression, adjusted for other CKD risk factors. Results During a follow-up period with a mean of 5.5 years, CKD progression occurred in 60 (6.5%) participants. The incidence rate (per 1,000 person-years) of CKD progression was 21.5 in the breakfast-skipping group and 10.7 in the breakfast-eating group (p = 0.029), respectively. The multivariable-adjusted HR (95% CI) for CKD progression was 2.60 (95% CI 1.29‒5.26) for the breakfast-skipping group (p = 0.028) compared with the group eating breakfast. There were no clear differences in the association of skipping breakfast with CKD progression in subgroup analyses by sex, age, obesity, hypertension, diabetes mellitus, baseline eGFR and baseline proteinuria. Conclusion Skipping breakfast was significantly associated with higher risk of CKD progression in a general Japanese population.

#1715 Role of T cell profile (Th1/Th2/Th17/Treg) and podocyturia in the peripheral blood of patients with preeclampsia versus normal pregnancy

Abstract Background and Aims The concept of the balance between Th17/Treg cell immunity plays important role in determining pregnancy outcomes. Does Treg/TH17 play a role in pathogenesis of preeclampsia associated proteinuria and its implication on irreversible renal damage was the research question. Method This hospital based prospective study conducted in the Department of obstetrics and gynecology at a tertiary care medical college between October 2018 till October 2020 and assessment of T cell profiling and urinary podocyturia among all pregnancies with clinical evidence of preeclampsia and compared it with normal pregnancy monitoring for maternal and foetal outcomes. Repeat assessment of Th profiling and podocyturia was done after 3 months post partum to look for any residual effect. Results A total of 40 patients of preeclampsia and 40 control were enrolled in the study with median age group (24.58 ± 1.22 vs 25.16 ± 1.01). The percentage of Th1 and Th2 were higher for the preeclampsia group as compared to the control group with no change in the percentage of Th17 subsets while Th17 1 were found higher and percentage of Treg (8.1 ± 3.19 vs 2.3 ± 1,05, p = 0.001) lower in the peripheral blood of the preeclampsia group at time of delivery however the ratio of Th1/Treg, Th2/Treg, Th17/Treg and Th17.1/Treg were found significantly lowered after 6 weeks of delivery among those with preeclampsia nearly comparable to the normal pregnancy group The quantitative assessment of podocyte in urine using antinephrin showed increase numbers among preeclamptic pregnancies compared to normal yet it settled within 6 weeks of delivery. Conclusion Women with preeclampsia per se does not increase the risk to exacerbation of kidney disease however greater research mandates to assess the women at greatest risk of kidney disease after pre-eclampsia to have good maternal and foetal outcomes.

Association of suPAR, ST2, and galectin-3 with eGFR decline and mortality in patients with advanced heart failure with reduced ejection fraction.

Patients with heart failure with reduced ejection fraction (HFrEF) are at risk for chronic kidney disease (CKD). Elevated levels of circulating biomarkers soluble urokinase plasminogen activator receptor (suPAR), galectin-3, soluble suppression of tumorigenicity 2 (ST2), and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are associated with CKD progression and mortality. The predictive value of these biomarkers in a population with HFrEF and kidney disease is relatively unknown. We sought to determine whether these biomarkers were associated with longitudinal trajectory of estimated glomerular filtration rate (eGFR) in HFrEF and assess their association with mortality using a joint model to account for competing risks of ventricular assist device (VAD) implantation and heart transplantation. We included participants from the Registry Evaluation of Vital Information for Ventricular Assist Devices in Ambulatory Life with repeated eGFR measures over 2 years. Of 309 participants, mean age was 59 years, median eGFR 60 ml/min/1.73 m2, 45 participants died, 33 received VAD, and 25 received orthotopic heart transplantation. Higher baseline serum standardized suPAR (β coefficient = -0.36 √(ml/min/1.73 m2), 95% confidence interval (-0.48 to -0.24), p < 0.001), standardized galectin-3 (-0.14 √(ml/min/1.73 m2) (-0.27 to -0.02), p = 0.02), and log NT-proBNP (-0.23 √(ml/min/1.73 m2) (-0.31 to -0.15), p < 0.001) were associated with eGFR decline. ST2 and log NT-proBNP were associated with mortality. Higher baseline suPAR, galectin-3, and NT-proBNP are associated with eGFR decline in patients with HFrEF. Only ST2 and NT-proBNP are associated with greater mortality after controlling for other factors including change in eGFR. These biomarkers may provide prognostic value for kidney disease progression in HFrEF and inform candidacy for advanced heart failure therapies.

MiR-486-5p protects against rat ischemic kidney injury and prevents the transition to chronic kidney disease and vascular dysfunction.

Acute kidney injury (AKI) increases the risk for progressive chronic kidney disease (CKD). MicroRNA (miR)-486-5p protects against kidney ischemia-reperfusion (IR) injury in mice, although its long-term effects on the vasculature and development of CKD are unknown. We studied whether miR-486-5p would prevent the AKI to CKD transition in rat, and affect vascular function. Adult male rats were subjected to bilateral kidney IR followed by i.v. injection of liposomal-packaged miR-486-5p (0.5 mg/kg). Kidney function and histologic injury were assessed after 24 h and 10 weeks. Kidney endothelial protein levels were measured by immunoblot and immunofluorescence, and mesenteric artery reactivity was determined by wire myography. In rats with IR, miR-486-5p blocked kidney endothelial cell increases in intercellular adhesion molecule-1 (ICAM-1), reduced neutrophil infiltration and histologic injury, and normalized plasma creatinine (P<0.001). However, miR-486-5p attenuated IR-induced kidney endothelial nitric oxide synthase (eNOS) expression (P<0.05). At 10 weeks, kidneys from rats with IR alone had decreased peritubular capillary density and increased interstitial collagen deposition (P<0.0001), and mesenteric arteries showed impaired endothelium-dependent vasorelaxation (P<0.001). These changes were inhibited by miR-486-5p. Delayed miR-486-5p administration (96 h, 3 weeks after IR) had no impact on kidney fibrosis, capillary density, or endothelial function. In rats, administration of miR-486-5p early after kidney IR prevents injury, and protects against CKD development and systemic endothelial dysfunction. These protective effects are associated with inhibition of endothelial ICAM-1 and occur despite reduction in eNOS. miR-486-5p holds promise for the prevention of ischemic AKI and its complications.

Organization and Structures for Detection and Monitoring of CKD Across World Countries and Regions: Observational Data From a Global Survey

Rationale & ObjectiveEstablished therapeutic interventions effectively mitigate the risk and progression of chronic kidney disease (CKD). Countries and regions have a compelling need for organizational structures that enable early identification of people with CKD who can benefit from these proven interventions. We aimed to report the current global status of CKD detection programs. Study DesignA multinational cross-sectional survey. Setting & ParticipantsStakeholders, including nephrologist leaders, policymakers, and patient advocates from 167 countries, participating in the International Society of Nephrology (ISN) survey from June to September 2022. OutcomesStructures for the detection and monitoring of CKD, including CKD surveillance systems in the form of registries, community-based detection programs, case-finding practices, and availability of measurement tools for risk identification. Analytical ApproachDescriptive statistics. ResultsOf all participating countries, 19% (n=31) reported CKD registries and 25% (n=40) reported implementing CKD detection programs as part of their national policies. There were variations in CKD detection program, with 50% (n=20) using a reactive approach (managing cases as identified) and 50% (n=20) actively pursuing case-finding in at-risk populations. Routine case-finding for CKD in high-risk populations was widespread, particularly for diabetes (n=152; 91%) and hypertension (n=148; 89%). Access to diagnostic tools, estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR), was limited, especially in low-income (LICs) and lower-middle-income (LMICs) countries, at primary (eGFR: LICs 22%, LMICs 39%, UACR: LICs 28%, LMICs 39%) and secondary/tertiary healthcare levels (eGFR: LICs 39%, LMICs 73%, UACR: LICs 44%, LMICs 70%), potentially hindering CKD detection. LimitationsA lack of detailed data prevented an in-depth analysis. ConclusionThis comprehensive survey highlights a global heterogeneity in the organization and structures (surveillance systems, detection programs and tools) for early identification of CKD. Ongoing efforts should be geared toward bridging such disparities to optimally prevent the onset and progression of CKD and its complications.

A multi-trait GWAS identifies novel genes influencing albuminuria.

Albuminuria is common and associated with increased risks of end-stage kidney disease and cardiovascular diseases, yet its underlying mechanism remains obscure. Previous genome-wide association studies (GWAS) for albuminuria did not consider gene pleiotropy and primarily focused on European ancestry populations. This study adopted a multi-trait analysis of GWAS (MTAG) approach to jointly analyze two vital kidney traits, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) to identify and prioritize the genes associated with UACR. Data from the Taiwan Biobank from 2012 to 2023 were analyzed. GWAS of UACR and eGFR were performed separately and the summary statistics from these GWAS were jointly analyzed using MTAG. The polygenic risk scores (PRS) of UACR were constructed for validation. The UACR-associated loci were further fine-mapped and prioritized based on their deleteriousness, eQTL associations, and relatedness to Mendelian kidney diseases. MTAG analysis of the UACR revealed 15 genetic loci, including 12 novel loci. The PRS for UACR was significantly associated with urinary albumin level (P<0.001) and microalbuminuria (P=0.001 ∼ 0.045). A list of priority genes was generated. Twelve genes with high priority included the albumin endocytic receptor gene LRP2 and ciliary genes IFT172. The findings of this multi-trait GWAS suggest that primary cilia play a role in sensing mechanical stimuli, leading to albumin endocytosis. The priority list of genes warrants further translational investigation to reduce albuminuria.

High body mass index and triglyceride levels at health checkups increase the risk of new-onset chronic kidney disease and worsening renal function: the TAMA MED Project-CKD

BackgroundHealth checkups are important in patients with chronic kidney disease (CKD), which is not easily accompanied by subjective symptoms. CKD can be caused or aggravated by factors that have not yet been identified.MethodsThis retrospective cohort study included 7 483 patients who underwent specific annual health checkups at a medical institution in Tama City, did not have CKD in 2012, and continued to undergo checkups (aged 40–74 years). We examined the risk factors for new-onset CKD and 1.5-fold increase in serum creatinine levels among laboratory values from 2012 to 2020.ResultsAge, body mass index (BMI), triglyceride levels, atrial fibrillation, and medication for hypertension (HT) and diabetes mellitus were independent risk factors for proteinuria, whereas current smoking, BMI, systolic blood pressure (SBP), and medication for HT were independent risk factors for estimated glomerular filtration rate < 60 mL/min/1.73 m2. SBP, triglyceride levels and medication for HT were risk factors for a 1.5-fold increase in serum creatinine levels during course of the study. The cut-off values of BMI for eGFR < 60 mL/min/1.73 m2 were 22.2 (men 24.7, women 22.1) kg/m2 and fasting triglyceride levels for a 1.5-fold increase in serum creatinine level were 171 (men 247, women 170) mg/dL, respectively.ConclusionsHealth checkups provide information to prevent new-onset CKD and worsening of renal function. It is necessary to increase the rate of health checkups and visits to medical institutions after health checkups as well as to use these results for health guidance.

Association between polypharmacy and chronic kidney disease among community-dwelling older people: a longitudinal study in southern China

BackgroundPolypharmacy would increase the risk of adverse drug events and the burden of renal drug excretion among older people. Nevertheless, the association between the number of medication and the risk of chronic kidney disease (CKD) remains controversial. Therefore, this study aims to investigate the association between the number of medication and the incidence of CKD in older people.MethodsThis study investigates the association between the number of medications and CKD in 2672 elderly people (≥ 65 years older) of the community health service center in southern China between 2019 and 2022. Logistic regression analysis was used to evaluate the relationship between polypharmacy and CKD.ResultsAt baseline, the average age of the study subjects was 71.86 ± 4.60, 61.2% were females, and 53 (2.0%) suffer from polypharmacy. During an average follow-up of 3 years, new-onset CKD developed in 413 (15.5%) participants. Logistic regression analysis revealed that taking a higher number of medications was associated with increase of CKD. Compared with people who didn’t take medication, a higher risk of CKD was observed in the older people who taken more than five medications (OR 3.731, 95% CI 1.988, 7.003), followed by those who take four (OR 1.621, 95% CI 1.041, 2.525), three (OR 1.696, 95% CI 1.178, 2.441), two drugs (OR 1.585, 95% CI 1.167, 2.153), or one drug (OR 1.503, 95% CI 1.097, 2.053). Furthermore, age, systolic blood pressure (SBP), white blood cell (WBC), blood urea nitrogen (BUN) and triglyceride (TG) were also independent risk factors CKD (P < 0.05).ConclusionThe number of medications was associated with CKD in older people. As the number of medications taken increased, the risk of CKD was increased.

Rheumatoid arthritis and the risk of chronic kidney diseases: a Mendelian randomization study.

The extra-articular lesions of rheumatoid arthritis (RA) are reported to involve multiple organs and systems throughout the body, including the heart, kidneys, liver, and lungs. This study assessed the potential causal relationship between RA and the risk of chronic kidney diseases (CKDs) using the Mendelian randomization (MR) analysis. Independent genetic instruments related to RA and CKD or CKD subtypes at the genome-wide significant level were chosen from the publicly shared summary-level data of genome-wide association studies (GWAS). Then, we obtained some single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs), which are associated with RA in individuals of European origin, and had genome-wide statistical significance (p5 × 10-8). The inverse-variance weighted (IVW) method was the main analysis method in MR analysis. The other methods, such as weighted median, MR-Egger, simple mode, and weighted mode were used as supplementary sensitivity analyses. Furthermore, the levels of pleiotropy and heterogeneity were assessed using Cochran's Q test and leave-one-out analysis. Furthermore, the relevant datasets were obtained from the Open GWAS database. Using the IVW method, the main method in MR analysis, the results showed that genetically determined RA was associated with higher risks of CKD [odds ratio (OR): 1.22, 95% confidence interval (CI) 1.13-1.31; p < 0.001], glomerulonephritis (OR: 1.23, 95% CI 1.15-1.31; p < 0.000), amyloidosis (OR = 1.43, 95% CI 1.10-1.88, p < 0.001), and renal failure (OR = 1.18, 95% CI 1.00-1.38, p < 0.001). Then, using multiple MR methods, it was confirmed that the associations persisted in sensitivity analyses, and no pleiotropy was detected. The findings revealed a causal relationship between RA and CKD, including glomerulonephritis, amyloidosis, and renal failure. Therefore, RA patients should pay more attention to monitoring their kidney function, thus providing the opportunity for earlier intervention and lower the risk of progression to CKDs.

Possible sarcopenia and risk of chronic kidney disease: a four-year follow-up study and Mendelian randomization analysis

ABSTRACT Introduction Chronic kidney disease (CKD) is a common risk factor for sarcopenia. However, whether sarcopenia increases the risk of CKD remains unclear. To investigate the longitudinal and causal associations between possible sarcopenia and CKD, this study was performed. Methods Possible sarcopenia was defined according to the Asian Working Group for Sarcopenia in 2019. Participants aged ≥ 40 years were recruited from the baseline survey of the China Health and Retirement Longitudinal Study and followed up for four years. Binary logistic regression was used to evaluate the cross-sectional and longitudinal associations between possible sarcopenia, low muscle strength, low physical performance and CKD. Propensity score matching was used to balance the intergroup differences. Subgroup and interactive analyses were adopted to identify potential interactive effects. Mendelian Randomization analysis was used to assess the causal association between appendicular lean mass (ALM) and CKD. Results After data cleansing, a total of 7296 participants were included in the baseline survey. In the cross-sectional analyses, the odds ratios (ORs) of prevalent CKD were 1.50 (95% CI = 1.23–1.84, p < 0.001) for possible sarcopenia, 1.37 (95% CI = 1.10–1.70, p < 0.01) for low muscle strength and 1.42 (95% CI = 1.16–1.74, p < 0.001) for low physical performance in the full models. No significant interaction effects of covariates were detected (all P for interaction > 0.05). After four years of follow-up, an increased risk of incident CKD was also observed in participants with possible sarcopenia (OR = 1.66, 95% CI = 1.13–2.44, p = 0.010) and low physical performance (OR = 1.69, 95% CI = 1.16–2.45, p = 0.006), but not in participants with low muscle strength (OR = 1.19, 95% CI = 0.75–1.88, p = 0.469). In the Mendelian Randomization analysis, the inverse variance weighted estimator showed that a 1-standard deviation increase of genetically predicted ALM was associated with a lower risk of CKD (OR = 0.92, 95% CI = 0.85–0.99, p = 0.035). All the sensitivity analyses supported the main findings. Conclusions Possible sarcopenia is an independent risk factor for CKD and may serve as a predictor of CKD for early identification and intervention.

Elevated apolipoprotein C3 augments diabetic kidney disease and associated atherosclerosis in type 2 diabetes.

Diabetes increases the risk of both cardiovascular disease and kidney disease. Notably, most of the excess cardiovascular risk in people with diabetes is in those with kidney disease. Apolipoprotein C3 (APOC3) is a key regulator of plasma triglycerides, and it has recently been suggested to play a role in both type 1 diabetes-accelerated atherosclerosis and kidney disease progression. To investigate if APOC3 plays a role in kidney disease in people with type 2 diabetes, we analyzed plasma levels of APOC3 from the Veterans Affairs Diabetes Trial. Elevated baseline APOC3 levels predicted a greater loss of renal function. To mechanistically test if APOC3 plays a role in diabetic kidney disease and associated atherosclerosis, we treated black and tan, brachyury, WT and leptin-deficient (OB; diabetic) mice, a model of type 2 diabetes, with an antisense oligonucleotide (ASO) to APOC3 or a control ASO, all in the setting of human-like dyslipidemia. Silencing APOC3 prevented diabetes-augmented albuminuria, renal glomerular hypertrophy, monocyte recruitment, and macrophage accumulation, partly driven by reduced ICAM1 expression. Furthermore, reduced levels of APOC3 suppressed atherosclerosis associated with diabetes. This suggests that targeting APOC3 might benefit both diabetes-accelerated atherosclerosis and kidney disease.