Risk Of End-stage Kidney Disease Research Articles

#594 Long-term risk of incident/progressive chronic kidney disease, or end-stage kidney disease post-acute kidney injury: systematic review, meta-analysis

Abstract Background and Aims Little is known about which patients to follow-up after an episode of acute kidney injury (AKI) for future risks. The aim of this review is to assess the association between AKI and the incidence or progression of chronic kidney disease (CKD) or end-stage kidney disease (ESKD), stratified by subcategories of AKI-stages, -durations, and clinical settings. Method A systematic search of the literature in PubMed and Embase was performed by two reviewers to identify studies that examined CKD incidence (development of CKD stage ≥3), CKD progression (worsening of kidney function in patients with CKD stage ≥3), or ESKD, in patients with AKI versus patients without AKI. The risk of bias was assessed using the Newcastle-Ottawa Scale. Relative effect estimates (odds and hazard ratios) were pooled using a random effects model. Results In total, 48 retrospective and 13 prospective studies, encompassing 140.985 patients with AKI, were included in this review. All the studies were of moderate or high quality. The pooled effect ratio was 3.36 (95% confidence interval (CI) 2.68-4.03) for CKD incidence (n = 31 studies). This remained 3.40 (95% CI 1.79-5.00) in a sub analysis including patients with a recovered kidney function post-AKI, and 1.49 (95% CI 1.44-1.55) in a sub analysis including patients with an AKI lasting less than 3 days (Fig. 1). Overall, the effect ratio for CKD progression (n = 11 studies) was 1.70 (95% CI 1.38-2.01) and 3.81 (95% CI 2.58-5.04) for ESKD (n = 24 studies). The increased risk of these two outcomes were not seen in the sub analyses only including patients with AKI lasting less than 3 days. Overall, there is an observable higher risk for CKD incidence, CKD progression, and ESKD with increased AKI staging, although not always statistically significant. Minimal variations were observed across clinical settings. Conclusion In our review, including over 60 studies, we found that AKI was associated with an increased risk of CKD incidence, CKD progression, and ESKD. Patients with higher AKI-stages had even larger risks. Notably, even brief episodes of AKI (lasting less than 3 days) were associated with a higher risk of CKD incidence compared to patients without AKI. In contrary, the risk for ESKD is not enlarged in a sub analysis including patients with recovered kidney function compared to patients without AKI. These result warrant close monitoring of the kidney function post-AKI, specifically in patients with AKI lasting 3 days or longer. Future research should focus more on the risk of CKD progression in order to tailor follow-up care in these more vulnerable patients.

#2088 Renal outcome, cardio-vascular events and infections in patients with lupus nephritis: MassiLUP cohort 2001-2022

Abstract Background and Aims Most epidemiological studies in lupus nephritis (LN) report the risk of end-stage kidney disease (ESKD) (10-20% of patients at 10-15 years in developed countries), but less data is available on the long-term risk of chronic kidney disease (CKD), even though CKD is a major risk factor for morbidity and mortality. While immunosuppressive therapy for LN aims to reach and maintain remission in order to prevent CKD, it also exposes patients to cardiovascular, infectious and neoplastic adverse events. We conducted a retrospective cohort study to evaluate survival without CKD and adverse events in patients with LN. Method The MassiLUP cohort comprises all patients who underwent a kidney biopsy for a first flare of LN between 2001 and 2022 in the University Hospital of Marseille, France. We assessed patient survival, renal survival and survival without CKD (defined by an estimated glomerular filtration rate < 60 mL/min/1.73 m2), without cardiovascular event, without severe infection (requiring hospitalization, or zoster), and without cancer. Results A total of 168 patients (82.7% female; mean age 33 years; mean serum creatinine 102 µmol/L at the time of the first kidney biopsy) were included, with a mean follow-up of 9.6 ± 5.7 years. One (0.6%) patient had class I LN (ISN/RPS 2003 classification), 17 (10.1%) class II LN, 45 (26.8%) had class III (± V) LN, 73 (43.5%) had class IV (± V) LN, 29 (17.3%) patients had pure class V LN; 3 biopsies could not be classified. Four patients died during the follow-up (3 of severe infections and 1 of stroke); 41 (24.4%) patients developed CKD, among whom 19 (11.3%) patients reached ESKD; 34 (20.2%) patients presented a cardiovascular event, 59 (35.1%) a severe infection, and 12 (7.1%) a cancer. Survival rates without CKD were 82.9%, 74.6% and 67.3% at 5, 10 and 15 years, respectively. Survival rates without ESKD were 94.4%, 88.6% and 79.9% at 5, 10 and 15 years, respectively. Survival rates without cardiovascular event were 85.7%, 77.3% and 75.5% at 5, 10 and 15 years, respectively. Survival rates without severe infection were 76.3%, 63.8% and 51.8% at 5, 10 and 15 years, respectively. Survival rates without cancer were 96.3%, 92.9% and 85.6% at 5, 10 and 15 years, respectively. Conclusion Despite free access to treatment and care in France, the long-term prognosis of patients with lupus nephritis remains burdened by both a risk of CKD and ESKD, and a significant risk of cardiovascular and infectious events. This calls for continued efforts to improve therapeutic strategies, both in terms of efficacy and toxicity, and to strengthen the therapeutic alliance in the care of patients with LN.

#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.

#2415 Estimated glomerular filtration rate thresholds associated with poor long-term outcomes in older patients with diabetes

Abstract Background and Aims Considering the natural decline of GFR with renal senescence, an age-adjusted estimated glomerular filtration rate (eGFR)-based chronic kidney disease (CKD) definition was recently proposed, which has been supported by that mortality risks start to increase at GFR <45 mL/min/1.73 m2 in older adults (≥65 years). However, the eGFR threshold for mortality and kidney outcomes in older patients with diabetes was less understood. We aimed to evaluate eGFR levels that raise the risk of mortality or end-stage kidney disease (ESKD) in older patients with diabetes. Method Older adult patients (≥65 years) with type 2 diabetes who visited our outpatient diabetes center during 2009 were retrospectively identified and followed up until 2017. Patients were categorized into four groups per their CKD-EPI equation-based eGFR: ≥60, 45–59, 30–44, and 15–29 mL/min/1.73 m2. Cox proportional hazard analysis for all-cause mortality and competing-risk analysis for ESKD (with a competing event of pre-ESKD death) were performed. Results Among 3,065 patients, 19%, 8%, and 2% of patients had eGFR 45–59, 30–44, and 15–29 mL/min/1.73 m2 at baseline, respectively. After adjusting various clinical covariates, including blood pressure, diabetes duration, urine albumin/creatinine ratio, HbA1c, serum cholesterol levels, and major comorbidities, patients with eGFR 30–44 and 15–29 mL/min/1.73 m2 had 1.51-fold (95% confidence interval [CI] 1.17–1.95, P < 0.001) and 2.66-fold (95% CI 1.87–3.79, P < 0.001) higher risks of mortality, respectively, whereas patients with eGFR 45–59 mL/min/1.73 m2 had a comparable risk (1.18, 95% CI 0.96–1.45, P = 0.127) to those with eGFR ≥60 mL/min/1.73 m2. Substitution hazard ratios for ESKD were 2.29 (95% CI 1.41–3.71, P = 0.001), 5.25 (95% CI 3.27–8.41, P < 0.001), and 16.74 (95% CI 9.73–28.80, P < 0.001) in patients with eGFR 45–59, 30–44, 15–29 mL/min/1.73 m2, respectively. In a subgroup of patients 75 or older (n = 800), patients with eGFR 45–59 mL/min/1.73 m2 exhibited comparable risks for both ESKD and mortality. Conclusion Reduced eGFR < 60 mL/min/1.73 m2 predicted an increased risk of ESKD in older patients with diabetes, suggesting that the current traditional eGFR threshold appears feasible. Thus, some high-risk individuals may be missed if age-adapted eGFR criteria with a lower eGFR threshold than 60 mL/min/1.73 m2 are universally applied for older adults ≥65 years.

#2051 Long-term follow-up of Israeli patients with lupus nephritis

Abstract Background and Aims Systemic lupus erythematosus (SLE) often affects the kidneys, and is associated with morbidity and mortality. Ethnic variations in clinical response to treatment and outcomes have been described. Information on real-life, long-term cohorts of the Middle Eastern Israeli population is lacking. We aimed to characterize the prevalence and long-term outcomes of kidney involvement in SLE patients in Israel and to identify variables associated with lupus nephritis (LN) and end-stage kidney disease (ESKD). Method This retrospective study, conducted between 2014-2023, included adult patients with SLE diagnosed for at least 12 months. Kidney involvement was based on a diagnosis of LN on a kidney biopsy. SLE patients without LN served as controls. Associated variables were collected including socio-demographics, disease-related characteristics, kidney-related factors, comorbidities, and all-cause mortality. Results A total of 182 adult patients with SLE were included. Of them, 54 (29.6%) had LN. Mean follow-up since diagnosis was 16.2 ± 13.8 years. Compared to the control group, patients with LN were diagnosed with SLE at younger ages (26.8 ± 12.9 vs. 35.5 ± 15.4 years, p < 0.01). Patients with LN and controls had similar proportions of females/males and Jewish/Arab patients (Table 1), and had comparable baseline eGFR before LN diagnosis (110 ± 48 vs. 107 ± 39 ml/min/m2, p = 0.66). The LN group had lower complement C3 levels at diagnosis and higher dsDNA titers (p = 0.001, 0.023 respectively; Table 1). Patients with LN had more hospitalization for SLE exacerbations [38.4% vs. 24.5%, odds ratio (OR) 1.9, 95% confidence interval (CI) 1-3.9, p = 0.06]. Of 54 patients with LN, 45 had available treatment information. All patients were treated with hydroxychloroquine, 19 patients (42.2%) were treated with cyclophosphamide, and 36 (80%) were treated with mycophenolate mofetil or mycophenolic acid. During follow-up of the LN patients, 5 patients (9.3%) were diagnosed with diabetes, 21 patients (38.9%) were diagnosed with hypertension, 5 patients (9.3%) had a stroke and 6 patients (11.1%) had an acute coronary syndrome. Eight of the LN patients (14.8%) developed ESKD as compared with one patient (0.8%) of the controls (OR 22.1, 95% CI 2.7-181.5, p < 0.001). On univariate analysis, ESKD was significantly associated with LN, hypertension, heart failure, and non-employment status. No difference in the rate of ESKD was found between Jewish and Arab patients. On multivariate regression analysis, LN and hypertension were the most important predictors for developing ESKD. Mortality among patients with ESKD was 22% vs. 4.6% among non-ESKD patients (p = 0.02) )Fig. 1). Conclusion This long-term study on Israeli SLE patients reveals that despite advances in SLE treatments, LN is associated with significant morbidity and mortality. The elevated risk of ESKD, particularly associated with LN and hypertension, underscores the imperative for targeted interventions to improve outcomes.

#1425 Anemia in patients with IgA nephropathy: an impact on the prognosis of IgA nephropathy

Abstract Background and Aims Immunoglobulin A Nephropathy (IgAN) has several well-known predictors of renal outcomes, including persistent proteinuria, hypertension, and baseline eGFR at the time of diagnosis. However, the effect of hemoglobin (Hb) levels on the progression of IgAN is rarely reported. This study aims to evaluate the impact of Hb levels on the prognosis of IgAN and to identify risk factors for anemia in patients with IgAN. Method A retrospective analysis of the data of 855 patients diagnosed with IgAN at Kyungpook National University Hospital between January 2002 and December 2021 was performed. We obtained the data on clinical parameters and pathological findings according to the Oxford classification at the time of the kidney biopsy. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors for anemia, and a Cox proportional hazard model was used to estimate the effects of anemia on the development of end-stage kidney disease (ESKD). Results Lower serum albumin, lower eGFR, severe interstitial fibrosis, and tubular atrophy were associated with anemia in patients with IgAN. The Kaplan-Meier survival curve revealed that patients with anemia had worse renal survival than those without anemia. The multivariable Cox analysis showed that anemia was an independent risk for the progression to ESKD (HR 2.86, confidence interval 1.58–5.17, p = 0.001). In a sex-specific analysis, only the female sex showed a significant and higher risk for ESKD (hazard ratio 4.07, confidence interval 1.53–10.8, p = 0.005). Conclusion A low Hb level at the time of biopsy, even if subclinical, was an independent risk factor for the development of ESKD in patients with IgAN. Therefore, it is necessary to monitor Hb levels at the time of diagnosis and take proactive measures to reduce the risk of disease progression.

#1355 Albuminuria after Induction Treatment and Kidney Prognosis in ANCA-associated Glomerulonephritis

Abstract Background and Aims Persisting proteinuria has been associated with worse kidney outcomes in ANCA-associated glomerulonephritis (AAGN). However, it remains unclear whether this reflects damage from the initial injury or ongoing inflammation. Method A retrospective, single centre study of biopsy-proven AAGN. The group “albuminuria” was defined as urine albumin-to-creatinine ratio (ACR) more than 300 mg/g and the group “no albuminuria”, defined as ACR less than or equal to 300 mg/g at 6 months. We sought the clinical and histopathological characteristics from both the initial and any subsequent biopsies, and long-term kidney outcomes stratified by albuminuria levels. Results 218 patients were included. Within the first six months, 28 (13%) had either died or progressed to end-stage kidney disease (ESKD). Among the remaining 190 patients, 37% had an ACR>300 mg/g at 6 months. The albuminuria group more frequently presented with a Berden mixed or crescentic class and had higher glomerular activity on the initial biopsy. They were also more often male [odds ratio (OR) 2.69; 95% CI 1.13-6.41], of younger age (OR 0.96; 95% CI, 0.93 to 0.99) and had fewer normal glomeruli in the biopsy (OR 0.96; 95% CI, 0.93 to 0.99) compared to the group without albuminuria. Over the initial 5-year period, the recovery in glomerular filtration rate (GFR) was lower in the albuminuria group (adjusted mean difference in delta GFR −12.5 ml/min per 1.73 m2; 95% CI, −15.8 to −9.1). In multivariable analysis, ACR greater than 300 mg/g was associated with a higher risk of ESKD, even after adjusting for age, Berden classification and GFR at diagnosis (Hazard ratio 7.25; 95% CI, 1.62 to 32.47). Conclusion In a well-defined cohort of AAGN, one third of the patients, primarily younger males with a lower percentage of normal glomeruli, had persisting albuminuria after induction treatment which was associated with worse kidney outcomes independent of Berden class and GFR at diagnosis.

#1942 Social deprivation and chronic kidney disease: a population based cohort study in Italy

Abstract Background and Aims The impact of social deprivation on the progression of Chronic Kidney Disease (CKD) to End Stage Kidney Disease (ESKD) requiring Renal Replacement Therapies (RRTs) and death has been demonstrated by large cohort studies produced both in the US and the UK. Nonetheless, there is still insufficient evidence, which might depend on the difficulty of comparing Health Care Systems from different countries, the lack of a standardized measure of social deprivation and the difficulty of obtaining follow-ups long enough to intercept all clinical outcomes. This study aims to fill this gap by analyzing a large cohort of patients affected by CKD identified in Healthcare Electronic Records through a validated algorithm. Method The study population consisted of all adult incident CKD cases treated conservatively, residents in the Lazio Region, that occurred between the 1st of January 2012 and the 31st of December 2021. The exposure was the deprivation index (DI), a composite indicator at the census block level, which integrates many aspects: low level of education, unemployment, non-home ownership, one parent family and overcrowding. The DI divided the Lazio residents in 5 classes according to the quintiles of its distribution (form very low to very high deprivation). The study outcomes were all-cause mortality and ESKD. The health status of CKD patients was characterized using the hospital discharges for hypertension, heart failure, diabetes, ischemic cardiopathy, obesity and other conditions, in the two years before the identification. Patients were followed form the incident date up to the date of death, ESKD, emigration from Lazio region or 31/12/2022, whichever came first. Cox regression analyses were performed to study the association between DI and adverse outcomes, estimating crude and adjusted Hazard Ratios (HR) and 95% Confidence Intervals (95% CI). The interaction between DI and sex was tested. Results From 2012 to 2021, there were 127 457 new CKD cases, 55.9% males. The average age was 72.2 (±13.7 SD) for males and 74.4 (±14.8 SD) for females, characteristics by deprivation index are reported in Table 1. During the follow-up, on average 4.3 years (±3.2 SD), 57 158 patients (45%) died and 5994 developed ESKD requiring RRTs (5%). The mortality analysis showed a statistically significant interaction between DI and sex. In males, there was a strong association between DI and mortality in both age-adjusted and fully-adjusted models (Fig. 1A), with a statistically significant trend across DI classes. In females, there was an association with a statistically significant trend across DI categories but the only statistically significant different HR was very high DI VS. very low DI (HR = 1.05; 95% CI = 1.00-1.09) (Fig. 1B). The association was much stronger for males then for females. In the ESKD outcome analysis there was not an interaction between sex and DI; hence, sex was used as confounder. The age-adjusted HR and the fully-adjusted HR of DI on ESKD did not show any trend across the DI categories and then the low and medium deprived had a lower ESKD risk compared to the very deprived. Conclusion The present study is so far the largest European prospective cohort regarding the association between socioeconomic position and CKD. The HR of mortality was inferior to the one found in the UK studies (HR 1.6). The most likely explanation is that we have stratified by sex and adjusted for comorbidities. In our study the most deprived patients have a higher risk of death, but not of ESKD requiring RRTs, showing socioeconomic inequalities in the worst possible outcome, that probably occurred before the progression of the disease in most deprived patients. Further studies are needed to confirm this association that can lead both individual and Public Health decisions.

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.

Risk Factors and Outcomes Associated With Heart Failure With Preserved and Reduced Ejection Fraction in People With Chronic Kidney Disease.

Heart failure (HF) is associated with poor outcomes in people with chronic kidney disease, yet it is unknown whether outcomes differ by HF subtype. This study aimed to examine associations of incident HF with preserved ejection fraction (HFpEF) versus HF with reduced ejection fraction (HFrEF) with progression to end-stage kidney disease (ESKD) and mortality. We studied individuals with chronic kidney disease in the CRIC study (Chronic Renal Insufficiency Cohort) who were free of HF at cohort entry. Incident HF hospitalizations were adjudicated and classified into HFpEF (ejection fraction, ≥50%) or HFrEF (ejection fraction, <50%) based on echocardiograms performed during the hospitalization or at a research study visit. ESKD was defined as need for chronic dialysis or kidney transplant. Cox proportional hazards were used to evaluate the association of time-updated HF subtype with risk of ESKD and mortality, adjusting for demographics, comorbidities, and medication use. Among the 3557 study participants without HF at cohort entry, mean age was 57 years and mean estimated glomerular filtration rate was 45 mL/min per 1.73 m2. A total of 682 participants had incident HF. Incidence rates for HFpEF and HFrEF were 0.9 (95% CI, 0.8-1.0) and 0.7 (95% CI, 0.6-0.8) per 100 person-years, respectively (Pdifference=0.005). Associations of incident HF with progression to ESKD were not statistically different for HFpEF (hazard ratio, 2.06 [95% CI, 1.66-2.56]) and HFrEF (hazard ratio, 1.80 [95% CI, 1.36-2.38]; P=0.42). The associations with mortality were stronger for HFrEF (hazard ratio, 2.73 [95% CI, 2.24-3.33]) compared with HFpEF (hazard ratio, 1.99 [95% CI, 1.65-2.40]; P=0.0002). In a chronic kidney disease population, the rates of HFpEF hospitalizations were greater than that of HFrEF. Risk of ESKD was high but not statically different across HF subtypes. There was a stronger association of HFrEF with mortality. Prevention and treatment of both HFpEF and HFrEF should be central priorities to improve outcomes in chronic kidney disease.

Five-Year Cumulative Cardiovascular Health and Clinical Events in Patients With Chronic Kidney Disease: The CRIC Study.

Higher cardiovascular health (CVH) score is associated with lower risks of cardiovascular disease (CVD) and mortality in the general population. However, it is unclear whether cumulative CVH is associated with CVD, end-stage kidney disease (ESKD), and death in patients with chronic kidney disease. Among individuals from the prospective CRIC (Chronic Renal Insufficiency Cohort) Study, we used the percentage of the maximum possible CVH score attained from baseline to the year 5 visit to calculate cumulative CVH score. Multivariable-adjusted Cox proportional hazards regression was used to investigate the associations of cumulative CVH with risks of adjudicated CVD (myocardial infarction, stroke, and heart failure), ESKD, and all-cause mortality. A total of 3939 participants (mean age, 57.7 years; 54.9% men) were included. The mean (SD) cumulative CVH score attained during 5 years was 55.5% (12.3%). Over a subsequent median 10.2-year follow-up, 597 participants developed CVD, 656 had ESKD, and 1324 died. A higher cumulative CVH score was significantly associated with lower risks of CVD, ESKD, and mortality, independent of the CVH score at year 5. Multivariable-adjusted hazard ratios and 95% CIs per 10% higher cumulative CVH score during 5 years were 0.81 (0.69-0.95) for CVD, 0.82 (0.70-0.97) for ESKD, and 0.80 (0.72-0.89) for mortality. Among patients with chronic kidney disease stages 2 to 4, a better CVH status maintained throughout 5 years is associated with lower risks of CVD, ESKD, and all-cause mortality. The findings support the need for interventions to maintain ideal CVH status for prevention of adverse outcomes in the population with chronic kidney disease.

Interstitial fibrosis increases the risk of end-stage kidney disease in patients with lupus nephritis.

To evaluate the risk of end-stage kidney disease (ESKD) in lupus nephritis (LN) patients using tubulointerstitial lesion scores. Clinical profiles and histopathological presentations of 151 biopsy-proven LN patients were retrospectively examined. Risk factors of ESKD based on characteristics and scoring of their tubulointerstitial lesions (e.g. interstitial inflammation [II], tubular atrophy [TA], and interstitial fibrosis [IF]) were analyzed. The mean age of 151 LN patients was 36 years old, and 136 (90.1%) were female. The LN cases examined included: class I/II (n = 3, 2%), class III/IV (n = 119, 78.8%), class V (n = 23, 15.2%), and class VI (n = 6, 4.0%). The mean serum creatinine level was 1.4 mg/dl. Tubulointerstitial lesions were recorded in 120 (79.5%) patients. Prior to receiving renal biopsy, 9 (6.0%) patients developed ESKD. During the follow-up period (mean, 58 months), an additional 47 patients (31.1%) progressed to ESKD. Multivariate analyses identified serum creatinine (hazard ratio [HR]: 1.7, 95% confidence interval [CI]: 1.42-2.03, p < 0.001) and IF (HR: 3.2, 95% CI: 1.58-6.49, p = 0.001) as independent risk factors of ESKD. Kaplan-Meier analysis further confirmed a heightened risk of ESKD associated with IF. Tubulointerstitial involvement is commonly observed in histopathological presentation of LN. However, IF, rather than II, or TA, was found to increase the risk of ESKD in our cohort. Therefore, to predict renal outcome in LN patients prior to adjusting immunosuppressive treatment, degree of IF should be reviewed.

Association of plasma ceramide with decline in kidney function in patients with type 2 diabetes

Circulating ceramide levels are dysregulated in kidney disease. However their associations with rapid decline in kidney function (RDKF) and end-stage kidney disease (ESKD) in patients with type 2 diabetes (T2D) are unknown. In this prospective study of 1746 T2D participants, we examined the association of plasma ceramide Cer16:0, Cer18:0, Cer24:0 and Cer24:1 with RDKF, defined as an estimated glomerular filtration rate (eGFR) decline of 5ml/min/1.73m2/yr or greater, and ESKD defined as eGFR <15/min/1.73m2 for at least three months, on dialysis, or renal death at follow-up. We performed multivariable logistic and cox regression analyses adjusted for traditional cardio-renal risk factors, including baseline renal functions. During a median (interquartile range) follow-up period of 7.7 (4.7-8.9) years, 197 (11%) patients experienced RDKF. Ceramide Cer24:0 (odds ratio [OR]=0.71, 95%CI 0.56-0.90) and ratios Cer16:0/Cer24:0 (OR=3.54, 95%CI 1.70-7.35), Cer18:0/Cer24:0 (OR=1.89, 95%CI 1.10-3.25) and Cer24:1/Cer24:0 (OR=4.01, 95%CI 1.93-8.31) significantly associated with RDKF in multivariable analysis. 124 patients developed ESKD. The ratios Cer16:0/Cer24:0 (hazard ratio [HR]=3.10, 95%CI 1.44-6.64), and Cer24:1/Cer24:0 (HR=4.66, 95%CI 1.93-11.24) significantly associated with a higher risk of ESKD. The Cer24:1/Cer24:0 ratio improved risk discrimination for ESKD beyond traditional risk factors by small but statistically significant margin (Harrell C-index difference 0.01; P=0.022). A high ceramide risk score, constructed using individual ceramide level and ceramide ratios, also associated with RDKF (OR=2.28, 95%CI 1.26-4.13) compared to lower risk score. In conclusion, specific ceramide levels and their ratios are associated with RDKF and conferred an increased risk of ESKD, independently of traditional risk factors in patients with T2D.

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.

C3 Hypocomplementemia Predicts the Progression of CKD towards End-Stage Kidney Disease in IgA Nephropathy, Irrespective of Histological Evidence of Thrombotic Microangiopathy.

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgAN causes end-stage kidney disease (ESKD) in 30-40% of all cases. The activation of the complement system by pathological circulating IgAs, which is often associated with low serum C3 levels (LowC3), seems to play a crucial role. Previous studies have shown an association between histological evidence of TMA, which is the result of alternative complement activation, and poor outcomes. However, it is not known to what extent the decrease in serum C3 levels reflects ongoing TMA injury. Our study aimed at assessing the association between LowC3 and ESKD and whether this association reflects ongoing TMA. Methods: We enrolled all patients with biopsy-proven IgAN and followed-up patients until their last visit, ESKD, or death. Results: Of the 56 patients included in the study, 12 (21%) presented low serum C3 (LowC3) at the time of renal biopsy. TMA was significantly more frequent in the LowC3 group [7/12 (58%) vs. 9/44 (20%), p = 0.02]. After adjusting for potential confounders, LowC3 was strongly associated with an increased hazard of ESKD (hazard ratio [HR]: 5.84 [95%CI: 1.69, 20.15; p = 0.005). The association was not affected by adjusting for TMA. The estimated overall proportion of the relation between C3 and ESKD mediated by TMA was low and not statistically significant. Conclusions: Our study provides evidence that C3 hypocomplementemia is associated with an increased risk of ESKD through mechanisms that are largely independent from TMA.

Renal Transplantation in HIV-positive and HIV-negative People With Advanced Stages of Kidney Disease: Equity in Transplantation.

People with HIV are at a greater risk of end-stage kidney disease than the general population. Considering the risk of death after end-stage kidney disease, access to renal transplantation in people with HIV is critically important. We included all adult patients on chronic dialysis in Ontario, Canada, between 1 April 2007 and 31 December 2020. We determined the probability of kidney transplantation with competing risk of death over time since the initiation of dialysis by calculating the adjusted subdistribution hazard ratios (sdHR; 95% confidence interval [CI]). We also compared long-term renal allograft and posttransplant mortality outcomes between HIV-negative and HIV-positive persons. Of 40 686 people (median age, 68 years; interquartile range, 57-77; 38.4% women), 173 were HIV-positive and 40 513 were HIV-negative. The incidence of kidney transplantation in HIV-negative and HIV-positive patients was 40.5 (95% CI, 39.4-41.6)/1000 person-years and 35.0 (95% CI, 22.8-53.7)/1000 person-years, respectively (P = .51). Considering the competing risk of death, HIV-positive people had a significantly lower chance of receiving kidney transplants than HIV-negative people (sdHR, 0.46 [95% CI, .30-.70]). The long-term allograft failure risk was not significantly different between HIV-negative and HIV-positive people, considering the competing risk of posttransplant death (sdHR, 1.71 [95% CI, .46-6.35]). Although the incidence and crude probability of kidney transplantation were similar among HIV-negative and HIV-positive persons in this cohort, those with HIV had a significantly lower likelihood of kidney transplantation than those without HIV. Having HIV was not significantly associated with a poor long-term allograft outcome compared with patients without HIV.

Early prediction of end-stage kidney disease using electronic health record data: a machine learning approach with a 2-year horizon.

In the United States, end-stage kidney disease (ESKD) is responsible for high mortality and significant healthcare costs, with the number of cases sharply increasing in the past 2 decades. In this study, we aimed to reduce these impacts by developing an ESKD model for predicting its occurrence in a 2-year period. We developed a machine learning (ML) pipeline to test different models for the prediction of ESKD. The electronic health record was used to capture several kidney disease-related variables. Various imputation methods, feature selection, and sampling approaches were tested. We compared the performance of multiple ML models using area under the ROC curve (AUCROC), area under the Precision-Recall curve (PR-AUC), and Brier scores for discrimination, precision, and calibration, respectively. Explainability methods were applied to the final model. Our best model was a gradient-boosting machine with feature selection and imputation methods as additional components. The model exhibited an AUCROC of 0.97, a PR-AUC of 0.33, and a Brier score of 0.002 on a holdout test set. A chart review analysis by expert physicians indicated clinical utility. An ESKD prediction model can identify individuals at risk for ESKD and has been successfully deployed within our health system.

A Klotho-Based Machine Learning Model for Prediction of both Kidney and Cardiovascular Outcomes in Chronic Kidney Disease

Introduction: This study aimed to develop and validate machine learning (ML) models based on serum Klotho for predicting end-stage kidney disease (ESKD) and cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Methods: Five different ML models were trained to predict the risk of ESKD and CVD at three different time points (3, 5, and 8 years) using a cohort of 400 non-dialysis CKD patients. The dataset was divided into a training set (70%) and an internal validation set (30%). These models were informed by data comprising 47 clinical features, including serum Klotho. The best-performing model was selected and used to identify risk factors for each outcome. Model performance was assessed using various metrics. Results: The findings showed that the least absolute shrinkage and selection operator regression model had the highest accuracy (C-index = 0.71) in predicting ESKD. The features mainly included in this model were estimated glomerular filtration rate, 24-h urinary microalbumin, serum albumin, phosphate, parathyroid hormone, and serum Klotho, which achieved the highest area under the curve (AUC) of 0.930 (95% CI: 0.897–0.962). In addition, for the CVD risk prediction, the random survival forest model with the highest accuracy (C-index = 0.66) was selected and achieved the highest AUC of 0.782 (95% CI: 0.633–0.930). The features mainly included in this model were age, history of primary hypertension, calcium, tumor necrosis factor-alpha, and serum Klotho. Conclusion: We successfully developed and validated Klotho-based ML risk prediction models for CVD and ESKD in CKD patients with good performance, indicating their high clinical utility.

Development and validation of a machine learning model to predict time to renal replacement therapy in patients with chronic kidney disease

BackgroundPredicting time to renal replacement therapy (RRT) is important in patients at high risk for end-stage kidney disease. We developed and validated machine learning models for predicting the time to RRT and compared its accuracy with conventional prediction methods that uses the rate of estimated glomerular filtration rate (eGFR) decline.MethodsData of adult chronic kidney disease (CKD) patients who underwent hemodialysis at Oita University Hospital from April 2016 to March 2021 were extracted from electronic medical records (N = 135). A new machine learning predictor was compared with the established prediction method that uses the eGFR decline rate and the accuracy of the prediction models was determined using the coefficient of determination (R2). The data were preprocessed and split into training and validation datasets. We created multiple machine learning models using the training data and evaluated their accuracy using validation data. Furthermore, we predicted the time to RRT using a conventional prediction method that uses the eGFR decline rate for patients who had measured eGFR three or more times in two years and evaluated its accuracy.ResultsThe least absolute shrinkage and selection operator regression model exhibited moderate accuracy with an R2 of 0.60. By contrast, the conventional prediction method was found to be extremely low with an R2 of -17.1.ConclusionsThe significance of this study is that it shows that machine learning can predict time to RRT moderately well with continuous values from data at a single time point. This approach outperforms the conventional prediction method that uses eGFR time series data and presents new avenues for CKD treatment.

Glycated Albumin and Adverse Clinical Outcomes in Patients With CKD: A Prospective Cohort Study

Rationale & ObjectiveHbA1c is widely used to estimate glycemia, yet it is less reliable in patients with chronic kidney disease (CKD). There is growing interest in the complementary use of glycated albumin (GA) to improve glycemic monitoring and risk stratification. However, whether GA associates with clinical outcomes in a non-dialysis dependent CKD population remains unknown. Study DesignProspective cohort study. Setting& Participants: 3110 participants with CKD from the Chronic Renal Insufficiency Cohort study. ExposureBaseline GA levels. OutcomesIncident end-stage kidney disease (ESKD), cardiovascular disease (CVD) events, and all-cause mortality. Analytical ApproachCox proportional hazards regression. ResultsParticipant characteristics included mean age 59.0 (SD 10.8) years; 1357 (43.6%) female; 1550 (49.8%) with diabetes. The median GA was 18.7 (interquartile range, 15.8-23.3)%. During an average 7.9-year follow-up, there were 980 ESKD events, 968 CVD events, and 1084 deaths. Higher GA levels were associated with greater risks of all outcomes, regardless of diabetes status: hazard ratios for ESKD, CVD, and death among participants with the highest quartile compared with quartile 2 (reference) were 1.42 (95%CI, 1.19-1.69), 1.67 (CI, 1.39-2.01), and 1.63 (CI, 1.37-1.94), respectively. The associations with CVD and death appeared J-shaped, with increased risk also seen at the lowest GA levels. Among patients with coexisting CKD and diabetes, the associations of GA with outcomes remained significant even after adjusting for HbA1c. For each outcome, we observed a significant increase in the fraction of new prognostic information when both GA and HbA1c were added to models. LimitationsLack of longitudinal GA measurements; HbA1c measurements were largely unavailable in participants without diabetes. ConclusionsAmong patients with CKD, GA levels were independently associated with risks of ESKD, CVD, and mortality, regardless of diabetes status. GA added prognostic value to HbA1c among patients with coexisting CKD and diabetes.