Higher Risk Of End-stage Kidney Disease Research Articles

Increased Risk of End-Stage Kidney Disease in Patients with Chronic Kidney Disease and Heart Failure with Reduced Ejection Fraction.

The prevalence of heart failure (HF) is more common in people with advanced non-dialysis chronic kidney disease (ND-CKD) compared to the general population. It is well known that HF with reduced ejection fraction (HFrEF) is associated with a higher risk of mortality in people with ND-CKD. However, the impact of HFrEF on progression into end-stage kidney disease (ESKD) is not well studied. Our study aimed to examine the independent association of HFrEF on progression to ESKD after correcting for confounding factors using two methods of propensity scoring. This study used data from the Salford Kidney Study, a longitudinal study which has recruited more than 3,000 patients with ND-CKD since 2002. Patients without a history of HF during the recruitment questionnaire were included in the control group. Patients with a reported history of HF and echo showing left ventricular ejection fraction <40% at enrolment were included in the HFrEF group. Two propensity score methods were used to attenuate the effects of confounding factors between the two groups - propensity score matching (PSM) and inverse probability weighting (IPW). Univariate and multivariate Cox-regression analyses were performed. A total of 2,383 patients were included in the analysis. Patients with HFrEF had significantly higher median age and a higher percentage of male gender compared to patients with no HF (72.5 vs. 66.6 years and 71.8 vs. 61.1%, respectively). Univariate and 5 models of multivariate Cox-regression analysis showed that HFrEF in people with CKD was a strong predictor for a higher incidence of ESKD (model 5: hazard ratio 1.38; 95% confidence interval = 1.01-1.90; p = 0.044). The association between HFrEF and the risk of ESKD remained significant after using the PSM and the IPW methods. Patients with concomitant advanced ND-CKD and prevalent HFrEF were found to have a higher risk of ESKD when compared to patients with no HF. This risk persists despite the adjustment of confounding factors using PSM and IPW.

Remnant cholesterol and the risk of diabetic nephropathy progression to end-stage kidney disease in patients with type 2 diabetes mellitus: a longitudinal cohort study.

Diabetic nephropathy (DN) is the most common cause of end-stage kidney disease (ESKD). Remnant cholesterol has been investigated as a predictor for the progression of DN in type 1 diabetes mellitus patients, as well as the incidence of DN in type 2 diabetes mellitus (T2DM) patients. This study aimed to evaluate the longitudinal relationship between baseline remnant cholesterol and kidney outcomes using a Chinese T2DM with biopsy-confirmed DN cohort. We included 334 patients with T2DM and biopsy-confirmed DN during 2010-2019 West China Hospital T2DM-DN cohort. Remnant cholesterol was defined by Martin-Hopkins equation. Patients were divided into four groups based on the median (IQR) remnant cholesterol concentration at the time of renal biopsy. The kidney outcome was defined as ESKD, which was defined as the need for chronic kidney replacement therapy or estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2. The relationship between remnant cholesterol and kidney outcome was analyzed using the Kaplan‒Meier method and Cox regression analysis. The mean age was 51.1 years, and 235 (70%) were men. During follow-up, a total of 121 (36.2%) patients reached ESKD. The Kaplan‒Meier analysis showed that patients in the highest quartile (quartile 4) group had lower cumulative renal survival (log-rank test, p = 0.033) and shorter median renal survival time [34.0 (26.4-41.6) vs. 55.0 (29.8-80.2) months] than patients in the lowest quartile (quartile 1) group. By univariate analysis, the high remnant cholesterol group was associated with a higher risk of progression to ESKD. Moreover, the risk of progression to ESKD in the highest quartile was still 2.857-fold (95% CI 1.305-6.257, p = 0.009) higher than that in the lowest quartile, and one-SD increase of remnant cholesterol was associated with a higher risk (HR = 1.424; 95% CI 1.075-1.886, p = 0.014) of progression to ESKD, after adjusted for confounding factors. High remnant cholesterol is independently associated with a higher risk of ESKD in patients with T2DM-DN, and it may be a new noninvasive marker of ESKD. Calculated remnant cholesterol has the advantages of being economical and clinically accessible. Moreover, to our knowledge, there are no longitudinal cohort studies for investigating the risk of progression of T2DM-DN to ESKD. In our study, higher remnant cholesterol was associated with a higher risk of ESKD in patients with T2DM-DN, and it may be a new noninvasive predictor of ESKD.

Genetic variants affecting mitochondrial function provide further insights for kidney disease

BackgroundChronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes.MethodsWe used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients.ResultsFourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI95%:4.440–21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR.ConclusionsWe identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.

#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&amp;gt;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.

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 5 ml/min/1.73 m2 per year or greater, and ESKD defined as eGFR <15/min/1.73 m2 for at least 3 months, on dialysis or renal death at follow-up. During a median follow-up period of 7.7 years, 197 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 [1.70–7.35]), Cer18:0/Cer24:0 (OR = 1.89 [1.10–3.25]), and Cer24:1/Cer24:0 (OR = 4.01 [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 [1.44–6.64]) and Cer24:1/Cer24:0 (HR = 4.66 [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 also associated with RDKF (OR = 2.28 [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, including baseline renal functions in patients with T2D.

Non-indicated initiation of proton pump inhibitor and risk of adverse outcomes in patients with underlying chronic kidney disease: a nationwide, retrospective, cohort study

ObjectiveEvidence related to the risk of kidney damage by proton pump inhibitor (PPI) initiation in patients with ‘underlying’ chronic kidney disease (CKD) remains scarce, although PPI use is generally associated...

Impact of red blood cell distribution width–albumin ratio on prognosis of patients with CKD

The red blood cell distribution width–albumin ratio (RAR) is a prognostic factor for adverse outcomes in various populations. However, whether RAR is associated with renal outcomes remains unclear. Therefore, we aimed to investigate the impact of RAR on the prognosis in patients with chronic kidney disease (CKD). We conducted a retrospective cohort study using 997 CKD patients who were enrolled in the Fukushima Cohort Study. Patients were categorized into tertiles (T1-3) according to the baseline RAR. The associations of RAR with end-stage kidney disease (ESKD) were assessed using Kaplan–Meier curves and multivariable cox regression analyses. Receiver operating characteristic (ROC) curves were performed to test whether significant differences were present between red cell distribution width (RDW) and RAR. The median age was 66, 57% were men, the median eGFR was 47.8 ml/min/1.73 m2, and the median value of RAR was 3.5. The higher RAR group showed an increased risk for ESKD in the Kaplan–Meier curve analysis. Compared to the lowest RAR group, higher RAR groups had a higher risk of ESKD (hazard ratio [HR] 1.37, 95% CI 0.68–2.78 and 2.92, 95% CI 1.44–5.94) for T2 and T3 groups, respectively. ROC curve analysis proved that the discriminating ability of RAR for ESKD was superior to RDW. A higher RAR value was associated with worse renal outcomes in patients with CKD. RAR could be a convenient and useful prognostic marker for renal prognosis.

Mediators between canagliflozin and renoprotection vary depending on patient characteristics: Insights from the CREDENCE trial.

To identify the mediators between canagliflozin and renoprotection in patients with type 2 diabetes at a high risk of end-stage kidney disease (ESKD). In this post hoc analysis of the CREDENCE trial, the effect of canagliflozin on potential mediators (42 biomarkers) at 52 weeks and the association between changes in mediators and renal outcomes were evaluated using mixed-effects and Cox models, respectively. The renal outcome was a composite of ESKD, serum creatinine doubling or renal death. The percentage of the mediating effect of each significant mediator was calculated based on changes in the hazard ratios of canagliflozin after additional adjustment of the mediator. Changes in haematocrit, haemoglobin, red blood cell (RBC) count and urinary albumin-to-creatinine ratio (UACR) at 52 weeks significantly mediated 47%, 41%, 40% and 29% risk reduction with canagliflozin, respectively. Further, 85% mediation was attributed to the combined effect of haematocrit and UACR. A large variation in mediating effects by haematocrit change existed among the subgroups, ranging from 17% in those patients with a UACR of more than 3000 mg/g to 63% in patients with a UACR of 3000 mg/g or less. In the subgroups with a UACR of more than 3000 mg/g, UACR change was the highest mediating factor (37%), driven by the strong association between UACR decline and renal risk reduction. The renoprotective effects of canagliflozin in patients at a high risk of ESKD can be significantly explained by changes in RBC variablesand UACR. The complementary mediating effects of RBC variables and UACR may support the renoprotective effect of canagliflozin in different patient groups.

#4292 PATIENT-REPORTED MENTAL HEALTH PROBLEMS, SUICIDE IDEATION, AND CLINICAL OUTCOMES IN ADULTS WITH NON-DIALYSIS CKD: RESULTS OF THE KNOW-CKD STUDY

Abstract Background and Aims Mental health is important for health and well-being at every stage of life and disease. Mental health problems are common and bothersome in chronic kidney disease (CKD). Mental health problems of CKD are poorly understood and evaluated. To address the importance of mental health in CKD, we analyzed a prospective cohort database from prospective CKD cohort. Method We analyzed 1897 participants from the KNOW-CKD cohort. We evaluated 4 items as indicators of patient-reported mental health: sleep duration, perceived stress, depressive symptoms, and suicidal ideation. To facilitate interpretation of the mental health problems in CKD, we measure a scaled effect size (ES) for the Kidney Disease Quality of Life Short Form (KDQOL-SF) differences among the groups of mental health problems. We investigated the association between patient-reported mental health problems and clinical outcomes of incident end-stage kidney disease (ESKD) all-cause death in non-dialysis CKD. Results The mean age was 53 ± 12 years and 62% were male. The participants had mental health problems of inadequate sleep duration (17.4%), subject distress (27.3%), experience of depression (13.2%), and suicide ideation (16.8%), but had not well taken care (psychiatric counselling 1.9%, antidepressant therapy 2.8%). The 4 item indicators of mental health showed large effect size between-groups KDQOL mental component summary (ES = 1.67). In the fully adjusted Cox proportional model, poor mental health (≥2 mental health problems) was associated with high risk of ESKD [HR = 1.46; 95% CI (1.18∼1.08)] and death [HR = 1.55; 95% CI (1.04∼2.32)] compared to good mental health (no mental health problems). Among 4 item indicators of patient-reported mental health, suicide ideation was the most predictive indicator of clinical outcomes. Conclusion Mental health problem is common and undertreated in CKD. Poor mental health is associated with high risk of ESKD and death in non-dialysis CKD and the single question of suicide ideation is significantly associated with high risk of ESKD and death. It suggests that the evaluation and management of mental health problem is important to the clinical outcomes in CKD.

#4727 FLOZINATION: A ROLLING QUALITY IMPROVEMENT PROGRAMME

Abstract Background and Aims Sodium glucose linked transporter-2 inhibitors (SGLT2i) reduce renal and cardiovascular end points in people with chronic kidney disease (CKD), both with and without diabetes. Despite exciting data from the CREDENCE and DAPA-CKD trials, implementation of new evidence to every day clinical practice can be challenging. We present the results of a rolling quality improvement project regarding SGLT2i prescription. The aim of the project was to support clinicians in the evidence based prescribing of SGLT2i for CKD. Method Three renal units who share a single electronic clinical database agreed a joint protocol and staged implementation programme. These tertiary referral renal units cover a population of around 2.3 million people. The important timeline regarding SGLT2i licensing and interventions is shown in Figure 1. Interventions were as follows: 1. Identification of patients meeting the licensing criteria for prescription of canagliflozin for CKD with diabetes. 2. Addition of an alert to the electronic patient record. 3. SGLT2i protocol developed and advertised via poster in outpatient clinic sites. 4. Evaluation of clinician attitude to prescribing. 5. Measurement of number of patients meeting the licensing criteria for prescription of dapagliflozin for CKD with and without diabetes. Measurement of SGLT2i prescription was audited from the electronic record. Results In the first wave of the programme, 326 patients were identified as suitable under the initial licensing criteria for canagliflozin, and electronic alerts were added to the records of these patients. When measuring number of patients who may be suitable under the dapagliflozin licensing, there were 562 patients with diabetes and 5262 without diabetes. In a survey of clinician attitudes, 94% suggested they felt well equipped to prescribe SGLT2i. Prescribing of SGLT2i across time is shown in Figure 2. 1146 patients have been prescribed SGLT2i. Age was 64±13 years, and the majority were male (68%) with type 2 diabetes mellitus (61%). Most (73.6%) were treated with angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). More than half (54%) of patients live in areas with high levels of socio-economic deprivation (Scottish Index of Multiple Deprivation quintiles 1 or 2). Estimated glomerular filtration rate was 40.9±23.5ml/min/1.73 m2 and Kidney Failure Risk Equation (KFRE) 5 year risk of end stage kidney disease (ESKD) was 23.2±28.2%. In comparison with the general outpatient clinic population, the distribution of socioeconomic deprivation was similar, but a higher proportion were female (46%). Conclusion An iterative quality improvement project was designed around the evolving drug licensing of SGLT2i and capitalised on local strengths, including an effective and well used clinical electronic database shared across renal units. Clinicians have been supported in SGLT2i prescribing with highly visible clinical protocols, and electronic alerts to highlight candidate patients. A high level of SGLT2i prescribing has been achieved in a population at high risk of ESKD. Further interventions should focus on prescribing in groups where gaps have been identified – such as women and those without diabetes. Other units would be recommended to capitalise on existing strengths, exploit the use of clinical databases, and ensure protocols are inclusive and well-advertised in order to optimise evidence based treatment of CKD.

Predicting kidney outcomes among Latin American patients with lupus nephritis: The prognostic value of interstitial fibrosis and tubular atrophy and tubulointerstitial inflammation.

To assess the effect of tubulointerstitial inflammation (TII) and interstitial fibrosis and tubular atrophy (IFTA) on kidney survival in lupus nephritis (LN). Two hundred eighty five patients with biopsy-proven LN were retrospectively studied. Kidney survival was defined as the time from initial biopsy to end-stage kidney disease (ESKD), dialysis, or transplant. Kidney survival analysis was performed by the Kaplan-Meier method and the statistical difference between survival curves compared by the log-rank test. Cumulative incidence functions with competing risk of death for kidney survival were also graphed. Multivariable Cox proportional hazards regression and competing-risk analyses were performed to identify independent predictors of ESKD. Fifty-seven patients (20%) progressed to ESKD during a median time of 4.2 (2.0-55.2)months after biopsy. TII was present in 206 (72.3%) biopsies, while IFTA in 99 (34.7%) biopsies. Patients with moderate-to-severe IFTA had worse kidney survival than those with none or mild IFTA in both the Kaplan-Meier (p = 0.018) and the competing-risk analyses (p = 0.017). Patients with class IV ± V LN had worse kidney survival than those with non-class IV LN by the Kaplan-Meier method (p = 0.050), but not in the competing-risk analysis (p = 0.154). Worse kidney survival was also found among those with fibrous crescents than those without, in both the Kaplan-Meier (p = 0.010) and the competing-risk (p = 0.011) analyses. By multivariable Cox regression analysis, older age (HR 1.04, 95% CI 1.01-1.07) and class IV ± V LN (HR 5.06, 95% CI 1.82-14.09) were associated with higher risk of ESKD after adjusting for sex, ethnicity, TII, and IFTA. By competing-risk analyses, class IV ± V LN (SHR 3.32, 95% CI 1.25-8.83) and no response to immunosuppressive therapy (SHR 4.55, 95% CI 1.54-13.41) were associated with a higher risk of ESKD, while eGFR >90mL/min/1.73m2 (SHR 0.98 for each ml/min/1.73m2, 95% 0.97-0.99) with a lower risk. Patients with moderate-to-severe IFTA had worse kidney survival than those with none or mild IFTA. Worse kidney survival was also found among those with class IV LN and fibrous crescents versus those without IV LN and fibrous crescents, respectively.

Age-based risk of end-stage kidney disease in patients with myelomeningocele

We aimed to quantify end-stage kidney disease (ESKD) risk after infancy in individuals with myelomeningocele (MMC) followed by urology in the modern medical era and to assess if ESKD risk was higher after surgery related to a hostile bladder. We retrospectively reviewed patients with MMC followed by urology at our institution born≥1972 (when clean intermittent catheterization was introduced) past 1 year of age (when mortality is highest, sometimes before establishing urology care). ESKD was defined as requiring permanent peritoneal/hemodialysis or renal transplantation. Early surgery related to hostile bladder included incontinent vesicostomy, bladder augmentation, detrusor Botulinum A toxin injection, ureteral reimplantation, or nephrectomy for recurrent urinary tract infections. Survival analysis and proportional hazards regression were used. Sensitivity analyses included: risk factor analysis with only vesicostomy, timing of surgery, including the entire population without minimal follow-up (n=1054) and only patients with≥5 years of follow-up (n=925). Overall, 1029 patients with MMC were followed for a median of 17.0 years (49% female, 76% shunted). Seven patients (0.7%) developed ESKD at a median 24.3 years old (5 hemodialysis, 1 peritoneal dialysis, 1 transplantation). On survival analysis, the ESKD risk was 0.3% at 20 years old and 2.1% at 30 years old (Figure). This was ∼100 times higher than the general population (0.003% by 21 years old, p<0.001). Patients who underwent early surgery for hostile bladder had higher ESKD risk (HR 8.3, p=0.001, 6% vs. 1.5% at 30 years). On exploratory analyses, gender, birth year, shunt status and wheelchair use were not associated with ESKD risk (p≥0.16). Thirty-year ESKD risk was 10% after early vesicostomy vs. 1.4% among children without one (p=0.001). Children undergoing bladder surgery between 1.5 and 5 years old had a higher risk of ESKD. No other statistically/clinically significant differences were noted. Patients with MMC remain at risk of progressive renal damage throughout life. We relied on the final binary ESKD outcome to quantify this risk, rather than imprecise glomerular filtration rate formulas. Analysis was limited by few people developing ESKD, inconsistent documentation of early urodynamic findings and indications for bladder-related surgery. While ESKD is relatively uncommon in the MMC population receiving routine urological care, affecting 2.1% of individuals in the first 3 decades, it is significantly higher than the general population. Children with poor bladder function are likely at high risk, underlining the need for routine urological care, particularly in adulthood.

The U-shaped association of post-lung transplant mortality with pretransplant eGFR underscores possible limitations of creatinine-based estimation equations for risk stratification.

Pre-existing chronic kidney disease (CKD) may have an impact on post-lung transplant survival and the development of end stage kidney disease (ESKD). We analyzed the US transplant database from 2006 to 2020. Adult patients who received their first lung transplant and were not on dialysis were included. Multivariable Cox regression was used to assess the effect of pretransplant eGFR on mortality and cumulative incidence competing risk was used to explore the effect on ESKD. The adjusted hazard ratio (aHR) for mortality showed a "U" shaped association with eGFR with a rising mortality at <60 and >100 ml/min/1.73m2. The increase in mortality with higher eGFR was only seen in those <30 year and were primarily in whites with a lower body mass index and in patients with cystic fibrosis (CF). The aHR for ESKD increased below an eGFR of 100 rising to 1.74 at an eGFR of 60. Any decrease in eGFR between listing and transplant >10% was associated with higher risk of ESKD. The U-shaped association of pretransplant eGFR with post-transplant mortality correlated with younger age, lower BMI and a diagnosis of CF. The aHR for ESKD following lung transplantation increased exponentially with worsening eGFR pretransplant.

Association of serum total bilirubin levels with progressive renal decline and end-stage kidney disease: 10-year observational cohort study in Japanese patients with diabetes.

ObjectivePrevious reports have demonstrated the association of serum bilirubin levels with the progression of diabetic nephropathy. The objective of this study is to assess the association of basal bilirubin levels with progressive renal decline (PRD) and end-stage kidney disease (ESKD).MethodsA total of 298 patients with diabetes who visited Kyushu University Hospital (Japan) were recruited and followed up for 10 years. PRD was defined as a negative change in estimated glomerular filtration ratio (eGFR) >3.7%/year, 2.5th percentile. Logistic regression analysis was performed to evaluate the association of total bilirubin levels with PRD and its cut-off point was determined by receiver operating characteristic (ROC) analysis. Kaplan-Meier method and Cox hazard regression analysis were used to evaluate the predictive ability of its cut-off point for ESKD.ResultsLogistic regression model showed that total bilirubin levels were significantly associated with PRD, and ROC analysis showed that its cut-off point was 0.5 mg/dL. Kaplan-Meier method showed that the percent of patients who reached two endpoints, composite endpoint (ESKD or doubling of creatinine level) or 30% eGFR decline, was significantly higher in the low bilirubin group than in the high bilirubin group (18.5% vs 11.0%, P = 0.045; 49.1% vs 42.1%, P = 0.045, respectively, log-rank test). Cox hazard regression models confirmed the independence of the predictive ability of its cut-off point.ConclusionsSerum total bilirubin levels were negatively associated with PRD in diabetic nephropathy and its cut-off point was 0.5 mg/dL. It may be clinically useful for identifying patients at high risk of ESKD.

Prediction model for the risk of ESKD in patients with primary FSGS.

The purpose of this study is to build a prediction model for accurate assessment of the risk of end-stage kidney disease (ESKD) in individuals with primary focal segmental glomerulosclerosis (FSGS) by integrating clinical and pathological features at biopsy. The prediction model was created based on a retrospective study of 99 patients with biopsy-proven primary FSGS diagnosed at our hospital between December 2012 and December 2019. We assessed discriminative ability and predictive accuracy of the model by C-index and calibration plot. Internal validation of the prediction model was performed with 1000-bootstrap procedure. Eight patients (8.1%) progressed to ESKD before 31 March 2021. Univariate analysis revealed that disease duration before biopsy, hematuria, hemoglobin, eGFR, and percentages of sclerosis and global sclerosis were associated with renal outcome. In multivariate analysis, three predictors were included in final prediction model: eGFR, hematuria, and percentage of sclerosis. The C-index of the model was 0.811 and 5-year calibration plot showed good agreement between predicted renal survival probability and actual observation. A nomogram and an online risk calculator were built on the basis of the prediction model. In conclusion, we constructed and internally validated the first prediction model for risk of ESKD in primary FSGS, which showed good discriminative ability and calibration performance. The prediction model provides an accurate and simple strategy to predict renal prognosis which may help to identify patients at high risk of ESKD and guide the management for patients with primary FSGS in clinical practice.

The Significance of Crescents on the Clinical Features and Outcomes of Primary Immunoglobin A Nephropathy

BackgroundIt is still controversial whether the proportion of crescents below 50% can be an independent predictive risk factor for poor prognosis in IgAN patients. We reported the significance of different proportions of crescents on the clinical features and the cut-off value of crescents in predicting the occurrence of end-stage kidney disease (ESKD) in patients with IgAN.MethodsWe retrospectively analyzed biopsy-proven primary IgAN patients in Sichuan Provincial People’s Hospital from 2007 to 2019. The patients were divided into 5 groups on the basis of crescent proportion as follows: 0 (n = 647), < 10% (n = 221), 10 to 24% (n = 272), 25 to 49% (n = 80), and ≥50% (n = 22). The primary endpoint was defined as ESKD, and the secondary endpoint was the combined renal endpoint (≥50% reduction in eGFR or ESKD). A validation cohort of 346 patients were enrolled from Affiliated Hospital of Southwest Medical University. Cox regression model and Kaplan-Meier survival analysis were performed.ResultsA total of 1242 eligible patients with biopsy-proven IgAN were recorded in the database, compared with the non-crescent group, patients in the crescent group had lower levels of hemoglobin (Hb) and albumin (Alb), higher levels of blood urea nitrogen (BUN), 24h urinary protein and hematuria, a higher proportion of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), and tubular atrophy/interstitial fibrosis (T1/T2) (p < 0.05). A higher crescent proportion was associated with lower levels of Hb, ALB, eGFR and serum IgG (p < 0.05), higher levels of SCr, BUN, increasing amounts of 24 h urinary protein, increasing proportion of M1 and E1, and increasing severity of interstitial inflammatory infiltration. During the median follow-up of 43 months (range 6-151), 63 individuals (7.0%) reached the primary outcome of ESKD and 99 patients (11.1%) reached the combined renal endpoint. 34(7.5%), 21 (13.3%), 24(12.2%), 14(21.5%) and 6(31.6%) patients reached the combined renal endpoint in the above five groups in crescents 0, <10%, 10∼24%, 25∼49% and ≥50%, respectively. A total of 274(62.6%) cases in the crescent group and 254 (55.7%) cases in the non-crescent group received immunosuppressive therapy. Multivariate Cox regression showed that crescents ≥50% was an independent risk factor for the progression of ESKD (p = 0.003) and crescents ≥25% was an independent risk factor for the combined renal endpoint(p < 0.001). The receiver operating characteristic curve showed that IgAN patients with crescents ≥43.7% had a higher risk of ESKD, even with immunosuppressants (Sensitivity = 75.7%,specificity = 89.6%,p < 0.001). This discovery cohort and the validation cohort further confirmed that patients with crescents <43.7% had better renal prognosis than those with crescents ≥43.7% in the whole group and those with immunosuppressants (p < 0.001).ConclusionIgAN patients with crescents had more severe clinicopathological features and poorer prognosis. Crescents ≥50% was an independent risk factor for the progression of ESKD and crescents ≥25% was an independent risk factor for ≥50% reduction in eGFR or ESKD in treated and untreated IgAN patients. Crescents ≥43.7% was an independent risk factor for ESKD in those with immunosuppressants.

Assessing Renal Function for Kidney Donation. How Low Is Too Low?

Kidney transplantation (KT) is the treatment of choice for patients with end-stage kidney disease (ESKD) with decreased morbi-mortality, improved life quality, and reduced cost. However, the shortage of organs from deceased donors led to an increase in KT from living donors. Some stipulate that living donors have a higher risk of ESKD after donation compared with healthy non-donors. The reason for this is not clear. It is possible that ESKD is due to the nephrectomy-related reduction in glomerular filtration rate (GFR), followed by an age-related decline that may be more rapid in related donors. It is essential to assess donors properly to avoid rejecting suitable ones and not accepting those with a higher risk of ESKD. GFR is a central aspect of the evaluation of potential donors since there is an association between low GFR and ESKD. The methods for assessing GFR are in continuous debate, and the kidney function thresholds for accepting a donor may vary according to the guidelines. While direct measurements of GFR (mGFR) provide the most accurate evaluation of kidney function, guidelines do not systematically use this measurement as a reference. Also, some studies have shown that the GFR decreases with age and may vary with gender and race, therefore, the lower limit of GFR in patients eligible to donate may vary based on these demographic factors. Finally, it is known that CrCl overestimates mGFR while eGFR underestimates it, therefore, another way to have a reliable GFR could be the combination of two measurement methods.

New-onset anemia and associated risk of ESKD and death in non-dialysis CKD patients: a multicohort observational study.

ABSTRACTBackgroundAnemia is a common complication of chronic kidney disease (CKD), but its incidence in nephrology settings is poorly investigated. Similarly, the risks of adverse outcomes associated with new-onset anemia are not known.MethodsWe performed a pooled analysis of three observational cohort studies including 1031 non-anemic CKD patients with eGFR <60 mL/min/1.73 m2 regularly followed in renal clinics. We estimated the incidence of mild anemia (hemoglobin 11–12 g/dL in women and 11–13 g/dL in men) and severe anemia (hemoglobin <11 g/dL or use of erythropoiesis-stimulating agents) during a 3-year follow-up period. Thereafter we estimated the risk of end-stage kidney disease (ESKD) and all-cause death associated with new-onset mild and severe anemia.ResultsThe mean age was 63 ± 14 years, 60% were men and 20% had diabetes. The mean estimated glomerular filtration rate (eGFR) was 37 ± 13 mL/min/1.73 m2 and the median proteinuria was 0.4 g/day [interquartile range (IQR) 0.1–1.1]. The incidence of mild and severe anemia was 13.7/100 patients-year and 6.2/100 patients-year, respectively. Basal predictors of either mild or severe anemia were diabetes, lower hemoglobin, higher serum phosphate, eGFR <30 mL/min/1.73 m2 and proteinuria >0.50 g/day. Male sex, moderate CKD (eGFR 30–44 mL/min/1.73 m2) and moderate proteinuria (0.15–0.50 g/day) predicted only mild anemia. The incidence of anemia increased progressively with CKD stages (from 8.77 to 76.59/100 patients-year) and the proteinuria category (from 13.99 to 25.02/100 patients-year). During a median follow-up of 3.1 years, 232 patients reached ESKD and 135 died. Compared with non-anemic patients, mild anemia was associated with a higher adjusted risk of ESKD {hazard ratio [HR] 1.42 [95% confidence interval (CI) 1.02–1.98]} and all-cause death [HR 1.55 (95% CI 1.04–2.32)]. Severe anemia was associated with an even higher risk of ESKD [HR 1.73 (95% CI 1.20–2.51)] and death [HR 1.83 (95% CI 1.05–3.19)].ConclusionsNew-onset anemia is frequent, particularly in patients with more severe renal damage and in those with diabetes mellitus. The occurrence of anemia, even of a mild degree, is associated with mortality risk and faster progression towards ESKD.

Longitudinal Follow-Up and Outcomes for Chinese Patients with Stage 1–4 Chronic Kidney Disease

Introduction: Understanding heterogeneity in the prognosis of chronic kidney disease (CKD) has implications in management of patients. We aimed to evaluate the comparative risk of end-stage kidney disease (ESKD), cardiovascular (CV) events, and death among patients with CKD in China. Methods: In total, 3,700 patients with CKD stage 1–4 were recruited from 39 clinical centers in China between 2011 and 2016. New occurrence of ESKD, CV events, and all-cause mortality was recorded until the end of 2017. The crude incidence rate was calculated for each outcome. Ratios of incidence between different outcomes were generated with 95% confidence interval (CI) estimated by 1,000 times of bootstrapping. Multivariable adjusted Cox regression models accounting for competing risk between the outcomes were used to evaluate the association of risk factors with the outcomes. Results: The population mean age was 50 ± 14 years, with 58.2% male and 60.3% of glomerulonephritis. After a median follow-up of 4.65 years (interquartile range [IQR]: 3.71–5.60 years) for ESKD, 4.76 years (IQR: 3.97–5.76 years) for CV events, and 4.84 years (IQR: 3.97–5.76 years) for death, the incidence rates of the 3 outcomes were 3.1, 1.5, and 0.92/100 patient-years, respectively. The ratio for the incidence of ESKD and CV events was 2.15 (95% CI: 1.87, 2.53) and that for incidence of ESKD and death was 3.41 (95% CI: 2.88, 4.08). Significant differences regarding the ratios were detected through levels of age, history of CV disease, the estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (uACR), and etiology of CKD. In the Cox regression model adjusting for traditional CV and kidney-specific risk factors, older age was associated with a higher risk of CV events and death but a lower risk of ESKD (hazard ratios [HRs] = 1.45 [95% CI: 1.29, 1.64], 1.48 [95% CI: 1.29, 1.70], and 0.78 [95% CI: 0.73, 0.84] per 10 year increase, respectively). By comparison, reduced eGFR was associated with a higher risk of ESKD and death, rather than CV events (HRs = 3.62 [95% CI: 2.96, 4.43], 1.30 [95% CI: 1.02, 1.66], and 1.22 [95% CI: 0.99, 1.49] per 30.26 mL/min/1.73 m2 increase, respectively). Similar patterns were seen for increased uACR (HRs = 1.42 [95% CI: 1.30, 1.55], 1.17 [95% CI: 1.05, 1.30], and 1.07 [95% CI: 0.99, 1.17] per 1 natural log-transformed value increase, respectively). Conclusion: ESKD was more likely to occur than CV events and death in the population with CKD stage 1–4 in China. Traditional risk factors contributed differently to the comparative risk of the outcomes.

Associations of kidney tests at medical facilities and health checkups with incidence of end-stage kidney disease: a retrospective cohort study

No study has assessed the association between no health checkup and end-stage kidney disease (ESKD). This retrospective cohort study, including 69,147 adults aged ≥ 40 years in Japan who were insured by the National Health Insurance and the Late-Stage Medical Care System for the Elderly, assessed the associations of kidney tests at medical facilities and health checkups with incident ESKD. The main exposure was the histories of kidney tests using dipstick urinalysis and/or serum creatinine measurement at medical facilities and checkups in the past year: “checkups,” “no kidney test (without checkup),” and “kidney tests (without checkup)” groups. During the median observational period of 5.0 years, ESKD was observed in 246 (0.8%) men and 124 (0.3%) women. The “no kidney test” group was associated with ESKD in men (adjusted subhazard ratio of “no kidney test” vs. “checkups”: 1.66 [95% confidence interval, 1.04–2.65], but not in women. Age-specific subgroup analyses identified the “no kidney test” group as a high-risk population of ESKD in elderly men (1.30 [0.70–2.41] and 2.72 [1.39–5.33] in men aged 40–74 and ≥ 75 years, respectively). Elderly men with no kidney test at medical facilities and no health checkup were at higher risk of ESKD.