Rapid Kidney Research Articles

Supaglutide alleviates hepatic steatosis in monkeys with spontaneous MASH

BackgroundGlucagon-like peptide 1 (GLP-1) is an incretin hormone and plays an important role in regulating glucose homeostasis. GLP-1 has a short half-life due to degrading enzyme dipeptidyl peptidase-IV and rapid kidney clearance, which limits its clinical application as a therapeutic agent. We demonstrated previously that supaglutide, a novel long-acting GLP-1 analog, exerted hypoglycemic, hypolipidemic, and weight loss effects in type 2 diabetic db/db mice, DIO mice, and diabetic monkeys. In the present study, we investigated supaglutide’s therapeutic efficacy in rhesus monkeys with spontaneous metabolic dysfunction-associated steatohepatitis (MASH).Methods15 rhesus monkeys with biopsy-confirmed MASH were divided into three groups, receiving supaglutide 50 µg/kg, supaglutide 150 µg/kg, and placebo, respectively, by weekly subcutaneous injection for 3 months. Liver fat content quantified by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), liver pathology, and metabolic parameters were assessed.ResultsWe found that once-weekly subcutaneous injections of supaglutide for 3 months significantly reduced hepatic fat accumulation, with a 40% percentage decrease in MRI-PDFF from baseline (P < 0.001 vs. Placebo). Treatment with supaglutide alleviated hepatic histological steatosis (nonalcoholic fatty liver disease activity score P < 0.001 vs. Placebo) without worsening of fibrosis, as assessed by ultrasound-guided liver biopsy. Supaglutide concomitantly ameliorated liver injury exemplified by a lowering tendency of hepatic alanine aminotransferase levels. Supaglutide also decreased body weight in a dose-dependent fashion accompanied by decreased food intake, improved lipid profile and glycemic control.ConclusionsSupaglutide exerts beneficial effects on hepatic and metabolic outcomes in spontaneous MASH monkeys.

Association between uric acid to high-density lipoprotein cholesterol ratio and chronic kidney disease among Chinese middle-aged and older adults with abnormal glucose metabolism: a nationwide cohort study.

Previous research has demonstrated a correlation between uric acid to high-density lipoprotein cholesterol ratio (UHR) and chronic kidney disease (CKD), yet the evidence remains unclear in individuals with abnormal glucose metabolism. The objective of this research was to investigate the correlation between UHR and the occurrence of CKD, as well as the rapid kidney function decline among individuals aged over 45years with abnormal glucose metabolism, using data from the China Health and Retirement Longitudinal Study (CHARLS). This study employed K-means clustering to categorize individuals based on UHR control levels into four classes. Subsequently, multivariate logistic regression analyses were utilized to explore the relationships between UHR and the occurrence of CKD as well as rapid kidney function decline. To examine the potential nonlinear relationship, restricted cubic spline (RCS) analyses were employed. Subgroup analyses and various sensitivity analyses were applied to validate the reliability of the results. This study encompassed 3902 participants, all of whom had prediabetes or diabetes. In the fully adjusted logistic regression model assessing the risk of CKD development, the odds ratios (ORs) for Class 2, Class 3, and Class 4, versus Class 1, were 1.08 (0.71 to 1.67), 1.71 (1.06 to 2.77), and 2.13 (1.02 to 4.35), respectively. For every 1 standard deviation (SD) increase in cumulative UHR exposure, there was a 32% elevation in the risk of CKD incidence (OR: 1.32, 95% CI 1.12 to 1.56). RCS curves suggested a linear association between cumulative UHR (CumUHR) and CKD occurrence, but a nonlinear association with rapid renal function progression. Subgroup analysis indicated an interaction between age and UHR on the development of CKD. The application of multiple sensitivity analyses yielded consistent outcomes, suggesting the robustness of the findings. In individuals with abnormal glucose metabolism, suboptimal control of UHR signifies an elevated risk of rapid kidney function decline and the incidence of CKD in the future. Therefore, close monitoring of long-term variations in UHR can facilitate early identification of the risk for CKD development.

Leveraging Explainable Artificial Intelligence (XAI) for Expert Interpretability in Predicting Rapid Kidney Enlargement Risks in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Autosomal dominant polycystic kidney disease (ADPKD) is the predominant hereditary factor leading to end-stage renal disease (ESRD) worldwide, affecting individuals across all races with a prevalence of 1 in 400 to 1 in 1000. The disease presents significant challenges in management, particularly with limited options for slowing cyst progression, as well as the use of tolvaptan being restricted to high-risk patients due to potential liver injury. However, determining high-risk status typically requires magnetic resonance imaging (MRI) to calculate total kidney volume (TKV), a time-consuming process demanding specialized expertise. Motivated by these challenges, this study proposes alternative methods for high-risk categorization that do not rely on TKV data. Utilizing historical patient data, we aim to predict rapid kidney enlargement in ADPKD patients to support clinical decision-making. We applied seven machine learning algorithms—Random Forest, Logistic Regression, Support Vector Machine (SVM), Light Gradient Boosting Machine (LightGBM), Gradient Boosting Tree, XGBoost, and Deep Neural Network (DNN)—to data from the Polycystic Kidney Disease Outcomes Consortium (PKDOC) database. The XGBoost model, combined with the Synthetic Minority Oversampling Technique (SMOTE), yielded the best performance. We also leveraged explainable artificial intelligence (XAI) techniques, specifically Local Interpretable Model-Agnostic Explanations (LIME) and Shapley Additive Explanations (SHAP), to visualize and clarify the model’s predictions. Furthermore, we generated text summaries to enhance interpretability. To evaluate the effectiveness of our approach, we proposed new metrics to assess explainability and conducted a survey with 27 doctors to compare models with and without XAI techniques. The results indicated that incorporating XAI and textual summaries significantly improved expert explainability and increased confidence in the model’s ability to support treatment decisions for ADPKD patients.

Development of a machine learning model for precision prognosis of rapid kidney function decline in people with diabetes and chronic kidney disease

AimsTo develop a machine learning model for predicting rapid kidney function decline in people with type 2 diabetes (T2D) and chronic kidney disease (CKD) and to pinpoint key modifiable risk factors for targeted interventions. MethodsWe conducted a retrospective cohort study on 6,924 individuals with T2D and CKD at Seoul National University Hospital. Kidney function decline was assessed using estimated glomerular filtration rate slopes. The performance of the eXtreme Gradient Boosting (XGBoost) model was evaluated through model diagnosis and time-to-event analyses. Copula simulation was conducted to stratify risk subgroups using modifiable risk factors. ResultsA total of 906 (13.1 %) individuals experienced rapid kidney function decline. The XGBoost model demonstrated optimal performance (area under the receiver operating characteristic curve: 0.826). The hazard of end-stage kidney disease within eight years increased across risk quartiles, with statistically significant hazard ratios in Q3 (2.06; 95 % confidence interval [CI]: 1.29–3.29) and Q4 (10.9; 95 % CI: 7.36–16.2). Simulation analysis identified high-risk subgroups by stage A3 albuminuria and at least two of the following: haematocrit < 39.0 %, systolic blood pressure > 120 mmHg, and glycated hemoglobin A1c > 6.5 %. ConclusionsThe XGBoost model, augmented by copula simulation, successfully stratified kidney prognosis in individuals with T2D and CKD.

Heart rate variability indices for predicting cardiorenal outcomes: A lesson from the PERL and ACCORD cohorts.

This commentary highlights the role of heart rate variability (HRV) indices in predicting diabetic kidney disease (DKD) progression, based on findings from the PERL and ACCORD trials. HRV-derived measures from routine ECGs are shown to be strong predictors of rapid kidney function decline in both type 1 and type 2 diabetes, suggesting their potential utility in identifying individuals at high risk for DKD and guiding early preventive interventions.

Beyond hemoglobin: Critical role of 2,3-bisphosphoglycerate mutase in kidney function and injury.

2,3-bisphosphoglycerate mutase (BPGM) is traditionally recognized for its role in modulating oxygen affinity to hemoglobin in erythrocytes. Recent transcriptomic analyses, however, have indicated a significant upregulation of BPGM in acutely injured murine and human kidneys, suggesting a potential renal function for this enzyme. Here we aim to explore the physiological role of BPGM in the kidney. A tubular-specific, doxycycline-inducible Bpgm-knockout mouse model was generated. Histological, immunofluorescence, and proteomic analyses were conducted to examine the localization of BPGM expression and the impact of its knockout on kidney structure and function. Invitro studies were performed to investigate the metabolic consequences of Bpgm knockdown under osmotic stress. BPGM expression was localized to the distal nephron and was absent in proximal tubules. Inducible knockout of Bpgm resulted in rapid kidney injury within 4 days, characterized by proximal tubular damage and tubulointerstitial fibrosis. Proteomic analyses revealed involvement of BPGM in key metabolic pathways, including glycolysis, oxidative stress response, and inflammation. Invitro, Bpgm knockdown led to enhanced glycolysis, decreased reactive oxygen species elimination capacity under osmotic stress, and increased apoptosis. Furthermore, interactions between nephron segments and immune cells in the kidney suggested a mechanism for propagating stress signals from distal to proximal tubules. BPGM fulfills critical functions beyond the erythrocyte in maintaining glucose metabolism in the distal nephron. Its absence leads to metabolic imbalances, increased oxidative stress, inflammation, and ultimately kidney injury.

Albuminuria and Rapid Kidney Function Decline as Selection Criteria for Kidney Clinical Trials in Type 1 Diabetes Mellitus.

The optimal criteria to select individuals with type 1 diabetes mellitus (T1D) and albuminuric or normoalbuminuric diabetic kidney disease (DKD), who are at risk of rapid kidney function decline, for clinical trials are unclear. This study analyzed data from the Preventing Early Renal Loss in Diabetes (PERL) clinical trial, which investigated whether allopurinol slowed kidney function decline in persons with T1D and early-to-moderate DKD. Rates of iohexol GFR (iGFR) and estimated GFR (eGFR) decline during the three-year study were compared by linear mixed effect regression between participants enrolled based on a history of moderately or severely increased albuminuria (N=394) and those enrolled based on a recent history of rapid kidney function decline (≥3 ml/min/1.73 m2/year) in the absence of a history of albuminuria (N=124). The association between baseline albuminuria and iGFR/eGFR decline during the trial was also evaluated. Rates of eGFR decline during the trial were higher in participants with a history of albuminuria than in those with a history of rapid kidney function decline (-3.56 [95% confidence intervals {CI} -3.17, -3.95] versus -2.35 [95% CI: -1.86, -2.84] ml/min/1.73 m2/year, p=0.001). Results were similar for iGFR decline, although the difference was not significant (p=0.07). Within the history of albuminuria group, the rate of eGFR decline was -5.30 (95% CI -4.52, -6.08) ml/min/1.73m2/year in participants with severely increased albuminuria as compared to -2.97 (95% CI 2.44, -3.50) and -2.32 (95% CI -1.61, -3.03) ml/min/1.73m2/year in those with moderately increased or normal/mildly increased albuminuria at baseline (p<0.001). Severely increased albuminuria at screening is a powerful criterion for selecting persons with T1D at high risk of kidney function decline. A history of rapid eGFR decline without a history of albuminuria is less effective for this purpose but it can still identify individuals with T1D who will lose kidney function more rapidly than expected from physiological aging. ClinicalTrials.gov, NCT02017171.

Pegloticase-Induced Rapid Uric Acid Lowering and Kidney and Cardiac Health Markers in Youth-Onset Type 2 Diabetes: A Pilot Clinical Trial

Rationale & ObjectiveElevated serum uric acid (SUA) is a risk factor for incident hypertension and diabetic kidney disease in young persons with type 2 diabetes (T2D), particularly men. The acute benefit of aggressively lowering SUA on kidney and cardiovascular function in this population remains underexplored. This study was conducted to investigate the impact of a single pegloticase infusion on kidney and cardiovascular function. Study DesignAn open-label pilot trial. Setting & ParticipantsThe study involved 10 young adult males with youth-onset T2D and SUA levels ≥5 mg/dL. Intervention(s)Participants received a single infusion of pegloticase (8 mg). Evaluations were conducted using iohexol-based measured glomerular filtration rate (mGFR) and cardiac/kidney MRI before and one week after infusion. OutcomesThe primary outcomes were changes in SUA and mGFR one week after pegloticase infusion. ResultsNine participants (mean [±SD] age 22±5 years, HbA1c 8.6±3.3%, BMI 40.1±11.0 kg/m2, SUA 6.7±1.1 mg/dL) completed the pegloticase infusion and were included in the analysis. One week after the infusion, median [p25,p75] SUA concentrations dropped from 6.4 [5.6,7.6] to 0.5 [0.5,4.6] mg/dL (p=0.01). Mean mGFR increased from 113±20 to 122±19 ml/min per 1.73 m2 (p=0.004). Among responders (SUA reduction ≥3 mg/dL), an increase in mGFR correlated with an increase in renal artery blood flow (r:0.60, p=0.24) and decrease in SUA (r:-0.79, p=0.05). Mean MRI peak longitudinal cardiac strain additionally decreased from 15.4±2.2 to 13.1±2.2 % (p=0.03) in these responders. LimitationsThe pilot nature of the study and the small sample size limit the generalizability of the findings. ConclusionsIn young adult males with T2D, a single pegloticase infusion decreased SUA levels, which increased mGFR and was strongly associated with increased renal blood flow and impaired cardiac global longitudinal strain. Further research is required to assess the long-term efficacy and safety of pegloticase in patients with T2D.

Lipid-lowering drugs and risk of rapid renal function decline: a mendelian randomization study.

Chronic kidney disease (CKD) patients face the risk of rapid kidney function decline leading to adverse outcomes like dialysis and mortality. Lipid metabolism might contribute to acute kidney function decline in CKD patients. Here, we utilized the Mendelian Randomization approach to investigate potential causal relationships between drug target-mediated lipid phenotypes and rapid renal function decline. In this study, we utilized two methodologies: summarized data-based Mendelian randomization (SMR) and inverse variance-weighted Mendelian randomization (IVW-MR), to approximate exposure to lipid-lowering drugs. This entailed leveraging expression quantitative trait loci (eQTL) for drug target genes and genetic variants proximal to drug target gene regions, which encode proteins associated with low-density lipoprotein (LDL) cholesterol, as identified in genome-wide association studies. The objective was to investigate causal associations with the progression of rapid kidney function decline. The SMR analysis revealed a potential association between high expression of PCSK9 and rapid kidney function decline (OR = 1.11, 95% CI= [1.001-1.23]; p = 0.044). Similarly, IVW-MR analysis demonstrated a negative association between LDL cholesterol mediated by HMGCR and kidney function decline (OR = 0.74, 95% CI = 0.60-0.90; p = 0.003). Genetically predicted inhibition of HMGCR is linked with the progression of kidney function decline, while genetically predicted PCSK9 inhibition is negatively associated with kidney function decline. Future research should incorporate clinical trials to validate the relevance of PCSK9 in preventing kidney function decline.

Effects of Body Mass Index on Rapid Kidney Function Decline: A Two-Sample Mendelian Randomization Study

Effects of Body Mass Index on Rapid Kidney Function Decline: A Two-Sample Mendelian Randomization Study

Effects of MAFLD defined by fatty liver index or ultrasonography on kidney function decline in the general population

This study aimed to investigate whether metabolic dysfunction-associated fatty liver disease (MAFLD) defined by the fatty liver index (FLI) affects the decline in kidney function and whether this relationship is still observed in MAFLD defined by ultrasonography (USG). A retrospective cohort study was conducted using de-identified data from participants who received health checkups at Samsung Changwon Hospital between 2002 and 2018. The primary and secondary exposures were the presence of FLI- and USG-defined MAFLD, respectively. The primary outcome was 5-years slope of eGFR. The secondary outcome was a rapid decline in kidney function, defined as a 5-years slope of estimated glomerular filtration rate (eGFR) of less than − 3 mL/min/1.73 m2 per year. A total of 37,500 participants were included in the analysis. Participants with FLI-defined MAFLD had a larger decline in 5-year eGFR slope than those without FLI-defined MAFLD (beta coefficients − 0.11; 95% CI − 0.14 to − 0.08). Participants with FLI-defined MAFLD had a higher risk of rapid kidney function decline than those without FLI-defined MAFLD (odds ratio 1.33; 95% confidence intervals (CIs) 1.05–1.69). However, USG-defined MAFLD was less related to kidney function decline. In conclusion, the presence of FLI-defined MAFLD was associated with larger and faster kidney function decline.

Artificial intelligence algorithms permits rapid acute kidney injury risk classification of patients with acute myocardial infarction

ObjectiveThis study aimed to develop and validate several artificial intelligence (AI) models to identify acute myocardial infarction (AMI) patients at an increased risk of acute kidney injury (AKI) during hospitalization. MethodsIncluded were patients diagnosed with AMI from the Medical Information Mart for Intensive Care (MIMIC) III and IV databases. Two cohorts of AMI patients from Changzhou Second People's Hospital and Xuzhou Center Hospital were used for external validation of the models. Patients' demographics, vital signs, clinical characteristics, laboratory results, and therapeutic measures were extracted. Totally, 12 AI models were developed. The area under the receiver operating characteristic curve (AUC) were calculated and compared. ResultsAKI occurred during hospitalization in 1098 (28.3 %) of the 3882 final enrolled patients, split into training (3105) and test (777) sets randomly. Among them, Random Forest (RF), C5.0 and Bagged CART models outperformed the other models in both the training and test sets. The AUCs for the test set were 0.754, 0.734 and 0.730, respectively. The incidence of AKI was 9.8 % and 9.5 % in 2202 patients in the Changzhou cohort and 807 patients in the Xuzhou cohort with AMI, respectively. The AUCs for patients in the Changzhou cohort were RF, 0.761; C5.0, 0.733; and bagged CART, 0.725, respectively, and Xuzhou cohort were RF, 0.799; C5.0, 0.808; and bagged CART, 0.784, respectively. ConclusionSeveral machines learning-based prediction models for AKI after AMI were developed and validated. The RF, C5.0 and Bagged CART model performed robustly in identifying high-risk patients earlier. Clinical trial approval statementThis Trial was registered in the Chinese clinical trials registry: ChiCTR1800014583. Registered January 22, 2018 (http://www.chictr.org.cn/searchproj.aspx).

Long-term effectiveness and safety of tolvaptan in autosomal dominant polycystic kidney disease

Background and objectivesEvidence on the long-term use of tolvaptan in autosomal dominant polycystic kidney disease (ADPKD) is limited. The aim was to evaluate the tolvaptan effectiveness and safety in real clinical setting. Material and methodsA single-center observational study (2016–2022) involving ADPKD patients treated with tolvaptan was conducted. Annual change in serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) before and after treatment initiation were evaluated. Change in total kidney volume (TKV), blood pressure (BP) and urinary albuminuria at 12, 24 and 36 months after initiation were also determined. Adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 were analyzed. ResultsA total of 22 patients were included. No significant differences pre- vs post tolvaptan treatment in annual rate of change in eGFR (−3.52ml/min/1.73m2 [−4.98%] vs −3.98ml/min/1.73m2 [−8.48%], p=0.121) and sCr (+0.06mg/dL [4.22%] vs +0.15mg/dL [7.77%], p=0.429) were observed. Tolvaptan improved urinary osmolality at 12 (p=0.019) and 24 months (p=0.008), but not at 36 months (p=0.11). There were no changes in TKV, BP control and urinary albuminuria at 12, 24 or 36 months. A worse response was shown in patients with rapid kidney function decline (p=0.042). A 36.4% of the patients developed grade III/IV AEs. A 22.7% discontinued treatment due to unacceptable toxicity. ConclusionsThis study shows a modest benefit of tolvaptan in ADPKD patients, as well as safety concerns.

Plasma metals, genetic risk, and rapid kidney function decline among type 2 diabetes

BackgroundRapid kidney function decline (RKFD) is a main clinical feature of early chronic kidney disease (CKD) in type 2 diabetes (T2D). Environmental and genetic factors influencing RKFD remain inadequately elucidated. ObjectivesThis study aimed to examine the associations of metals with RKFD among T2D and to further investigate the effect of metal mixtures on RKFD with the modifying effect of genetic susceptibility. MethodsThis study included 2209 people with T2D (1942 had genotyping data) free of CKD at baseline from the Dongfeng-Tongji cohort. We used inductively coupled plasma-mass spectrometry (ICP-MS) to measure 23 metals in baseline plasma. Using elastic net (ENET), multivariate logistic regression, and Bayesian kernel machine regression (BKMR) model, we examined independent associations of multiple metals with RKFD. We calculated the environmental risk score (ERS) to assess the effects of metal mixtures on RKFD and the genetic risk score (GRS) to assess genetic susceptibility. RKFD was defined as estimated glomerular filtration rate (eGFR) loss > 3 mL/min/1.73 m2/year. ResultsDuring a median of 9.8 years follow-up, 262 participants developed RKFD. Aluminum, vanadium, zinc, selenium, rubidium, tin, barium, and tungsten were screened from ENET. In multivariate logistic models, vanadium, selenium, and tungsten were negatively associated with RKFD, while zinc, tin, and rubidium were positively associated. The BKMR showed a nonlinear association of vanadium and rubidium with RKFD and interactions between metals (barium‑vanadium, barium‑rubidium). The ERS was positive associated with RKFD (per SD increase in ERS, OR = 1.94, 95% CI: 1.66, 2.27). No significant interaction between ERS and GRS was observed on RKFD, however, participants in the highest ERS and GRS group had the highest RKFD risk. ConclusionVanadium and rubidium were associated with RKFD in T2D. Metal mixtures was associated with an increased risk of RKFD in T2D, particularly in those at high genetic risk.

#2478 Multiparametric magnetic resonance imaging predicts decline of kidney function but does not perform better than diffusion-weighted MRI alone

Abstract Background and Aims Renal cortical interstitial fibrosis, typically measured by biopsy, is a critical factor for kidney function prognosis. Diffusion-weighted magnetic resonance imaging (DW-MRI) has emerged as a novel promising non-invasive method to assess the degree of fibrosis. We have previously shown that there is a strong correlation between the cortico-medullary apparent diffusion coefficient difference (ΔADC) and histologically assessed fibrosis. We also developed a model based on ΔADC, eGFR and proteinuria that calculates a risk score for future renal function decline. Multiparametric MRI combines DW-MRI with other sequences and can provide synchronized insights into perfusion, diffusion, oxygenation, and tissue characterization (T1 and T2 mappings). Our current research evaluates whether additional multiparametric MRI sequences increase the power of the DW-MRI based model to predict renal function decline. Method We used data from 197 patients with either chronic kidney disease (42) or allograft kidneys (155). Each participant underwent a biopsy followed by a multiparametric MRI within the following week. The median follow-up period was 2.2 years, during which laboratory parameters were recorded. The primary endpoint was defined as a rapid decline in kidney function, characterized by a reduction in eGFR of over 30%, or the initiation of dialysis. Prognostic factors for the primary outcome were analyzed using both univariable and multivariable Cox regression models, incorporating MRI parameters (ΔADC, cortical and ΔT1, cortical and ΔT2), eGFR, and proteinuria. Results At baseline, mean eGFR was 54.5 ml/min/1.73 m2 (SD 23.8) and mean proteinuria was 0.90 g/24 h (SD 2.4). Rapid decline of renal function occurred in 54 patients after a median time of 1.1 years (interquartile range, 0.9–2.1 years). In univariable survival analysis, cortical T1 measure and cortico-medullar difference ΔT2 have showed the best association to rapid kidney function decline. Compared to our previously established model incorporating ΔADC, eGFR, and proteinuria, adding cortical T1 did not significantly improve the hazard ratio (from 4.62 (95% CI: 1.56–13.67) to 4.36 (95% CI: 1.46–13.02) with cortical T1 inclusion). Harrell's C-index marginally increased with cortical T1, suggesting no significative improvement in prognostic capacity (0.77 versus 0.79 with cortical T1). Additionally, adjusting the regression model for ΔT2 yielded no enhancement in predictive power. Conclusion Our results did not demonstrate an enhancement of the prognostic power of the composite score with the inclusion of additional MRI sequences. Consequently, no clear benefit of multiparametric MRI on top of DW-MRI was observed. Additional research is required to investigate this issue more thoroughly.

#1968 IgA nephropathy and impact of proteinuria and kidney function decline on healthcare resource utilisation among adults in the United Kingdom

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and can result in kidney failure, especially if left untreated. Proteinuria ≥1.0 g/day is a major risk factor for IgAN progression and rapid kidney function decline. This study describes the characteristics of patients with IgAN in the United Kingdom (UK) and the impact of proteinuria and chronic kidney disease (CKD) stage on healthcare resource utilisation (HRU) and costs. Method In this retrospective, descriptive analysis, eligible patients had at least one code among ICD-9 583.9, ICD-10 N02.8, and ICD-10 N02.9 between 1 October 2015 and 1 October 2022. They were stratified by CKD stage and proteinuria level. CKD stage was defined by ICD-10 N18 code and estimated glomerular filtration rate. Proteinuria level was grouped as low or high by protein excretion rate (&amp;lt;1 g/day vs ≥1 g/day), protein/creatinine ratio (&amp;lt;0.88 g/g vs ≥0.88 g/g), or albumin/creatinine ratio (&amp;lt;100 mg/mmol vs ≥100 mg/mmol). HRU data for 1 year from the index date were obtained from electronic medical records, and costs were obtained from the National Schedule of the National Health Service 2021/22. Weighted average costs were calculated for inpatient, outpatient, and emergency visits. Results We identified 6 940 patients with IgAN. The mean age was 62 years, and most patients (n = 3 980; 57%) were male. For all visit types, HRU (Fig.) and costs (Table) increased with advancing CKD. For all visit types combined, the mean total cost per patient was &amp;gt;23 times higher for CKD stage 5 than stage 1 (£60 259 vs £2 609). Of 2 080 patients with proteinuria data, 560 (27%) had high proteinuria. Annual costs per patient (Table) and the numbers of all visit types (Figure) were higher for patients with a protein excretion rate ≥1 g/day than those with a rate &amp;lt;1 g/day (£12 622 vs £2 822). Conclusion In patients with IgAN in the UK, elevated proteinuria and advanced CKD stage were associated with higher HRU and costs across visit types. Treatments that reduce proteinuria can slow disease progression and prevent rapid decline in kidney function while potentially reducing IgAN-related resource utilisation and costs.

Urinary Dickkopf 3 Is Not an Independent Risk Factor in a Cohort of Kidney Transplant Recipients and Living Donors.

Urinary dickkopf 3 (uDKK3) is a marker released by kidney tubular epithelial cells that is associated with the progression of chronic kidney disease (CKD) and may cause interstitial fibrosis and tubular atrophy. Recent evidence suggests that uDKK3 can also predict the loss of kidney function in CKD patients and kidney transplant recipients, regardless of their current renal function. We conducted a prospective study on 181 kidney transplant (KTx) recipients who underwent allograft biopsy to determine the cause, analyzing the relationship between uDKK3 levels in urine, histological findings, and future allograft function progression. Additionally, we studied 82 living kidney donors before unilateral nephrectomy (Nx), 1-3 days after surgery, and 1 year post-surgery to observe the effects of rapid kidney function loss. In living donors, the uDKK3/creatinine ratio significantly increased 5.3-fold 1-3 days after Nx. However, it decreased significantly to a median level of 620 pg/mg after one year, despite the absence of underlying primary kidney pathology. The estimated glomerular filtration rate (eGFR) decreased by an average of 29.3% to approximately 66.5 (±13.5) mL/min/1.73 m2 after one year, with no further decline in the subsequent years. uDKK3 levels increased in line with eGFR loss after Nx, followed by a decrease as the eGFR partially recovered within the following year. However, uDKK3 did not correlate with the eGFR at the single time points in living donors. In KTx recipients, the uDKK3/creatinine ratio was significantly elevated with a median of 1550 pg/mg compared to healthy individuals or donors after Nx. The mean eGFR in the recipient group was 35.5 mL/min/1.73 m2. The uDKK3/creatinine ratio was statistically associated with the eGFR at biopsy but was not independently associated with the eGFR one year after biopsy or allograft loss. In conclusion, uDKK3 correlates with recent and future kidney function and kidney allograft survival in the renal transplant cohort. Nevertheless, our findings indicate that the uDKK3/creatinine ratio has no prognostic influence on future renal outcome in living donors and kidney recipients beyond the eGFR, independent of the presence of acute renal graft pathology, as correlations are GFR-dependent.

Accessing the relationship between six surrogate insulin resistance indexes and the incidence of rapid kidney function decline and the progression to chronic kidney disease among middle-aged and older adults in China: Results from the China health and retirement longitudinal study

AimsInsulin resistance is closely related to kidney function decline, but which insulin resistance index could better predict rapid kidney function decline (RKFD) remains unclear. We aimed to evaluate the prospective association between six insulin resistance indexes: Chinese Visceral Adiposity Index (CVAI), Lipid Accumulation Product (LAP), Atherogenic Index of Plasma (AIP), triglyceride-glucose (TyG) index, triglyceride-glucose × Body Mass Index (TyGBMI) and triglyceride-glucose × waist circumference (TyGWC) with RKFD and further the progression to chronic kidney disease (CKD). Methods and measurementsData were obtained from the China Health and Retirement Longitudinal Study. Participants with normal kidney function (eGFRcr-cys ≥60 ml/min per 1.73 m2) and ≥45 years old were included at the baseline (year 2011). The eGFR was estimated by a combination of serum creatinine and cystatin C. The primary outcome was RKFD, defined as an annualized decline in eGFRcr-cys of 5 ml/min per 1.73 m2 or more. Secondary outcome was progression to CKD under the condition of RKFD, defined as an annualized decline in eGFRcr-cys of 5 ml/min per 1.73 m2 or more combined with eGFRcr-cys <60 ml/min per 1.73 m2 at the exit visit. Logistic analysis was applied for analysis of the association between six insulin resistance indexes and RKFD or progression to CKD. We use receiver operating characteristic curves to study the predictive performance of six insulin resistance indexes. Subgroup analysis were conducted by diabetes or hypertension status of the participants. ResultsA total of 3899 participants with normal kidney function were included in this study. After a 3.99 years follow-up, 191 of them ended up with RKFD. Among them, 66 participants progressed to CKD. Logistic analysis showed that per SD increase of all the six insulin resistance indexes were significantly associated with the incidence of RKFD (all P < 0.01), among which, TyGWC had the best predictive value for RKFD. There were significant association between per SD increase of CVAI, LAP, TyGBMI and TyGWC with progression to CKD (all P < 0.01), and CVAI had better predictive role than other indexes. In subgroup analysis, we found that the association between insulin resistance indexes and progression to CKD was more significant in subjects with hypertension or without diabetes. However, no significant differences were observed in the RKFD group. ConclusionsIn this study we proved six insulin resistance indexes were predictively associated with RKFD in Chinese with normal renal function over age 45. TyGWC is the best insulin resistance index for predicting RKFD. CVAI is the best index for predicting further progression to CKD.

Effect of proteinuria on the rapid kidney function decline in chronic kidney disease depends on the underlying disease: A post hoc analysis of the BRIGHTEN study

AimsIt is unclear whether the effect of proteinuria on rapid kidney function decline is equivalent among diabetic kidney disease (DKD), non-DKD with diabetes (NDKD+DM), and nephrosclerosis without diabetes (NS-DM), particularly in advanced chronic kidney disease patients. MethodsIn total, 1038 chronic kidney disease patients who participated in the BRIGHTEN study were included in the present study. A linear mixed effect model was applied to estimate the annual estimated glomerular filtration rate decline in each disease group. ResultsThe prevalence of rapid decliners (rapid kidney function decline, defined as an eGFR loss of > 5 mL/min/1.73 m2/year) in the DKD group (44.6 %) was significantly higher compared with the NDKD+DM (27.9 %) and NS-DM (27.0 %) groups. By contrast, the prevalence of rapid decliners in different urine total protein to creatinine ratio (UPCR) categories (<0.5, 0.5 to < 1.0, 1.0 to < 3.5, and ≥ 3.5 g/g) were equivalent between the DKD and NS-DM groups. Moreover, the prevalence of a UPCR < 1.0 g/g in rapid decliners of the NS-DM group was more than double than in those of the DKD and NDKD+DM groups. ConclusionsThe risk of rapid kidney function decline in NS-DM patients with low levels of proteinuria may be greater than initially predicted.

Visceral Adiposity and Progression of ADPKD: A Cohort Study of Patients From the TEMPO 3:4 Trial

Rationale & ObjectiveBody-mass index (BMI) is an independent predictor of kidney disease progression in individuals with autosomal dominant polycystic kidney disease (ADPKD). Adipocytes do not simply act as a fat reservoir but are active endocrine organs. We hypothesized that greater visceral abdominal adiposity would associate with more rapid kidney growth in ADPKD and influence the efficacy of tolvaptan. Study DesignA retrospective cohort study. Setting & Participants1053 patients enrolled in the TEMPO 3:4 tolvaptan trial with ADPKD and high risk of rapid disease progression. PredictorEstimates of visceral adiposity extracted from coronal plane MRIs using deep learning. OutcomeAnnual change in total kidney volume (TKV) and effect of tolvaptan on kidney growth. Analytical ApproachMultinomial logistic regression and linear mixed models. ResultsIn fully adjusted models, the highest tertile of visceral adiposity was associated with greater odds of annual change in TKV of ≥7% vs. <5% (OR: 4.78 [3.03, 7.47]). The association was stronger in females than males (interaction p<0.01). In linear mixed models with an outcome of % change in TKV per year, tolvaptan efficacy (% change in TKV) was reduced with higher visceral adiposity (three-way interaction of treatment*time*visceral adiposity p=0.002). Visceral adiposity significantly improved classification performance of predicting rapid annual % change in TKV for individuals with a normal BMI (De-Long’s test Z-score: -2.03; p=0.04). Greater visceral adiposity was not associated with estimated glomerular filtration rate (eGFR) slope in the overall cohort; however, visceral adiposity was associated with more rapid decline in eGFR slope (below the median) in females (fully adjusted OR 1.06 [1.01, 1.11] per 10 unit increase in visceral adiposity) but not males (0.98 [0.95, 1.02]). LimitationsRetrospective; rapid progressors; computational demand of deep learning. ConclusionsVisceral adiposity that can be quantified by MRI in the coronal plane using a deep learning segmentation model, independently associates with more rapid kidney growth, and improves classification of rapid progression in individuals with a normal BMI. Tolvaptan efficacy decreases with increasing visceral adiposity.