Kidney Function Decline Research Articles

Metabolic acidosis in pediatric kidney transplant recipients.

Metabolic acidosis is a risk factor for faster kidney function decline in chronic kidney disease (CKD) and in adult kidney transplant recipients (KTRs). We hypothesized that metabolic acidosis would be highly prevalent and associated with worse allograft function in pediatric KTRs. Pediatric KTRs at Montefiore Medical Center from 2010 to 2018 were included. Metabolic acidosis was defined as serum bicarbonate < 22mEq/L or receiving alkali therapy. Regression models were adjusted for demographic factors and donor/recipient characteristics. Sixty-three patients were identified with a median age at transplant of 10.5 (interquartile range (IQR) 4.4-15.2) years and post-transplant follow-up of 3 (IQR 1-5) years. Baseline serum bicarbonate was 21.7 ± 2.4mEq/L, serum bicarbonate < 22mEq/L was present in 28 (44%), and 44% of all patients were receiving alkali therapy. The prevalence of acidosis ranged from 58 to 70% during the first year of follow-up. At baseline, each 1-year higher age at transplant and every 10ml/min/1.73m2 higher eGFR were associated with 0.16mEq/L (95% CI: 0.03-0.3) and 0.24mEq/L (95% CI: 0.01-0.5) higher serum bicarbonate, respectively. Older age at transplant was associated with lower odds of acidosis (OR: 0.84; 95% CI: 0.72-0.97). During follow-up, metabolic acidosis was independently associated with 8.2ml/min/1.73m2 (95% CI 4.4-12) lower eGFR compared to not having acidosis; furthermore, eGFR was significantly lower among KTRs with unresolved acidosis compared with resolved acidosis. Among pediatric KTRs, metabolic acidosis was highly prevalent in the first year post-transplantation and was associated with lower eGFR during follow-up. A higher resolution version of the Graphical abstract is available as Supplementary information.

DUBIOUS APPENDICITIS TO BE ACCOMPANIED BY RIGHT XANTHOGRANULOMATOUS PYELONEPHRITIS: A CASE REPORT

Xanthogranulomatous pyelonephritis (XGP) is a rare chronic kidney infection that can cause a progressive decline in kidney function and lead to kidney removal or death. Symptoms of right flank pain due to XGP, sometimes radiating to the lower abdomen were difficult to assess and distinguish from urinary tract diseases alone or accompanied by the involvement of other organs like appendicitis. We report a fifty-year-old woman was referred because of a suspected mass in the right kidney based on ultrasound, but the results of the Ct-Scan with contrast showed stones and chronic parenchymal kidney with a tendency to right pyelonephritis. There were no post-contrast enhancing masses in both kidneys. Then, decided to perform a nephroureterectomy and found inflammation in her appendices. Histopathology showed xanthogranulomatous pyelonephritis and chronic appendicitis. The patient was diagnosed with Chronic pyelonephritis based on CT-Scan, but the previous ultrasound showed no appendicitis, there was a mass in the right kidney. During nephroureterectomy, there were chronic appendicitis and Xanthogranulomatous Pyelonephritis after histopathology examination. This report describes uncommon pyelonephritis and confirms the difficulty of differentiating right XGP from appendicitis, even though it occurred in a large city. Moreover, it can be a lesson for general practitioners to be more thorough in diagnosing right abdominal or flank pain.

Proteomic profiling of longitudinal changes in kidney function among middle-aged and older men and women: the KORA S4/F4/FF4 study

BackgroundDue to the asymptomatic nature of the early stages, chronic kidney disease (CKD) is usually diagnosed at late stages and lacks targeted therapy, highlighting the need for new biomarkers to better understand its pathophysiology and to be used for early diagnosis and therapeutic targets. Given the close relationship between CKD and cardiovascular disease (CVD), we investigated the associations of 233 CVD- and inflammation-related plasma proteins with kidney function decline and aimed to assess whether the observed associations are causal.MethodsWe included 1140 participants, aged 55–74 years at baseline, from the Cooperative Health Research in the Region of Augsburg (KORA) cohort study, with a median follow-up time of 13.4 years and 2 follow-up visits. We measured 233 plasma proteins using a proximity extension assay at baseline. In the discovery analysis, linear regression models were used to estimate the associations of 233 proteins with the annual rate of change in creatinine-based estimated glomerular filtration rate (eGFRcr). We further investigated the association of eGFRcr-associated proteins with the annual rate of change in cystatin C-based eGFR (eGFRcys) and eGFRcr-based incident CKD. Two-sample Mendelian randomization was used to infer causality.ResultsIn the fully adjusted model, 66 out of 233 proteins were inversely associated with the annual rate of change in eGFRcr, indicating that higher baseline protein levels were associated with faster eGFRcr decline. Among these 66 proteins, 21 proteins were associated with both the annual rate of change in eGFRcys and incident CKD. Mendelian randomization analyses on these 21 proteins suggest a potential causal association of higher tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) level with eGFR decline.ConclusionsWe reported 21 proteins associated with kidney function decline and incident CKD and provided preliminary evidence suggesting a potential causal association between TNFRSF11A and kidney function decline. Further Mendelian randomization studies are needed to establish a conclusive causal association.

Pathological Approach to Kidney Allograft Infection.

Infectious agents can pose a significant challenge in kidney transplantation, as they have the potential to cause direct infections in the transplanted kidney. These infections can lead to a decline in kidney function and reduce the longevity of the transplanted kidney. Common post-transplant allograft infections include bacterial pyelonephritis and the BK virus infection, while adenovirus, JC virus, and cytomegalovirus are less frequent but can also lead to significant allograft dysfunctions. The histopathological features of these infections are characterized by the infiltration of inflammatory cells in the kidney interstitial area and the presence of viral nuclear inclusions or cytopathic changes in the renal tubular epithelial cells. The confirmation of causative organisms can be achieved by immunohistochemical staining or the visualization of viral particles using electron microscopic examination. However, these methods typically require a longer turnaround time and are not readily available in developing countries, unlike standard hematoxylin-eosin staining. Notably, the differential diagnosis of interstitial inflammation in kidney allografts almost always includes T cell-mediated rejection, which has a different treatment approach than allograft infections. The aim of this review was to prompt clinicians to identify diverse pathological alterations as observed in kidney allograft biopsies, thereby facilitating further investigations and the management of suspected kidney allograft infections.

A 5-Year Follow-Up Study to Explore Factors Associated with Rapid Kidney Function Decline Among Bus Drivers.

Owing to the stressful occupational characteristics, bus drivers have been reported to have a higher risk of renal dysfunction. However, the related factors associated with rapid kidney function decline among bus drivers have not been explored in the existing literature. Therefore, our research aimed to investigate factors related with rapid kidney function decline, and to explore the correlation of baseline SUA (serum uric acid), longitudinal changes in SUA, and rapid eGFR (estimated glomerular filtration rate) decline for bus drivers. This was a five-year cohort study in Shenzhen, China, between 2017 and 2021. We included 832 bus drivers with normal kidney function at baseline. Study subjects were stratified into four quartiles of change in eGFR, and rapid eGFR decline was regarded as the highest (4th) quartile of ΔeGFR (eGFR in 2017-eGFR in 2021). Univariable and multivariable logistic regressions were conducted to explore factors affecting rapid eGFR decline. The incidence of hyperuricemia among bus drivers was 37.7% in 2017 and 40.5% in 2021. The overall subjects had a median 5-year decrease in eGFR of 6.72 mL/min/1.73 m2, and individuals with increased SUA from normal to hyperuricemia group had the greatest decline of eGFR. Multivariate analysis showed bus drivers' age (Odds radio: OR, 1.04), elevated baseline eGFR (OR, 1.08), and SUA increase (OR, 1.38) were significantly associated with rapid eGFR changes. The high prevalence of hyperuricemia among bus drivers should warrant more attention from health professionals. Subjects' age, elevated baseline eGFR, and SUA increase were risk factors for rapid eGFR decline over 5-year. The findings can provide significant evidence for timely prevention and intervention to decrease the incidence of rapid renal function decline among bus drivers.

A Comparative Effectiveness and Renoprotective Effects of Hypoglycemic Drugs for Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus (T2DM) is a huge burden on healthcare systems globally and it can lead to impaired kidney function, albuminuria, end-stage renal disease (ESRD). T2DM impact on the kidneys could results in diabetic nephropathy (DN) or diabetic kidney disease (DKD). It increases morbidity and mortality rate, therefore, decreases the quality of life. Present treatment protocol relies on lowering glucose levels, and strict blood pressure control by targeting blockade of the renin–angiotensin–aldosterone system. Such approaches might slow-down the decline in kidney function but many patients get end-stage kidney failure, despite optimal therapy. The need for new pharmacologic strategies for T2DM, that could prevent the development of DN and safeguard the kidneys, is rising. In this article, an overview of recent clinical data pertaining to novel therapeutic approaches for the management of DN is provided. Moreover, this review evaluates comparative effectiveness of hypoglycemic drugs like sodium-glucose cotransporter-2 inhibitors (SGLT2-i), glucagon-like peptide-1 receptor agonists (GLP1-RA), dipeptidyl peptidase-4 inhibitors (DPP4-i), and finerenone in treating T2DM and their renoprotective effects. This manuscript also highlights the need for selecting suitable drugs for a patient, as the optimal treatment significantly depends upon the patient-specific conditions.

Neutrophils - to - Lymphocytes Ratio and Clinical Outcomes in Patients with Kidney Diseases in COVID 19

Introduction: Kidney Disease is structural and functional abnormality of Nephrons, where abrupt deterioration to progressive decline in Kidney function leads to acute to chronic Kidney Disease, respectively. The objective of this research was to find the Neutrophil-to-Lymphocyte ratio and Clinical outcomes of patients with Kidney Diseases in COVID-19.Methods: A descriptive cross-sectional study was conducted in the Department of Nephrology of College of Medical Sciences and Teaching Hospital, Bharatpur-10, Chitwan from 2021-04-01 to 2021-06-29 in among 31 Covid-19 positive cases. Collected data was entered and analyzed by using SPSS 20.Results: In this study 58% were male while 42% were female. Among the total cases 35.48% cases had NRL ratio &lt;8 while 65.52% cases had NRL ratio ≥8. Among total cases 48.38% were discharged whereas, 51.62% were declared dead. Also, among those cases whose NRL ratio &lt;8, 27.27%were declared dead while in NRL≥8, 65% cases were declared dead during treatment.Conclusions: In Covid-19 cases early diagnosis and supportiv e treatment, prognosis could be good. Regular follow-up could give insight about kidney function whereas in case Covid-19 various awareness programme and practice to prevent should be implied.

Understanding Hypervolemia in Chronic Kidney Disease

Introduction: Chronic Kidney Disease (CKD) is a progressive and irreversible decline in kidney function and a decreased Glomerular Filtration Rate (GFR). Decreased kidney function contributes to decreased water excretion and fluid overload caused by decreased GFR. A progressive decrease in GFR in renal disease leads to hypertension, sodium retention, and fluid overload. Discussion: CKD is kidney damage or also defined as a decrease in glomerular filtration rate (GFR) of less than 60 ml/minute/1.73m2 that occurs for 3 months or more. CKD is most caused by Diabetes Mellitus 64.1% and Hypertension 80.7%. One clinical manifestation in patients with CKD is an increase in fluid volume (hypervolemia). Hypervolemia is one of the nursing problems in the nursing care process. Based on the Indonesian Nursing Diagnosis Standard Book, hypervolemia is an increase in intravascular, interstitial, and/or intracellular fluid volume. The etiology of hypervolemia in CKD patients is a regulatory mechanism disorder associated with decreased GFR. Signs and symptoms both major and minor in hypervolemia nursing problems show that most patients have peripheral oedema of 53.8%, the prevalence of anemia is 52.3%, the prevalence of Haemoglobin 7-10 mg/dl is 68.3%, and the prevalence of oliguria is 16.3%. One of the actual nursing diagnosis in patients with CKD is hypervolemia related to the disturbance of regulatory mechanisms (a decrease in GFR). A progressive decrease in GFR can lead to sodium and fluid retention which causes fluid balance disturbances.

The urine-to-plasma urea concentration ratio is associated with eGFR and eGFR decline over time in a population cohort.

Evaluation of renal function and of factors associated with its decline are important public health issues. Besides markers of glomerular function [e.g. glomerular filtration rate (GFR)], those of tubular functions are rarely evaluated. Urea, the most abundant urinary solute, is markedly concentrated in urine when compared with plasma. We explored the urine-to-plasma ratio of urea concentrations (U/P urea ratio) as a marker of tubular functions. We evaluated the relationship of the U/P urea ratio with eGFR at baseline in 1043 participants (48±17 years) from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH) population-based cohort, using mixed regression. In 898 participants, we assessed the relation between U/P urea ratio and renal function decline between two study waves 3 years apart. We studied U/P ratios for osmolarity, Na, K and uric acid for comparison. In a transversal study at baseline, estimated GFR (eGFR) was positively associated with U/P-urea ratio [βscaled=0.08, 95% CI (0.04; 0.13)] but not with the U/P ratio of osmolarity. Considering separately participants with renal function >90 or ≤90mL/min × 1.73 m2, this association was observed only in those with reduced renal function. In the longitudinal study, eGFR declined at a mean rate of 1.2mL/min per year. A significant association was observed between baseline U/P urea ratio and eGFR decline [βscaled=0.08, 95% CI (0.01; 0.15)]. A lower baseline U/P urea ratio was associated with a greater eGFR decline. This study provides evidence that the U/P urea ratio is an early marker of kidney function decline in the general adult population. Urea is easy to measure with well-standardized techniques and at low cost. Thus, the U/P urea ratio could become an easily available tubular marker for evaluating renal function decline.

Rapid kidney function decline and increased risk of heart failure in patients with type 2 diabetes: findings from the ACCORD cohort

BackgroundImpaired kidney function and albuminuria are associated with increased risk of heart failure (HF) in patients with type 2 diabetes (T2D). We investigated whether rapid kidney function decline over time is an additional determinant of increased HF risk in patients with T2D, independent of baseline kidney function, albuminuria, and other HF predictors.MethodsIncluded in the study were 7,539 participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study with baseline urinary albumin-to-creatinine ratio (UACR) data, who had completed 4 years of follow-up and had ≥ 3 eGFR measurements during that period (median eGFR/year = 1.9, IQR 1.7–3.2). The association between rapid kidney function decline (eGFR loss ≥ 5 ml/min/1.73 m2/year) and odds of HF hospitalization or HF death during the first 4 years of follow-up was estimated by logistic regression. The improvement in risk discrimination provided by adding rapid kidney function decline to other HF risk factors was evaluated as the increment in the area under the Receiving Operating Characteristics curve (ROC AUC) and integrated discrimination improvement (IDI).ResultsOver 4 years of follow-up, 1,573 participants (20.9%) experienced rapid kidney function decline and 255 (3.4%) experienced a HF event. Rapid kidney function decline was associated with a ~ 3.2-fold increase in HF odds (3.23, 95% CI, 2.51–4.16, p < 0.0001), independent of baseline CVD history. This estimate was not attenuated by adjustment for potential confounders, including eGFR and UACR at baseline as well as at censoring (3.74; 95% CI 2.63–5.31). Adding rapid kidney function decline during follow-up to other clinical predictors (WATCH-DM score, eGFR, and UACR at study entry and end of follow-up) improved HF risk classification (ROC AUC = + 0.02, p = 0.027; relative IDI = + 38%, p < 0.0001).ConclusionsIn patients with T2D, rapid kidney function decline is associated with a marked increase in HF risk, independent of starting kidney function and/or albuminuria. These findings highlight the importance of serial eGFR measurements over time to improve HF risk estimation in T2D.

Impact of Proteinuria and Kidney Function Decline on Health Care Costs and Resource Utilization in Adults With IgA Nephropathy in the United States: A Retrospective Analysis

Among patients with IgA nephropathy (IgAN), proteinuria and decline in kidney function may be associated with increased economic burden. This study aimed to provide current information on the epidemiology and economic burden of IgAN in the United States. Retrospective cohort study. Overall, 9,984 patients in the Optum's Market Clarity database identified by the presence of at least 2 natural language processing-derived IgAN signs and disease and symptoms terms; 813 with linked claims data included in a health care resource utilization/cost subcohort. High-risk proteinuria (≥1g/d), chronic kidney disease (CKD) stage. Standardized prevalence, health care resource utilization, costs. Descriptive statistics for categorical and continuous variables. Direct standardization for prevalence estimation. Generalized linear models for health care resource utilization/costs, reported as per-patient-per-month (PPPM) costs in 2020 US dollars. The estimated standardized US prevalence of IgAN (2016-2020) was 329.0 per 1,000,000 persons. High-risk proteinuria (≥1 vs<1 g/d) was associated with a higher mean PPPM number of outpatient visits (3.49 vs 1.74; P=0.01) and pharmacy claims (3.79 vs 2.41; P=0.01), contributing to higher mean total costs PPPM ($3,732 vs $1,457; P=0.01). Furthermore, higher CKD stage was also associated with higher health care resource utilization (number of outpatient visits PPPM, number of pharmacy claims PPPM, proportion of patients with inpatient visits and emergency department visits; P<0.001) and mean total cost PPPM (from $2,111 CKD stage 1 to $10,703 CKD stage 5/kidney failure; P<0.001). Generalizability outside of the catchment group for the database, missing data/errors inherent in retrospective database studies, relatively small sample size, use of Optum Market Clarity standardized pricing algorithms, exclusion of out-of-pocket costs. Health care resource utilization and costs were higher for IgAN patients with high-risk proteinuria and worsening kidney function. Treatments that reduce proteinuria and slow CKD disease progression may reduce the economic burden associated with IgAN. Immunoglobulin A nephropathy (IgAN) is a rare kidney disease. Over time, the kidneys may leak protein into the urine (proteinuria). IgAN can lead to kidney failure. Because IgAN is rare, it is hard to know how many people have it. This study used electronic health records to estimate the number of patients with IgAN in the United States, describe the characteristics of patients, and understand their treatments and the costs. The number of patients with IgAN increased between 2016 and 2020. The researchers think this is because doctors learned more about IgAN. Patients with severe disease used more health care resources and had higher costs. The authors believe treatments that slow kidney damage may reduce the cost of treating IgAN.

CKD Progression Prediction in a Diverse US Population: A Machine-Learning Model

Chronic kidney disease (CKD) is a major cause of morbidity and mortality. To date, there are no widely used machine-learning models that can predict progressive CKD across the entire disease spectrum, including the earliest stages. The objective of this study was to use readily available demographic and laboratory data from Sonic Healthcare USA laboratories to train and test the performance of machine learning-based predictive risk models for CKD progression. Retrospective observational study. The study population was composed of deidentified laboratory information services data procured from a large US outpatient laboratory network. The retrospective data set included 110,264 adult patients over a 5-year period with initial estimated glomerular filtration rate (eGFR) values between 15-89mL/min/1.73m2. Patient demographic and laboratory characteristics. Accelerated (ie,>30%) eGFR decline associated with CKD progression within 5 years. Machine-learning models were developed using random forest survival methods, with laboratory-based risk factors analyzed as potential predictors of significant eGFR decline. The 7-variable risk classifier model accurately predicted an eGFR decline of>30% within 5 years and achieved an area under the curve receiver-operator characteristic of 0.85. The most important predictor of progressive decline in kidney function was the eGFR slope. Other key contributors to the model included initial eGFR, urine albumin-creatinine ratio, serum albumin (initial and slope), age, and sex. The cohort study did not evaluate the role of clinical variables (eg, blood pressure) on the performance of the model. Our progressive CKD classifier accurately predicts significant eGFR decline in patients with early, mid, and advanced disease using readily obtainable laboratory data. Although prospective studies are warranted, our results support the clinical utility of the model to improve timely recognition and optimal management for patients at risk for CKD progression. Defined by a significant decrease in estimated glomerular filtration rate (eGFR), chronic kidney disease (CKD) progression is strongly associated with kidney failure. However, to date, there are no broadly used resources that can predict this clinically significant event. Using machine-learning techniques on a diverse US population, this cohort study aimed to address this deficiency and found that a 5-year risk prediction model for CKD progression was accurate. The most important predictor of progressive decline in kidney function was the eGFR slope, followed by the urine albumin-creatinine ratio and serum albumin slope. Although further study is warranted, the results showed that a machine-learning model using readily obtainable laboratory information accurately predicts CKD progression, which may inform clinical diagnosis and management for this at-risk population.

Effects of tolvaptan discontinuation in patients with autosomal dominant polycystic kidney disease: a post hoc pooled analysis

BackgroundTolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) who are at risk of rapid progression. Given that treatment requires commitment to long-term use, we evaluated the effects of tolvaptan discontinuation on the trajectory of ADPKD progression.MethodsThis was a post hoc analysis of pooled data from two clinical trials of tolvaptan (TEMPO 2:4 [NCT00413777] and TEMPO 3:4 [NCT00428948]), an extension trial (TEMPO 4:4 [NCT01214421]), and an observational study (OVERTURE [NCT01430494]) that enrolled patients from the other trials. Individual subject data were linked longitudinally across trials to construct analysis cohorts of subjects with a tolvaptan treatment duration > 180 days followed by an off-treatment observation period of > 180 days. For inclusion in Cohort 1, subjects were required have ≥ 2 outcome assessments during the tolvaptan treatment period and ≥ 2 assessments during the follow-up period. For Cohort 2, subjects were required to have ≥ 1 assessment during the tolvaptan treatment period and ≥ 1 assessment during the follow-up period. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). Piecewise-mixed models compared changes in eGFR or TKV in the on-treatment and post-treatment periods.ResultsIn the Cohort 1 eGFR population (n = 20), the annual rate of eGFR change (in mL/min/1.73 m2) was -3.18 on treatment and -4.33 post-treatment, a difference that was not significant (P = 0.16), whereas in Cohort 2 (n = 82), the difference between on treatment (-1.89) and post-treatment (-4.94) was significant (P < 0.001). In the Cohort 1 TKV population (n = 11), TKV increased annually by 5.18% on treatment and 11.69% post-treatment (P = 0.06). In Cohort 2 (n = 88), the annual TKV growth rates were 5.15% on treatment and 8.16% post-treatment (P = 0.001).ConclusionsAlthough limited by small sample sizes, these analyses showed directionally consistent acceleration in measures of ADPKD progression following the discontinuation of tolvaptan.

411-P: Extended Validation of KidneyIntelXTM in Diabetic Kidney Disease

We have previously shown that plasma TNFR1, TNFR2, and KIM-1 combined with clinical variables provides effective risk stratification for kidney outcomes in individuals with diabetic kidney disease (DKD) stages 1-3. With the recommended use of a race-free eGFR and a refinement of our progression endpoint, we sought to develop and independently validate a version 2.0 of KidneyIntelX assay in a previously untested, independent, contemporary cohort of subjects from BioMe Biobank (Mount Sinai Health System, NYC, NY). The primary outcome was a composite of ≥40% sustained decline in eGFR or kidney failure (sustained eGFR&amp;lt;15 ml/min/1.73 m2) within 5 years from enrollment. In a training cohort of 573 patients with DKD from the Penn Medicine Biobank (PMBB), 15.4% experienced the progressive decline in kidney function over a median of 3.1 years. The following features were selected in a training model utilizing optimized random forests to predict the kidney outcome: TNFR1, TNFR2, KIM-1, baseline UACR, HbA1c, and blood urea nitrogen. The external validation cohort (BioMe, n=657) had an 11.7% event rate over a median of 3.8 years. Based on risk categorization cutoffs derived from training, 57%, 35% and 8.3% of participants were classified as low, intermediate and high-risk, respectively. The cumulative event incidence probability in the low, intermediate, and high-risk groups were 5.9% (95% CI: 3.6-9.4%), 21.2% (95% CI: 15.6-28.3%) and 66.9% (95% CI:, 49.3-83.5%). The unadjusted HRs for high vs. low and intermediate vs. low were 18.4 (95% CI: 9.4 -34.6) and 4.2 (95% CI: 2.4-7.4), respectively. After adjustment for age, sex, race, baseline eGFR, uACR, SBP, and HbA1c, the adjusted HRs were 7.7 (95% CI: 3.0-19.6) and 3.7 (95% CI: 2.0-6.8), respectively. In summary, we developed and independently validated a version 2.0 KidneyIntelX with previously established biomarkers combined with selected clinical variables and demonstrated robust prediction of progressive decline in kidney function, independent of common risk factors. Disclosure G.N.Nadkarni: Advisory Panel; Renalytix, Consultant; Renalytix, Other Relationship; Renalytix, Speaker's Bureau; Daiichi Sankyo, GlaxoSmithKline plc., Menarini Group, Stock/Shareholder; Renalytix. F.Fleming: Employee; Renalytix. M.J.Donovan: Employee; Renalytix. S.Coca: Advisory Panel; Renalytix, Bayer Inc., Boehringer Ingelheim International GmbH, Consultant; Renalytix, Nuwellis, 3ive Labs, Reprieve Cardiovascular, Vifor Pharma Management Ltd., Stock/Shareholder; Renalytix. Funding Renalytix

12-LB: Clinical Impact of Risk Profiling with KidneyIntelX on DKD Progression in a Large Integrated Health Care System

KidneyIntelXTM combines 3 plasma biomarkers with clinical variables to categorize adults with DKD stages 1-3b for risk of a progressive decline in kidney function over 5 years. We previously demonstrated that using KidneyIntelX to assess risk and guide treatment does lead to optimized medication use, lifestyle changes, and specialist referrals. We now report the one-year pre and posttest clinical impact on eGFR slope and hemoglobin A1C (HbA1c) in the Mount Sinai Health System. Among the 1087 patients with follow-up data, the median age was 69 years, 52% were women, 32% self-identified Black, baseline eGFR 59 ml/min/1.73m2, baseline HbA1c was 7.2%, and 146 (13%), 439 (40%), and 502 (46%) were scored as high, intermediate, and low risk by KidneyIntelX. In high-risk patients, median eGFR slope slowed from -5.7 ml/min/year pre-test to -2.1 ml/min/year post-test (p&amp;lt;0.001), and from -1.8 ml/min/year to -1.0 ml/min/year in intermediate-risk (p=0.005) (Table). The median HbA1c decreased from 8.4 to 7.7% (p&amp;lt;0.001) in high risk, and from 7.5 to 7.2% (p&amp;lt;0.001) in intermediate risk. In conclusion, deployment and risk stratification by KidneyIntelX was associated with reduced rate of kidney function decline and improved glycemic control, particularly in those scored as high risk. Disclosure J. Tokita: Other Relationship; Renalytix. C. Sinfield: None. M. J. Donovan: Employee; Renalytix. T. McNicholas: Employee; Renalytix. M. Kattan: Research Support; Novo Nordisk. Consultant; Renalytix, Verici. Research Support; Bayer Inc. D. W. Lam: None.

413-P: Intensive Insulin Therapy Delays the “Breakpoint” to Progressive Kidney Function Decline—New Findings and Implications of eGFR Trajectory Analysis in DCCT/EDIC Data

Patterns of kidney function decline vary among those with T1D. End-stage kidney disease (ESKD) develops after progressive kidney function decline that begins when kidney function is normal, regardless of albuminuria. We aimed to determine if these findings were observed in the DCCT/EDIC cohort, which enrolled 1,441 individuals and randomly assigned them to intensive insulin therapy (n=711) or conventional insulin therapy (n=730). Baseline mean eGFR and AER were 125 ml/min/1.73m2 and 12 mg/24 hours, respectively. During 27 years of follow-up 129 individuals reached reduced eGFR &amp;lt;60ml/min/1.73m2 or ESKD. For these individuals we applied latent class trajectory analysis minimizing sum of squares of linear spline models with varying knot placement to identify patterns of eGFR decline. We identified two patterns: i) slow decline without eGFR breakpoint (n=56) and ii) fast decline with clear breakpoint (n=73). Slow decliners reached reduced eGFR but rarely ESKD (2%), while many fast decliners progressed to ESKD (35%) within 5-15 years after the breakpoint. Fast decline was less frequent in intensive compared to conventional insulin therapy [26 (3.7%) vs 47 (6.4%), respectively, p=0.022] and had longer median time from enrollment to breakpoint (18 vs 13 years, respectively, p=0.0004). However, the slope of annual loss of eGFR after breakpoint did not differ. In conclusion, we identified a unique phenotype - the “breakpoint” to fast decline in eGFR - as the main predictor of ESKD in T1D. This breakpoint started while eGFR was normal, subsequent decline was linear, and the onset of the breakpoint was substantially delayed by intensive insulin therapy rather than the slope of decline itself. Research on biomarkers that predict the onset of the eGFR ‘breakpoint’ is needed. Disclosure K.Ihara: None. J.K.Skupien: None. E.Satake: None. B.A.Perkins: Advisory Panel; Dexcom, Inc., Insulet Corporation, Novo Nordisk, Sanofi, Vertex Pharmaceuticals Incorporated, Other Relationship; Abbott, Medtronic, Sanofi, Research Support; Novo Nordisk, Bank of Montreal (BMO). A.Krolewski: None.

1226-P: A Rapid Rate of Kidney Function Decline Is Associated with Increased Risk of Heart Failure in Patients with Type 2 Diabetes—Results from ACCORD Study

Impaired kidney function and albuminuria are associated with increased risk of heart failure (HF) in patients with type 2 diabetes (T2D). We investigated whether rapid kidney function decline over time is an additional determinant of increased HF risk in patients with T2D. We further assessed whether accounting for the rate of estimated glomerular filtration rate (eGFR) decline over time improved prediction of HF risk as compared to standard clinical predictors. Included in the study were 9,192 participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study with available baseline urinary albumin-to-creatinine ratio (UACR) data and ≥3 eGFR measurements during follow-up. The association between rapid kidney function decline (eGFR loss ≥5 ml/min/1.73 m2/year) and odds of HF hospitalization or HF death during follow-up was estimated by logistic regression. We calculated integrated discrimination improvement (IDI) by adding rapid kidney function decline to HF predictors. Over a median follow-up of 5.0 years (interquartile range 4.1-5.7), 1,432 participants (15.6%) experienced rapid kidney function decline and 355 (3.9%) experienced a HF event. Rapid kidney function decline was associated with a 3.57-fold increase in HF odds (odds ratio [OR] 3.57; 95% confidence interval [CI] 2.86-4.45). This estimate was not attenuated by adjustment for potential confounders, including eGFR and UACR at baseline and censoring (OR 4.47; 95% CI 3.7-6.11). Adding rapid kidney function decline during follow-up to other predictors (WATCH-DM score, eGFR, and UACR) significantly improved HF risk classification (relative IDI=+49%, p&amp;lt;0.0001). In patients with T2D, rapid kidney function decline was associated with a marked increase in HF risk, independent of starting kidney function and/or albuminuria. These findings highlight the importance of serial eGFR measurements over time to improve HF prediction in patients with T2D. Disclosure A.Bano: None. C.Bueno junior: None. Y.Tang: None. X.Sun: None. E.Hall: None. J.Mitri: Other Relationship; Novo Nordisk, Research Support; Kowa Company, Ltd. M.Morieri: Advisory Panel; Merck Sharp &amp; Dohme Corp., Amarin Corporation, Servier Laboratories, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. H.Shah: None. A.Doria: None. Funding National Heart, Lung, and Blood Institute (N01HC95178, N01HC95179, N01HC95180, N01HC95181, N01HC95182, N01HC95183, N01HC95184, IAAY1HC-9035, IAAY1HC1010); National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; General Clinical Research Centers

409-P: Post Hoc Analyses of Longitudinal Changes of Plasma Proteins Associated with Progression to End-Stage Kidney Disease in Type 2 Diabetes Patients with Chronic Kidney Disease Treated with GLP-1 Receptor Agonist Dulaglutide (AWARD-7)

The AWARD-7 clinical trial of patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) reported a slower decline in estimated glomerular filtration rate (eGFR) and decreased urinary albumin-to-creatinine ratio (UACR) in patients treated with dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, compared to insulin glargine over one year. Previous studies identified 21 circulating plasma risk proteins highly associated with progression to end stage kidney disease (ESKD) in patients with diabetes (Joslin Kidney Panel). The aim of this study was to determine the longitudinal changes of these proteins in AWARD-7 to evaluate their predictive performance as biomarkers of kidney disease progression. Plasma samples were obtained from patients with T2D and CKD stages 3-4 who received dulaglutide 1.5 mg (n=124) or insulin glargine as basal therapy (n=125) for 52 weeks. Using the Olink custom platform we measured the concentration of 21 proteins at baseline, 26-weeks, and 52-weeks of treatment. At baseline all 21 proteins were correlated with eGFR (r=-0.2 to -0.8; all p&amp;lt;0.0003) and UACR (r=0.2 to 0.6; all p&amp;lt;0.0001). After 26 weeks of treatment, 13 risk proteins significantly increased in glargine group (3 to 13%; all p&amp;lt;0.05) whereas no significant change was observed in dulaglutide group at 26 weeks. By 52 weeks, 5 proteins remained significantly elevated in the glargine group compared to dulaglutide. Several proteins were correlated with declining kidney function (change of eGFR) and increasing UACR in patients with glargine, but not in patients treated with dulaglutide. In this study, the increase of plasma risk proteins associated with ESKD was slowed in dulaglutide-treated patients and is consistent with the hypothesis that several proteins within the Joslin Kidney Panel can serve as predictive biomarkers of treatment efficacy. Disclosure B.E.Mcfarlin: Employee; Eli Lilly and Company. E.Satake: None. Z.Md dom: None. J.Ricca: None. A.V.Kechter: Employee; Eli Lilly and Company. J.M.Wilson: Employee; Eli Lilly and Company. K.L.Duffin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company, Pfizer Inc. A.Krolewski: None.

531-P: The Multidisciplinary Team Education for Subjects with DKD Could Affect the Prevention of eGFR Decline

Background: It still remains unclear as to whether or not multidisciplinary individual team approach (MTA) affects the decline of kidney function in persons with diabetic kidney disease (DKD). We examined the effects of MTA on 24 DKD subjects compared with effects on 24 control subjects with DKD who are managed by dietitian approach alone (DA) between January 2012 and December 2021. Methods: The team was composed of doctors, nurses (CDE, RN) and dietitians (CDE, RD). The team provided broad education, including advice on medication, medical diet therapy, management of home blood pressure, SMBG, weight measurement, self-check of edema, foot care, giving information of stage of DKD and medical examinations. Results: There was no significant difference in types of diabetes (types 1 and 2; 2/22 vs. 1/23), gender (men/women; 15/9 vs.18/6), duration of diabetes (15 ± 9 vs. 19 ± 11 yrs.), observation period (7.9 ± 1.3 vs. 7.3 ± 2.4 yrs.) between MTA and DA. MTA is significantly younger (57 ± 12 years old) than DA (67 ± 9 years old) (p=0.002). Number of interventions per year were 3.6 ± 1.4 vs. 2.6 ± 1.9 times between MTA and DA (p=0.046). Also the initial eGFR (61.0 ± 26.6 vs. 60.1 ± 19.4 mL/min/1.73m2) and albuminuria levels (246 (33-1923) vs. 382 (35-2008) mg/g•Cr) were comparable between the groups. Annual eGFR decline rate in MTA group (−1.38 ± 2.11 mL/min 1.73m2) was significantly lower than that in DA group (−3.89 ± 6.34). Two subjects were initiated hemodialysis only in the DA group (likelihood ratio 2.86, p=0.091). Four subjects died in only the DA group (likelihood ratio 5.91, p=0.015). Summary: It is possible that MTA affects the prevention of renal function decline compared with the intervention provided by DA alone. Subjects with DKD, even with normal renal function, may be recommended to have MTA to prevent the progression of renal failure. Disclosure M.Hitomi: None. N.Hiki: None. U.Sakamoto: None. Y.Usui: None. T.Miyatsuka: Speaker's Bureau; Eli Lilly Japan K.K., Novo Nordisk, Sanofi K.K., Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Teijin Pharma Limited, Sanwa Kagaku Kenkyusho, Daiichi Sankyo. T.Moriya: None.

884-P: Decentralized N=1 Study—A Feasible Approach to Evaluate Individual Therapy Response to Dapagliflozin

Background: The SGLT2 inhibitor dapagliflozin reduces kidney function decline and urine albumin:creatinine ratio (UACR) on a population level. However, there is marked heterogeneity in the efficacy among individual patients. We conducted a decentralized (i.e. at home) N=1 trial to assess the effect of dapagliflozin in individual patients and the feasibility of remote data collection. Methods: Twenty patients with type 2 diabetes, UACR &amp;gt;20 mg/g and eGFR &amp;gt;30 mL/min/1.73m2 entered the randomized placebo-controlled double-blind N=1 trial. Patients were randomly assigned to two periods of 1-week treatment with dapagliflozin 10 mg/day and two periods of 1-week treatment with placebo in random order with 1-week wash-out periods in between. Patients collected and sent their own data with automatic uploading to an online platform and sent early morning urines 5 times/week to the laboratory for albumin and creatinine assessment. Primary outcome was UACR change from baseline (mixed effects model). The study had 80% power to detect a correlation in UACR change between first and second dapagliflozin period of 0.6. Results: Patients had a mean eGFR of 70.2 mL/min/1.73m2 and median UACR of 94.7 mg/g. During the study, dapagliflozin compared to placebo reduced albuminuria by 15.1% (95%CI 3.3 - 28.2; p=0.013). There was a marked variation in the change from baseline in UACR during dapagliflozin treatment periods (range first and second exposure -26.9 to -4.7% and -30.5 to -5.8%, respectively). The individual change in UACR during the first and second exposure correlated in the dapagliflozin periods (r=0.50; p=0.026) but not in the placebo periods (r=0.09; p=0.69). Of all scheduled urine collections (N=816), only 5 collections (0.61%) were not delivered in the laboratory. Conclusion: The individual UACR response to dapagliflozin varies among individual patients and is consistent upon re-exposure. Remote data collection was very reliable with nearly any missed urine collection. Disclosure J.Beernink: None. G.D.Laverman: Advisory Panel; AstraZeneca, Vifor Pharma Management Ltd., Boehringer Ingelheim Inc., Astellas Pharma Inc., Lilly, Other Relationship; Sanofi, AstraZeneca. H.L.Heerspink: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Bayer Inc., Eli Lilly and Company, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., George Clinical, Merck &amp; Co., Inc., Janssen Research &amp; Development, LLC, Traveere Pharmaceuticals, Novo Nordisk. N.Jongs: Speaker's Bureau; AstraZeneca.