Slow Kidney Disease Progression Research Articles

#2549 Real world data of dapagliflozin effect on proteinuria in primary glomerulopathies in Croatia

Abstract Background and Aims SGLT2 inhibitors, namely dapagliflozin, proved to slow progression of kidney disease in randomized clinical trials. Our aim was to assess real world efficacy of dapagliflozin on proteinuria level in primary glomerulopathies (GN). Method adult patients with biopsy proven glomerulonephritis from all university hospitals in Croatia who started dapagliflozin as a standard of care were enrolled. Data were analyzed if patients had at least six months of follow up. None of the patients were on immunosuppression. Data are shown as N (%) or median with interquartile range (IQR) and accompanied p levels. Results Overall 118 patients, predominantly male 84 (71.8%) of average age of 52 years (min–max 20–76), were enrolled. Most of the patients had IgA nephropathy (IgAN) (N = 55;46.6%), followed by membranous nephropathy (N = 27;22.9%), FSGS (N = 19;16.1%), membranoproliferative GN (N = 8;6.8%), Alport syndrome (N = 8;6.8%). 95.8% of patients were on ACE inhibitors or angiotensin receptor blockers and 10.7% were on mineralocorticoid receptor inhibitors and RAAS blockage was not significantly upscaled during follow up. During the median follow up of 12.2 (7.5-18.6) months, proteinuria was significantly reduced from 1139 (534–2265) to 701 (305-1543) mg/dU; p < 0.001. When divided by glomerulonephritis type, statistically significant reduction of proteinuria was observed in patients with IgAN and Alport syndrome, while trend of reduction of proteinuria was observed in all types of GN. There was a slight reduction in eGFR levels (54 (43-78) vs. 52 (39–73) ml/min/1,73 m²; p < 0.001) and rise in creatinine values (122 (89–149) vs. 128 (91–159) μmol/l; p < 0.001). There was a significant reduction in systolic (130 (120-140) vs.125 (115-134) mmHg; p < 0.001) and diastolic blood pressure (80 (75-90) vs. 80 (70-85) mmHg; p < 0.001). Reduction of uric acid level was noticed (377 (313–460) vs.343 (294–422); p < 0.001), while there was no effect on LDL levels (2.6 (2.12–3.53) vs.2.3 (1.9–3.30); p = 0.073). Dapagliflozin was well tolerated, one patient discontinued the therapy due to intolerance, one due to urinary infection and two due to relapse of GN which needed immunosuppressive therapy. One patient was excluded from analysis due to non-adherence. Conclusion SGLT2 inhibitor dapagliflozin has significant effect on reduction of proteinuria in patients with primary glomerulonephritis. Our data support a growing body of evidence that SGLT2 inhibitors should be used as a standard of care in patients with glomerular kidney diseases, especially IgAN. Future research should address earlier use of SGLT2 inhibitors during the treatment of glomerulonephritis alongside immunosuppressive therapy as well as look into the effect of SGLT2 inhibitors on mesangial cells.

#308 The impact of multimorbidity on the effects of empagliflozin in chronic kidney disease (CKD): exploratory analyses from the EMPA-KIDNEY trial

Abstract Background and Aims Sodium-glucose co-transporter-2 (SGLT2) inhibitors slow kidney disease progression and reduce cardiovascular risk in patients with CKD. Multimorbidity is common in CKD and associated with poor prognosis. Multimorbidity may identify patients with most to gain from, or at increased risk of adverse effects of, such treatment, so uncertainty exists around the risk-benefit profile. We assessed the effects of empagliflozin according to baseline multimorbidity, polypharmacy and health-related quality of life in EMPA-KIDNEY trial participants. Method EMPA-KIDNEY was a double-blind, placebo-controlled randomised trial which compared empagliflozin 10 mg once daily versus placebo among 6609 patients with CKD (Clinicaltrials.gov: NCT03594110). Eligible patients had an eGFR of 20 to <45; or 45 to <90 ml/min/1.73 m2 with a urinary albumin-to-creatinine ratio (uACR) ≥200 mg/g. Multimorbidity was defined by the presence or absence of eight self-reported conditions at randomisation (diabetes, heart failure, ischaemic heart disease [any history of myocardial infarction or angina], cerebrovascular disease [any history of stroke or transient ischaemic attack], peripheral arterial disease, atrial fibrillation, peripheral neuropathy and gout), in addition to CKD. Polypharmacy was derived from the number of concomitant medications recorded at randomisation. Health-related quality of life at randomisation was assessed using the EuroQoL EQ-5D-5L tool. To enable subgroup analyses, participants were categorised into approximate thirds of each variable's distribution. The relative effects of allocation to empagliflozin versus placebo on the trial's pre-specified efficacy and safety outcomes were assessed using Cox regression models adjusted for age, sex, region, eGFR, uACR and diabetes status. Tests for heterogeneity across subgroups were used to assess for any evidence that multimorbidity modifies relative treatment effects, and used to inform approaches to estimate absolute benefits. Results The median (Q1-Q3) number of comorbid conditions (other than CKD) recorded at randomisation was 1 (0-2); range 0-7. At randomisation, the median (Q1-Q3) number of concomitant medications recorded was 7 (5-10), range 0-36, and polypharmacy (≥5 medications) was prevalent in 5044/6609 (76%) of participants. There was considerable overlap between multimorbidity, polypharmacy and deficits in health-related quality of life (Fig. 1). Empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio 0.72, 95% CI 0.64-0.82). There was no evidence of heterogeneity relative effects by categories reflecting multimorbidity, nor by level of polypharmacy or self-reported quality of life at randomisation (P value for heterogeneity all >0.05; Fig. 2). Absolute benefits for the primary outcome were at least as large in the highest categories of multimorbidity or polypharmacy versus the lowest (and for those with poorer versus greater health-related quality of life). Safety outcomes were infrequent with no evidence of a difference in effect by baseline levels of multimorbidity, polypharmacy or quality of life, including no excess of symptomatic dehydration or fractures. Conclusion In EMPA-KIDNEY, the estimated absolute benefits of empagliflozin on kidney disease progression or cardiovascular death substantially outweigh potential for harm, irrespective of multimorbidity, polypharmacy or quality of life. The analyses encourage safe widespread use of SGLT2 inhibitors in CKD.

Withdrawal of renin-angiotensin system inhibitors’ effect on estimated glomerular filtration rate in adults with advanced kidney disease: the STOP-ACEi RCT

Background Renin–angiotensin system inhibitors, both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, slow progression of mild and moderate chronic kidney disease. However, some evidence suggests that discontinuation of renin–angiotensin system inhibitors in patients with advanced chronic kidney disease might increase estimated glomerular filtration rate or slow its decline. Objective To test the hypothesis that stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or a combination of both, compared with continuing these treatments, improves or stabilises kidney function in patients with progressive stages 4 or 5 chronic kidney disease based on assessment of kidney function using the modification of diet in renal disease four-variable estimated glomerular filtration rate at 3 years, follow-up. Setting Thirty-seven UK hospitals with kidney services. Design An investigator-led multicentre open-label, randomised controlled trial of 411 participants with advanced (stage 4 or 5) progressive chronic kidney disease. Participants Adult patients with advanced (estimated glomerular filtration rate < 30 ml/minute/1.73 m2) and progressive chronic kidney disease who were receiving either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or a combination of both. Interventions Participants were randomised in a 1 : 1 ratio using a centralised internet-based system to either discontinue renin–angiotensin system inhibitors (n = 206) or continue renin–angiotensin system inhibitors (n = 205). Main outcome measures The primary outcome was the estimated glomerular filtration rate at 3 years; measurements of estimated glomerular filtration rate made after commencing kidney replacement therapy were excluded. Secondary outcomes included development of end-stage kidney disease or starting kidney replacement therapy, a composite of either a > 50% decline in estimated glomerular filtration rate or commencement of kidney replacement therapy (including end-stage kidney disease), cystatin C, hospitalisations, blood pressure, exercise capacity and quality of life. Cardiovascular events, death and safety were recorded. Results At 3 years, the least-squares mean (± standard error) estimated glomerular filtration rate was 12.6 ± 0.7 ml/minute/1.73 m2 in the discontinuation group and 13.3 ± 0.6 ml/minute/1.73 m2 in the continuation group [difference −0.7, 95% confidence interval (−2.5 to 1.0; p = 0.42)] with a negative value favouring the continuation group. The treatment effect did not differ (heterogeneity) when data were analysed by the pre-specified subgroups. End-stage kidney disease or kidney replacement therapy occurred in 128 (62%) and 115 (56%) participants randomised to the discontinue and continue renin–angiotensin system inhibitor groups, respectively (hazard ratio 1.28, 95% confidence interval 0.99 to 1.65). The numbers of cardiovascular events and deaths observed were similar for those randomised to discontinue (108 events and 20 deaths) or continue (88 events and 22 deaths) renin–angiotensin system inhibitors. Limitations Non-white ethnic backgrounds were poorly represented, limiting the generalisability of our findings. The open-label nature of the trial may have affected clinical care and subjective end points, such as quality of life and exercise capacity. We only included patients who were receiving renin–angiotensin system inhibitors at the time of randomisation, thus excluding those who had already discontinued these agents. Conclusions Discontinuing renin–angiotensin system inhibitors in advanced and progressive chronic kidney disease does not cause a clinically relevant change in estimated glomerular filtration rate or difference in its long-term decline. Future work Future work should focus on updating clinical guidelines. Further analyses, in addition to the prespecified analyses, may be undertaken if new estimated glomerular filtration rate equations are introduced into clinical practice. Subgroup analysis by kidney disease aetiology and gender may be undertaken to look for potential differences in outcome in specific groups. Trial registration This trial is registered as STOP ACEi EudraCT Number, 2013-003798-82; ISRCTN62869767. Funding This award was funded by the Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 11/30/07), a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership. This is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 5. See the NIHR Funding and Awards website for further award information.

Integrated Care Model by the Village Health Volunteers to Prevent and Slow down Progression of Chronic Kidney Disease in a Rural Community, Thailand.

Chronic kidney disease (CKD) is a major health problem in Thailand and health behaviors are central to its risk and progression. Because of the shortage of healthcare personnel, village health volunteers (VHVs) have been collaborating in the primary health care system. However, the contribution of VHVs to CKD reduction has not been evaluated yet. This study aimed to evaluate the efficacy of the VHV-integrated model in preventing and slowing down CKD and its risk factors. The population-based cohort study was conducted in a rural community of Thailand between 2017 and 2019. Baseline clinical and behavioral characteristics including CKD, diabetes, hypertension, and other high-risk factors of the participants were collected. The integrated care model was initiated by the multidisciplinary care team that facilitated, empowered, and trained VHVs targeting risk factors of CKD, health literacy, and health promotion. Then the participants were educated and trained for lifestyle modification and were monitored continuously for 18 months by VHVs. Changes in the CKD risk factors, and kidney functions before and after the application of integrated care model were compared. A total of 831 subjects participated in the study with an average age of 57.5 years, and 69.5% were female. Among them, 222 participants (26.7%) were diagnosed as having CKD, the vast majority (95%) of which were in the early stages (G1-G3 and A1-A2). CKD risk factors such as high salt intake, smoking, alcohol consumption, self-NSAID (non-steroidal anti-inflammatory drugs) use were significantly decreased after application of the care model. Also, hemoglobin A1c was significantly reduced in diabetic patients, and blood pressure was controlled better than before in the hypertensive patients. Most importantly, a decline of estimated glomerular filtration rate of the CKD group was improved and lower than the non-CKD group. The integrated care model through VHV significantly attenuated the risk factors associated with CKD in the general and high-risk population and effectively slowed down the progression of CKD.

Statin therapy in patients with early-stage autosomal dominant polycystic kidney disease: Design and baseline characteristics

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss of kidney function in most patients. Currently, tolvaptan is the only agency approved therapy to slow kidney disease advancement in patients with faster progressing disease underscoring the need for additional ADPKD therapies suitable for all patients. We previously showed that pravastatin slowed kidney disease progression in children and young adults with ADPKD. However, the intervention has not been tested in an adult cohort. AimsThe aim of the study is to conduct a single center, randomized, placebo-controlled double-blinded clinical trial to determine the efficacy of pravastatin on slowing kidney disease progression in adult patients with early stage ADPKD. MethodsOne hundred and fifty adult patients with ADPKD and eGFR ≥60 ml/min/1.73m2 will be enrolled in the study and randomized to receive 40 mg/day pravastatin or placebo for a period of 2-years. OutcomesThe primary outcome of the trial is change in total kidney volume assessed by magnetic resonance imaging (MRI). Secondary outcomes include change in kidney function by iothalamate GFR and renal blood flow and markers of inflammation and oxidative stress. ConclusionThis study will assess the kidney therapeutic benefits of pravastatin in adult patients with ADPKD. The recruitment goal of 150 subjects was attained and the study is ongoing.Registration: This study is registered on Clinicaltrials.gov # NCT03273413

Ataxia Syndrome With Hearing Loss and Nephronophthisis Associated With a Novel Homozygous Variant in XPNPEP3.

Biallelic variants in XPNPEP3 are associated with a rare mitochondrial syndrome characterized by nephronophthisis leading to kidney failure, essential tremor, hearing loss, seizures, and intellectual disability. Only 2 publications on this condition are available. We report a man with a complex ataxia syndrome, hearing loss, and kidney failure associated with a new biallelic variant in XPNPEP3. Clinical evaluation, neuroimaging studies, a kidney biopsy, and whole genome sequencing (WGS) were applied. Since the phenotype was compatible with a mitochondrial disease, a muscle biopsy with morphological and mitochondrial biochemical investigations was performed. Axial ataxia, cerebellar atrophy, hearing loss, myopathy, ptosis, supranuclear palsy, and kidney failure because of nephronophthisis were the prominent features in this case. WGS revealed the novel biallelic variant c.766C>T (p.Gln256*) in XPNPEP3. A muscle biopsy revealed COX negative fibers, a few ragged red fibers, and ultrastructural mitochondrial changes. Enzyme activity in respiratory chain complex IV was reduced in muscle and fibroblasts. This is the first report of a slowly progressive cerebellar ataxia associated with a novel biallelic variant in XPNPEP3. Abnormalities typical for mitochondrial disease and the slow progression of kidney disease are also striking. Our report expands the spectrum of XPNPEP3-related diseases.

Prevalence and Clinicopathological Characteristics of NDRD in Type 2 DM Patients

The prevalence of non-diabetic renal disease (NDRD) in type 2 diabetes mellitus (DM) varies depending on selection criteria and populations studied. Renal biopsies are not routinely performed in diabetic patients, but are indicated when NDRD is suspected. This study evaluated kidney biopsy histopathology and its correlation with clinical and biochemical parameters. Patients with type 2 DM who underwent renal biopsy for suspected NDRD from January 2015 to May 2023 were selected. Data analysis included clinical, laboratory, and histopathology findings. Patients were grouped as follows: Group I (pure diabetic nephropathy [DN]), Group II (NDRD with underlying DN), and Group III (pure NDRD). 41 biopsies were performed on type 2 DM patients. Mean age: 48.07±11.9 years, mean diabetes duration: 8.23±7.4 years, mean proteinuria: 11.37±8.0 mg/mmol, and mean creatinine: 2.19±2.05 mg/dl. 46.3% were hypertensives, 46.34% had diabetic retinopathy and 34.14% had hematuria. Among the studied group, 12 patients (29.26%) had pure DN, 10 patients (24.39%) had NDRD with underlying DN, and 19 patients (46.34%) had pure NDRD. The most common NDRD findings were membranous nephropathy 5 cases (26.31%) and focal segmental glomerulosclerosis 4 cases (21.05%). This study found a 46.34% incidence of NDRD in diabetic patients. NDRD should be suspected in atypical diabetic presentations, as early diagnosis and treatment may slow kidney disease progression.

Female but Not Male Mice Deficient in Soluble IgM Are Susceptible to Chemically Induced Glomerular Injury.

B cell-targeted therapies are effective for treating multiple different kidney diseases in humans and also protect mice from Adriamycin nephropathy. Because glomerular IgM is frequently seen in both humans and mice with "nonimmune" forms of glomerular disease, we hypothesized that natural IgM binds to epitopes displayed in the injured glomerulus, exacerbating injury. To test this hypothesis, we induced Adriamycin nephropathy in BALB/C mice that cannot secrete soluble IgM (sIgM-/- mice) and compared them with BALB/C controls. Contrary to our prediction, we found that female sIgM-/- mice developed higher mortality and more severe kidney injury after injection of Adriamycin. The absence of soluble IgM did not reduce glomerular complement activation, and IgG was seen deposited within the injured glomeruli. Furthermore, we discovered that female sIgM-/- mice have higher levels of anti-cardiolipin IgG, and that IgG from these mice binds to epitopes in the injured kidney. These findings indicate that natural IgM may prevent generation of autoreactive IgG. Circulating levels of anti-cardiolipin IgG decreased after induction of kidney injury in female mice, consistent with deposition of the Abs in injured tissues. Better understanding of the mechanisms by which the immune system modulates and amplifies kidney injury may enable the development of targeted therapies to slow kidney disease progression.

Association of Plant Protein Intake With Risk of Incident CKD: A UK Biobank Study

Data suggest that various dietary interventions slow kidney disease progression and improve clinical outcomes for those with chronic kidney disease (CKD). However, the association between plant protein intake and incident CKD has been uncertain. Prospective cohort study. 117,809 participants who completed at least 1 dietary questionnaire and had an estimated glomerular filtration rate (eGFR)≥ 60mL/min/1.73m2, a urinary albumin-creatinine ratio (UACR)<30mg/g, and no history of CKD. Daily plant protein intake in g/kg/day. Incident CKD based on the International Classification of Diseases, 10th Revision (ICD-10) or the Office of Population Censuses and Surveys Classification of Interventions and Procedures, version 4 (OPCS-4) codes. A cause-specific proportional hazards analysis incorporating competing risks that treated death occurring before incident CKD as a competing event. During a median follow-up period of 9.9 years, incident CKD occurred in 3,745 participants (3.2%; incidence rate, 3.2 per 1,000 person-years). In a multivariable model, the adjusted hazard ratio (AHR) for the second, third, and highest quartiles of plant protein intake was 0.90 (95% CI, 0.82-0.99), 0.83 (95% CI, 0.75-0.92), and 0.82 (95% CI, 0.73-0.93), respectively, compared with the lowest quartile. Modeled as a continuous variable, the AHR per 0.1g/kg/day plant protein intake increase was 0.96 (95% CI, 0.93-0.99). This beneficial association was also consistent in secondary analyses for which CKD was defined based on codes or 2 consecutive measures of eGFR<60mL/min/1.73m2 or UACR>30mg/g. Various sensitivity analyses demonstrated consistent findings. Potential incomplete dietary assessments; limited generalizability due to the characteristics of participants in the UK Biobank Study. In this large, prospective cohort study, greater dietary plant protein intake was associated with a lower risk of incident CKD. Further interventional studies demonstrating the kidney-protective benefits of plant protein intake are warranted. Plant-based diets confer various health benefits, including lowering the risk of cardiovascular disease and certain cancers. However, the relationship between plant protein intake and the risk of chronic kidney disease (CKD) remains unclear. Our study investigated the association between plant protein intake and the development of CKD. Using the UK Biobank Study data, we found that participants with a higher plant protein intake had a lower risk of developing CKD. Our finding suggests that a higher dietary intake of plant-based protein may be beneficial for kidney health and provides insight into dietary interventions to prevent CKD in primary care settings.

#4519 CAN WE REPLACE URINE TESTING AND DELIVER A STEP CHANGE IN ACCESS TO RENOPROTECTIVE MEDICATIONS?

Abstract Background and Aims Albuminuria is a medical condition characterized by leakage of albumin into the urine due to kidney damage. The condition is diagnosed by heightened Albumin to Creatinine ratio in the urine (ACR) and is typically categorized into microalbuminuria (ACR ≥ 30, &amp;lt; 300 mg/g mg/g) and macroalbuminuria (ACR ≥ 300 mg/g). Currently, despite compelling data, only a minority of patients with diabetes, and rarely individuals without diabetes, are screened for albuminuria in a systematic way. ACR tests also present high intra-person variability, making it harder to identify meaningful biologic changes and increasing complexity of clinical trials. In this study we develop a method using machine learning to predict ACR level from Electronic Health Records, excluding urine tests, and validated the model for identifying patients with albuminuria. Identifying patients with undiagnosed albuminuria could help slow progression of kidney disease and be used to speed up recruitment to, and reduce screen failures in, clinical trials. Method We developed a Quantile Regression model for ACR using US Limited IBM MarketScan Explorys Claims-EMR Data Set (LCED). We included subjects who had an ACR test (0 &amp;lt; ACR ≤ 5000 mg/g) and was of at least 18 years of age. Patient demographics (age, sex), vital signs (BMI, Blood Pressure) and 8 common blood tests (Albumin, Bilirubin, Creatinine, HbA1C, Triglyceride, Glucose, White Blood Cell count &amp; ALT) were used as covariates. A tree based gradient boosting framework (LightGBM) was used to train the quantile regression models, viz., the 25-, 50-, and 75-percentiles of ACR conditioned on the covariates. The model was then validated on all qualified subjects in Optum's de-identified Clinformatics® Data Mart Database (2007-2021). We evaluated performance using the metrics Area Under the Curve (AUC), precision (PPV), specificity (TNR), and sensitivity (TPR). Finally, we use Kaplan-Meier estimates to compare the risk of progression to kidney failure as identified by ICD codes (Chronic kidney disease, stage 5; End stage renal disease; Dependence on renal dialysis; Unspecified kidney failure; Kidney transplant) of both the predicted and measured ACR values. Results A final cohort of 63,459 individuals matched the inclusion and exclusion criteria in LCED and 5,857,385 individuals in Optum. Using the 25% quantile to predict patients at risk, the model consistently reaches a PPV greater than 0.8 and a specificity (TNR) greater than 0.99 (Table 1). The risk of progression to kidney failure increases with both increased predicted and measured ACR (Figure 1). Conclusion The results show that the models have discriminative power in all datasets. It predicts both micro- and macro-albuminuria with a PPV above 80% for the 25-quartile. However, classification performance is lacking in sensitivity, i.e., subjects suffering from albuminuria may not be classified as such. By using the median prediction of ACR we identify patient subpopulations that have a risk of kidney failure at least on par with the true ACR subpopulation targeted. This means that the method can be used confidently to identify at-risk individuals. Therefore, our model is advantageous in applications such as identifying undiagnosed albuminuria and pre-screening for clinical trials, where high PPV is more important than sensitivity. We intend to validate the model further for outcomes prediction in an upcoming CKD trial.

#3901 PROGRESSION OF INCIDENT CHRONIC KIDNEY DISEASE: A DANISH NATIONWIDE POPULATION-BASED COHORT STUDY

Abstract Background and Aims The increasing global burden of kidney failure calls for targeted interventions to slow progression of chronic kidney disease (CKD). However, the understanding of progression from CKD stage G3 is limited. We aimed to characterise individuals with incident CKD stage G3 in Denmark and to examine CKD progression defined by three different measures. Method We conducted a nationwide, population-based cohort study using routinely collected individual-level data from national health and administrative databases in Denmark (population ∼5.9 million). Using creatinine tests performed in general practice and the outpatient hospital setting from 1 January 2017 to 31 December 2020, we included all adults in Denmark with incident CKD stage G3, based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria (≥2 creatinine measurements corresponding to an estimated glomerular filtration rate (eGFR) between 30-59 ml/min/1.73 m2 separated by ≥90 days). We used the 2009 CKD Epidemiology Collaboration Creatinine Equation for calculating eGFR. The three years leading up to the study period comprised a washout period to minimise inclusion of individuals with prevalent CKD. We explored CKD progression based on three outcome measures of different sensitivity, including 1) rapid CKD progression (decline in eGFR of ≥5 ml/min/1.73 m2/year, that is, for each eGFR measurement taken during follow-up, we considered this and the measurements taken in the prior year (requiring ≥3 eGFR measurements separated by ≥90 days)); 2) drop in GFR category (drop between GFR categories, 45–59 [G3a], 30–44 [G3b], 15–29 [G4], &amp;lt;15 [G5] ml/min/1.73 m2, accompanied by ≥25% drop in eGFR from baseline); and 3) kidney failure (≥2 eGFR measurements &amp;lt;15 ml/min/1.73 m2 separated by ≥90 days and/or kidney replacement therapy). The 1- and 3-year risks of CKD progression according to the three definitions and all-cause mortality were examined as cumulative incidences using the Aalen-Johansen method. Results We included 133,443 individuals with incident CKD stage G3. The median age at inclusion was 75 years (interquartile range (IQR): 69-82) and 55% were females with 59% having hypertension, 18% having diabetes and 10% having heart failure. The median eGFR at inclusion was 56 ml/min/1.73 m2 (IQR: 51-58) and the median number of eGFR measurements was 3 (IQR: 2-5) in the prior year. Among the 133,443 individuals with incident CKD stage G3, 48,997 (37%) fulfilled the criteria for rapid CKD progression at inclusion. Among the 84,446 individuals without rapid progression on the day of inclusion, the 1- and 3-year risks of rapid CKD progression were 25.0% (95% confidence interval (CI): 24.7-25.3) and 46.0% (95% CI: 45.6-46.4), respectively. The risk of a drop in GFR category was 6.9% (95% CI: 6.8-7.1) after 1 year and 16.6% (95% CI: 16.4-16.8) after 3 years. The risks of kidney failure/renal replacement therapy were 0.1% (95% CI: 0.1-0.1) and 0.3% (95% CI: 0.3-0.4) after 1 and 3 years, respectively. All-cause mortality was 6.8% (95% CI: 6.7-6.9) in the first year and the 3-year mortality was 18.1% (95% CI: 17.9-18.4) (Table 1). Conclusion This nationwide, population-based cohort study showed that a substantial proportion of individuals experienced rapid CKD progression in the 3 years following incident CKD stage G3, whereas the risk of drop in GFR category was considerably lower. Kidney failure within 3 years was rare, while all-cause mortality was relatively modest, taking the high average age into account. This highlights the potential for preventive interventions in patients at risk of rapidly deteriorating kidney function, who might benefit from regular monitoring and targeted treatment.

Allopurinol

Allopurinol

Do SGLT2 inhibitors slow progression of chronic kidney disease?

Do SGLT2 inhibitors slow progression of chronic kidney disease?

Risks and Benefits of Different Dietary Patterns in CKD

Food has the potential to cause and exacerbate many lifestyle diseases. Or it can be used to prevent and treat illnesses like primary hypertension, the metabolic syndrome, and insulin resistance. In parallel, there is also a growing body of evidence of the role of diet in the treatment of kidney disease and its ensuing complications. Popular diets for this purpose have included low-carbohydrate diets, including the ketogenic diet, and higher carbohydrate diets like Mediterranean diets and other plant-based dietary patterns. Low-carbohydrate diets have not shown harm in patients with kidney disease and may benefit a select few. Mediterranean diets have an established record of cardioprotective benefits but also may be beneficial for the kidney. Intermittent fasting has benefits for metabolic health, but limited research exists on the risk or benefit for patients with kidney disease. Plant-based diets, especially those that are lower in protein, may slow kidney disease progression, mitigate uremia, and delay dialysis initiation. Although each dietary pattern has its unique pros and cons, most healthful dietary patterns favor the inclusion of whole, unprocessed foods, preferably from plant-based sources. In this perspective, we discuss the risks and benefits of major popular diets to help guide health care professionals in treating patients with kidney disease.

S-41-2: ROLE OF TERTIARY LYMPHOID TISSUES IN KIDNEY INFLAMMATION

Kidneys are vulnerable organs, and often fail to repair. In particular, renal damage is prolonged and severe in the elderly, but the mechanism behind this was unknown. Recently, we identified a unique microenvironment orchestrating kidney injury and inflammation. Tertiary lymphoid tissues (TLTs), which mainly consist of lymphocytes and fibroblasts, are formed in the chronic phase after injury in aged kidneys, contributing to prolonged inflammation and delayed regeneration. Resident fibroblasts in the kidney play critical roles in the formation of TLTs by acquiring the abilities to produce retinoic acid and homeostatic chemokines, and to support B cell area formation. Notably, therapeutic strategy targeting TLTs attenuates tubular injury and fibrosis in mouse models. Furthermore, TLTs are found in human kidneys, and the presence of advanced-stage TLTs correlates with the severity of kidney injury and inflammation. Specifically, TLTs are commonly found in protocol biopsies of transplanted kidneys, and advanced-stage TLTs are associated with progressive graft dysfunction. Recently, we identifed TNF superfamily CD153-CD30 signaling between two unique age-dependent lymphocyte subpopulations, senescence-associated T (SAT) cells and age-associated B cells (ABCs), as a driver for TLT expansion, and demonstrated that CD153 or CD30 deficiency resulted in attenuated TLT formation with improved inflammation, fibrosis and renal function. Understanding the mechanism of TLT formation may provide clues for the development of therapeutic agents for slowing kidney disease progression.

Dapagliflozin and Kidney Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Sodium-glucose cotransporter 2 inhibitors are known to reduce heart failure events and slow progression of kidney disease among patients with heart failure and a reduced ejection fraction. To determine the effect of dapagliflozin on cardiovascular and kidney outcomes and the influence of baseline kidney disease among patients with heart failure and a mildly reduced or preserved ejection fraction enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. This was a prespecified analysis conducted from July 1 to September 18, 2022 of the DELIVER randomized clinical trial. This was an international, multicenter trial including patients with ejection fraction greater than 40% and estimated glomerular filtration rate (eGFR) of 25 mL/min/1.73 m2 or higher. Dapagliflozin, 10 mg, per day or placebo. Outcomes assessed were whether baseline kidney function modified the treatment effect on the primary outcome (cardiovascular death or worsening heart failure). Also examined was the treatment effect on the prespecified outcomes of eGFR slope and a post hoc composite kidney outcome (first ≥50% decline in eGFR from baseline; first eGFR <15 mL/min/1.73 m2; end-stage kidney disease; death from kidney causes). A total of 6262 patients (mean [SD] age, 72 [10] years; 3516 male [56%]) had mean (SD) eGFR measurements available: 61 (19) mL/min/1.73 m2; 3070 patients (49%) had an eGFR less than 60 mL/min/1.73 m2. The effect of dapagliflozin on the primary outcome was not influenced by baseline eGFR category (eGFR ≥60 mL/min/1.73 m2: hazard ratio [HR], 0.84; 95% CI, 0.70-1.00; eGFR 45-<60 mL/min/1.73 m2: HR, 0.68; 95% CI, 0.54-0.87; eGFR <45 mL/min/1.73 m2: HR, 0.93; 95% CI, 0.76-1.14; P for interaction = .16). Over a median (IQR) follow-up of 2.3 (1.7-2.8) years, the overall incidence rate of the kidney composite outcome was low (1.1 events per 100 patient-years) and was not affected by treatment with dapagliflozin (HR, 1.08; 95% CI, 0.79-1.49). However, dapagliflozin attenuated the decline in eGFR from baseline (difference, 0.5; 95% CI, 0.1-0.9 mL/min/1.73 m2 per year; P = .01) and from month 1 to 36 (difference, 1.4; 95% CI, 1.0-1.8) mL/min/1.73 m2 per year; P < .001). Results of this prespecified analysis showed that baseline kidney function did not modify the benefit of dapagliflozin in patients with heart failure and a mildly reduced or preserved ejection fraction. Dapagliflozin did not significantly reduce the frequency of the kidney composite outcome, although the overall event rate was low. However, dapagliflozin slowed the rate of decline in eGFR compared with placebo. ClinicalTrials.gov Identifier: NCT03619213.

Hepatic and Renal Consequences of Single-Ventricle Physiology Palliated With the Fontan Operation.

Over time, long-term survival has dramatically increased for patients with complex congenital heart disease who undergo the Fontan operation. With this increased survival, it has become apparent that such a circulation has important consequences for other organ systems, particularly the liver and kidney. The adverse milieu created by chronic venous hypertension, low cardiac output, and an inflammatory state contribute to the pathologic changes observed in the liver and kidneys over the long term in Fontan patients. The clinical importance of these hepatic and renal comorbidities have only recently begun to be recognized in the context of increasing life expectancy in this population. The objectives of this review are to provide an overview of the pathophysiology of the Fontan circulation and how liver and kidney disease evolve in this setting; to summarize the current evidence base as it relates to the diagnostic approach to liver and kidney disease in Fontan patients; and to discuss the therapeutic approaches to Fontan- associated liver and kidney disease. Given that this is a very active area of research in congenital heart disease, we have identified knowledge gaps and priority research areas to improve the care of Fontan patients. These include establishing the optimal diagnostic tests to detect and track liver and kidney disease change over time, determining which treatable risk factors contribute to the development of liver and kidney disease, and evaluating therapies to prevent or slow progression of liver and kidney disease.

Lack of renoprotective effects of targeting the endothelin A receptor and (or) sodium glucose transporter 2 in a mouse model of Type 2 diabetic kidney disease.

Two recent clinical trials, using sodium glucose cotransporter (SGLT2) or endothelin-A receptor (ET-A) blocker, reported the first efficacious treatments in 18 years to slow progression of diabetic kidney disease (DKD). We hypothesized that combined inhibition of SGLT2 and ET-A receptor may confer greater protection against renal injury than either agent alone. Uninephrectomized male db/db mice were randomized to four groups: vehicle, SGLT2 inhibitor (dapagliflozin (dapa), 1mg/kg/day), ET-A blocker (atrasentan (atra), 5mg/kg/day), or dual treatment from 10 weeks until 22 weeks of age. At 10 weeks of age, no differences were observed in body weight, blood glucose or urinary albumin excretion among the four groups. At 16 and 22 weeks of age, body weight was lower and blood glucose levels higher in the vehicle and atra groups compared with dapa- and dual-treated groups. No notable differences were observed among the four groups in urinary albumin excretion at weeks 16 and 22. Histological analysis showed mild glomerulosclerosis and tubular injury (<5%) in all four groups with reduced glomerulosclerosis in the dual treatment group compared with vehicle. Individual or combined treatment with an SGLT2 inhibitor and (or) an ET-A antagonist did not confer renoprotective effects in this model.

Soy Phospholipids Exert a Renoprotective Effect by Inhibiting the Nuclear Factor Kappa B Pathway in Macrophages.

Complications associated with chronic kidney disease (CKD), which involves kidney inflammation, are a major health problem. Soy protein isolate (SPI) reportedly inhibits CKD exacerbation; however, its detailed action mechanism remains obscure. Therefore, the role of the polar lipid component of SPI in suppressing inflammation was investigated. Zucker fatty rats were divided into three groups and fed a diet containing casein, SPI, or casein + SPI ethanol extract (SPIEE) for 16 weeks. The isoflavones and phospholipids of SPIEE were evaluated for their anti-inflammatory effects. Rats in the SPI and casein + SPIEE groups showed reduced levels of the urinary N-acetyl-β-d-glucosaminidase and renal IL-1β mRNA (an inflammatory marker) compared with those in the casein group. In proximal tubular cells, genistein significantly inhibited monocyte chemoattractant protein-1 (MCP-1) expression induced by an IL-1β stimulus. In macrophages, soybean phospholipids suppressed lipopolysaccharide-induced IL-1β gene expression by inhibiting the phosphorylation of inhibitor κB and p65. Phosphatidylinositol (PI) was found to be essential for inhibition of IL-1β expression. SPIEE inhibited the exacerbation of kidney disease. Genistein and soybean phospholipids, especially soybean-specific phospholipids containing PI, effectively inhibited the inflammatory spiral in vitro. Hence, daily soybean intake may be effective for inhibiting chronic inflammation and slowing kidney disease progression.

A Retrospective Combination Health Outcomes Study among Diabetic Patients with Chronic Kidney Disease: A Multi-Level Study

Diabetes is the prominent cause of the progression of chronic kidney diseases (CKD) worldwide. Effective implementation of healthcare services and healthcare delivery system to control glycemic level and slow annually declining eGFR remain a challenge in many countries including Thailand. The aims of this study were to investigate the association between individual and health service delivery factors on the combination health outcomes. This multi-level study applied case-control method was conducted. The 397 participants were recruited from 11 hospitals during December 2018 to May 2019 in Thailand. The samples were categorized into 4-group combination health outcome. Data analysis was performed by descriptive analysis and multi-level multinomial logistic regression analysis. The multinomial logistic regression in bivariate analysis showed that diabetes self-care activities score were more likely to control glycemic and CKD progression compared with those with a low-level of DSCA (OR 3.47; 95 % CI: 1.19 - 10.15). The rational drug uses (RDU) as the health service-level factors increased combination health outcomes 2 times (OR 2.41; 95 % CI: 1.05 - 5.53). The multi-level analysis found that performing with high-level of DSCA (OR 5.36; 95 % CI :1.99 - 14.46) and rational drug uses of metformin and NSAIDs (OR 2.33; 95 % CI: 1.25 - 4.36) increased probability to achieve combination health outcomes. Findings highlight the importance of diabetes self-care activities and health service delivery system to optimize the combination health outcomes among diabetic patients with CKD.&#x0D; HIGHLIGHTS&#x0D; &#x0D; The glycemic control and slow kidney disease progression could decrease diabetic complications&#x0D; The challenges of complicate diseases management involved patient-level and health service-level factors&#x0D; The high-level of DSCA showed the significant association with glycemic control and slow kidney disease progression&#x0D; This study encourages professional nurses promote the model of care that appropriate for individual person who had the difference of age, BMI and self-care activities level&#x0D; &#x0D; GRAPHICAL ABSTRACT