eGFR Slope Research Articles

#2119 Long-term efficacy of tolvaptan therapy in patients with ADPKD

Abstract Background and Aims Currently, the only available therapy to ameliorate disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) is tolvaptan, a vasopressin V2 receptor antagonist. Real-life data on tolvaptan treatment effect is sparce, with several limitations including restricted follow-up, relatively small patient groups, no control groups, or only data reported on kidney function without total kidney volume. We studied, therefore, the long-term effect of tolvaptan on kidney function as well as kidney growth in a relatively large number of real-life ADPKD patients and controls. Moreover, we investigated the effect of salt and protein intake on long-term treatment efficacy. Method Data from two national ADPKD cohorts were pooled. Kidney function (creatinine-based eGFR) was measured at least yearly and total kidney volume (TKV, measured by MRI or CT) at least 3-yearly. Salt and protein intake were measured by 24 h urine excretion. To investigate the long-term effects of tolvaptan we assessed change in eGFR and TKV before as well as after start of tolvaptan using linear mixed effects models. For this purpose, we excluded the acute treatment effect from start to 6 months after initiation of tolvaptan. As a control group, we included all patients who were not treated with tolvaptan, assessing change in eGFR and TKV before and after the theoretical start of treatment (based on the average time of tolvaptan initiation observed in the tolvaptan-treated group) as well as a matched control group. Subgroup analyses of salt and protein intake were based on the median urinary excretion of sodium or urea. Results 697 patients (47 ± 12 years, 59.1% female) were included, of which 104 patients used tolvaptan. Mean duration of tolvaptan use was 6.0 ± 4.5 years (range: 0.8 to 15.6). Tolvaptan use reduced yearly eGFR decline by 17.4% (−4.43 to −3.66 mL/min/1.73 m2/year, p = 0.03, number of measurements: n = 817), whereas in the non-tolvaptan control group after the theoretical start of treatment, eGFR decline increased by 13.3% (−1.95 to −2.21 mL/min/1.73 m2/year, p = 0.2, n = 2804). Long-term TKV growth did not change after start of tolvaptan treatment (4.90 to 5.53%/year, p = 0.5, n = 316). Similar results were obtained in the matched control group. A more substantial treatment effect of tolvaptan on eGFR slope was noted in patients with high compared to low salt intake (assessed as ≥ versus < median urinary sodium excretion of 146 mmol/24 h (difference 1.62 (0.22 to 3.02) mL/min/1.73 m2/year, p = 0.02). Subgroup analysis according to median protein intake did not show a significant difference in tolvaptan treatment effect. Conclusion In this study, with real-life patient data, long-term follow-up, and a control group, we found that tolvaptan attenuated long-term kidney function decline but, notably, did not influence kidney growth. Higher daily salt intake was associated with a more substantial tolvaptan treatment effect, perhaps due to higher vasopressin levels before treatment, and consequently more vasopressin antagonism by tolvaptan.

#2456 Real world outcomes of Fabry disease in Italian excellence centers: the ground study

Abstract Background and Aims Fabry disease (FD) is an X-linked lysosomal storage disorder with an estimated prevalence from 1:1368 to 1:8882, caused by galactosidase alpha gene (GLA) mutations, resulting in renal, cardiac and central nervous system involvement with significant morbidity and mortality in both sexes. Treatment includes enzyme replacement therapies (ERTs) and chaperone therapy. A better understanding of this disorder from its diagnostic journey, along with the impact of patient characteristics and available treatments on disease prognosis are relevant topics for physicians dealing with FD. The Global buRden and treatment trajectOries in Italian patients with Fabry disease: a retrospective longitUdinal and cross-sectioNal study–GROUND describes a cohort of FD Italian patients, addressing the unmet needs arising from this condition while providing a real-world picture from which further research insights can be derived. Methods This was a retrospective, longitudinal and cross-sectional study. Data about adult patients of either sex living or deceased with a documented FD diagnosis and at least 3 years of follow-up or early occurrence of severe/fatal outcomes were collected. Occurrence of severe/fatal events (renal, cardiac, cerebral events, death) from birth to last follow-up visit was the composite primary outcome. Other outcomes assessed were disease progression measured by FAbry STabilization indEX (FASTEX), occurrence of clinically significant events/FD related symptoms (i.e., renal function decline, detection/worsening of left ventricular hypertrophy (LVH), lysoGb3 increase, new FD symptoms), time from first manifestation to diagnosis, treatment trajectories. Results From June 2021 to June 2022, 199 patients, 73 males and 126 females, including 169 classic and 30 late-onset phenotypes, were enrolled at 8 Italian centers. Median time from onset of FD symptoms to diagnosis was 60.3 months [95% confidence interval (IC) 38.8-89.7], with a median of 0.64 years (range 0-19.29) from diagnosis to beginning of treatment. Chronic pain and angiokeratomas were the most common initial symptoms (18.1% and 13.1% of patients respectively); acroparesthesia and abdominal pain were reported in 12.5% of patients and LVH in 8.5%. Among the 143 missense/nonsense mutations identified, 14 were Variants of Uncertain Significance (VUS). Overall, 82% of patients were treated with 1 FD specific therapy, of whom 24% switched at least one treatment, while 5% definitively stopped. The composite primary outcome was experienced by 31.7% of patients for a total of 85 severe/fatal events. Specifically, 7.5% (n = 15, all treated) patients experienced a renal event; 20.6% of patients had a cardiac event (n = 41, 38/41 treated); 11.1% (n = 22, all but 1 treated) of subjects experienced a cerebral event; fatal events occurred in 7 patients of whom 1 was untreated. In addition, 88.9% of patients reported at least one clinically significant event, among which detection/worsening of LVH was the most common (41.2%). Estimated Glomerular Filtration rate (eGFR) slopes in the last 1-3 years of follow up were −2.07 [Standard Error (SE): 1.38] and −0.76 (SE: 1.75) in classic males and females, respectively. Long-term (i.e., from diagnosis to last available measure) FASTEX identified 31.1% of patients as being unstable. Conclusions In this real-world Italian FD cohort, patients were promptly treated after diagnosis according to existing guidelines, following expert evaluation. Nevertheless, severe clinical events occurred in about 30% of the cohort, mainly among classic treated males, revealing persistent unmet needs such as a better assessment of determinants of disease progression and outcomes, as well as response to treatment and further insights on the potential benefit of new therapeutic options.

#2424 Higher 24-hour urine sodium-to-potassium ratio is associated with worse renal outome

Abstract Background and Aims Low sodium and high potassium intake are advised to control blood pressure and may improve long term cardiorenal outcomes. The optimal potassium intake for patients with chronic kidney disease remains to be defined. We investigated whether the 24-hour urine sodium-to-potassium ratio (Na/K-ratio), which incorporates estimates of both sodium and potassium intake, could predict long-term renal outcome. Method We selected adult outpatients of a Dutch tertiary hospital who collected at least one 24-hour urine collection with available sodium and potassium measurements between 1998-2023. Patients with a history of dialysis or kidney transplantation were excluded. We examined the need for persistent renal replacement therapy (RRT), defined as dialysis or kidney transplantation, using Cox regression. The association between the 24-hour urine Na/K-ratio and the estimated glomerular filtration rate (eGFR) slope was assessed using linear regression in patients who had ≥3 eGFR measurements available in ≥3 years. The linear regression analysis was adjusted for age, sex, baseline eGFR, diabetes mellitus and hypertension. In the Cox regression analysis, we additionally adjusted for the interaction between the 24-hour urine Na/K-ratio and baseline eGFR. Hypertension was defined as a clinical diagnosis or an office blood pressure ≥140/90 mmHg. Results We included 720 patients aged 50 ± 15 years, of whom 52% were male, 58% had hypertension and 31% diabetes mellitus. The baseline eGFR was 64 ± 34 ml/min/1.73 m2. The 24-hour urine Na/K ratio was 2.5 ± 1.2 in a median number of 1 (IQR = 1-2) urine collection. During a median follow-up of 11.2 (14.0) years, 29% of patients needed RRT. In 575 patients with sufficient eGFR measurements (mean 12 ± 8 measurements per subject) the median annual eGFR decline was 1.51 (IQR = 0.49-3.98) ml/min/1.73 m2. Every unit increase in the 24-hour urine Na/K-ratio was associated with a 19% higher risk for persistent RRT need (HR 1.19, 95% CI 1.03-1.39; p = 0.02) and an additional 0.44 ml/min/1.73 m2 (95% CI −0.83, −0.04; p = 0.03) decline in eGFR. Conclusion This study suggests that higher 24-hour urine Na/K-ratio is associated with faster kidney function decline and the need for RRT, independent of hypertension, in a selected group of outpatients.

#1743 Kidney outcomes associated with SGLT2 inhibitors compared to other glucose-lowering drugs: a real-world study from China

Abstract Background and Aims Currently, there is insufficient real-world study on the kidney outcomes of SGLT2i in mainland Chinese patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). This study aimed to investigate the association between the utilization of Sodium-dependent glucose cotransporters inhibitors (SGLT2i) in real-world settings and kidney outcomes in patients with T2D and CKD in mainland China. Method In a retrospective analysis of electronic medical records from West China Hospital of Sichuan University, patients with T2D and CKD were included. Patients were divided into two groups, those initiating treatment with SGLT2i and those receiving other glucose-lowering drugs (oGLDs). The primary focus lies in examining the impact of SGLT2i on the decline slope of eGFR and major kidney events in these patients. Results We enrolled 944 patients diagnosed with both T2D and CKD. Out of these, 605 patients were prescribed SGLT2i, while the remaining 339 patients received oGLDs. The median follow-up duration were 16.8 months and 20.6 months, respectively. Throughout the follow-up period, we observed a significant decrease in the rate of eGFR decline in patients using SGLT2i (4.94 ml/min/1.73 m2 per year reduction compared to oGLDs, 95% CI: 4.73–5.15). A total of 101 kidney composite endpoint events occurred, with 31 events in the SGLT2i group and 70 events in the oGLDs group. The use of SGLT2i was associated with a 65% decrease in the risk of kidney composite endpoint events (hazard ratio 0.35, 95% CI 0.19–0.63). Conclusion In clinical practice, SGLT2i have shown favorable effects on kidney prognosis in patients with T2D and CKD in mainland China. These effects remain consistent across patients with varying risks of CKD progression.

#1905 Sex differences in primary distal renal tubular acidosis: a single-centre retrospective study

Abstract Background and Aims The kidney has been described as one of the most estrogen-responsive organs after reproductive ones. Many non-X-linked renal diseases present with sex differences. Although not completely elucidated, an influence of estrogens has been described in several transporters along the renal tubule such as the Na+/phosphate cotransporter (NaPi-IIa) in the proximal tubule, the Na+/K+/2Cl⁻ cotransporter (NKCC) in the thick ascending limb of the loop of Henle, the thiazide-sensitive Na+/Cl⁻ cotransporter (NCC) in the distal convoluted tubule and the epithelial sodium channel (ENaC) expressed by the principal cells of the collecting duct. Our study aimed to investigate possible phenotypic sex differences over the natural history of primary distal renal tubular acidosis (dRTA), a rare genetic condition characterized by impaired urinary acidification in the collecting duct that results in non-anion gap metabolic acidosis, hypokalemia, hypercalciuria, nephrolithiasis and nephrocalcinosis, which can lead to chronic kidney disease (CKD). Method We included a cohort of 31 genetically confirmed dRTA patients (19 women and 12 men) followed at the London Tubular Centre. We retrospectively collected data from 2012 to 2023. Estimated glomerular filtration rate (eGFR) was calculated with the CKD-EPIcr formula. Hypokalemia was defined as serum potassium < 3.5 mmol/L, hypercalciuria was defined as urinary calcium/creatinine (uCa/Cr) > 0.7 mmol/mmol and acidosis was defined as HCO3− ≤ 22 mmol/L. Data were analyzed using non-parametric Mann-Whitney as appropriate (Prism GraphPad 8.0.2). A p value < 0.05 was considered as statistically significant. Results Baseline characteristics and prevalence of different mutations are shown in Table 1. At baseline, both cohorts were young, with preserved kidney function. 60% of women were acidotic compared to 50% of men, and 30% of men were hypokalemic compared to 8% of women. The majority of patients in both cohorts presented with overt hypercalciuria (60% of women vs 90% of men). Prevalence of nephrolithiasis and nephrocalcinosis was similar among women and men. At baseline, no statistically significant difference between sexes was found for serum or urinary parameters. Interestingly, men exhibited a tendency towards higher annual mean slope of eGFR (−3.3 ± 2.5 mL/min/1.73 m2) compared to women (−0.5 ± 1.5 mL/min/1.73 m2) in a statistically significant fashion (Fig. 1a). Although not statically significant, we noticed a tendency towards higher fractional excretion of phosphate (FEPO4) (Fig. 1b) and dyslipidemia in men (Fig. 1c). There was no difference in PTH between the two groups (Fig. 1c). Conclusion Men affected by primary dRTA are at increased risk of CKD progression, tend to have a more severe phenotype at baseline and appear to be more dyslipidemic than women. This is consistent with findings in the literature that report accelerated CKD progression and higher cardiovascular morbidity and mortality in men. To our knowledge, this is the first study reporting sex differences in primary dRTA.

#887 Complement biomarkers in IgA nephropathy and IgA vasculitis with renal involvement: can urine rather than blood be the answer?

Abstract Background and Aims IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. Dysregulation of the complement system is considered a part of the pathogenesis and can occur both in the circulation and locally in the kidney. Despite this, most studies have focused on complement biomarkers in the blood, rather than in urine. Our aim was to evaluate a wide range of complement-related proteins in blood and urine at diagnosis and their association with disease activity in biopsy findings, proteinuria, and outcome. We added PTX-3, a protein expressed in activated endothelial cells, which can be both produced by and activate mesangial cells in IgAN and has a function in all three complement pathways. Adult-onset IgA vasculitis with renal involvement (IgAVN) shares many similarities with IgAN and cannot currently be distinguished by kidney biopsy or any established biomarker. We therefore also aimed to compare the same biomarkers between these two disorders. Method In a Swedish cohort of 96 patients with IgAN (n = 65) and IgAVN (n = 31), who had been followed prospectively for a median of 10.8 years, we performed the following analysis in plasma and urine in samples stored at the time of kidney biopsy. Analyses in plasma (p-) included C3bc, C4c, C5b-9, MASP2, MASP3, MAP1, FCN 1-3, MBL, CL11 and PTX-3 and in urine (u-) C3bc, C4c, C5b-9, MASP3, FCN2, FCN3, MBL and PTX-3. An in-house developed sandwich ELISA was used for all analyses. Kidney biopsies were classified according to the Oxford MEST-C score, describing (simplified for this small cohort) the presence vs absence (1 vs 0) of mesangial proliferation (M), endocapillary proliferation (E), segmental sclerosis (S), tubular atrophy/interstitial fibrosis (T) and crescents (C). Severe outcome was defined by a combination of an eGFR slope > 2.5 ml/min/1.73 m2 per year or end stage kidney disease. For statistical analysis, Mann-Whitney U test was performed for comparison between independent groups, Chi squared test and Fisher's test for categorical variables and Spearman's ranks test for correlation analysis. Median values are presented without IQR for this abstract. Results Urine samples were available in 59 patients (IgAN n = 39, IgAVN n = 20). Patients with detectable u-MBL (28.9%) and u-C5b-9 (27.1%) had higher levels of proteinuria than those with undetectable levels (1.5 g/d vs 0.71g/d; p = 0.009 and 2.3 g/d vs 0.7 g/d respectively; p < 0.001). Lower eGFR (71 ml/min/1.73 m2 vs 88 ml/min/1.73 m2; p = 0.034) were observed if u-C5b-9 was measurable. Detectable levels of u-PTX-3 and u-MBL were more often found in the presence of M1 vs M0 (53% vs 20%; p = 0.022 and 47% vs 12.5%; p = 0.011), E1 vs E0 (55% vs 14%; p = 0.001 and 40% vs 11%; p = 0.020) and C1 vs C0 (56% vs 11%; p = 0.003 and 44% vs 11%; p = 0.012). No differences in proteinuria or eGFR were seen in patients with or without detectable u-PTX-3. The degree of proteinuria was positively correlated to the levels of u-C3bc (r = 0.33; p = 0.011) and u-C4c (r = 0.39; p < 0.001). U-C4c levels were higher in patients with M1 vs M0 (54.4 Au/mL vs 23.8 Au/mL; p = 0.037) and T1 vs T0 (53.2 Au/mL vs 23.8 Au/mL; p = 0.034). Concerning the analyses in plasma (n = 95), lower p-MASP3 and p-CL11 levels were correlated with lower eGFR (r = 0.29; p = 0.004 and r = 0.31, p = 0.002). Moreover, lower p-MASP3 levels were detected in patients with E1 vs E0 (2918 ng/mL vs 3404 ng/mL; p = 0.002) and C1 vs C0 (3053 ng/mL vs 3427 ng/mL; p = 0.015). Both p-C5b-9 (13.3 Au/mL vs 8.2 Au/mL; p = 0.001) and p-FCN 1 (395 ng/mL vs 289 ng/mL; p = 0.001) were higher in patients with C1 vs C0. No single complement-related protein was associated with severe outcome, and no statistically significant differences in plasma or urine levels between patients with IgAN and IgAVN were observed. Conclusion Increased urinary levels of MBL and PTX-3 could be potential biomarkers of disease activity in both IgAN and IgAVN, whereas excretion of C5b-9 might be more unspecific and associated with chronic damage. However, these results need to be confirmed in larger and more ethnically diverse cohorts. The impact of treatment on these potential biomarkers for disease activity need to be evaluated in longitudinal studies.

#217 Renin-angiotensin-aldosterone system blockers effect in CKD progression in hypertensive elderly patients without proteinuria: PROERCAN trial

Abstract Background and Aims Evidence about nefroprotective effect with RAAS blockers in elderly patients with chronic kidney disease (CKD) without proteinuria is lacking. The primary outcome of our study is to evaluate the impact of RAAS blockers in CKD progression in elderly patients without proteinuria. Method Multicenter open-label, randomized controlled clinical trial including patients over 65 year-old with hypertension and CKD stages 3-4 without proteinuria. Patients were randomized in a 1:1 ratio to either receive RAAS blockers or other antihypertensive drugs and were followed up for three years (Figure). Primary outcome is estimated glomerular filtration rate (eGFR) decline at 3 years. Secondary outcome measures include BP control, renal and cardiovascular events and mortality. Results 88 patients were included with a mean age of 77.9 ± 6.1 years and a follow up period of 3 years: 40 were randomised to RAAS group and 48 to standard treatment. Etiology of CKD was: 53 vascular, 16 interstitial and 19 of unknown etiology. In the RAAS group eGFR slope during follow up was −4.3 ± 1.1 ml/min, whereas in the standard treatment group an increase on eGFR was observed after 3 years (+4.6 ± 0.4 ml/min), p = 0.024. We found no differences in blood pressure control, number of antihypertensive drugs, albuminuria, potassium serum levels, incidence of cardiovascular events nor mortality during the follow up period. Conclusion In elderly patients without diabetes nor cardiopathy and with non proteinuric CKD the use of RAAS blockers does not show a reduction in CKD progression.

#1829 Intravenous contrast exposure in stable CKD 4 and 5 patients and adverse renal outcomes: a propensity-score matched study

Abstract Background and Aims Previous studies of intravenous (IV) contrast administration in patients with CKD have focused on the association between contrast exposure and AKI. Here we explore the association of IV contrast administration for CT imaging with a broader range of adverse renal outcomes in patients with advanced CKD (stages 4 and 5). Method Data covering nephrology care in the West of Scotland were obtained from the Strathclyde Electronic Renal Patient Record. We included adult patients with an incident CT scan and an eGFR < 30 mL/min/1.73 m2 between April 2008 and May 2020. Patients with AKI were excluded. Structured query language (SQL) was used to analyse CT scan reports and identify whether IV contrast had been administered or not. Patient demographics (age, sex, Scottish index of multiple deprivation), co-morbidities, laboratory tests (including eGFR slope for 6 months preceding the study calculated by linear regression, eGFR at time of CT, C-reactive protein, urine protein:creatinine ratio), anthropometric measurements (blood pressure, body mass index), and medications were collected. The primary outcome was a composite renal outcome (AKI, sustained eGFR drop, renal replacement therapy [RRT], and renal death). Secondary outcomes included individual components of the composite outcome and all-cause death. AKI was defined as a 25% creatinine rise from index creatinine between days 7 and 14 post CT. Sustained eGFR drop was defined as two consecutive eGFR < 15 mL/min/1.73 m2 more than 4 weeks apart. Renal death was defined as death from acute kidney injury, chronic kidney disease or end stage renal disease without dialysis. A propensity-score matched dataset was created using a 1:2 ratio with no replacement. Multivariable logistic, proportional hazards and Fine-Gray (competing risks) regressions were used to identify independent correlates of the primary and secondary outcomes. Missing data were multiply imputed using the “mice: Multivariate Imputation by Chained Equations” package on R studio. Results 9226 patients with an eGFR < 30 mL/min/1.73 m2 underwent an incident CT scan during the study period. Among 6371 patients meeting the inclusion criteria (3067 (48.1%) men; mean [SD] age 72.8 [13.8] years; mean [SD] eGFR 20.4 [6.9] ml/min/1.73 m2), 875 had received IV contrast. A propensity-score matched dataset was generated consisting of 875 patients who had a contrast CT and 1750 patients with non-contrast CT. On multivariable analysis, contrast administration was associated with a higher risk of AKI (HR 1.49, 95% CI 1.06-2.10, p = 0.02) but not with the composite renal outcome (HR 0.89, 95% CI 0.66-1.20, p = 0.45). Contrast administration did not change the risk of a sustained eGFR drop (HR 0.88, 95% CI 0.54-1.43, p = 0.60), RRT (HR 0.85, 95% CI 0.61-1.20, p = 0.36), or all-cause death (HR 0.95, 95% CI 0.76-1.19, p = 0.65). We did not identify an effect of contrast administration on the time to composite renal outcome, RRT, or all-cause death by Cox regression (HR 0.92, 95% CI 0.70-1.22, p = 0.56; HR 0.88, 95% CI 0.64-1.23, p = 0.46; and HR 1.07, 95% CI 0.94-1.20, p = 0.30, respectively). On Fine-Gray regression, we did not identify an impact of contrast administration on the risk of RRT (HR 0.84, 95% CI 0.63-1.12, p = 0.24) or death (HR 1.07, 95% CI 0.95-1.20, p = 0.27). In subgroup analysis in patients with an index eGFR < 20 mL/min/1.73 m2, contrast administration was not associated with the composite renal outcome (HR 0.79, 95% CI 0.51-1.22, p = 0.28), RRT (HR 0.85, 95% CI 0.52-1.39, p = 0.51), AKI (HR 1.28, 95% CI 0.66-2.45, p = 0.46), or death (HR 0.94, 95% CI 0.64-1.39, p = 0.76). Conclusion In a stable population with advanced CKD, we identified an association between IV contrast administration and the risk of AKI, but this did not translate in adverse long-term renal outcomes. These findings suggest that increases in serum creatinine post-IV contrast in patients with stable CKD are not clinically significant.

#3124 How well do risk assessment guidelines perform for ADPKD?

Abstract Background and Aims The approval of Tolvaptan for treatment of ADPKD heralds a new era when mechanism-based therapy is now possible. However, Tolvaptan is an expensive drug associated with potentially serious side effects and is currently reserved for patients at high-risk for progression to ESKD. Two sets of risk assessment guidelines for ADPKD are now available based on the consensus of two panels of nephrologists from Canada and Europe. However, how well do these guidelines perform in risk assessment has not been formally assessed. Method We conducted a prospective study in 474 patients with typical imaging pattern of ADPKD by MRI who also had detailed clinical and laboratory data. We used age- and height-adjusted total kidney volume to derive the Mayo Clinic Imaging Class as a “gold-standard” for risk assessment (i.e. low-risk: 1A-1B; high-risk: 1C-1E). We then applied the revised Canadian guidelines (Can J Kidney Health Dis. 2018) and the updated European guidelines (NDT 2022) to our patient cohort to assess their performance. Results The study cohort consisted of 286/474 (60%) high-risk patients with MCIC 1C-1E. Applying the updated Canadian risk assessment algorithm resulted in exclusion of 245/474 (52%) patients including 86/286 (30%) of the high-risk patients. The resultant cohort (229/474) was enriched with 88% high-risk patients but also included 12% of low-risk patients. The updated European guidelines provide a 3-step hierarchal algorithm, when applied resulted in exclusion of 55% (157/286) of high-risk patients. During the last step, 122 patients could not be classified due to a lack of eGFR slope information. The resultant cohort (180/474) was enriched with 72% high-risk patients but also included 28%(51/180) of low-risk patients. Conclusion Risk assessment in ADPKD is an evolving process that needs to be redefined by new clinical data and test technologies. Clinical guidelines should be evaluated using real-life data and those that enrich high-risk patients while minimizing low-risk patients have the most clinical utility

#1737 Kidney function, kidney function decline, and the risk of abdominal aortic aneurysm: the Stockholm CREAtinine Measurements (SCREAM) project

Abstract Background and Aims Small, cross-sectional, cohort studies suggest a relationship between low estimated glomerular filtration rate (eGFR) and risk of developing abdominal aortic aneurysm (AAA). We here explored the possible association between eGFR and annual eGFR decline with future risk of AAA in a large community-based sample. Method Observational study from the SCREAM project, including participants free from AAA history. We used Cox regression to explore associations between eGFR and the rate of incident AAA and fatal-AAA (followed by death within 30 days). Among those with repeated eGFR tests within a year, we used linear mixed models to explore associations between the annual slope in eGFR and AAA rates. Results We included 1 586,543 eligible participants (mean age 47 years, 53% female, median eGFR 97 ml/min/1.73 m2). During median 7.6 years, 5,248 (0.34%) participants experienced AAA, of which 317 were fatal. In multivariable analyses, compared with individuals with eGFR 90 mL/min/1.73 m2, the rates of AAA and fatal-AAA were higher across lower eGFR: for eGFR 30 mL/min/1.73 m2, the HR of AAA was 1.23 (95% CI 1.09-1.39), and for fatal-AAA was 2.59 (1.71-3.90); for eGFR 15 mL/min/1.73 m2, the HR of AAA was 1.58 (1.31-1.90) and for fatal-AAA was 3.92 (2.28-6.70). Total 639 607 participants had repeated eGFR measures within a year, and experienced 3,416 AAA events during median 8.8 years of follow-up. Compared with participants showing a stable eGFR slope (−1 to 1 mL/min/y), the rate of AAA was 10% higher (HR 1.10 [1.00-1.21]) in those with an eGFR decline of 1-3 mL/min/y, and 30% higher (HR 1.30 [1.03-1.65]) in those with an eGFR decline >3 mL/min/y. Conclusion Both a single point eGFR and the annual slope of eGFR decline were associated with future risks of AAA. The incidence rate of AAA, and particularly fatal AAA, was higher with greater severity of chronic kidney disease or speed of eGFR decline.

Inosine monophosphate dehydrogenase type 2 polymorphism IMPDH2 3757T>C (rs11706052) and 12-month evolution of the graft function in renal transplant recipients on mycophenolate-based immunosuppression.

Variant allele at the inosine monophosphate dehydrogenase type 2 polymorphism IMPDH2 3757T>C has been associated with increased enzyme activity and reduced susceptibility to mycophenolic acid (MPA) in vitro. It has been suggested associated with an increased risk of acute rejection in renal transplant recipients on MPA-based immunosuppression, but not unambiguously. We assessed one-year evolution of the estimated glomerular filtration rate (eGFR) in transplanted variant allele carriers and wild-type subjects, while controlling for a number of demographic, pharmacogenetic, (co)morbidity, and treatment baseline and time-varying covariates. The eGFR slopes to day 28 (GMR = 1.01, 95% CI 0.93-1.09), and between days 28 and 365 (GMR = 1.01, 95% CI 0.99-1.02) were practically identical in 52 variant carriers and 202 wild-type controls. The estimates (95%CIs) remained within the limits of ±20% difference even after adjustment for a strong hypothetical effect of unmeasured confounders. Polymorphism IMPDH2 3757T>C does not affect the renal graft function over the 1st year after transplantation.

The reduced function allele SLCO1B1 c.521T>C is of no practical relevance for the renal graft function over the first post-transplant year in patients treated with mycophenolic acid.

It is unclear whether renal transplant recipients treated with mycophenolic acid (MPA) who carry the reduced-function allele at polymorphism SLCO1B1 c.521T>C differ from their wild-type peers regarding renal outcomes and tolerability. We aimed to estimate the effect of this polymorphism on the graft function (estimated glomerular filtration rate, eGFR) over the first 12 post-transplant months in patients on MPA-based maintenance immunosuppression. In a 12-month observational cohort study, consecutive adult patients were repeatedly assessed for eGFR. The SLCO1B1 c.521C>T variant allele carriers (exposed) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and eGFR trajectory was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation. The adjusted eGFR slopes from day 1 to day 28 (daily), and from day 28 to day 365 (monthly) were practically identical in exposed (n = 86) and control (n = 168) patients [geometric means ratios (GMR) = 0.99, 95% confidence interval (CI) = 0.92-1.06 and GMR = 0.98, 0.94-1.01, respectively]. The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in exposed and controls [rate ratios (RR) = 0.94, 0.49-1.84 and RR = 1.08, 0.74-1.58, respectively]. The pharmacokinetic analysis did not signal meaningful differences regarding exposure to MPA, overall (exposed n = 23, control n = 45), if cotreated with cyclosporine (n = 17 vs. n = 26) or with tacrolimus (n = 8 vs. n = 17). In patients treated with MPA, variant allele SLCO1B1 c.521T>C appears of no practical relevance regarding the 12-month renal graft function, MPA safety and exposure to MPA at early steady-state.

TIME IN TARGET RANGE OF SYSTOLIC BLOOD PRESSURE AND EGFR SLOPE IN PATIENTS WITH TYPE 2 DIABETES

Objective: Time in target range (TTR) of systolic blood pressure, a novel measure to assess the effect of blood pressure control, is attracting attention in recent European guidelines. However, few studies have explored the renoprotective value of systolic TTR in patients with type 2 diabetes (T2D). Design and method: We used the database of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure (BP) trial, and 4409 eligible participants were enrolled in the present study. The systolic target range for the standard and intensive therapy was defined as 120 to 140 mm Hg and 110 to 130 mm Hg, respectively. Results: After adjustment for covariates, systolic TTR was significantly and positively associated with 2 indices of eGFR slope (P <= 0.0016), regardless of additional adjustment for systolic blood pressure average and variability. The association of systolic TTR and eGFR slope was significantly stronger in CKD patients than those without CKD (P for interaction <=0.044). When TTR was treated as a categorical variable, participants with the highest systolic TTR in the CKD group had a significantly positive association with eGFR slope (P <= 0.00046). Similar results were obtained in the further subgroup analysis. Conclusions: Among patients with diabetes, systolic TTR showed a significant and positive association with eGFR slope, with a stronger association observed in those with CKD. TTR reflects both blood pressure level and stability across blood pressure management, emphasizing the importance of maintaining stable blood pressure control for renoprotection in T2D patients, particularly in those with CKD.

Temporal alteration of serum bilirubin levels and its renoprotective effects in diabetic kidney disease: exploring the hormonal mechanisms.

This current study represents a novel endeavor to scrutinize the correlation between the temporal alteration in serum total bilirubin (TBIL) concentrations and the rate of estimated glomerular filtration rate (eGFR). Additionally, this study aims to probe the plausible molecular mechanism underpinning the renoprotective effects of bilirubin concerning its hormonal characteristics. In this study, a cohort of 103 patients diagnosed with DKD and receiving medical care at Dongzhimen Hospital were recruited and monitored over a period of 2-7 years. The progression of DKD was ascertained using a threshold of eGFR decline > -5.48%/year. To assess the relationship between the annual change in serum TBIL levels (%/year) and the slope of eGFR, multivariate binary logistic regression analysis was employed. Furthermore, the ROC curve analysis was employed to determine the cut-off value for TBIL levels (%/year). The use of multivariate binary logistic regression models revealed that serum TBIL levels (%/year) exhibited a significant correlation with the slope of eGFR. Moreover, the ROC curve analysis indicated a cut-off value of -6.729%/year for TBIL levels (%/year) with a sensitivity of 0.75 and specificity of 0.603, in diagnosing eGFR decline >-5.48%/year. The findings of this study suggest that the sustained elevation of serum bilirubin concentration within the physiological range can effectively retard the progression of Diabetic Kidney Disease (DKD). Furthermore, the hormonal attributes of bilirubin may underlie its renoprotective effects.

Nephrology referral slows the progression of chronic kidney disease, especially among patients with anaemia, diabetes mellitus, or hypoalbuminemia: A single-centre, retrospective cohort study.

The Kidney Disease Improving Global Outcomes guidelines recommend nephrology referral for patients with chronic kidney disease (CKD) stages 4 to 5, significant proteinuria and persistent microscopic haematuria. However, the recommendations are opinion-based and which patients with CKD benefit more from nephrology referral has not been elucidated. In this retrospective cohort study, patients referred to our nephrology outpatient clinic from April 2017 to March 2019 were included. We excluded patients considered to have an acute decline in kidney function (annual decline in estimated glomerular filtration rate [eGFR] >10 mL/min/1.73 m2). The slopes of eGFR before and after nephrology referral were estimated and compared by linear mixed effects models. Interaction between time and referral status (before or after referral) was assessed and effect modifications by the presence of diabetes, proteinuria (defined by urine dipstick protein 2+ or more), urine occult blood, hypoalbuminemia (defined by albumin levels less than 3.5 g/dL) and anaemia (defined by haemoglobin levels less than 11.0 g/dL) were evaluated. The eGFR slope significantly improved from -2.05 (-2.39 to -1.72) to -0.96 (-1.36 to -0.56) mL/min/1.73 m2/year after nephrology referral (p < .001). The improvement in eGFR slope was more prominent among those with diabetes mellitus, anaemia, and hypoalbuminemia (all p-values for three-way interaction <.001 after adjustment for covariates). Further adjustments for time-dependent haemoglobin levels, the use of erythropoiesis-stimulating agents, iron supplementation, anti-hypertensives and anti-diabetic medications did not change the significance of the interactions. Nephrology referral slows CKD progression, especially among those with hypoalbuminemia, diabetes or anaemia. Patients with hypoalbuminemia, diabetes or anaemia might benefit more from specialized care and lifestyle modifications by nephrologists. The inclusion of anaemia and hypoalbuminemia in nephrology referral criteria should be considered.

A hierarchical kidney outcome using win statistics in patients with heart failure from the DAPA-HF and DELIVER trials

Win statistics offer a new approach to the analysis of outcomes in clinical trials, allowing the combination of time-to-event and longitudinal measurements and taking into account the clinical importance of the components of composite outcomes, as well as their relative timing. We examined this approach in a post hoc analysis of two trials that compared dapagliflozin to placebo in patients with heart failure and reduced ejection fraction (DAPA-HF) and mildly reduced or preserved ejection fraction (DELIVER). The effect of dapagliflozin on a hierarchical composite kidney outcome was assessed, including the following: (1) all-cause mortality; (2) end-stage kidney disease; (3) a decline in estimated glomerular filtration rate (eGFR) of ≥57%; (4) a decline in eGFR of ≥50%; (5) a decline in eGFR of ≥40%; and (6) participant-level eGFR slope. For this outcome, the win ratio was 1.10 (95% confidence interval (CI) = 1.06–1.15) in the combined dataset, 1.08 (95% CI = 1.01–1.16) in the DAPA-HF trial and 1.12 (95% CI = 1.05–1.18) in the DELIVER trial; that is, dapagliflozin was superior to placebo in both trials. The benefits of treatment were consistent in participants with and without baseline kidney disease, and with and without type 2 diabetes. In heart failure trials, win statistics may provide the statistical power to evaluate the effect of treatments on kidney as well as cardiovascular outcomes.

Real-world effectiveness of sodium-glucose cotransporter-2 inhibitors on the progression of chronic kidney disease in patients without diabetes, with and without albuminuria.

To examine the renal effects of sodium-glucose cotransporter-2 (SGLT2) inhibition among non-diabetic individuals with chronic kidney disease (CKD) in a real-world setting. We collected de-identified data on adults without diabetes and with an estimated glomerular filtration rate (eGFR) of 25-60 mL/min/1.73 m2, who initiated the SGLT2 inhibitors dapagliflozin or empagliflozin between September 2020 and November 2022 at Maccabi Healthcare Services, an Israeli health maintenance organization. We assessed the effects of SGLT2 inhibitors on renal function (changes in eGFR slope/time). Index date was defined as the date of the first dispensing of SGLT2 inhibitors. Annual baseline slope was calculated using all eGFR measurements during the 2 years prior to index date (median = 7 measurements), while annual follow-up slope was calculated from all evaluations during 90-900 days post index date, along with baseline measurement at index date (median = 6 measurements). Paired t tests were used to compare differences between baseline and follow-up annual slopes. Of a total of 354 participants with CKD, without diabetes, who received SGLT2 inhibitors and were followed for a median of 527 days, the mean age was 72.8 ± 11.8 years, 26% were female, and 91% used renin-angiotensin system blockade. The mean eGFR was 45.4 ± 9.5 mL/min/1.73 m2. The mean body mass index was 29.1 ± 5.4 kg/m2. During the year before index date, 146 participants (41%) had a urinary albumin to creatinine ratio (UACR) <30 mg/g, 81 (23%) had a UACR of 30-300 mg/g, 74 (21%) had a UACR >300 mg/g, and 53 (15%) had no UACR evaluation. The mean eGFR slope over time was -5.6 ± 7.7 mL/min/1.73 m2 per year at baseline, which improved to -1.7 ± 6.8 mL/min/1.73 m2 per year after SGLT2 inhibitor administration (p <0.001). This effect was independent of UACR. In a real-world study of primarily older non-diabetic adults with CKD, SGLT2 inhibition was associated with a slower rate of kidney function decline, regardless of baseline UACR level.

Comparative effects of sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors on kidney function decline in Japanese individuals with type 2 diabetes.

Limited direct comparative studies exist in terms of the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase-4 inhibitors (DPP4is) on the kidney outcomes in Japanese individuals with type 2 diabetes. This retrospective cohort study included 561 Japanese adults with type 2 diabetes, who were newly prescribed either an SGLT2i or a DPP4i and had an eGFR≥30mL/min/1.73m2. The cohort comprised 207 women and 354 men, with a mean (± standard deviation) age of 63 (± 12) years. The exposure and outcome were SGLT2i or DPP4i initiation and eGFR slope during the overall follow-up period, restricted to participants who were followed for ≥2years. We adopted the on-treatment analysis. Analysis of covariance was used to compare the adjusted eGFR slope between the two groups, incorporating 10 variables at baseline. During the median follow-up period of 3.4years, least square mean (95% CI) eGFR slopes were -1.91 (-2.15, -1.67) and -1.12 (-1.58, -0.67) mL/min/1.73m2/year in individuals treated with a DPP4i (n=460) and an SGLT2i (n=101), respectively, demonstrating statistical significance (p=0.002). The robustness of this finding was strengthened by sensitivity analyses. This study provides potential evidence of the superiority of SGLT2is over DPP4is in slowing kidney function decline in Japanese adults with type 2 diabetes and eGFR≥30mL/min/1.73m2.

Use of a Belatacept-based Immunosuppression for Kidney Transplantation From Donors After Circulatory Death: A Paired Kidney Analysis.

Efficacy and safety of belatacept have not been specifically reported for kidney transplantations from donors after circulatory death. In this retrospective multicenter paired kidney study, we compared the outcome of kidney transplantations with a belatacept-based to a calcineurin inhibitor (CNI)-based immunosuppression. We included all kidney transplant recipients from donors after uncontrolled or controlled circulatory death performed in our center between February 2015 and October 2020 and treated with belatacept (n = 31). The control group included the recipients of the contralateral kidney that were treated with CNI in 8 other centers (tacrolimus n = 29, cyclosporine n = 2). There was no difference in the rate of delayed graft function. A higher incidence of biopsy-proven rejections was noted in the belatacept group (24 versus 6 episodes). Estimated glomerular filtration rate (eGFR) was significantly higher in the belatacept group at 3-, 12-, and 36-mo posttransplant, but the slope of eGFR was similar in the 2 groups. During a mean follow-up of 4.1 y, 12 patients discontinued belatacept and 2 patients were switched from CNI to belatacept. For patients who remained on belatacept, eGFR mean value and slope were significantly higher during the whole follow-up. At 5 y, eGFR was 80.7 ± 18.5 with belatacept versus 56.3 ± 22.0 mL/min/1.73 m2 with CNI (P = 0.003). No significant difference in graft and patient survival was observed. The use of belatacept for kidney transplants from either uncontrolled or controlled donors after circulatory death resulted in a better medium-term renal function for patients remaining on belatacept despite similar rates of delayed graft function and higher rates of cellular rejection.

Dapagliflozin treatment of patients with chronic kidney disease without diabetes across different albuminuria levels (OPTIMISE-CKD).

We compared kidney and cardiorenal protection in patients without type 2 diabetes across urine albumin-creatinine ratio (UACR) levels after initiation on dapagliflozin for the treatment of chronic kidney disease (CKD). OPTIMISE-CKD is an observational study describing dapagliflozin treatment for CKD. Adult patients with CKD without type 2 diabetes were included in the primary analysis. Baseline UACR was grouped as normal/mildly elevated (0-29mg/g), low (30-200mg/g) and high (>200mg/g). Outcomes were estimated glomerular filtration rate (eGFR) trajectories/slopes, cardiorenal complications and all-cause mortality. In total, 1480 patients had low (n=796) and high (n=684) UACR. The two groups were similar at baseline, aged 75 and 74years, and 42% and 39% female, respectively. After dapagliflozin initiation, an acute eGFR dip of 3mL/min/1.73m2 was observed, followed by a flat development in both groups. The eGFR slope [95% confidence interval (CI)] for patients with low UACR was 0.79mL/min/1.73m2 per year (-0.59, 2.56), and similar to patients with high UACR [0.40mL/min/1.73m2 per year (-0.46, 1.38)]. Risks of cardiorenal complications and all-cause mortality were similar, with adjusted hazard ratios of 0.89 (95% CI 0.66, 1.19) and 1.10 (95% CI 0.63, 1.92), respectively. Analogous results were found in those with normal/mildly elevated UACR. Dapagliflozin in patients without type 2 diabetes for the treatment of CKD demonstrated similar kidney protection, cardiorenal and all-cause mortality risk across UACR levels. This suggests that the efficacy of dapagliflozin found in clinical trials expands to real-world patients with CKD, regardless of albuminuria levels.