Baseline Renal Function Research Articles

Impact of renal function eligibility criteria in clinical trials and real-world survival outcomes among patients with metastatic renal cell carcinoma.

407 Background: Registration trials in metastatic renal cell carcinoma (mRCC) establishing the efficacy of first-line (1L) combination regimens employed strict renal function eligibility criteria (NCT02853331, NCT02811861, NCT03141177, NCT02231749); however, pharmacokinetics and safety of immune checkpoint inhibitors and anti-vascular endothelial growth factor therapies have been shown to be similar regardless of baseline renal function. Therefore, we aim to evaluate the impact of renal function eligibility criteria used in previous trials on real world outcomes. Methods: Data from the US nationwide Flatiron Health electronic health record-derived de-identified database included adult patients (pts) with mRCC who received any 1L systemic treatment on or after 4/16/2018 (first FDA combination regimen approval), had hemoglobin level ≥9 g/dL and ECOG performance status (ECOG) 0-1 at 1L. Renal function eligibility criteria at 1L (-60 days to +7 days) include serum creatinine (≤1.5 vs >1.5 x ULN), eGFR (≥30 vs <30 ml/min/1.73m2) and calculated CrCl (≥40 vs <40 ml/min) based on registration trial protocols. Outcomes include real world progression free survival (rwPFS), time to next treatment (rwTTNT), and overall survival (rwOS) from 1L. Inverse probability of treatment weighted (IPTW) Kaplan Meier methods and Cox proportional hazard models with multiple imputation were applied. Results: Of 2038 pts in this cohort, 1390 (68.2%) met all criteria for renal function (included), 140 (6.9%) met at least one criteria (relaxed), 46 (2.3%) met none (excluded), and 462 (22.7%) had unknown renal function. Compared to included pts, excluded pts were more likely to be older (median age: 74 vs 66), female (35% vs 27%), have recurrent disease (61% vs 53%), less likely to have ECOG 0 (24% vs 40%) and favorable IMDC risk (9% vs 14%). Excluded pts are also more likely to be Non-Latinx Black (13% vs 6%) and have lowest SES quintile (22% vs 15%) compared to included pts. Although, after weighting included pts had higher median rwPFS of 9.3 (95% CI 8.4 - 10.1) vs 6.9 (95% CI 3.7 - 9.9), rwTTNT 12.0 (95% CI 11.0 - 13.1) vs 9.1 (95% CI 5.5 - 16.4) and rwOS 38.5 mo (95% CI 35.9 - 44.5) vs 19.3 mo (95% CI 16.6 - 41.8) compared to relaxed/excluded pts, none of the hazard ratios (HRs) were statistically significant after multiple imputation (Table). Conclusions: In this real world study, we found that although only 68.2% of patients met all renal function eligibility criteria, survival outcomes were not different across pts groups. This suggests that mRCC patients with reduced renal function may benefit similarly to 1L treatment and should not be excluded from clinical trials. [Table: see text]

Relationship Between Lipoprotein(a), Renal Function Indicators, and Chronic Kidney Disease: Evidence From a Large Prospective Cohort Study.

Chronic kidney disease (CKD) poses a significant global public health challenge. While lipoprotein(a) (Lp[a]) has been established as a significant factor in cardiovascular disease, its connection to CKD risk remains a topic of debate. Existing evidence indicates diverse risks of kidney disease among individuals with various renal function indicators, even when within the normal range. This study aims to investigate the joint associations between different renal function indicators and Lp(a) regarding the risks of incident CKD in the general population. The analysis involved a cohort of 329,415 participants without prior CKD who were enrolled in the UK Biobank between 2006 and 2010. The participants, with an average age of 56 (SD 8.1) years, included 154,298/329,415 (46.84%) males. At baseline, Lp(a) levels were measured using an immunoturbidimetric assay and classified into 2 groups: low (<75 nmol/L) and high (≥75 nmol/L). To assess participants' baseline renal function, we used the baseline urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). The relationship between Lp(a), renal function indicators, and the risk of CKD was evaluated using multivariable Cox regression models. These models were adjusted for various factors, including sociodemographic variables, lifestyle factors, comorbidities, and laboratory measures. A total of 6003 incident CKD events were documented over a median follow-up period of 12.5 years. The association between elevated Lp(a) levels and CKD risk did not achieve statistical significance among all participants, with a hazard ratio (HR) of 1.05 and a 95% CI ranging from 0.98 to 1.13 (P=.16). However, a notable interaction was identified between Lp(a) and UACR in relation to CKD risk (P for interaction=.04), whereas no significant interaction was observed between Lp(a) and eGFR (P for interaction=.96). When compared with the reference group with low Lp(a) and low-normal UACR (<10 mg/g), the group with high Lp(a) and low-normal UACR exhibited a nonsignificant association with CKD risk (HR 0.98, 95% CI 0.90-1.08; P=.74). By contrast, both the low Lp(a) and high-normal UACR (≥10 mg/g) group (HR 1.16, 95% CI 1.08-1.24; P<.001) and the high Lp(a) and high-normal UACR group (HR 1.32, 95% CI 1.19-1.46; P<.001) demonstrated significant associations with increased CKD risks. In individuals with high-normal UACR, elevated Lp(a) was linked to a significant increase in CKD risk, with an HR of 1.14 and a 95% CI ranging from 1.03 to 1.26 (P=.01). Subgroup analyses and sensitivity analyses consistently produced results that were largely in line with the main findings. The analysis revealed a significant interaction between Lp(a) and UACR in relation to CKD risk. This implies that Lp(a) may act as a risk factor for CKD even when considering UACR. Our findings have the potential to provide valuable insights into the assessment and prevention of CKD, emphasizing the combined impact of Lp(a) and UACR from a public health perspective within the general population. This could contribute to enhancing public awareness regarding the management of Lp(a) for the prevention of CKD.

Pharmacokinetics of recombinant human annexin A5 (SY-005) in patients with severe COVID-19.

Objective: Annexin A5 is a phosphatidylserine binding protein with anti-inflammatory, anticoagulant and anti-apoptotic properties. Preclinical studies have shown that annexin A5 inhibits pro-inflammatory responses and improves organ function and survival in rodent models of sepsis. This clinical trial aimed to evaluate the pharmacokinetic (PK) properties of the recombinant human annexin A5 (SY-005) in severe COVID-19. Methods: This was a pilot randomized, double-blind, placebo-controlled trial. Severe COVID-19 patients were randomly assigned to receive intravenous 50μg/kg (low dose, n = 3), 100μg/kg (high dose, n = 5) of SY-005 or placebo (n = 5) every 12h for 7 days. Plasma SY-005 levels were assessed using enzyme-linked immunosorbent assay (ELISA) and the PK parameters were determined using non-compartmental analysis. Results: All patients treated with SY-005 had a normal baseline estimated glomerular filtration rate (eGFR, 104-125mL/min/1.73m2). Both low and high doses of SY-005 were cleared within 6h after intravenous administration. Plasma maximum concentrations (Cmax), half-life, clearance and volume distribution of low and high doses of SY-005 were 402.4 and 848.9ng/mL, 0.92 and 0.96h, 7.52 and 15.19L/h, and 9.98 and 20.79 L, respectively. Daily pre-dose circulating annexin A5 levels were not significantly different when SY-005 was administered at the low or the high dose 12-h intervals. There was no significant effect on activated partial thromboplastin time (aPTT) or INR (international normalized ratio of prothrombin time) during 7days of SY-005 treatment. Conclusion: SY-005 doses of 50 and 100μg/kg were detectable and subsequently cleared from the plasma in severe COVID-19 patients with normal baseline renal function. There was no significant plasma SY-005 accumulation 6h after drug administration and coagulation was not altered during 7days of treatment. Clinical trials Registration: This study was registered with ClinicalTrials.gov (NCT04748757, first posted on 10 February 2021).

P08 An usual case of pandrug-resistant Serratia marcescens in a 63 year-old-male: a case report

Abstract Objectives To highlight the growing burden of antimicrobial resistance in developing countries where there are no officially agreed local antibiotics guidelines. We are characterizing a case of growth of pandrug-resistant (PDR) Serratia marcescens in the urine culture of a 63-year-old-male. Patient and methods Our patient, who had a history of recurrent renal stones, underwent multiple urological procedures (including ureteroscopy and DJ stenting) in various regional hospitals in northern Pakistan. It is postulated that he became infected during these repeated procedures which were done in various hospitals without adequate sterile equipment. He presented with recurrent UTIs to GPs and was subsequently treated with oral fosfomycin for over 1 year in total. His baseline renal function remains unknown due to the absence of online records, but he was noted to have CKD IV. Subsequently, during his later visits to the hospital, he developed sepsis and his urine cultures confirmed carbapenem-resistant Pseudomonas aeruginosa, which was treated with IV antibiotics as per the susceptibility report. He was prescribed IV piperacillin/tazobactam (Tazocin) for a total period of 3 months on various occasions due to repeated presentations with urosepsis. He improved clinically with IV piperacillin/tazobactam. Following this, the patient was lost to follow-up. The patient once again presented acutely unwell with urosepsis. This time urine cultures confirmed the presence of S. marcescens (May 2023). The patient had pandrug resistance to all antibiotics including IV piperacillin/tazobactam. However it was decided to treat him with IV piperacillin/tazobactam due to previous good results. The patient improved clinically but his renal functions declined to CKD stage V. He was once again lost to follow up. He presented again to renal consultants with uraemic symptoms and at the moment he is being counselled for dialysis due to his end-stage renal disease. At present the patient is having asymptomatic bacteriuria; his urine cultures remain positive without any symptoms. A more recent urine culture (September 2023) showed growth of Escherichia coli (ESBL). Due to lack of symptoms, renal consultants agreed to manage the patient without further antibiotics. Results In May 2023, an antibiotic susceptibility profile was done under supervision of microbiologists. Unfortunately for the patient, the urine culture reported growth of S. marcescens and that the patient had pandrug-resistance. The profile included testing for the following antibiotics: amikacin, co-amoxiclav, aztreonam, cefepime, cefoxitin, ceftazidime/avibactam, cefalexin, co-trimoxazole, fosfomycin, meropenem, amoxicillin, ampicillin, cefaclor, cefixime, cefpodoxime, cefuroxime, ciprofloxacin, colistin, imipenem, nitrofurantoin, norfloxacin, polymyxin, piperacillin/tazobactam and sulbactam/cefoperazone. In September 2023, the second urine culture report with the growth of E. coli showed susceptibility to amikacin, cefoperazone/sulbactam, fosfomycin, imipenem and tigecycline. This report also confirmed resistance co-amoxiclav, ampicillin, cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cefradine, levofloxacin, nalidixic acid, nitrofurantoin, piperacillin/tazobactam and trimethoprim/sulfamethoxazole. Conclusions Unfortunately, the urine culture and susceptibility report signify the threat this patient faces in case he develops further urine infections. It is imperative to encourage development of local guidelines in developing countries too. We would recommend a multidisciplinary approach in treating difficult and long-term infections with constant support of microbiologists.

Early protein delivery in critically ill patients with acute kidney injury: post hoc analysis of a multicenter cluster-randomized controlled trial.

There is controversy over the optimal early protein delivery in critically ill patients with acute kidney injury (AKI). This study aims to evaluate whether the association between early protein delivery and 28-day mortality was impacted by the presence of AKI in critically ill patients. This is a post hoc analysis of data from a multicenter cluster-randomised controlled trial enrolling newly admitted critically ill patients (n = 2772). Participants without chronic kidney disease and with complete data concerning baseline renal function were included in this study. The primary outcome was 28-day mortality. Cox proportional hazards models were used to analyze the association between early protein delivery, reflected by mean protein delivery from day 3-5 after enrollment, 28-day mortality and whether baseline AKI stages interacted with this association. Overall, 2552 patients were included, among whom 567 (22.2%) had AKI at enrollment (111 stage I, 87 stage II, 369 stage III). Mean early protein delivery was 0.60 ± 0.38g/kg/day among the study patients. In the overall study cohort, each 0.1g/kg/day increase in protein delivery was associated with a 5% reduction in 28-day mortality[hazard ratio (HR) = 0.95; 95% confidence interval (CI) 0.92-0.98, p< 0.001]. The association between early protein delivery and 28-day mortality significantly interacted with baseline AKI stages (adjusted interaction p= 0.028). Each 0.1g/kg/day increase in early protein delivery was associated with a 4% reduction in 28-day mortality (HR = 0.96; 95%CI 0.92-0.99, p= 0.011) among patients without AKI and 9% (HR = 0.91; 95%CI 0.84-0.99, p= 0.021) among those with AKI stage III. However, such associations cannot be observed among patients with AKI stages I and II. Increased early protein delivery (up to close to the guideline recommendation) was associated with reduced 28-day mortality in critically ill patients without AKI and with AKI stage III, but not in those with AKI stage I or II.

Association Between Decreased Renal Function and Pulmonary Function Decline in Community-dwelling Adults.

Emerging evidence suggests that there is a close relationship between the human lung and kidney. This study evaluated whether decreased renal function was associated with accelerated pulmonary function decline in a large-scale community-based cohort. A total of 10,028 subjects of the prospective Ansung-Ansan cohort were eligible for the longitudinal analysis of changes in pulmonary function associated with decreased renal function (glomerular filtration rate <60 ml/min/1.73 m2). Logistic regression analysis was performed to evaluate factors associated with decreased baseline renal function, and a linear mixed model compared changes in pulmonary function in participants with and without decreased renal function after propensity score matching (PSM). At baseline, subjects with and without decreased renal function showed distinct characteristics, and the factors associated with decreased renal function were age, baseline forced vital capacity, hypertension, and white blood cell (WBC) count. A 1:4 PSM of age, sex, body mass index, and smoking status showed that the proportion of those with hypertension and the WBC count differed between the patients with decreased and normal renal function. In the PSM population, those with decreased renal function had a greater decline in forced expiratory volume in the first second (FEV1) than those without (p=0.0402); however, these differences were not found to be evident when hypertension and WBC count were further matched (p=0.0807). The results of our study demonstrated that decreased renal function was not directly associated with the rapid decline in pulmonary function in a community-based general population setting.

Renal functional outcomes after robot-assisted partial nephrectomy and percutaneous cryoablation of clinical T1 renal cell carcinoma - A prospective study.

The objective of this study was to investigate renal function after robot-assisted partial nephrectomy (RAPN) and percutaneous cryoablation (PCA) in clinical stage T1 (cT1) renal cell carcinoma (RCC) and evaluate the relationship between baseline renal function and renal functional outcome. Patients with cT1 RCC treated with RAPN or PCA were prospectively enrolled between June 2019 and January 2021. Renal function was evaluated using estimated glomerular filtration rate, Tc-99m diethylenetriamine-pentaacetate plasma clearance, Tc-99m mercaptoacetyltriglycine renography, and renal volume at baseline and 6 months after treatment. Fifty-six patients were included (18 RAPN, 38 PCA). PCA patients had a significantly higher age (68.5 years; P = 0.019) and Charlson comorbidity index (3.0; P = 0.007). Tumor characteristics did not differ significantly between RAPN and PCA. Total renal volume decreased significantly after PCA (-18.2 cm3; P = 0.001). Baseline chronic disease stage IIIb-IV leads to a greater reduction in renal volume (-31.8 cm3; P = 0.003) but not other renal function measures. Renal function declined significantly after either treatment without significant differences between RAPN and PCA. This study found a small, similar decrease in renal function 6 months after RAPN or PCA, despite significant differences in baseline patient characteristics. Reduced renal function at baseline did not lead to a worse renal functional outcome.

ASO Visual Abstract: Practical Prediction of New Baseline Renal Function After Partial Nephrectomy.

ASO Visual Abstract: Practical Prediction of New Baseline Renal Function After Partial Nephrectomy.

Extended peptide receptor radionuclide therapy: evaluating nephrotoxicity and therapeutic effectiveness in neuroendocrine tumor patients receiving more than four treatment cycles.

Currently, the most used peptide receptor radionuclide therapy (PRRT) regimen for neuroendocrine tumors comprises 4 treatment cycles, and there is not enough large-scale data to support the safety of more individualized extended PRRT. This study aims to evaluate the therapeutic effectiveness and potential nephrotoxicity related to PRRT using more than four treatment cycles. In this retrospective analysis, we included patients who had received at least four PRRT cycles and had available follow-up data. We analyzed renal function indicators before and after multiple treatments, comparing nephrotoxicity in patients receiving four cycles ("standard") with those receiving more than four ("extended treatment"). Nephrotoxicity was assessed via creatinine levels and CTCAE creatinine grades. Treatment effectiveness was gauged using Kaplan-Meier survival analysis, focusing on overall survival and disease-specific survival (DSS). Statistical analyses were performed using SPSS version 26 (IBM), R 4.2.3, and GraphPad Prism 9.0.0. Statistical significance was defined as a P-value of less than 0.05. Our study cohort consisted of 281 patients in the standard group and 356 in the extended treatment group. No significant differences in baseline characteristics or renal function were noted between the two groups pre-treatment. Mean post-treatment creatinine levels did not significantly differ between the standard (89.30 ± 51.19μmol/L) and extended treatment groups (93.20 ± 55.98μmol/L; P = 0.364). Similarly, there was no statistical significance between the CTCAE creatinine grades of the two groups (P = 0.448). Adverse renal events were observed in 0.4% of patients in the standard group and 1.1% in the extended treatment group. After a median follow-up time of 88.3months, we found that median overall survival was significantly higher in the extended treatment group (72.8months) compared to the standard treatment group (52.8months). A Cox regression analysis further supported these findings, indicating a better prognosis for the extended treatment group in terms of overall survival (HR: 0.580, P < 0.001) and DSS (HR: 0.599, P < 0.001). Our findings suggest that extending PRRT treatment beyond the standard four cycles may be a safe and effective therapeutic strategy for NET patients. This approach could be particularly beneficial for patients experiencing disease recurrence or progression following standard treatment.

Influence of Pre-Transplant Estimated Glomerular Filtration Rate (eGFR) on Outcomes after Allogeneic Hematopoietic Cell Transplantation

Assessment of pre-transplant renal function as measured by estimated Glomerular Filtration Rate (eGFR) is a standard criterion for selection of patients for allogeneic hematopoietic cell transplantation (alloHCT). Despite refinements in alloHCT and reductions in toxicity over time, we hypothesized that baseline renal function is still independently associated with differences in outcomes in the contemporary era. The aim of this study was to identify an optimal eGFR cut point for identifying those at increased risk of HCT-related mortality. Patients who underwent first alloHCT from January 2012 to December 2021 were identified from our institutional database, excluding syngeneic and umbilical cord grafts. eGFR was calculated using the CKD-EPI Creatinine Equation (Inker et a. NEJM 2021). Optimal pre-HCT eGFR cut point for high-risk of non-relapse mortality (NRM) after alloHCT was identified using Cox restricted cubic spline plot. eGRF was grouped into multiple categories based upon the observed association in the spline plot alone with an established cut point of 90 ml/min/1.73 m² for abnormal kidney function. Associations of eGFR, demographics, prognostic factors, and HCT characteristics with NRM and overall survival (OS) were evaluated using survival analysis; non-HCT related death was considered as a competing risk in the NRM analysis. 724 adult patients were studied with a median age of 58 yrs (range, 18-79), 57% males, 92% Caucasian, and 76% KPS &amp;gt;90. HCT-CI: 52% high, 31% intermediate, and 17% low risk. Transplants included 43% myeloablative and 57% reduced-intensity conditioning; 64% peripheral blood and 36% bone marrow grafts. Donor type: 28% related, 55% unrelated and 17% haploidentical. The median (IQR) of pre-transplant eGFR was 96.7 ml/min/1.73 m² (79.6, 107.5). eGFR was categorized as &amp;lt;70 (15.8%), 70-89 (22.4%), 90-119 (52.4%), and &amp;gt;120 ml/min/1.73 m² (9.4%). NRM was significantly higher for the eGFR &amp;lt;70 ml/min/1.73 m² group compared to the others (3-year NRM: 44.9% in eGFR &amp;lt;70 vs 25.0% in 70-89, 23.6% in 90-119, and 13.8% in &amp;gt;120 ml/min/1.73 m²) which was confirmed on multivariate analysis (Figure and Table). Overall survival (OS) was also significantly worse for those with an eGFR &amp;lt;70 ml/min/1.73 m² on multivariate analysis (3-year OS: 34.1% in eGFR &amp;lt;70 vs 51.7% in 70-89, 52.4% in 90-119, and 64.8% in &amp;gt;120 ml/min/1.73 m²) (Table) along with baseline KPS and high ASBMT Request for Information (RFI). The most common causes of death for both the eGFR&amp;lt;70 and &amp;gt;70 ml/min/1.73 m² groups were relapse (44% vs 60%, respectively) and infection (25% vs. 19%, respectively). Both NRM and OS differences among the 3 higher eGFR groups were not statistically significant in multivariate analyses. eGFR was not associated with relapse. We conclude that pre-transplant eGFR &amp;lt;70 ml/min/1.73m 2 is an independent prognostic factor for mortality after alloHCT. Future investigation with larger subgroup analyses regarding specific diagnoses, conditioning regimens and transplant modalities may further identify which patients are more appropriate for transplant and those who may benefit from alternative treatment approaches. Our results also suggest that additional efforts to preserve renal function prior to transplant by limiting nephrotoxic exposures may have implications for optimizing outcomes after transplant, particularly in those with other comorbidities.

Outcomes Associated with Clone-Directed Therapies for Monoclonal Gammopathy of Renal Significance

Background: Monoclonal Gammopathy of Renal Significance (MGRS) is a category of diseases not meeting criteria for cancer, in which a clonal population of B-lymphoid or plasma cells produces a nephrotoxic protein leading to kidney injury. Informal consensus has arisen that therapy targeting the causal clone is most likely to be efficacious, and the primary goal of therapy is to prolong renal survival. Light chain (AL) amyloidosis has been extensively studied, yet there is a paucity of data describing outcomes associated with clone-directed therapy for the various subtypes of non-AL MGRS. Methods: This was a retrospective analysis of patients treated at two National Cancer Institute (NCI)-designated cancer centers in the United States. Medical records of adult patients seen between January 2010 and March 2023 were screened for MGRS. Patients were eligible if they had renal biopsy-confirmed histopathologic findings compatible with MGRS. AL amyloidosis was excluded. The primary outcome was renal survival, defined as time from diagnosis of MGRS to requiring renal replacement therapy (RRT) or renal transplant, with patients censored at last follow up or death. Baseline characteristics were described, including 24-hour proteinuria, estimated glomerular filtration rate (eGFR), whether a clonal population of B cells or plasma cells could be identified on histopathologic examination of marrow or lymph node biopsy, concentration of monoclonal protein, and involved serum free light chain concentration. Initial therapy was reported, although differences in outcomes across therapeutic strategies were not compared. Baseline clinical characteristics between patients who required RRT and those who did not were compared. Baseline clinical variables and time to RRT were compared across the two most common MGRS subtypes in the cohort: proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and light chain deposition disease (LCDD). Continuous variables were compared across subgroups using Wilcoxon rank-sum test. Time-to-event outcomes were analyzed according to the Kaplan-Meier method. All analyses were conducted using R version 3.6.1. Results: In total, 65 patients were included, 23 (35%) of whom ultimately required RRT or transplant. Four patients died, all after RRT. Median baseline proteinuria was 2802 mg/24h (IQR 972.5 - 4492.0) and median eGFR was 33.0 mL/min (IQR 23 - 53) for the entire cohort. In all cases proteinuria was mostly albumin. Median baseline involved light chain concentration was 8.3 mg/dL (IQR 3.1 - 26.4). A majority of patients (n=33, 51%) had no identifiable serum monoclonal protein. The two most common MGRS subtypes were PGNMID (n = 26) followed by LCDD (n = 21). Clonal populations thought to be causing MGRS were identified in 41/64 patients (64%), including 37 (58%) with plasma cell clones, 1 (2%) with a lymphoplasmacytic lymphoma clone, and 3 (4.7%) with other B-cell clones. Clones were not identified in 23 (36%). The most common chemotherapy agents included bortezomib (n=42, 64%) and rituximab (n=14, 22%). Compared to patients not requiring RRT, patients requiring RRT had higher baseline proteinuria (median 3531 vs. 1980 mg/24h, p&amp;lt;0.001) and lower eGFR (median 16 v. 44 mL/min, p&amp;lt;0.001); differences in serum free light chain concentrations were not significant ( Figure 1). A clonal population thought to be causing MGRS was identified on bone marrow biopsy in a majority of LCDD patients (n = 20, 95%), while clones were infrequently found in PGNMID (n = 6, 23%). The vast majority (n=20, 95%) of patients with LCDD received bortezomib-based therapy. Initial therapy in patients with PGNMID was more evenly divided: 9 (35%) received bortezomib-based therapy, 10 (38%) received rituximab-based therapy, and 6 (23%) received other regimens. Despite differences in therapeutic approach, patients with LCDD and in patients with PGNMID had similar risk of RRT (cumulative risk 35% v. 43%, p=0.54; HR 0.83 (95% CI 0.52-1.33); p =0.44) ( Figure 2). Conclusion: Patients with MGRS remain at high risk of requiring RRT even with clone-directed therapy. Despite differences in pathogenic clones and therapeutic strategies, outcomes of patients with PGNMID and LCDD are similar. Because the severity of baseline renal function across MGRS histologies predicts renal survival, early diagnosis and treatment is likely critical to improving renal outcomes.

Practical Prediction of New Baseline Renal Function After Partial Nephrectomy.

Partial nephrectomy (PN) is generally preferred for localized renal masses due to strong functional outcomes. Accurate prediction of new baseline glomerular filtration rate (NBGFR) after PN may facilitate preoperative counseling because NBGFR may affect long-term survival, particularly for patients with preoperative chronic kidney disease. Methods for predicting parenchymal volume preservation, and by extension NBGFR, have been proposed, including those based on contact surface area (CSA) or direct measurement of tissue likely to be excised/devascularized during PN. We previously reported that presuming 89% of global GFR preservation (the median value saved from previous, independent analyses) is as accurate as the more subjective/labor-intensive CSA and direct measurement approaches. More recently, several promising complex/multivariable predictive algorithms have been published, which typically include tumor, patient, and surgical factors. In this study, we compare our conceptually simple approach (NBGFRPost-PN = 0.90 × GFRPre-PN) with these sophisticated algorithms, presuming that an even 90% of the global GFR is saved with each PN. A total of 631 patients with bilateral kidneys who underwent PN at Cleveland Clinic (2012-2014) for localized renal masses with available preoperative/postoperative GFR were analyzed. NBGFR was defined as the final GFR 3-12 months post-PN. Predictive accuracies were assessed from correlation coefficients (r) and mean squared errors (MSE). Our conceptually simple approach based on uniform 90% functional preservation had equivalent r values when compared with complex, multivariable models, and had the lowest degree of error when predicting NBGFR post-PN. Our simple formula performs equally well as complex algorithms when predicting NBGFR after PN. Strong anchoring by preoperative GFR and minimal functional loss (≈10%) with the typical PN likely account for these observations. This formula is practical and can facilitate counseling about expected postoperative functional outcomes after PN.

ASO Author Reflections: Predicting New Baseline Renal Function After Partial Nephrectomy: The Importance of Accuracy, Conceptual Simplicity, and Clinical Practicality.

ASO Author Reflections: Predicting New Baseline Renal Function After Partial Nephrectomy: The Importance of Accuracy, Conceptual Simplicity, and Clinical Practicality.

Impact of worsening renal function in patients with incident heart failure across the spectrum of ejection fraction: a population-based longitudinal study

Abstract Background Renal dysfunction is a common occurrence in patients with heart failure (HF) and may impact on HF treatment and outcomes. HF clinical trial data suggest that worsening renal function (WRF) is associated with worse prognosis, however many of the medications used in HF cause a short-term decline in renal function that may improve in the longer-term. The real-world incidence and implications of WRF following an initial diagnosis of HF across the spectrum of ejection have not been well-characterised. Purpose The present study was designed to establish the incidence and outcomes associated with WRF in patients with incident HF on the risk of mortality and HF hospitalisation (hHF) in a real-world setting. Methods Electronic health records were linked to echocardiography data between 2016 to 2021 to define incident HF with reduced/mildly reduced/preserved EF (HFrEF/HFmrEF/HFpEF). Incidence of WRF at 6 months was determined as a composite endpoint of (i) having two consecutive eGFR declined by 40% or greater; (ii) having an eGFR &amp;lt;15 mL/min/1.73m^2; (iii) on sustained dialysis; or (iv) receiving kidney transplantation. Incidence of hHF and all-cause mortality were compared in HF patients with versus without WRF. We performed a stratified analysis according to baseline renal function (eGFR: &amp;gt;60, 45-59, 30-44, 15-29, or &amp;lt;15 mL/min/1.73m2). Results 4254 individuals were identified, 1100 HFrEF, 650 HFmrEF, 1252 HFpEF, and 1252 HF with unknown EF. Within 6 months of HF diagnosis, 592 patients died and 349 had WRF. Baseline eGFR &amp;lt;60 was present in 32% of individuals with HFrEF, 32% in HFpEF, 27% in HFmrEF, and 37% in HF with unknown EF. The incidence of WRF was similar in HFrEF (20.7 [95% CI: 16.9 – 25.1] per 100 person-years) and in HF with unknown EF (20.9 [17.1 – 25.3]), but was significantly lower in HFmrEF (13.6 [9.8 – 18.4]) and HFpEF (16.8 [13.7 – 20.5]). Patients with WRF were more likely to be female (adjusted hazard ratio [aHR]: 1.32 [1.06 – 1.64], p=0.014), having diabetes (1.34 [1.07 – 1.69], p = 0.012), and with lower baseline renal function (eGFR categories 45-59, 30-44, 15-29, or &amp;lt;15 compared with &amp;gt;60: aHR 1.75 [1.29 – 2.38], p&amp;lt;0.001; 1.64 [1.12 – 2.42], p=0.012; 5.65 [4.06 – 7.87], p&amp;lt;0.001; 90.74 [63.2 – 130.28], p&amp;lt;0.001). Individuals with WRF had significantly higher incidence of subsequent hHF (HR adjusted for age, sex, baseline renal function, and diabetes: 1.79 [1.35 – 2.39], p&amp;lt;0.001) and all-cause death (2.18 [1.66 – 2.88], p&amp;lt;0.001), compared to those without WRF. This was driven by patients diagnosed with HFrEF (2.46 [1.45 – 4.18], p&amp;lt;0.001) or HFpEF (3.45 [2.21 – 5.40], p&amp;lt;0.001), but was not seen in HFmrEF (1.91 [0.91 – 3.99], p=0.086) or HF within unknown EF (1.28 [0.65 – 2.52], p=0.484). Conclusion WRF is an important and common consequence following initial diagnosis of HF across the spectrum of EF with associated severe clinical outcomes in HF. Priority should be given to prevention of WRF in patients with incident HF.Impact of WRF on Clinical Outcomes

Multiplex screening for biomarkers associated with subsequent heart failure hospitalisation in patients with atrial fibrillation: insights from the ARISTOTLE trial

Abstract Background Atrial fibrillation (AF) is associated with heart failure (HF) with a complex cause and effect relationship. We performed multiplex screening of plasma proteins in order to identify biomarkers and pathways associated with subsequent HF hospitalisation in patients with AF. Methods Using a case-cohort design of patients with AF from the ARISTOTLE trial, the study cohort consisted of 596 cases of HF hospitalisations during follow-up and 4029 randomly selected controls without HF hospitalization. The median follow-up time was 1.9 years. Plasma obtained at randomisation was analysed with conventional immunoassays and three OLINK proximity extension assay panels; CVDII, CVDIII and the inflammation panel. Biomarker associations with subsequent HF hospitalisation was evaluated using Random Survival Forest (RF), Boruta and Cox-regression analyses adjusted for baseline characteristics, renal function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) as well as cardiac troponin-T (cTnT-hs). Results The biomarkers most associated with HF hospitalisation, using all three statistical methods (Table), were (hazard ratio for inter-quartile comparison [95% CI]), NT-proBNP (2.07 [1.76 - 2.4]), cTnT-hs (1.35 [1.15 - 1.58]), fibroblast growth factor 23 (FGF-23; 1.26 [1.15 - 1.39]), spondin-1 (SPON-1; 1.21 [1.10, 1.33]), TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2; 1.19 [1.07 - 1.32]), insulin Growth Factor Binding Protein 7 (IGFBP7; 1.25 [1.13 - 1.39]), urokinase receptor (uPAR) 1.4 [1.19 - 1.66]), vascular Endothelial Growth Factor D (VEGF-D; 1.28 [1.08 - 1.53]), pro-adrenomedullin (ADM; 1.20 [1.03 - 1.40]), and C-C motif chemokine 3 (CCL3; 1.15 [1.06 - 1.24]). Conclusions Out of 269 evaluated biomarkers, this comprehensive screening study identified biomarkers representing cardiorenal dysfunction (NT-proBNP, cTnT-hs, FGF-23), cell adhesion (SPON-1), apoptosis (TRAILR2), growth factors (IGFBP7, VEGF-D), fibrinolysis (uPAR), vasodilation (ADM) and inflammation (CCL3) as being the most strongly associated with subsequent HF hospitalisation in patients with AF. These findings highlight the most important pathophysiological pathways involved in new or worsening HF in patients with AF.Biomarkers associated with HF hospitalis

The serum haemoglobin to creatinine ratio predicts 1-year adverse outcomes in patients undergoing transcatheter aortic valve implantation

Abstract Background The baseline serum haemoglobin and renal function are both important predictors of adverse outcomes in patients with severe aortic valve stenosis (AS) after transcatheter aortic valve implantation (TAVI), there are no reports that has examined the correlation between those combined data and adverse outcomes, however. Purpose In this study, we examined whether the combined index of anaemia and renal failure is predictive of 1-year prognosis in patients undergoing TAVI. Methods and Results This study is a retrospective, single-centre, and observational study. Between January 2015 and June 2021, 469 consecutive patients with severe AS underwent TAVI in our hospital. After excluding dialysis patients, 458 patients were analysed in this study. Patients were categorized into three groups (tertiles) according to their value of haemoglobin to creatinine (Hgb/Cr) raio. The Hgb/Cr ratio was calculated from the serum haemoglobin and creatinine on the day before TAVI. The primary and secondary clinical outcomes measure was defines as all-cause mortality and heart failure hospitalization at 1-year after TAVI. Results The mean age was 85.5 ± 4.8 years, and the mean the Society of Thoracic Surgeons score (STS) was 7.0 ± 4.7, the mean serum creatinine, eGFR and haemoglobin were 0.97 ± 0.47 mg/dL, 49.1 ± 21.3 mL/min/1.73 m2 and 13.8 ± 5.9 g/dL, respectively. The procedural success rate and length of admission day after TAVI were equivalent for tertile 1, tertile 2, and tertile 3 groups. In-hospital mortality was higher in tertile 1, tertile 2, and tertile 3 groups, in that order (8.7% vs. 2.6% vs. 0%; p&amp;lt;0.01). Cumulative incidences all-cause mortality and heart failure hospitalization rate were significantly better in tertile 1, tertile 2, and tertile 3 groups, in that order, respectively (16.9% vs. 7.2% vs. 2.0%; p&amp;lt;0.01, 10.7% vs. 3.4% vs. 0.7%; p&amp;lt;0.01, respectively). The index of the area under curve of Hgb/Cr ratio for all-cause mortality and heart failure hospitalization at 1-year after TAVI were 0.73 and 0.73, respectively. The cut-off values were 10.1 for all-cause mortality (odds ratio: 4.78; 95% confidence interval; 2.43-9.74; p&amp;lt;0.01) and 10.4 for heart failure hospitalization (odds ratio: 5.3; 95% confidence interval; 2.21-14.1; p&amp;lt;0.01). Conclusions The Hgb/Cr ratio was associated with all-cause mortality and heart failure hospitalization in patients who underwent TAVI. Calculation of Hgb/Cr ratio on the day before TAVI could be useful for predicting adverse outcomes at 1-year in patients undergoing TAVI.

Androgen deprivation therapy for prostate cancer, measures of adiposity and strength, and adverse cardiovascular outcomes: observations from 3000 men in 5 countries in the RADICAL PC study

Abstract Background Androgen deprivation therapy (ADT) is prescribed to nearly half of patients with prostate cancer (PC). ADT is associated with weight gain, reduced muscle strength and increased cardiovascular (CV) risk. However, no PC study has examined the relationship between these physical characteristics, their change with ADT and cardiovascular outcomes. Purpose In men with PC: To compare 1-year changes in physical measures in those receiving versus not receiving ADT To evaluate the relationship between physical measures and adverse CV outcomes Methods We prospectively studied 3080 men with PC from 37 sites in 5 countries (mean age 68 years), 41% on ADT. Inclusion criteria were one of: PC diagnosed in the past 12 months; started ADT within the past 6 months; or plan to start ADT in the next month. Weight, waist and hip circumference, handgrip strength and get-up-and-go time were recorded at baseline and 1 year. Change in measurements were adjusted for age, education, race, tobacco and alcohol use, baseline cardiovascular disease and renal function. Participants were followed for a median 3 years from enrolment to document adverse CV outcomes associated with adiposity: myocardial infarction, angina, stroke, cerebrovascular disease, peripheral arterial disease, arterial revascularization, heart failure, venous thromboembolism and atrial fibrillation. The relationship between baseline physical measures and outcomes was evaluated by Cox proportional hazards models adjusted for age, diabetes, hypertension, total cholesterol, tobacco use and physical activity levels. Results Changes in physical measures are displayed in Table. ADT recipients gained 5x more weight than non-recipients. Weight gain was distributed evenly between waist and hips, resulting in no difference in waist:hip ratio. Muscle strength decreased in both groups but with 43% larger decrease among ADT recipients. The ratio of strength to body weight fell twice as much in ADT recipients as non-recipients. Gait speed slowed by 13% after 12 months’ ADT. We observed 144 adverse CV events. There was a continuous relationship between handgrip strength and CV events. Each quartile reduction in strength was associated with adjusted hazard ratio (95% CI) 1.24 (1.01-1.52). There was no detectable association between other physical measures and CV events. Conclusion ADT use is associated with increased adiposity and reduced muscle strength. Low muscle strength, reflected by low handgrip strength is a better predictor of adverse CV outcomes than increased adiposity. These findings may explain help the association between ADT use and adverse CV outcomes.Table

Every third patient with advanced renal failure dies within one year following non st-segment elevation myocardial infarction treated with percutaneous coronary intervention

Abstract Background and Aims Kidney failure is highly prevalent in patients with the non-ST-elevation myocardial infarction (NSTEMI). The aim of the study was to evaluate the prognostic significance of baseline renal function regarding in-hospital and 1-year mortality among patients with NSTEMI who were treated with percutaneous coronary intervention (PCI). Methods Data were obtained from the Polish Registry of Acute Coronary Syndromes (PL-ACS). We extracted all patients with NSTEMI (n=47,052) who were treated with PCI between 2017 and 2021. The cumulative incidence of all-cause mortality during the 1-year follow-up was presented using the Kaplan-Meier curves. The linearity of the association between the Esimated Glomerular Filtration Rate (eGFR) with all-cause mortality was evaluated using a likelihood ratio test. The multivariate Cox regression model was created to adjust the relationship between eGFR and all-cause mortality for potential confounders. Results After considering the exclusion criteria, 20,834 cases were evaluated, with a median eGFR of 72.7 (IQR 56.6-87.5) mL/min/1.73 m². The median age was 69 (62-76) years. The study comprised 4,505 patients with normal (90-120), 10,189 with mild (60-89), 5,539 with moderate eGFR (30-59), and 601 with severe renal impairment (15-29). There was a stepwise increase in the crude all-cause death rates across the groups at 1 year. The cox regression model revealed that the relationship between eGFR and the risk of death at 1 year was non-linear (reverse J-shaped, Fig. 1), and the risk was the lowest in patients with eGFR∼90 mL/min/1.73 m². Conclusions There is a J-curve relationship between the eGFR value and 1-year all-cause mortality in patients with NSTEMI and treated with PCI.

Abstract 14756: The Effect of Torsemide vs Furosemide Across the Renal Function Spectrum - Insights From the TRANSFORM-HF Trial

Introduction: Among patients discharged after hospitalization for heart failure (HF), a strategy of torsemide versus furosemide showed no difference in all-cause mortality or hospitalization. Hypothesis: Clinicians may favor torsemide in the setting of renal dysfunction due to better oral bioavailability and longer half-life. However, the impact of baseline renal function on these findings is unknown. Methods: The TRANSFORM-HF trial randomized patients hospitalized for HF to a long-term strategy of torsemide versus furosemide, and enrolled patients across the spectrum of renal function excluding patients on dialysis. In this post-hoc analysis, baseline renal function during the index hospitalization was assessed as tertiles of estimated glomerular filtration rate (eGFR) (using 2021 CKD EPI formula), blood urea nitrogen (BUN), and BUN/creatinine ratio. The interaction between baseline renal function and treatment effect of torsemide vs furosemide was assessed for endpoints of (1) all-cause mortality and (2) all-cause mortality and all-cause readmissions at 12 months. Results: Of 2859 patients randomized, 336 (11.7%) had eGFR&lt;30ml/min/1.73m 2 , 1138 (39.8%) had eGFR 30-60 ml/min/1.73m 2 , and 1385 (48%) had eGFR≥60ml/min/1.73m 2 . Baseline eGFR and BUN did not clearly modify the treatment effect of torsemide vs furosemide for either all-cause mortality (Figure, Panel A) or all-cause mortality and all-cause readmissions at 12 months (Figure, Panel B) . For the composite outcome, BUN/creatinine ratio showed evidence of heterogeneity of treatment effect potentially in favor of torsemide in the middle tertile (interaction p-value&lt;0.01). Conclusion: Across the spectrum of baseline eGFR and BUN, a strategy of torsemide versus furosemide did not significantly impact mortality or readmission outcomes following hospitalization for HF..

Abstract 12593: Associations of Serum Uric Acid and Cardiovascular Events in a Clinical Trial of IL-1β Blockade

Background: Serum uric acid (SUA) associates with CV events, mortality, and gout. We assessed whether SUA predicts CV risk in a trial of IL-1β inhibition with canakinumab, a therapy known to reduce both CV events and gout. Aims: To validate associations between SUA and CV risk in a large cohort with chronic CAD and determine whether these associations were altered by IL-1β blockade or baseline renal function. Methods: The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) randomized 10,061 patients with prior MI and hsCRP ≥ 2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo subcutaneously every four weeks. SUA levels were obtained at baseline. Cox proportional hazards models compared the outcomes of major adverse cardiovascular events (MACE), CV death (CVD), and all-cause mortality (ACM) among those with baseline SUA ≤ 6.8 mg/dL, 6.8- 9.0 mg/dL, and ≥ 9.0 mg/dL (format: HR (95% CI); p). This analysis was repeated separately within canakinumab, placebo, eGFR ≥ 60 mL/min, and eGFR &lt; 60 mL/min sub-groups. Results: High SUA associated with MACE (1.66 (1.38-1.99); p&lt;0.0001), CVD (2.52 (1.98-3.21); p&lt;0.0001), and ACM (2.43 (2.01-2.94); p&lt;0.0001) compared to low SUA. These associations were minimally attenuated after adjustment for age, sex, BMI, smoking, hypertension, diabetes, LDL-C, and hsCRP. After further adjusting for eGFR and diuretic use, high SUA independently predicted CVD and ACM. In the IL-1β blockade arm, high SUA associated with MACE (1.82 (1.46-2.26); p&lt;0.0001), CVD (2.80 (2.10-3.73); p&lt;0.0001), and ACM (2.72 (2.17-3.40); p&lt;0.0001). In participants with normal eGFR, high SUA associated with CVD and ACM, but not MACE. Conclusions: These data from a large cohort of patients with chronic CAD confirm that individuals with elevated SUA have increased CV risk despite aggressive medical therapies. IL-1β blockade did not modify these associations. Future trials may consider inclusion of patients with high SUA and CKD as a method to increase absolute risk.