Severe Chronic Kidney Disease Research Articles

Risk of chronic kidney disease in patients with acute kidney injury following a major surgery: a US claims database analysis.

Acute kidney injury (AKI) is a common complication after major surgery. This study assessed the risk of developing or worsening of chronic kidney disease (CKD) and other clinical outcomes in patients experiencing AKI after major surgery. This retrospective observational study used Optum's de-identified Clinformatics Data Mart Database to investigate cardiorenal outcomes in adult patients at the first AKI event following major surgery. The primary outcome was CKD stage ≥3; secondary outcomes included myocardial infarction (MI), stroke, heart failure, all-cause hospitalization, end-stage kidney disease, need for dialysis or kidney transplant and composite measures. Follow-up was up to 3years. Additionally, the effect of intercurrent events on the risk of clinical outcomes was assessed. Of the included patients (N=31252), most were male (61.9%) and White (68.9%), with a median age of 72years (interquartile range 64-79). The event rates were 25.5 events/100 patient-years (PY) for CKD stage ≥3, 3.1 events/100 PY for end-stage kidney disease, 3.0 events/100 PY for dialysis and 0.1 events/100 PY for kidney transplants. Additionally, there were 6.9 events/100 PY for MI, 8.7 events/100 PY for stroke and 49.8 events/100 PY for all-cause hospitalization during follow-up. Patients with AKI relapses as intercurrent events were more likely to develop CKD stage ≥3 than those with just one AKI event after major surgery. This analysis demonstrated that patients experiencing AKI following major surgery are at high risk of developing severe CKD or worsening of pre-existing CKD and other cardiorenal clinical outcomes such as MI and stroke.

Vascular, valvular and kidney calcification manifested in mouse models of adenine-induced chronic kidney disease

Background Ectopic calcification (EC) involves multiple organ systems in chronic kidney disease (CKD). Previous CKD-animal models primarily focused on a certain histological abnormality but did not show the correlation with calcified development among various tissues. This study compared calcified deposition in various tissues during CKD progression in mice. Methods Male 8-week-old C57BL/6J mice were randomly allocated to the seven groups: a basic, adenine, high-phosphorus, or adenine and high-phosphorus diet for 12–16 weeks (Ctl16, A12, P16, or AP16, respectively); an adenine diet for 4–6 weeks; and a high-phosphorus or adenine and high-phosphorus diet for 10–12 weeks (A6 + P10, A4 + P12, or A4 + AP12, respectively). Results Compared to the Ctl16 mice, the P16 mice only displayed a slight abnormality in serum calcium and phosphorus; the A12 mice had the most serious kidney impairment; the A4 + P12 and A6 + P10 mice had similar conditions of CKD, mineral abnormalities, and mild calcification in the kidney and aortic valves; the A4 + AP12 and AP16 groups had severe kidney impairment, mineral abnormalities and calcification in the kidneys, aortic valves and aortas. Furthermore, calcium-phosphate particles were deposited not only in the tubulointerstitial compartment but in the glomerular and tubular basement membrane. The elemental composition of EC in various tissues matched the calcification of human cardiovascular tissue as determined by energy dispersive spectroscopy. Conclusions The severity of CKD was unparalleled with the progression of mineral metabolism disorder and EC. Calcification was closely related in different tissues and observed in the glomerular and tubular basement membranes.

432-P: Role of Patatin-Like Phospholipase Domain–Containing 3 Gene for Kidney Dysfunction in Diabetes Endotypes

Recent studies identified distinct endotypes of diabetes with differences in metabolic features and in risk for diabetes-related comorbidities. Of note, persons allocated to the severe insulin resistant diabetes (SIRD) endotype, who show increased prevalence of nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD), are more frequently carriers of the G-allele in the single-nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase domain containing 3 (PNPLA3) gene. This SNP associates with increased risk of NAFLD yet the association between the presence of the PNPLA3 SNP and CKD remains controversial. The present study examined whether this SNP differently associates with CKD in endotypes of recent-onset diabetes. Participants with newly diagnosed diabetes (n=707) from the prospective German Diabetes Study underwent k-means clustering, genotyping, magnetic resonance spectroscopy to determine hepatocellular lipid content (HCL) and laboratory analyses to calculate the glomerular filtration rates (eGFR). SIRD had the lowest eGFR and highest HCL compared to severe insulin deficient, moderate obesity-related, moderate age-related and severe autoimmune diabetes clusters (all p<0.05). HCL was negatively associated with eGFR (r=-0.287, p<0.01) across all groups. Further stratification by PNPLA3 G-allele carrier status did not reveal any association between HCL and eGFR in any of the diabetes types, irrespective of G-allele carrier status. However, with declining eGFR the proportion of G-allele carriers increased from 44% for eGFR >60 ml/min to 52% for eGFR <60 ml/min (p<0.05). In conclusion, increased hepatic lipid content is associated with reduced kidney function across all diabetes endotypes. This association is independent of the presence of the PNPLA3 polymorphism in newly diagnosed diabetes, but there might be role for PNPLA3 for the severity of CKD. Disclosure O.P. Zaharia: None. K. Strassburger: None. B. Knebel: None. Y. Kupriyanova: None. J. Kotzka: None. K. Bódis: None. M. Schön: None. M. Bombrich: None. C. Möser: None. K. Prystupa: Other Relationship; Berlin-Chemie AG. H. Al-Hasani: None. V. Schrauwen-Hinderling: None. K. Jandeleit-Dahm: None. R. Wagner: Speaker's Bureau; Novo Nordisk, Sanofi. Advisory Panel; Daiichi Sankyo. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis. Consultant; TARGET PharmaSolutions, Inc. Research Support; Sanofi. Funding German Research Foundation; European Foundation for the Study of Diabetes; German Diabetes Association; German Federal Ministry of Education and Research; Heinrich Heine University

#4368 THE PERSISTENT UNDERREPRESENTATION OF PEOPLE WITH CHRONIC KIDNEY DISEASE IN CARDIOVASCULAR TRIALS: A SYSTEMATIC REVIEW AND EVIDENCE MAP

Abstract Background and Aims People with chronic kidney disease (CKD) have a markedly higher risk for cardiovascular disease. Systematic underrepresentation of people with CKD in cardiovascular randomised controlled trials (RCTs) limits evidence to guide cardiovascular risk management (CVRM). In this systematic review we aimed to identify evidence gaps regarding CVRM medication for people with CKD and evaluated the prevalence of exclusion of people with CKD from cardiovascular RCTs. Method We searched Clinicaltrials.gov through the Cochrane Central Register of Controlled Trials from inception until October 2021. Eligible studies were randomised controlled trials (RCTs) that investigate the efficacy of guideline-recommended CVRM medications on (cardiovascular) mortality, cardiovascular morbidity, and end-stage kidney disease in adults with a history of cardiovascular disease or one or more major risk factors for cardiovascular disease. Two reviewers independently determined the eligibility of references and extracted data. Outcomes were an overview of studies that report results for people with CKD, evidence gaps in results, and the rate of exclusion of people with CKD. Results We included 1180 of the 2794 eligible RCTs involving 2,158,869 participants (mean age 63±6 years, 36% female). Overall, 841 (71%) RCTs excluded (subgroups of) people with CKD based on heterogenous exclusion criteria. Since 2000, this prevalence has increased from 70% to 75%. Of included RCTs, only 157 (13%) reported results for people with CKD (again in heterogenous subgroups). The prevalence of RCTs with results for people with CKD has increased since 2000 from 10% to 23%. Nevertheless, significant evidence gaps remain for most CVRM interventions, particularly for those with an eGFR <30 ml/min/1.73m2 (22 RCTs), and people who are treated with dialysis (14 RCTs) or received a kidney transplant (1 RCTs). Conclusion The majority of cardiovascular RCTs continues to exclude (subgroups of) people with CKD and this has only increased over the years. Although more RCTs report results for people with CKD, evidence gaps for the efficacy most CVRM medications persist, particularly for those with severe CKD.

#3953 TOXIC MICROBIOME AND CHRONIC KIDNEY DISEASE: INSIGHTS FROM THE CKD-REIN COHORT STUDY

Abstract Background and Aims Many uremic toxins (UTs) originate from gut microbiome, and contribute to chronic kidney disease (CKD) progression and cardiovascular morbidity. In order to reduce uremic symptoms and CKD progression, patients have several dietary restrictions, which may influence gut microbiome composition, and impact UTs production. An altered microbiome may contribute to UTs increase in those patients. However, the role of key bacterial taxa in producing UTs and the impact of diet on UTs variance in non-dialyzed patients are not well known. The objectives of this study were, first, to compare microbial features between CKD patients and healthy controls, and, second, to investigate the relation of gut microbiome with uremic toxicity, as well as the potential impact of diet on such relationship. Method Characterization of gut metagenomes, 10 UTs and 3 precursors’ serum concentrations by LC-MS/MS, host characteristics and diet were obtained from 240 non-dialysis CKD patients from the CKD-REIN cohort (mean ± SD): age: 68 ± 11 years, 71% male, estimated glomerular filtration rate (eGFR): 33.2 ± 12.7 ml/min/1.73m². First, to identify microbial biomarkers characterizing the gut microbiome-related toxicity in CKD, we compared microbiome features between 78 CKD patients and 78 age-, sex-, and BMI-matched healthy controls from the Milieu Interieur (MI) cohort: age: 58 ± 10 years, 60% male, eGFR: 89 ± 13. Second, we performed a multiomics’ data integration analysis via a supervised modelling to investigate cross-sectionally the association between host characteristics, gut microbiome, UTs, and diet-related features according to CKD severity (eGFR<30, n = 110 vs eGFR ≥30 mL/min/1.73m², n = 130). Results Compared to healthy controls, CKD patients had a significant reduced gut microbiome health index. Several Metagenomic Species Pan-genomes (MSPs) were significantly contrasted between MI and CKD cohorts: 43 species were enriched in CKD patients vs 24 in controls. Species most enriched in CKD patients included several UTs producers such as Lachnospiraceae spp, Dysosmobacter – Oscillibacter spp, Butyricimonas faecihominis, Victivallis vadensis and Hungatella spp, some of which were positively correlated with the following UTs: 3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), trimethylamine-N-oxide (TMAO), and indole-3-acetic acid (3-IAA). Moreover, species belonging to Enterocloster and Hungatella genera (both members of Lachnospiraceae family) were found to be negatively correlated with eGFR. Among species associated with CKD severity, species carrying genes for UTs production were observed such as Desuflovibiro fairfieldensis, Bacteroides clarus and Blautia obeum along with increasing alcohol and hot drinks consumption, CRP and several UTs (kynurenic acid, indoxyl sulfate and Phenylacetylglutamine) levels. In contrast, some taxa like Faecalibacterium prausnitzii and Dysosmobacter welbionis were associated with legume intake but not with UTs. Conclusion Our study highlights an alteration of gut microbiome in CKD patients compared to healthy controls, with increased abundance of UTs producer species. The results of the multidimensional data integration modelling suggest a strong interplay between food intake, gut microbiome modifications, UTs accumulation and clinical features. These findings might open to promising therapeutic strategies to reduce microbiome-related toxicity.

#6009 MUSCLE OXYGENATION AND MICROVASCULAR REACTIVITY ACROSS DIFFERENT STAGES OF CHRONIC KIDNEY DISEASE: A NEAR-INFRARED SPECTROSCOPY STUDY

Abstract Background and Aims Previous studies in chronic kidney disease (CKD) showed that vascular dysfunction in different circulatory beds is progressively deteriorating with CKD severity. This study evaluated muscle oxygenation and microvascular reactivity at rest, during an occlusion-reperfusion maneuver, and during exercise in patients with pre-dialysis CKD versus controls, as well as between different CKD stages Method Continuous measurement of muscle oxygenation [tissue saturation index (TSI%)] via near-infrared-spectroscopy at rest, during occlusion-reperfusion, and during a 3-min handgrip exercise(at 35% of maximal-voluntary-contraction). Aortic pulse wave velocity (PWV) and carotid intima-media thickness (cIMT) were also recorded. Results Resting muscle oxygenation did not differ among the study groups (controls: 64.3±2.9 stage-2: 63.8±4.2stage-3a: 64.1±4.1 stage-3b: 62.3±3.3 stage-4: 62.7±4.3%; p = 0.6). During occlusion, no significant differences among groups were detected in TSIocl magnitude- and occlusion-slope. However, during reperfusion, theTSImax and the hyperemic response were significantly lower in groups of patients with more advanced CKD stages (controls: 11.2±3.7 stage-2: 8.3±4.6 stage-3: 7.8±5.5 stage-3b: 7.3±4.4 stage-4: 7.2±3.3; p = 0.04). During handgrip exercise, muscle oxygenation (TSIaverage-decline) was marginally lower in CKD patients than controls, but no significant differences were detected between CKD stages. Conclusion Although no differences were observed in muscle oxygenation at rest and during occlusion, the microvascular hyperemic response during reperfusion was significantly impaired in CKD and deteriorated in more advanced CKD stages. This impaired ability of microvasculature to respond to stimuli may be a crucial component of the adverse vascular profile of CKD patients and may contribute to exercise intolerance

Non-contrast transcatheter aortic valve implantation for patients with aortic stenosis and chronic kidney disease: a pilot study.

Acute kidney injury (AKI) is frequently observed after transcatheter aortic valve implantation (TAVI). Of note, it is associated with a threefold increase in all-cause and cardiac death. We propose a new non-contrast strategy for evaluating and performing the TAVI procedure that can be especially valuable for patients with aortic stenosis (AS) and chronic kidney disease (CKD) to prevent AKI. Patients with severe symptomatic AS and CKD stage ≥3a were evaluated for TAVI using four non-contrast imaging modalities for procedural planning: transesophageal echocardiogram (TEE), cardiac magnetic resonance, multidetector computed tomography (MDCT), and aortoiliac CO2 angiography. Patients underwent transfemoral (TF) TAVI using the self-expandable Evolut R/Pro, and the procedures were guided by fluoroscopy and TEE. Contrast MDCT and contrast injection at certain checkpoints during the procedure were used in a blinded fashion to guarantee patient safety. A total of 25 patients underwent TF-TAVI with the zero-contrast technique. The mean age was 79.9 ± 6.1 years, 72% in NYHA class III/IV, with a mean STS-PROM of 3.0% ± 1.5%, and creatinine clearance of 49 ± 7 ml/min. The self-expandable Evolut R and Pro were implanted in 80% and 20% of patients, respectively. In 36% of the cases, the transcatheter heart valve (THV) chosen was one size larger than the one by contrast MDCT, but none of these cases presented adverse events. Device success and the combined safety endpoint (at 30 days) both achieved 92%. Pacemaker implantation was needed in 17%. This pilot study demonstrated that the zero-contrast technique for procedural planning and THV implantation was feasible and safe and might become the preferable strategy for a significant population of CKD patients undergoing TAVR. Future studies with a larger number of patients are still needed to confirm such interesting findings.

#4695 LOSS OF NLRP6 INCREASES THE SEVERITY OF KIDNEY FIBROSIS

Abstract Background and Aims The burden of chronic kidney disease (CKD) is growing worldwide, illustrating the need for better prevention and therapeutic approaches. Kidney fibrosis is a hallmark of CKD that is not specifically addressed by current therapeutic options. The nucleotide-binding oligomerization domain-like receptor (NLR) family has 22 members. The NLRP3 inflammasome has been most extensively studied in the context of kidney disease where it plays a pathogenic role. However, the role of NRLP6 during CKD and kidney fibrosis remains unexplored. The aim of the study was to explore the role for endogenous Nlrp6 in protecting from kidney fibrosis. Method A hypothesis-driven analysis of non-biased human kidney disease transcriptomics databases was performed to identify NLRs other than NLRP3 of potential therapeutic interest, based on differential gene expression during CKD and the relationship of gene expression to severity of CKD. We explored Nlrp6 expression in preclinical accelerated CKD and kidney fibrosis (UUO) and characterized the function of endogenous Nlrp6 by inducing UUO in Nlrp6-deficient mice and validated the results in a second model of kidney fibrosis. Once tubular cells were identified as the key cells expressing NLRP6 and regulating NLRP6 expression during UUO, we explored the drivers of Nlrp6 downregulation in tubular cells, as well as the consequences of Nlrp6 downregulation in these same cells. Results The role of Nlrp6 in experimental CKD was explored in wild-type and Nlrp6-deficient mice with unilateral ureteral obstruction (UUO). Whole kidney Nlrp6 mRNA and tubular cell Nlrp6 protein decreased following UUO. Low kidney Nlrp6 immunostaining was also observed in human CKD. Genetic Nlrp6 deficiency resulted in increased kidney p38 MAP kinase activation and more severe kidney inflammation and fibrosis, as assessed by kidney inflammatory gene expression, interstitial macrophage infiltration, expression of profibrotic cytokines and extracellular matrix encoding genes, Smad3 phosphorylation, Sirius red staining, collagen, and fibronectin deposition and myofibroblast numbers. Similar results were obtained in adenine-induced kidney fibrosis. Cytokines involved in the pathogenesis of kidney fibrosis, such as the profibrotic cytokine TGF-β1 and the proinflammatory cytokine TWEAK, decreased Nlrp6 expression in cultured tubular cells, while siRNA targeting Nlrp6 resulted in increased TGF-β1 and CTGF expression, which was limited by inhibiting p38 MAPK. Conclusion In conclusion, endogenous constitutive Nlrp6 dampens sterile kidney inflammation and fibrosis likely by dampening tubular cell responses. Loss of Nlrp6 expression may contribute to CKD progression.

#3256 LONGITUDINAL ASSOCIATION BETWEEN IRON STORES BIOMARKERS AND MAJOR ADVERSE CARDIOVASCULAR EVENTS IN CHRONIC KIDNEY DISEASE

Abstract Background and Aims Iron deficiency is a frequent condition in moderate to severe chronic kidney disease (CKD), often left under-screened, and infrequently supplemented. Iron deficiency is a major contributor to anemia, which is known to negatively impact outcomes and quality of life in CKD. However, evidence of an anemia-independent effect of iron deficiency on cardiovascular morbidity and all-cause mortality has emerged. Current challenges of studying the association between iron deficiency and the risk of events in CKD are the definition of critical thresholds for these biomarkers, the potential interaction between them, and their evolution over time. Previous observational cohort studies have only focused on baseline values of transferrin saturation and ferritin, the two traditional biomarkers of iron deficiency. Our aim was to study the longitudinal association between iron stores biomarkers and cardiovascular risk in CKD by evaluating the total effect of these biomarkers on major adverse cardiovascular events (MACE). Method We used data from the CKD-REIN cohort, which included 3033 patients with moderate to severe CKD from 40 nationally representative nephrology clinics in France between 2013 and 2016. All patients with at least one measurement of TSAT and ferritin were included in the present study. Our primary endpoint was MACE, defined as the first event among cardiovascular death, myocardial infarction, stroke or hospitalization for acute heart failure. Repeated measures of TSAT and ferritin were included as time-dependent variables in cause-specific Cox proportional hazard models for risk of MACE, with initiation of kidney replacement therapy (KRT) and death as competitive events. Models were adjusted for time-varying estimated glomerular filtration rate (eGFR), white cells and baseline age, sex, iron supplementation, and erythropoietin stimulating agents. Analyses were not adjusted for hemoglobin level because the aim of the study was to investigate the total effect of iron deficiency on MACE. Non-linear effects of TSAT and ferritin and their interaction were modeled using natural splines functions. Results A total of 2670 patients were included in the analysis: 65% were men, median age was 68 years (interquartile range IQR 60-76). Median baseline eGFR was 34 ml/min/1.73 m2 (IQR 25-44), TSAT was 24% (IQR 18-30) and ferritin was 127 ng/ml (IQR 72-230). Over a median follow-up period of 4.4 years, participants had a median of 5 (IQR 2-8) and 4 (IQR 2-6) measurements of ferritin and TSAT, respectively; 396 MACE before KRT were recorded. The negative nonlinear association of iron deficiency with MACE was essentially captured by TSAT, and the interaction terms between TSAT and ferritin were not statistically significant (p = 0.94). Compared with patients with TSAT of 20% and ferritin of 100 ng/ml, those with TSAT values < 20% had a higher adjusted hazard of MACE independently of ferritin values (See Figure 1); for example, for TSAT = 10% and ferritin = 100 ng/ml, the hazard ratio (HR) was 1.96, 95% CI (1.60-2.39). Conclusion In CKD patients under nephrology care, current value of TSAT below 20% was associated with higher risk of MACE regardless of ferritin current value. Before investigating strategies of treatment in clinical trials as PIVOTAL in dialysis patients, further studies clarifying critical thresholds of TSAT and ferritin in non-dialysis CKD patients, in presence or absence of anemia and among specific CKD subpopulations are highly desirable.

#3381 PROFILES OF HEMOGLOBIN TRAJECTORY IN CKD PATIENTS AND ASSOCIATED RISKS OF MAJOR ADVERSE CARDIOVASCULAR EVENTS: THE CKD-REIN COHORT STUDY

Abstract Background and Aims Anemia in chronic kidney disease (CKD) has been repeatedly associated with increased cardiovascular and all-cause morbidity and mortality. Most observational studies have focused on one single measurement of hemoglobin, but very few have investigated the trajectory of hemoglobin over time. Our aim was to identify, in moderate to severe CKD, typical profiles of hemoglobin trajectories, and to estimate their associated risk of major adverse cardiovascular event (MACE). Method We used data from the CKD-REIN cohort, which included 3033 patients with moderate to severe CKD from 40 nationally representative nephrology clinics in France between 2013 and 2016. A minimum of one hemoglobin measurement was necessary to be included. The primary endpoint was MACE defined as the first event among cardio-vascular death, myocardial infarction, stroke or hospitalization for acute heart failure. Secondary events included initiation of kidney replacement therapy (KRT) and death. A joint latent class mixed model was used to identify classes of hemoglobin trajectory and estimate the risk of each event. Once the model had identified classes and assigned participants in their class, we described the characteristics of patients in each class a posteriori. We also performed a posterior analysis to describe the course of estimated glomerular filtration rate (eGFR) in each class. Results A total of 3011 subjects were included in the analysis: 66% were men, median age at inclusion was 69 years. A total of 33874 hemoglobin measurements have been analyzed (median of 10 per patient). A total of 460 MACE, 522 KRT before MACE and 216 deaths before MACE or KRT, were recorded over a median follow-up of 4.3 years (Interquartile Range IQR 2.3-5.0). Five distinct classes were identified with a predominant one, Class-1 (‘constant’) including 63% (n = 1885) of the studied population with an overall stable trajectory surrounding a hemoglobin concentration of 13 g/dL (See figure below). For this class, risks of events were very low throughout the follow-up. Patients in this class had fewer cardiovascular risk factors, lower eGFR, and less often increased proteinuria at baseline than in other classes. Class-2 trajectory (‘late strong decline’, n = 75, 2.5%) had an abrupt decline at 2 years of follow-up; concomitantly risks of KRT and death before MACE emerged but the risk of MACE remained low over the follow-up. Patients classified in this class had more often tubulo-interstitial or unknown nephropathy than in other classes. Classes 3 ‘(late moderate decline, n = 438, 14.6%) and 4 (‘early moderate decline, n = 356, 11.8%) exhibited more moderate decline of hemoglobin level occurring on average at 3 and 1 year of follow-up, respectively. For these two classes, the risk of KRT before MACE increased from the start of these declines but their risks of MACE increased from the cohort entry. Class-5 (‘early strong decline’, n = 257, 8.5%) had a collapsing trajectory right from the entry into the cohort, and had a risk of MACE increasing rapidly in the very first year. Patients from Class-3 and Class-5, who had the highest risk of MACE, also had a worse cardiovascular profile at baseline. The average eGFR trajectories estimated in each of the 5 identified classes of hemoglobin showed similar patterns as those for hemoglobin. Conclusion In patients with CKD under nephrology care, most of patients have normal and stable hemoglobin values over time. In about one third of patients, 4 profiles of hemoglobin decline were observed, likely matching those of eGFR decline. These 4 classes with declining profiles had different levels of MACE risk and a strong increased risk of KRT after hemoglobin decline. This study suggests that more attention should be paid to dynamic changes of hemoglobin in the management of CKD.

#6706 ACUTE KIDNEY DISEASE FOLLOWING COVID-19 VACCINATION: A RETROSPECTIVE, SINGLE- CENTER STUDY

Abstract Background and Aims The rare de novo or relapsed kidney diseases associated with coronavirus disease 2019 (COVID-19) vaccination have been increasingly reported. The aim of the study was to investigate the incidence, characteristics, and outcome of acute kidney disease (AKD) following COVID-19 vaccination. Method This retrospective study scrutinized the data from renal registry in a single academic medical center from Jan. 1st, 2020, to Apr. 30th, 2022. Patients who developed AKD within 90 days after COVID-19 vaccination were first included. Naranjo score as a causality assessment tool for adverse vaccination reaction and charts review by peer nephrologists were utilized for the exclusion of other causes. The etiologies of AKD, their characteristics, treatment, and outcome attributing to the COVID-19 vaccines were examined (Fig. 1). Results Twenty-seven aged 23 to 80 patients with AKD were identified from 1897 patients (incidence of 6.3 per 1000 patient-years). Their Naranjo score was 7.7± 1.5, and 14 of 27 patients (51.9%) had definite diagnosis (Naranjo score ≥ 9). They incorporated both glomerular disease (n = 16) including IgA nephropathy (n = 7), anti-neutrophil cytoplasmic antibodies-associated glomerulonephritis (AAN) (n = 4), membranous glomerulonephritis (n = 3), minimal change disease (MCD) (n = 2), and chronic kidney disease (CKD) with acute deterioration (n = 11). The majority (21 of 27, 77.8%) of COVID-19 vaccination was messenger RNA (mRNA)-based regimen. Four patients (14.8%) rapidly progressed to end stage kidney disease (ESKD) requiring dialysis despite aggressive management. Extra-renal features such as pulmonary hemorrhage, myopericarditis and hepatitis/pancreatitis were observed in 4 patients. Conclusion In summary, AKD after COVID-19 vaccination may occur with more alarm in this renal registry. In addition to GN, patients with pre-existing moderate to severe CKD should also receive more intensive evaluation before vaccination despite the established benefits of vaccination in this vulnerable population likely outweigh the risk.

#5705 EFFICACY AND SAFETY OF SACUBITRIL/VALSARTAN IN PATIENTS WITH STAGE 3B-5 CKD AND HYPERTENSION

Abstract Background and Aims Sacubitril/valsartan (SV) plays a key role in improving left ventricular remodeling and prognosis in patients with heart failure. However its effects on kidney function in people with moderate to severe chronic kidney disease (CKD3b-5) are unknown. The present study was designed to assess the efficacy and safety of sacubitril-valsartan in patients with stage 3b-5 CKD and hypertension. Method In this randomized, double-blind, 3-month trial, patients with stage 3b-5 CKD and hypertension were randomly assigned to sacubitril/valsartan treatment group (n = 44, the doses of SV were up-titrated to sacubitril/valsartan 400 mg), and conventional antihyperensive treatment group (n = 40). The primary outcome was reduction in GFR from baseline at week 12. Results In total, 44 participants were assigned to sacubitril/valsartan group and 40 to crontol group (conventional antihyperensive group). Baseline measured GFR was 29.94±11.83, 27.86±10.14 mL/min/1.73 m2, respectively. There was no difference in measured GFR (P = 0.064). At week 12, there was a reduction in measured GFR in control group: 27.86±9.15 versus 22.03±11.41, but there was no significant difference (P = 0.155). Sacubitril/ valsartan could improve eGFR: 29.94±11.83 versus 32.05±14.57 (P = 0.018). We also observed that, compared with control group, sacubitril/valsartan decreased albuminuria: reductions in urinary albumin:creatinine ratio (ACR) in sacubitril/valsartan group was 89.5mg/g and reductions in urinary ACR in control group was -44.55mg/g. At week 12, Sacubitril/valsartan provided a significantly greater reduction in office mean sitting (ms) systolic BP (msSBP) than control group (20.75mmHg vs 12.88mmHg, P = 0.046). There was no serious adverse events in both groups. The incidence of hyperkalemia (potassium≥5.5 mmol/L) was 4.5% in SV group and 7.5% in control group. Conclusion The present data suggested that, in patients with stage 3b-5 CKD and hypertension, Sacubitril-valsartan could improve kidney function and decrease albuminuria, and was generally safe and well tolerated.

Medication safety in chronic kidney disease.

Several drugs cause nephrotoxicity and accelerate progression of chronic kidney disease (CKD). The objective of this review is to summarize recent evidence on drugs that either increase the risk of nephrotoxicity, progression of CKD or drug induced harm in patients with CKD. Bisphosphonates and hypnotics increase the progression of CKD, whereas denosumab does not accelerate progression of CKD. Tenofovir disoproxil fumarate (TDF) increases the risk of renal tubular toxicity and adverse effects on bone, but Tenofovir alafenamide (TAF) and Tenofovir amibufenamide (TMF) have favorable safety profile on the kidneys and bones. Although no dosage adjustment is needed for Oral Nirmatrelvir/Ritonavir in patients with mild renal impairment and coronavirus disease 2019, the dosage is reduced to twice daily in those with moderate renal impairment. It is not recommended in patients with severe renal impairment. The prescribing information does not recommend use of remdesevir below glomerular filtration rate (eGFR) < 30 ml/min but recent studies suggest that remdesevir may be safe and effective in patients with varying levels of CKD severity. Molnupiravir does not require dose adjustment in patients with CKD. Several medications increase the risk of development of acute kidney injury or progression of CKD. Close attention is needed to select the appropriate dose or safer alternatives to reduce the risk of drug-induced harm in patients with CKD.

Simultaneous Heart-kidney Transplant With Planned Delayed Implantation of the Kidney Graft After Ex Vivo Perfusion.

Simultaneous heart-kidney transplant (SHK) is an established option for patients with severe heart failure and chronic kidney disease. Recent studies in simultaneous liver-kidney transplantation demonstrate favorable outcomes achieved by delaying implantation of the kidney for over 24 h. This report describes a case series of consecutive patients listed for SHK who had planned delayed implantation of the kidney graft. This case series represents a retrospective analysis of SHK patients extracted from the transplant database at a single center. There were 7 patients who underwent SHK during the study period. In all cases, kidney grafts were maintained on hypothermic ex vivo pulsatile perfusion for delayed implantation (mean cold ischemia 53 h [range, 31-69]). The first 5 patients had 100% 1-y heart and kidney graft survival with good function. Patient 6 was unstable on extracorporeal membrane oxygenation post-heart transplant. The kidney was implanted at 69 h, and the patient died soon thereafter. Patient 7 was also unstable on extracorporeal membrane oxygenation after heart transplant. The decision was made to implant the kidney into a backup kidney recipient. The heart transplant recipient subsequently died several days later, whereas the kidney was successfully transplanted in the alternate candidate. This case series highlights the potential utility of delayed kidney implantation in SHK patients. SHK with delayed renal transplant may provide an improved physiologic environment for renal transplant, which may result in improved early renal graft function. Delayed kidney transplant also provides the opportunity to transplant the kidney graft into an alternate candidate.

Immune related adverse events (irAEs) in patients with solid tumors and advanced chronic kidney disease (CKD) receiving checkpoint inhibitors (CPIs).

2650 Background: Randomized controlled trials evaluating CPIs in the management of solid tumors have typically excluded patients with advanced CKD and end-stage renal disease (ESRD). Limited available data evaluating the safety of CPI use in this patient population demonstrated a similar incidence of irAEs in patients with advanced CKD compared to those with normal or mildly impaired renal function, with majority of irAEs being grade 1 or 2. CPIs are not modified by dialysis due to their molecular size and, as such, do not require renal dosing. Methods: We performed a retrospective analysis of patients over 18 years of age with solid tumors and advanced CKD, who received CPIs at the University of California Irvine from 1/2015 to 6/2021. Advanced CKD was defined as glomerular filtration rate (GFR) less than 60 ml/min. Patients must have received at least one dose of a PD-1/PD-L1 or CTLA-4 inhibitor as a single-agent or in combination with another therapy. Patients were stratified by severity of CKD, including CKD3 (GFR of 30-59 ml/min), CKD4 (GFR of 15-29 ml/min), and CKD 5/ESRD (GFR less than 15 ml/min). Results: A total of 32 patients were included, 24 (75.00%) with CKD3, 6 (18.25%) with CKD4, and 2 (6.25%) with CKD5/ESRD. 10 (31.25%) patients were female and 22 (68.75%) were male. Median age was 73.5 years [range: 26 to 98]. 22 (68.75%) received CPI monotherapy and 10 (31.25%) received a combination of CPI with another agent. After initiation of CPI therapy, 16 (50.00%) patients experienced an irAE, with a total of 23 unique irAEs due to some patients experiencing multiple irAEs. In patients with irAEs, 13 (81.25%) received CPI monotherapy and 3 (18.75%) received CPI combined with another agent. In patients with CKD3, CKD4, and CKD5/ESRD, 14 (87.50%), 2 (12.60%), and 0 (0.00%) experienced irAEs, respectively. Types of irAEs observed are listed, with the most common being colitis in 6 (26.1%) patients, endocrinopathies in 4 (17.39%) patients, and dermatologic in 4 (17.39%) patients. 18 (78.26%) of unique irAEs were grade 1 or 2, while 5 (21.74%) were grade 3 or higher. 10 (43.48%) of irAEs were managed with steroids as per physician discretion, 8 (80.00%) with CKD3 and 2 (20.00%) with CKD4. Conclusions: The safety of CPIs in patients with solid tumors and advanced CKD has not been rigorously evaluated. Recognizing the small sample size and retrospective nature of this dataset, the incidence and type of irAEs in patients with advanced CKD appears similar to that of patients with normal renal function or mild renal impairment. More prospective data in this population is needed, particularly in patients with CKD5/ESRD. Types of irAEs in patients with advanced CKD. [Table: see text]

Impact of Successful Secondary Hyperparathyroidism Treatment on Cardiovascular Morbidity in Patients with Chronic Kidney Disease Stage IIIB-V

Abstract Background Chronic kidney disease (CKD) patients grade III B(GFR 30-44ml/min), IV (GFR 15-29ml/min) and grade V (GFR &amp;lt;15ml/min) are patients with a severe chronic Kidney disease that are shortly before or in need of dialysis. 61.7% of patients on hemodialysis have been found to have secondary hyperparathyroidism. It has been associated with high cardiovascular morbidity by calcification of tissue leading to lung fibrosis and right heart insufficiency. Aims To assess the effect of treatment success of secondary renal hyperparathyroidism (SHPT) on cardiovascular morbidity. Methods Retrospective single-center analysis. 211 patients chronic kidney disease (CKD) stages IIIB-V undergoing computed tomography for coronary artery calcium (CAC) scoring at the University Hospital of Zurich between 2015 and 2019. Presence of and control of SHPT was assessed at the timepoint of CAC scoring, and 6-12 months prior. Information on left ventricular ejection fraction (LVEF), and left ventricular hypertrophy (LVH) were obtained from echocardiography at the timepoint of CAC scoring. Independent predictive factors for ACS and LVH were assessed by multivariable analysis. Results 34% (n=72) of the patients had uncontrolled SHPT, whereas 66% (n=139) had either no-(n=98) or a controlled SHPT(n=41). Patients with uncontrolled SHPT had a significantly lower LVEF (p=0.028), significantly more pronounced LVH (p=0.003), a higher left ventricular myocardial mass index (LVMMI) (p=0.002) than the group with no SHPT or well controlled SHPT. Uncontrolled SHPT had a significant higher risk for developing ACS (p=0.011) compared to no-or controlled SHPT patients (41.7% vs 31.7%). Conclusions Insufficient control of SHPT has a negative impact on cardiovascular morbidity with lower LVEF, increased LVH and a higher incidence of ACS. Increased focus on SHPT control in CKD patients is important and may have a beneficial impact on cardiovascular outcomes. If all conservative measures do not lead to a sufficient alignement of the secondary hyperparathyroidism parathyroidectomy may be indicated.

Serum malondialdehyde in different stages of chronic renal disorder

Background: Chronic kidney disease (CKD) is a widespread public health problem, which may have several adverse consequences such as renal failure, cardiovascular disease, and premature death. Kidney-related pathologies have increasing prevalence rates, produce a considerable financial burden, and are characterized by elevated levels of oxidative stress (OS). Several markers emerged as well-suited indicators of OS such as malondialdehyde (MDA) and lipid hydroperoxides. The reduced activities of antioxidant enzymes status and increased production of MDA in the CKD patients confirm the presence of OS. The alteration in antioxidant status and MDA in CKD patients supports the role of OS in CKD patient. Aims and Objectives: The aim of the study was to compare serum MDA in different stages of CKD with that of control. It is well known that inflammation has an important role in CKD and MDA is an oxidant biomarker. Materials and Methods: This was a cross-sectional study having 400 participants with 300 known cases of CKD and 100 healthy controls. Serum MDA levels were measured by thiobarbituric acid assay. Results: There was a significant difference between the groups regarding the MDA values (P&lt;0.001) with that of control. The mean MDA value in Stage III (5.64±1.93 Umol/L), Stage IV (6.14±1.584 Umol/L), and Stage V (10.761±3.347 U moL/L) of CKD patients were high in comparison to healthy control (1.88±0.181 U mol/L). Conclusion: We concluded that MDA is a useful biomarker in CKD patients. The correlations of serum MDA among different stages of CKD patients were significant. Larger studies focused on CKD severity and antioxidant/oxidant biomarkers are required.

MUSCLE OXYGENATION AND MICROVASCULAR REACTIVITY ACROSS DIFFERENT STAGES OF CHRONIC KIDNEY DISEASE: A NEAR-INFRARED SPECTROSCOPY STUDY

Objective: Previous studies in chronic kidney disease(CKD) showed that vascular dysfunction in different circulatory beds is progressively deteriorating with CKD severity. This study evaluated muscle oxygenation and microvascular reactivity at rest, during an occlusion-reperfusion maneuver, and during exercise in patients with pre-dialysis CKD versus controls, as well as between different CKD stages Design and method: This observational controlled study included 90 participants (18 per CKD stage 2, 3a, 3b, 4 and 18 controls). Continuous measurement of muscle oxygenation [tissue saturation index (TSI%)] via near-infrared-spectroscopy at rest, during occlusion-reperfusion, and during a 3-min handgrip exercise(at 35% of maximal-voluntary-contraction). Aortic pulse wave velocity (PWV) and carotid intima-media thickness (cIMT) were also recorded. Results: Resting muscle oxygenation did not differ among the study groups (controls: 64.3±2.9 stage-2: 63.8±4.2 stage-3a: 64.1±4.1 stage-3b: 62.3±3.3 stage-4: 62.7±4.3%; p = 0.6). During occlusion, no significant differences among groups were detected in TSIocl magnitude- and occlusion-slope. However, during reperfusion, the TSImax and the hyperemic response were significantly lower in groups of patients with more advanced CKD stages (controls: 11.2±3.7 stage-2: 8.3±4.6 stage-3: 7.8±5.5 stage-3b: 7.3±4.4 stage-4: 7.2±3.3; p = 0.04). During handgrip exercise, muscle oxygenation (TSIaverage-decline) was marginally lower in CKD patients than controls, but no significant differences were detected between CKD stages. Conclusions: Although no differences were observed in muscle oxygenation at rest and during occlusion, the microvascular hyperemic response during reperfusion was significantly impaired in CKD and deteriorated in more advanced CKD stages. This impaired ability of microvasculature to respond to stimuli may be a crucial component of the adverse vascular profile of CKD patients and may contribute to exercise intolerance

8-Hydroxy-2'-deoxyguanosine and malondialdehyde in plasma and their association with disease severity in 20 cats with chronic kidney disease.

Oxidative stress is associated with the development and progression of chronic kidney disease (CKD) in humans. The aim of this study was to evaluate the concentrations of oxidative stress markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA), in the plasma and urine of cats with different stages of CKD. Plasma and urine samples were collected from cats with CKD that were referred to the Veterinary Medical Center of the University of Tokyo between April 2019 and October 2022. Plasma and urine samples were collected from healthy cats (n = 6 at most), cats with stage 2 CKD (n = 8) and stage 3-4 CKD (n = 12), and cats with idiopathic cystitis (disease control, n = 5). Plasma and urine concentrations of 8-OHdG and MDA were measured using ELISA and thiobarbituric acid reactive substances assay kits, respectively. The median plasma 8-OHdG concentrations were 0.156 ng/ml (<0.125-0.210 ng/ml) in the healthy group, <0.125 ng/ml (range <0.125 ng/ml) in the idiopathic cystitis group, 0.246 ng/ml (range 0.170-0.403 ng/ml) in cats with stage 2 CKD and 0.433 ng/ml (range 0.209-1.052 ng/ml) in cats with stage 3-4 CKD. Concentrations in stage 3-4 CKD were significantly higher than those in the healthy and disease control groups. Plasma MDA concentrations were low in the healthy and disease control groups and significantly higher in cats with stage 3-4 CKD. In every cat with CKD, plasma 8-OHdG and MDA concentrations were positively correlated with plasma creatinine concentrations (8-OHdG, rs = 0.68; MDA, rs = 0.67). Urinary 8-OHdG/urinary creatinine (u-CRE) and urinary MDA/u-CRE levels did not differ significantly between the groups; however, it was difficult to evaluate them because of the small sample size. This report shows that plasma 8-OHdG and MDA concentrations increase with the severity of feline CKD. These markers may be useful for assessing oxidative stress in cats with CKD.

Renal tubular damage and clinical outcome in heart failure with preserved ejection fraction and chronic kidney disease.

Despite advances in heart failure (HF) treatment, HF with preserved ejection fraction (HFpEF) remains a health problem with a high mortality rate. HFpEF is composed of diverse phenogroups, of which patients with concomitant renal impairment have worse outcomes. Renal tubular damage (RTD) is associated with the development of HF and chronic kidney disease (CKD). However, the impact of RTD on HF progression in patients with HFpEF and CKD remains unclear. The aim of the present study was to examine whether RTD could predict HF-related events in patients with HFpEF and CKD. We measured RTD markers, such as urinary β2 -microglobulin to creatinine ratio (UBCR) and N-acetyl-β-d-glucosamidase (NAG) level, in 319 consecutive patients with HFpEF and CKD who were hospitalized for acute HF (49% females, mean age 76±12). Based on previous reports, high UBCR and high NAG levels were defined as UBCR ≥300μg/gCr and NAG >14.2U/gCr, respectively. There were 91 HF-related events, defined as HF hospitalizations or HF deaths, during the median follow-up period of 5.2years. The prevalence of high UBCR increased with advancing New York Heart Association functional class and albuminuria. Kaplan-Meier analysis demonstrated that patients with high UBCR had more HF-related events than those with normal or low UBCR. Multivariate Cox proportional hazards regression analyses demonstrated that high UBCR, but not high NAG level, was an independent predictor of HF-related events after adjusting for confounding risk factors in patients with HFpEF and CKD (hazard ratio, 2.60; 95% confidence interval, 1.52-4.72; P=0.0009). UBCR significantly improved the C-statistic, with a significant net reclassification index and integrated discrimination improvement (0.738 vs. 0.684; P=0.0244). RTD, as assessed by a high UBCR, was associated with the severity and clinical outcomes of HFpEF and CKD, indicating that it could be a feasible marker for HF progression.