Renal Death Research Articles

MO198: Outcomes with Finerenone in Patients with Stage 4 Chronic Kidney Disease and Type 2 Diabetes: A Fidelity Subgroup Analysis

Abstract BACKGROUND AND AIMS Patients with stage 4 chronic kidney disease (CKD) and type 2 diabetes (T2D) have a high residual risk of cardiovascular (CV) and kidney disease progression, and effective treatment options to reduce the risk are limited. The non-steroidal selective mineralocorticoid receptor antagonist finerenone has previously demonstrated significant cardiorenal benefits versus placebo in patients with stage 1–4 CKD [1–3]. This FIDELITY subgroup analysis investigated the effects of finerenone in patients with stage 4 CKD [estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2) versus those with stage 1–3 CKD (eGFR ≥ 30 mL/min/1.73 m2). METHOD FIDELIO-DKD and FIGARO-DKD were phase III trials of patients with CKD and T2D randomised 1:1 to finerenone or placebo. FIDELITY was an individual patient-level prespecified pooled efficacy and safety analysis of these studies. Efficacy outcomes included change in urine albumin-to-creatinine ratio (UACR) between baseline and month 4, change in eGFR over time, a kidney composite outcome (kidney failure, a sustained ≥57% decrease in eGFR from baseline over ≥ 4 weeks or renal death) and a CV composite outcome [CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure (HHF)], as well as the individual components of these composite outcomes. RESULTS Of 13 023 patients included in the analysis, 890 patients (6.8%) had stage 4 CKD; key baseline characteristics are listed in Table 1. In patients with stage 4 CKD, finerenone reduced UACR by 31% vs placebo between baseline and month 4 [ratio of least-squares (LS) mean change 0.69; 95% confidence interval (CI) 0.63–0.77), an effect maintained for the duration of the study. Total eGFR slope (LS mean change in eGFR from randomisation to end of treatment) in patients with stage 4 CKD was –0.7 mL/min/1.73 m2/year with finerenone versus –1.6 mL/min/1.73 m2/year with placebo; the chronic eGFR slope (LS mean change in eGFR from month 4 to end of treatment) was –1.8 mL/min/1.73 m2/year with finerenone vs –3.2 mL/min/1.73 m2/year with placebo. The hazard ratio (HR) for risk of the kidney composite in stage 4 CKD was 1.01 (95% CI 0.75–1.37; Figure 1) for finerenone versus placebo. Reduction in risk of sustained ≥ 57% decrease in eGFR with finerenone (stage 4 CKD: HR 0.69, 95% CI 0.43–1.11) was similar between CKD subgroups (pinteraction = 0.71). Reduction in risk of the composite CV outcome (stage 4 CKD: HR 0.78, 95% CI 0.57–1.07) and HHF (stage 4 CKD: HR 0.99, 95% CI 0.62–1.58) was also consistent between CKD subgroups (pinteraction = 0.67 and 0.31, respectively). Overall, incidences of adverse events were balanced between treatment arms in patients with stage 4 CKD and stage 1–3 CKD. The incidence of hyperkalaemia leading to permanent discontinuation was low in patients with stage 4 CKD (3.2% versus 2.2% for finerenone versus placebo). CONCLUSION The cardiorenal benefits and safety profile of finerenone in FIDELITY were also observed in the subgroup of patients with stage 4 CKD.

MO240: The Evolution and Epidemiology of Membranous Nephropathy at a Single Centre Over Two Decades

Abstract BACKGROUND AND AIMS Membranous nephropathy (MN) commonly presents with nephrotic syndrome and carries significant risk of progression to end-stage kidney disease (ESKD) (33% without treatment, 10%–20% with). Patients may spontaneously remit (up to 40%), but are also at risk of relapse. A total of 80% of cases are primary (kidney-specific) and the majority of these are associated with antibodies to the M-type phospholipase A2 receptor (anti-PLA2R) or thrombospondin type 1 domain containing 7A antibodies (THS7DA). Treatment ranges from supportive care with renin–angiotensin system (RAS) blockade through to immunosuppression. Here we assessed the epidemiology of MN over 20 years at our centre (Salford Royal Hospital, UK) with particular reference to treatment administered and key clinical outcomes. METHOD A total of 238 patients with kidney biopsy-proven MN were identified from the local database between January 2000 and December 2020. Twenty-one were excluded (see Fig. 1) resulting in a total of 217 patients in whom demographic data, co-morbidities, remission and relapse rates, baseline laboratory values, treatment given, and outcomes were collected. Analyses compared effects of (i) immunosuppressed versus non-immunosuppressed, (ii) effect of modified Ponticelli versus other forms of immunosuppression and (iii) rates of remission. Univariate and multivariate cox regression determined factors that were associated with increased risk of renal replacement therapy (RRT) or death. RESULTS A total of 63.6% of the cohort were male, 88% Caucasian, 10.1% diabetic, 50.2% hypertensive and 15.2% had coexisting cardiovascular disease (Table 1). A total of 82.0% had primary MN. Median baseline eGFR was 72.7 mL/min/1.73 m2 and median baseline uPCR was 664 g/mol. A total of 157 patients (72.4%) went into remission (either spontaneous—75 (47.8%) or with treatment—85 (52.2%)), and of these 41.4% subsequently relapsed. A total of 89.4% received RAS blockade and 48.8% received immunosuppression. The median follow-up period was 56 months; 9.7% progressed to ESKD and 32.3% died. Patients who received immunosuppression had significantly more proteinuria than those who did not (765 g/mol versus 514 g/mol, P ≤ 0.001), were more likely to relapse (53.7% versus 28.0%, p ≤0.001) and were more likely to require RRT (15.1% versus 4.9%, P = .028). Those who received modified Ponticelli were less likely to relapse than those who received other forms of immunosuppression (34% versus 46%, P = .019), less likely to require RRT (3% versus 22%, P = .018) and less likely to die (11% versus 38%). Multivariate cox regression showed that pre-existing cardiovascular disease was a risk factor for death (HR 2.47, P < .001) and higher baseline eGFR and use of RAS blockade was associated with reduced risk of death (HR 0.98, P < .001 and HR 0.34, P = .012, respectively). CONCLUSION Despite advances in knowledge of underlying pathogenesis and increased treatment options, MN continues to pose a significant risk of progression to ESKD and death. This real-world study suggests that immunosuppression with modified Ponticelli is associated with lower rates of progressive CKD compared with MMF and calcineurin-inhibitor based therapy. Whilst many patients respond to treatment and can achieve remission, a significant proportion of these subsequently relapse. Identifying these patients early with judicial use of appropriate immunosuppression is key.

MO249: Characteristics of Glomerulonephritis (GN) with Dominant C1Q Precipitation Compared to Corresponding GN without C1Q Staining on Immunofluorescent Examination

Abstract BACKGROUND AND AIMS Although C1q nephropathy (C1QN) was introduced three decades ago, the clinical significance and renal outcomes of C1QN remain unclear. Furthermore, it is uncertain whether the diagnosis of C1QN could be a new pathologic entity with clinical meanings. This study aimed to compare the clinical characteristics of the GN reclassified into C1QN based on the criteria described by Jennette and Falk (Pediatr Nephrol 2010: 25: 1385–1396) and corresponding GN not included in C1QN. METHOD We enrolled 21 212 patients with native kidney biopsy between 1979 and 2018 from 18 hospitals throughout Korea, retrospectively. We primarily adopted the findings and diagnosis by the pathologist in each hospital and then reclassified into C1q nephropathy (C1QN) on the basis of the criteria as follows: (i) presence of ≥ 2 + C1q in the mesangium on immunofluorescence (IF), (ii) corresponding mesangial or para-mesangial electron dense deposits on electron microscopy (EM), and (iii) lack of clinical and pathological evidence of systemic lupus erythematosus. Among 21212 patients, 77 patients were selected as C1QN with the criteria; however, six patients were excluded because of presence of primary diseases, such as renal amyloidosis, Henoch-Schölein Nephritis and systemic vasculitis, and myeloma cast nephropathy. The data of final outcomes, incidences of end-stage renal disease (ESRD) and death, were gathered from each hospital’s data registry, from the ESRD registry of the Korean Society of Nephrology, and from the Statistics of Korea, and were merged based on the identifier of Koreans. The follow-up duration for ESRD was 69.1 ± 67.8 months and, for mortality, 77.9 ± 65.5 months. RESULTS There were pathologic findings of 71 patients reclassified into C1QN including 41 (57.7%) males. Mean age of patients were 42.9 ± 18.9 years. There were 9 (12.7%) patients with DM and 39 (54.9%) hypertensive patients. The levels of creatinine, eGFR, and UPCR were 1.24 ± 0.92 mg/dL, 84 ± 43 mL/min/1.73 m2 and 2.58 ± 2.80 g/g creatinine, respectively. There were 22 (31.0%) patients with eGFR < 60 mL/min/1.73 m2 and 22 (31.0%) patients with UPCR ≥ 3.5 g/g creatinine. There were various pathologic diagnoses classified into C1QN, such as, original C1QN (21), IgA nephropathy (IGAN) (21), membranous nephropathies (MN) (11), focal segmental glomerulosclerosis (7), mesangial glomerulopathy (6), diabetic nephropathy (3), minimal change lesion (1), and acute tubulointerstitial nephritis (1). We compared the characteristics among the pathologic finding classified into C1QN, the pathologic finding without C1q stain, and the pathologic finding with non-dominant C1q stain which did not fulfill the criteria of C1QN. The identified GNs, which included enough number of patients to compare, were FSGS, IGAN and MN. Some differences of clinico-pathologic findings and incidence of ESRD were not evident after re-analysis with groups matched age and gender with 1:3 manner between the GN re-categorized into C1QN and the corresponding GN without C1q staining. The only difference was lesser amount of proteinuria in MN patients re-classified into C1QN compared with MN patients without C1q staining. Immunoglobulins showed higher intensity in IF staining of C1QN compared with non-C1QN of the corresponding GN. Intensity of C3 was also higher in IGAN and MN re-categorized into C1QN compared with the corresponding IGAN and MN not included in C1QN, respectively. CONCLUSION Reclassification into C1QN with the pre-defined criteria did not indicate a different clinico-pathologic identity based on comparison with the original diagnosis of GN. Activation of C1q, presumed activation of classical complement pathway in kidney tissues, in so-called C1QN could not be classified into new disease entity. Further studies on this topic are needed.

MO505: Prevalence of Lupus Nephritis Among Patients With Systemic Lupus Erythematosus In Germany

Abstract BACKGROUND AND AIMS Lupus nephritis (LN) is the most common severe manifestation of systemic lupus erythematosus (SLE) and can lead to end-stage renal disease and death. However, there are limited data to contextualize the burden of LN in Germany, with no published studies using national claims data. This cross-sectional study aimed to estimate the annual prevalence of SLE and LN from 2011–17 using claims data from the Betriebskrankenkassen (BKK) German Sickness Fund Database. METHOD For each study year (2011–17), three patient populations were identified using International Classification of Diseases, Tenth Revision, German Modification (ICD-10-GM) codes: (1) Patients with SLE (≥1 SLE inpatient claim or ≥1 outpatient claim with a confirmatory claim in a separate quarter within ± 3 years); (2) Patients with LN, sensitive definition (based on the presence of SLE [as above] with ≥ 1 nephritis claim within ± 1 year from the initial SLE claim) and (3) Patients with LN, specific definition (based on the presence of SLE [as above] with ≥ 2 nephritis claims in separate quarters within ± 1 year from the initial SLE claim). For each year, the annual prevalence of SLE and LN/100 000 was estimated by dividing the number of patients identified in each population by the number of individuals insured in the database in that year. The proportion of SLE patients with LN was also estimated. To estimate the total number of patients with SLE and LN in Germany by age and sex standardization, the German statutory health insurance (SHI) system (covering 87% of the German population) was used to extrapolate from the prevalence calculated in the BKK database. RESULTS Approximately 5 million patients were insured in the BKK database between 2011–17; the ratio of insured males to females was ∼1:1 throughout the study period. The annual prevalence of SLE and LN/100 000 increased from 2011 (SLE, 37.68; LN sensitive, 12.79; LN specific, 9.99) to 2017 (SLE, 54.74; LN sensitive, 19.06; LN specific, 15.16) (Fig. 1). In 2017, the ratio of males to females/100 000 patients was ∼1:5.5 for the SLE cohort, 1:4.5 for the LN-sensitive cohort and 1:4.4 for the LN-specific cohort. The proportion of SLE patients with LN remained consistent across the study period, ranging from 26.51% (specific definition) and 33.96% (sensitive definition) in 2011 to 27.69% and 34.82%, respectively, in 2017. When extrapolating the prevalence estimates to the wider German SHI system, the estimated number of SLE patients was >41 000 in 2017, with the total LN patient population ranging from 11 515 (specific definition) to 14 483 (sensitive definition) (Fig. 2). CONCLUSION The prevalence of LN increased between 2011 and 2017 among patients insured in the BKK database and is estimated to impact >11 000 patients in the wider German SHI system. Limitations include an absence of renal biopsy information and the inability to distinguish patients with active nephritis from those with historical or inactive LN based on clinical parameters. Nonetheless, these data highlight the prevalence of LN among patients with SLE and the need for effective screening and disease management to improve patient outcomes. Further work to understand the treatment and economic burden of LN among patients with SLE in Germany is ongoing.

MO485: Chronic Kidney Disease in Patients With Lung Transplant

Abstract BACKGROUND AND AIMS The incidence of chronic kidney disease (CKD) in patients with lung transplantation (LTx) has increased over the last decades. Progression factors recognized in the development of CKD are: older age and comorbidity of recipients, immunosuppressive (IS) toxicity and longer survival. There is a lack of specific information about other risk factors or specific preventive management of CKD. METHOD Retrospective, single-centre study including all patients with LTx on Nephrology outpatient clinic among 2007 and 2020. Demographic, comorbidity and intercurrent events, renal function impairment, proteinuria and IS treatment were analyzed. We defined composite renal event (MARE) as renal replacement therapy (RRT), death or doubling serum creatinine. RESULTS A total of 69 LTx receptors (79.4% double LTx) were followed in a dedicated outpatient nephrology clinic. A total of 52.2% male, mean age at LTx 48.3 years (SD 16.6). Etiology of lung disease: cystic fibrosis (30.4%), obstructive lung disease or emphysema (33.3%) and interstitial disease (30.4%). After LTx, as complications, infection was the most frequent event (89.7%) and 49.3% presented neoplasic illness. The mean time from LTx until first nephrologist evaluation was 6.6 years (2 months–19.9 years) and main comorbidities were: hypertension (81.2%), diabetes mellitus (52.2%), dyslipidemia (50.7%), 60.3% former smokers and 26.1% had suffer from a previous CV event. After 1 year of LTx, mean eGFR decreased to 49.8 mL/min, which means that only in the first year after LTx there is a loss of ∼50% of mean kidney function. Factor associated with impaired kidney function at the first year after LTxw was cystic fibrosis (higher percentage in the rapid progression group). At first evaluation by Nephrology, the mean eGFR was 30.9 mL/min (SD 15.3), with a CKD distribution: 39.4% CKD 3; 45.5% CKD 4 and 12.1% CKD 5 (<15). Clinical study and biopsy define CKD etiologies: CNI toxicity (68.1%) thrombotic microangiopathy (11.6%), tubular (10.1%), vascular (7.3%) and glomerulopathies (2.9%). A total of 88.4% patients reached MARE at the end of the study. A total of 24 patients required RRT (mean time since LTx 9.2 years) and thereafter, 10 received a kidney transplantation (KTx). In Dyalisis group, a higher mortality was observed versus no dialysis group (24 versus 2.2%), a higher percentage of vascular origin disease with a further deterioration of eGFR at the time of referral to Nephrology. At the end of follow-up, 15 patients died (14 were in RRT), 5 continued on HD and 5 with a functional KTx, and 44 patients were still without RRT. CONCLUSION

Tanshinone IIA down-regulates -transforming growth factor beta 1 to relieve renal tubular epithelial cell inflammation and pyroptosis caused by high glucose

ABSTRACT Diabetic nephropathy (DN) is a microvascular disease caused by diabetes. Tanshinone IIA has been indicated to ameliorate streptozotocin-induced DN. This study explores the effect of tanshinone IIA on high glucose-induced renal tubular epithelial cell pyroptosis and inflammation. High glucose-stimulated HK-2 cells were used as the in-vitro model of DN and were treated with tanshinone IIA at concentrations of 1, 5, 10 μM for 24 h with the same doses of tolbutamide as the control. After tanshinone IIA treatment, HK-2 cells were transfected with pcDNA-transforming growth factor beta 1 (TGFB1) or sh-TGFB1 for 48 h. RT-qPCR was used to detect the mRNA levels of TNF-α, IL-6, IL-1β, and IL-18. Cell apoptosis and pyroptosis were detected by flow cytometry and cell immunofluorescence. Bioinformatics screening predicted that tanshinone IIA might be an effective component of Salvia miltiorrhiza Bunge (Labiatae) for the treatment of DN. Tanshinone IIA exerted a protective effect in the in-vitro model of DN by suppressing inflammation and pyroptosis via the TGFB1-dependent pathway. Tanshinone IIA inhibited high glucose-induced renal tubular epithelial cell inflammation and cell death through pyroptosis by regulating TGFB1, indicating the therapeutic potential of tanshinone IIA for DN treatment.

Glutathione peroxidase 4 prevents 12/15 LOX induced renal oxidative cell death and improves renal post Ischemic recovery in Male Spontaneous Hypertensive Rats (SHR)

Acute kidney injury (AKI) due to ischemia‐reperfusion (IR) is a serious and frequent complication in hospital setting with high mortality rates. The mechanisms mediating renal IR injury leading to increased risk of later developing cardiovascular and renal diseases in either sex remain poorly understood. Glutathione peroxidase 4 (GPx4) is a negative regulator of 12/15 lipoxygenase (12/15 LOX) and any alteration in 12/15 LOX and GPx4 activity has been reported to contribute to the progression of kidney diseases. The goal of the current study was to test the hypothesis that an imbalance of 12/15 LOX/GPx4 activity in males leads to impaired recovery following IR compared to females. 13‐week‐old male and female SHR were subjected to sham or 30‐minute warm bilateral IR (n=6/group). Additional male SHR were randomized to receive vehicle or the GPx4 activity mimic ebselen (10 mg/kg i.p.; n=5/group) 1 hr prior to sham/IR, 1 day and 3‐day post IR. Blood and urine were collected from all rats 1 and 7 days after IR; kidneys were harvested 7 days post‐IR for biochemical, histological, and Western blot analysis. IR increased plasma creatinine (Pcr) and blood urea nitrogen (BUN) in both male and female SHR compared to respective sham controls at 24 hrs (PIR =0.0001; Psex*IR=0.2). At 7 days post‐IR, Pcr and BUN remained elevated in male SHR but returned to baseline levels in females (Pcr: PIR =0.03; Psex*IR=0.04; BUN: PIR <0.05; Psex*IR=0.05). Histological examination of kidneys 7 days post‐IR showed greater tubular damage (PIR=0.0003, Psex*IR=0.0019) and renal cell death (PIR=0.001; Psex*IR=0.001) in male vs. female SHR. Delayed recovery of renal function in male SHR was associated with activation of renal 12/15 LOX (PIR<0.05; Psex*IR=0.008), reduced renal GPx4 protein expression (PIR=0.05; Psex*IR<0.001), activity (PIR=0.01; Psex*IR=0.0016), and intracellular glutathione (GSH; PIR=0.01; Psex*IR=0.003), and increased lipid peroxidation (PIR=0.008; Psex*IR=0.018) compared to females. Pre‐treatment of male SHR with ebselen significantly reduced 12/15 LOX induced lipid peroxidation (PIR*TxT =0.02), prevented IR‐induced renal cell death (PIR*TxT=0.04) and tubular damage (PIR*TxT=0.02) and improved renal function (Pcr: PIR*TxT =0.027; BUN: PIR*TxT =0.022) compared to vehicle‐treated IR males 7 days post‐IR. In conclusion, our data demonstrate that increased GPx4 activity enhanced renal recovery post‐IR via inhibiting 12/15 LOX induced oxidative renal cell death in male SHR.

No additional benefit of prescribing a very low-protein diet in patients with advanced chronic kidney disease under regular nephrology care: a pragmatic, randomized, controlled trial

Whether a very low-protein diet supplemented with ketoanalogues (sVLPD), compared with a standard low-protein diet (LPD), improves outcomes in patients with chronic kidney disease (CKD) under stable nephrology care is undefined. To compare the effectiveness of sVLPD compared with LPD in patients regularly seen in tertiary nephrology care. Participants were patients with CKD stages 4-5, followed for at least 6 mo, randomly allocated to receive sVLPD or LPD [0.35 or 0.60g/kg ideal body weight (IBW)/d, respectively], stratified by center and CKD stage. The primary outcome was time to renal death, defined as the first event between end-stage renal disease (ESRD) and all-cause mortality; secondary outcomes were the single components of the primary outcome, cardiovascular outcome, and nutritional status. We analyzed 223 patients (sVLPD, n=107; LPD, n=116). Mean age was 64 y, 61% were male, and 35% had diabetes. Median protein intake (PI), which was 0.8g/kg IBW/d at baseline in both groups, was 0.83 and 0.60g/kg IBW/d in LPD and sVLPD, respectively, during the trial with a large decrease only in sVLPD (P = 0.011). During a median of 74.2 mo, we recorded 180 renal deaths (141 dialysis and 39 deaths before dialysis). Risk of renal death did not differ in sVLPD compared with LPD (HR: 1.17; 95% CI: 0.88, 1.57; P = 0.28). No difference was observed for ESRD (HR: 1.12; 95% CI: 0.81, 1.56; P = 0.51), mortality (HR: 0.95; 95% CI: 0.62, 1.45; P = 0.82), or time to fatal/nonfatal cardiovascular events (P=0.2, log-rank test). After 36 mo, still active patients were 45 in sVLPD and 56 in LPD. No change of nutritional status emerged during the study in any arm. This long-term pragmatic trial found that in patients with CKD under stable nephrology care, adherence to protein restriction is low. Prescribing sVLPD compared with standard LPD is safe but does not provide additional advantage to the kidney or patient survival.

Lupus Nephritis: Improving Treatment Options.

Despite improvements in patient and renal death rates following the introduction of potent immunosuppressive drugs in earlier decades, a sizeable fraction of patients with lupus nephritis is burdened with suboptimal or delayed responses, relapses, chronic use of glucocorticoids and accrual of renal (chronic renal insufficiency) and extra-renal organ damage. The recently approved combinatory treatments comprising belimumab or voclosporin added to conventional agents, especially mycophenolate, hold promise for further improving disease outcomes and enabling a faster steroid tapering, thus being relevant to the treat-to-target context. However, it remains uncertain whether these dual regimens should become the first-line choice for all patients or instead be prioritized to certain subgroups. In the present article, we summarize the existing lupus nephritis management recommendations, followed by a critical appraisal of the randomized trials of belimumab and voclosporin, as well as the available data on obinutuzumab and other novel compounds under development. We conclude that pending the identification of accurate clinical, histological, or translational predictors for guiding personalized decisions, it is of utmost importance that lupus nephritis patients are monitored closely with appropriate treatment adjustments aiming at a prompt, deep response to ensure long-term preservation of kidney function.

Surgery in platinum-resistant recurrent epithelial ovarian carcinoma.

BACKGROUNDOvarian cancer is one of the three most common malignant tumors of the female reproductive tract and ranks first in terms of mortality among gynecological tumors. Epithelial ovarian carcinoma (EOC) is the most common ovarian malignancy, accounting for 90% of all primary ovarian tumors. The clinical value of cytoreductive surgery in patients with platinum-resistant recurrent EOC remains largely unclear.AIMTo evaluate the feasibility of secondary cytoreductive surgery for treating platinum-resistant recurrent EOC.METHODSThis was a retrospective study of the clinical data of patients with platinum-resistant EOC admitted to the Cancer Hospital of the University of Chinese Academy of Sciences between September 2012 and June 2018. Patient baseline data were obtained from clinical records. Routine follow-up of disease progression was performed as follows. CA125 assessment and physical examination were performed every 3 wk during treatment, including gynecological examination. Imaging assessment was carried out every 12 wk by B-mode ultrasound, computed tomography, or magnetic resonance imaging. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), chemotherapy-free interval (CFI), and complications. Follow-up ended on April 15, 2019.RESULTSA total of 38 patients were included. R0 resection was achieved in 25 (65.8%) patients and R1/2 in 13 (34.2%). Twenty-five (65.8%) patients required organ resection. Nine (23.7%) patients had operative complications, 36 (94.7%) received chemotherapy, and five (13.2%) had targeted therapy. Median PFS and OS were 10 (95%CI: 8.27-11.73) months and 28 (95%CI: 12.75-43.25) months, respectively; median CFI was 9 (95%CI: 8.06-9.94) months. R0 resection and postoperative chemotherapy significantly prolonged PFS and OS (all P < 0.05), and R0 resection also significantly prolonged CFI (P < 0.05). Grade ≥ 3 complications were observed, including rectovaginal fistula (n = 1), intestinal and urinary fistulas (n = 1), and renal failure-associated death (n = 1). Except for the patient who died after surgery, all other patients with complications were successfully managed. Two patients developed intestinal obstruction and showed improvement after conservative treatment.CONCLUSIONSecondary cytoreductive surgery is feasible for treating platinum-resistant recurrent EOC. These findings provide important references for the selection of clinical therapeutic regimens.

Kidney outcomes with finerenone: an analysis from the FIGARO-DKD study.

In FIGARO-DKD, finerenone reduced the risk of cardiovascular events in patients with type 2 diabetes (T2D) and stage 1-4 chronic kidney disease (CKD). In FIDELIO-DKD, finerenone improved kidney and cardiovascular outcomes in patients with advanced CKD. This analysis further explores kidney outcomes in FIGARO-DKD. FIGARO-DKD (NCT02545049) included patients with urine albumin-to-creatinine ratio (UACR) 30-<300mg/g and estimated glomerular filtration rate (eGFR) 25-90mL/min/1.73 m2 or UACR 300-5000mg/g and eGFR≥60mL/min/1.73 m2. Outcomes included two composite kidney endpoints, a composite of ≥40% decrease in eGFR from baseline sustained over ≥4 weeks, kidney failure or renal death, and a composite of ≥57% decrease in eGFR from baseline sustained over ≥4 weeks, kidney failure or renal death. Changes in albuminuria and eGFR slope were also analyzed. Kidney and CV outcomes were evaluated by baseline UACR. A lower incidence rate for the eGFR≥40% kidney composite endpoint was observed with finerenone compared with placebo, but the between-group difference was not significant [hazard ratio (HR)=0.87; 95% confidence interval (CI): 0.76-1.01; P=.069]. A greater treatment effect was observed on the eGFR≥57% kidney composite endpoint (HR=0.77; 95% CI: 0.60-0.99; P=0.041) with a 36% relative risk reduction for end-stage kidney disease. A larger magnitude of effect on kidney outcomes was observed with finerenone versus placebo for patients with severely increased albuminuria than with moderately increased albuminuria. Improvements in UACR, eGFR slope and cardiovascular risk were evident in both subgroups with finerenone. The present analyses suggest that finerenone protects against kidney disease progression and cardiovascular events in patients with T2D and early- or late-stage CKD.

FGF1ΔHBS delays the progression of diabetic nephropathy in late-stage type 2 diabetes mouse model by alleviating renal inflammation, fibrosis, and apoptosis

Elderly adults are at higher risk for developing diabetic complications including diabetic nephropathy (DN), contributing to excess morbidity and mortality in elderly individuals. A non-mitogenic variant of fibroblast growth factor 1 (FGF1ΔHBS) was demonstrated to prevent DN in an early-stage (2-month-old) type 2 diabetes (T2D) mouse model. The present study aimed to investigate the potential therapeutic effects of FGF1ΔHBS against the progression of renal dysfunction in a late-stage T2D mouse model with established DN. Nine-month-old db/db mice were administered FGF1ΔHBS every other day for 3 months. db/db mice at 12-month-old without FGF1ΔHBS treatment exhibited high blood glucose level and elevated urine albumin-to-creatinine ratio. FGF1ΔHBS treatment effectively reversed hyperglycemia, delayed the development of renal dysfunction, and reduced kidney size and weight. Furthermore, FGF1ΔHBS treatment significantly prevented the progression of renal morphologic impairment. FGF1ΔHBS treatment demonstrated anti-inflammatory and anti-fibrotic effects, with significantly decreased protein levels of key pro-inflammatory cytokines and pro-fibrotic factors in kidney. Moreover, FGF1ΔHBS treatment greatly decreased apoptosis of renal tubular cells, accompanied by significant downregulation of the proapoptotic protein and upregulation of the antiapoptotic protein and peroxisome proliferator-activated receptor α (PPARα) expression in kidney. Mechanistically, FGF1ΔHBS treatment directly protected mouse proximal tubule cells against palmitate-induced apoptosis, which was abolished by PPARα inhibition. In conclusion, this study demonstrated that FGF1ΔHBS delays the progression of renal dysfunction likely through activating PPARα to prevent renal tubule cell death in late-stage T2D, exhibiting a promising translational potential in treating DN in elderly T2D individuals by ameliorating renal inflammation, fibrosis and apoptosis.

Association of Bowman's capsule rupture with prognosis in patients with lupus nephritis.

Lupus nephritis is one of the most severe manifestations of systemic lupus erythematosus. The clinical and prognostic significance of Bowman's capsule rupture in patients with lupus nephritis is unknown. One hundred eighty patients with lupus nephritis were enrolled in the study and the integrity of Bowman's capsule was assessed. Both inflammatory and proliferative cells were detected by immunochemistry staining. The primary events of interest were end-stage renal disease and death. After retrospective analysis of the data, 52 (28.9%) patients were found to have Bowman's capsule rupture, which was accompanied by high levels of serum creatinine, 24h urine protein, and Activity/Chronicity Index. Bowman's capsule rupture was correlated with the level of crescents, tubular atrophy, and interstitial fibrosis. The number of CD20+ cells was higher in the Bowman's capsule rupture ( +) group compared with the Bowman's capsule rupture (-) group, while no differences in other inflammatory cells were observed. In addition, the end stage renal disease-free survival in the Bowman's capsule rupture ( +) group was lower than in the Bowman's capsule rupture (-) group. Moreover, serum creatinine (HR 39.56, P < 0.001), Activity Index (HR 1.50, P < 0.05) as well as Bowman's capsule rupture (HR 1.09, P < 0.05) predicted end-stage renal disease progression. Notably, for patients with existing crescents, Bowman's capsule rupture increased the cumulative risk of end-stage renal disease. Bowman's capsule rupture is an important renal pathological lesion, which correlates with severe clinical manifestations, pathological changes, and poor prognosisinpatients with lupus nephritis.

Evaluation of a newly proposed renal risk score for Japanese patients with ANCA-associated glomerulonephritis

We determined the usefulness and prognostic ability of the renal risk score (RRS), proposed in Europe, for Japanese patients with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) and high myeloperoxidase (MPO)-ANCA positivity; these aspects remain to be verified. This retrospective study was conducted on 86 Japanese patients with new, biopsy-confirmed AAGN. We calculated the RRS and analyzed the relationship between this classification, and clinicopathological features and prognosis. We also compared the predictive values between RRS for endpoints including renal death and conventional prognostic tools for patients with AAGN. There were 33, 37, and 16 patients in the low-, medium-, and high-risk groups, respectively. All patients were MPO-ANCA positive. The median follow-up period was 33months; 16 (18.6%) patients progressed to end-stage renal disease (ESRD). In the high-risk group, 9/16 (56.3%) patients progressed to ESRD, and renal prognosis was significantly poorer than that in other groups (low-risk group, P < 0.001; medium-risk group, P = 0.004). In Cox multivariate regression analysis, RRS was an independent, poor renal prognostic factor (hazard ratio 5.22; 95% confidence interval 2.20-12.40; P < 0.001). The receiver-operating characteristic curves of the RRS for each endpoint were comparable with those of the 2010 histological classification and those of the severity classification of Japanese rapidly progressive glomerulonephritis. This is the first study to report the usefulness of the RRS for predicting renal outcomes among Japanese patients with AAGN. Our predictive value of the RRS was comparable with that of conventional prognostic tools.

Effect of Hemoglobin A1c Trajectories on Future Outcomes in a 10-Year Cohort With Type 2 Diabetes Mellitus.

BackgroundHemoglobin A1c (HbA1c) variability may be a predictor of diabetic complications, but the predictive values of HbA1c trajectories remain unclear. We aimed to classify long-term HbA1c trajectories and to explore their effects on future clinical outcomes in a 10-year cohort with type 2 diabetes mellitus (T2DM).MethodsA total of 2,161 participants with T2DM from the Beijing Community Diabetes Study were included. The 10-year follow-up was divided into two stages for the present data analysis. Stage I (from 2008 to 2014) was used to identify the HbA1c trajectories and to calculate the adjusted SD of HbA1c (HbA1c-adjSD), or the coefficient of variation of HbA1c (HbA1c-CV). Stage II (from 2014 to 2018) was used to collect the records of the new occurrence of diabetes-related clinical outcomes. Latent growth mixture models were used to identify HbA1c trajectories. Cox proportional hazards models were used to explore the relationship between HbA1c trajectories, HbA1c-adjSD, or HbA1c-CV and the future outcomes.ResultsThree HbA1c trajectories were identified, including low stable (88.34%), gradual decreasing (5.83%), and pre-stable and post-increase (5.83%). Either the risk of death or the chronic complications were significantly higher in the latter two groups compared to the low stable group after adjustment for average HbA1c and other traditional risk factors, the adjusted hazard ratios (HRs) for renal events, composite endpoint, and all-cause death for the pre-stable and post-increase group were 2.83 [95%CI: 1.25–6.41, p = 0.013], 1.85 (95%CI: 1.10–3.10, p = 0.020), and 3.01 (95%CI: 1.13–8.07, p = 0.028), respectively, and the adjusted HR for renal events for the gradual decreasing group was 2.37 (95%CI: 1.08–5.21, p = 0.032). In addition, both univariate and multivariate Cox HR models indicated that participants in the fourth and third quartiles of HbA1c-CV or HbA1c-adjSD were at higher risk of renal events compared to participants in the first quartile.ConclusionsHbA1c trajectories, HbA1c-CV, and HbA1c-adjSD could all predict diabetes-related clinical outcomes. HbA1c trajectories could reflect long-term blood glucose fluctuation more intuitively, and non-stable HbA1c trajectories may predict increased risk of renal events, all-cause death, and composite endpoint events, independent of average HbA1c.

Glomerular filtration rate as a kidney outcome of diabetic kidney disease: a focus on new antidiabetic drugs

Diabetes has reached epidemic proportions, both in Korea and worldwide and is associated with an increased risk of chronic kidney disease and kidney failure (KF). The natural course of kidney function among people with diabetes (especially type 2 diabetes) may be complex in real-world situations. Strong evidence from observational data and clinical trials has demonstrated a consistent association between decreased estimated glomerular filtration rate (eGFR) and subsequent development of hard renal endpoints (such as KF or renal death). The disadvantage of hard renal endpoints is that they require a long follow-up duration. In addition, there are many patients with diabetes whose renal function declines without the appearance of albuminuria, measurement of the eGFR is emphasized. Many studies have used GFR-related parameters, such as its change, decline, or slope, as clinical endpoints for kidney disease progression. In this respect, understanding the trends in GFR changes could be crucial for developing clinical management strategies for the prevention of diabetic complications. This review focuses on the clinical implication of the eGFR-related parameters that have been used so far in diabetic kidney disease. We also discuss the use of recently developed new antidiabetic drugs for kidney protection, with a focus on the GFR as clinical endpoints.

Association Of Kidney And Cardiovascular Outcomes: Insights From The Empagliflozin Cardiovascular Outcome Event Trial In Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) Trial

<h3>Introduction</h3> Cardiovascular and kidney disease are closely inter-related. In EMPA-REG OUTCOME, empagliflozin (10 or 25mg once daily) reduced the risk of hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes and established cardiovascular (CV) disease. <h3>Hypothesis</h3> We evaluated whether kidney events increase risk for subsequent HF or CV outcomes and vice versa. <h3>Methods</h3> Bi-directional associations of kidney events and subsequent CV events were explored using Cox regression with time-varying covariates. <h3>Results</h3> Of 2,061 placebo patients, 18.8% experienced a kidney event (progression to macroalbuminuria with urine albumin-creatinine ratio [UACR] >300mg/g, doubling of serum creatinine with estimated glomerular filtration rate [eGFR] ≤45 ml/min/1.73 m², initiation of renal-replacement therapy or renal death). Factors significantly associated with risk of experiencing a kidney event included: low baseline eGFR, albuminuria ≥30mg/g, high uric acid and LDL-C, prior HF but no coronary artery disease. In placebo patients, occurrence of a non-fatal kidney event increased subsequent HHF risk (hazard ratio [95% CI]) (2.40 [1.42,4.05]) but not 3P-MACE (1.30 [0.89,1.91]) (panel A). Vice versa, HHF (2.03 [1.22,3.39]) but not myocardial infarction (MI)/stroke (0.94 [0.56,1.56]) increased subsequent kidney event risk in the placebo arm (panel B). For 3-P MACE following kidney event, risk was significantly increased in the empagliflozin and overall groups although to a lesser extent and not significant from placebo (panel A). <h3>Conclusions</h3> These findings demonstrate strong bi-directional inter-relationship between HHF and kidney events. Strategies to optimize the use of therapies such as empagliflozin, reducing both kidney and HF outcomes, are warranted, as their benefits may be compounded.

Incidence and Outcomes of Postoperative Atrial Fibrillation after Coronary Artery Bypass Grafting of a Randomized Controlled Trial: A Blinded End-of-cycle Analysis.

The objective of this study is to analyse the incidence of postoperative atrial fibrillation (POAF), demography, post-operative outcomes including morbidity and mortality, length of Cardiac Intensive Care Unit (CICU) stay, High Dependency Unit (HDU) stay, and total hospital stay in patients undergoing coronary bypass grafting (CABG) at Institut Jantung Negana (IJN). We conducted a prospective, randomised, controlled trial. We supplied the treatment group with Tocovid capsules and the control group with placebo containing palm superolein. Since January 2019, we have recruited the target population of 250 patients. However, the result is still blinded as we are still analysing blood samples for tocotrienol levels. 89.2% of patients completed the study with a 3.6% mortality and a 7.6% attrition rate. 35.2% of the patients developed POAF, the mean time being 46.06 26.96 hours post-CABG. We did not observe any statistically significant difference when we compared left atrial size, New York Heart Association (NYHA) functional class, ejection fraction and premorbid history, besides EuroSCORE II (The European System for Cardiac Operative Risk Evaluation II) status except for older age group, right atrial size, and pleural effusion. There was also no difference in bypass time, cross clamp time or number of anastomoses. However, we noted a significant difference in death (p = 0.01) and renal failure requiring dialysis (p = 0.007) among patients with POAF; those patients also had a longer CICU stay (p = 0.005), HDU stay (p = 0.02), and total hospital stay (p = 0.001). POAF is associated with a higher incidence of renal failure and death while it increases CICU, HDU, and total hospital stay. It remains to be seen whether Tocovid reduces POAF and its associated sequelae. NCT03807037 (Registered on 16 January 2019).

New-Onset Diabetes in Patients Post-Heart Transplantation; the Role of Hypertension and Novel Diabetic Medications

<h3>Purpose</h3> New-onset post-transplantation diabetes mellitus (DM) is common among heart transplant (HT) recipients and has been shown to be associated with higher rates of renal dysfunction and death or re-transplantation. There are limited data to describe the use of novel anti-diabetic therapies in this population. We aimed to describe the prevalence of newly diagnosed DM and DM treatment patterns in HT patients at a single high-volume transplant center<b>.</b> <h3>Methods</h3> Patients undergoing HT between 1/2010-12/2017 were retrospectively reviewed. Patients undergoing repeat HT were excluded from the analysis. New-onset DM was defined by HbA1c >= 6.5% or initiation of anti-diabetic therapy. Data were collected from the electronic medical record. <h3>Results</h3> 280 transplant patients were identified with a median follow-up of 5.1 (IQR 2.6-8.1) years. 95 (33.9%) had pre-transplant DM. Of the 185 remaining patients, 45 (24.3%) developed post-HT DM with a median time to diagnosis of 109 (IQR 20-439) days. Median age of those with new-onset DM was 54 (IQR 47-61) years and 37.8% were female. Risk of PTDM was 18.2% at 1 year, 20.0% at 2 years, 23.8% at 5 years, and 33.1% at 10 years (<b>Fig 1a</b>). Hypertension was independently associated with post-HT DM (p = 0.014, <b>Fig 1b</b>). Among all patients with DM in the post-transplant period (N=140), 10 (7.1%) were started on a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and 17 (12.1%) were treated with a glucagon-like peptide-1 receptor agonist (GLP-1 RA). Adverse events with SGLT2i included polyuria in 2 patients, and adverse events with GLP-1 RA included gastrointestinal disturbance in 2 patients, palpitations in 1 patient, and discontinuation for unknown reasons in 1 patient. <h3>Conclusion</h3> DM is a common co-morbidity among HT recipients, with a high rate of pre-existing DM and post-HT DM. Utilization of the newest anti-diabetic agents with known cardiovascular benefits remains low in this cohort.

712 Association between administration of hydroxycobalamin and acute kidney injury in patients with burn injury

IntroductionHydroxycobalamin (HC) is administered to patients with suspected hydrogen cyanide poisoning. Some reports suggest that this practice may be associated with acute kidney injury (AKI). We aimed to evaluate the association between HC administration and AKI after burn injury.MethodsWe conducted a retrospective matched cohort study. All adults admitted to a regional ABA-verified burn center within 24 hours of injury between 2015-2019 with >10% total body surface area (TBSA) flame burn injury were reviewed. We excluded patients who were palliated within 48 hours of admission, and those with pre-existing renal disease. Patients who received HC, either pre-hospital, in the emergency department, or the burn center, were matched on age (+/-2 years) and %TBSA (+/-5%) to up to 5 patients who did not receive HC. Rates of AKI within 7 days of admission, as defined by KDIGO criteria, were then compared. Secondary outcomes included receipt of renal replacement therapy, death, ventilator days, and discharge disposition.ResultsWe identified 10 patients who received HC; these patients were matched to 42 patients who did not receive HC. The median age of the HC group was 57 (IQR 43-66), compared to 65 in the non-HC group (IQR 57-65) (p= 0.98). The median %TBSA burn and %TBSA full thickness burn in the HC group and control was 16.5 (14-19) vs 13.5 (11-18) respectively (p= 0.22) and 3.5 vs 3.5 (0-9.5) respectively (p= 0.93). The incidence of inhalation injury in the HC group (n=8, 80%) was significantly higher than in the non-HC group (n=7, 17%)(p< 0.001). All HC patients were intubated within 24 hours of admission vs. only 48% of controls (p=0.003). The HC group also had significantly higher median SOFA scores on admission (9.5 vs 4, p< 0.001) and had a significantly higher admission creatinine [1.08 (0.95-1.26) vs 0.86 (0.71-1.02) mg/dl), p= 0.02]. The median 24-hour crystalloid fluid administered was 5911 mL/kg/%TBSA in the HC group vs 2774 mL/kg/%TBSA burn in controls (p= 0.004). All patients in the HC group developed AKI (n=10, 100%), compared to 64% (n=27) of non-HC patients (p=0.03). There was no significant difference in rates of death (20% vs 10%, p=0.35), Renal Replacement Therapy (20% vs 7%, p=0.21), discharge disposition, or ventilator days between groups.ConclusionsWe identified a small number of patients who received HC over a 5-year period at our burn center. There was an association between HC administration and development of AKI, but there were no differences in mortality, RRT, or ventilator days. HC administration is rare, and our data suggest that the sickest burn injured patients receive it. Larger studies are required to determine if HC administration is associated with AKI, or whether the increased rate of AKI in our study reflects illness severity.