Renal Outcomes In Patients Research Articles

Association between the triglyceride glucose (TyG) index and the risk of acute kidney injury in critically ill patients with heart failure: analysis of the MIMIC-IV database

BackgroundInsulin resistance (IR) can be effectively assessed using the dependable surrogate biomarker triglyceride-glucose (TyG) index. In various critical care contexts, like contrast-induced acute kidney injury (AKI), an elevated TyG index has demonstrated a robust correlation with the incidence of AKI. Nonetheless, the potential of the TyG index to predict AKI in critically ill patients with heart failure (HF) remains uncertain.MethodsA cohort of participants was non-consecutively selected from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database and divided into quartiles based on their TyG index values. The incidence of AKI was the primary outcome. The secondary endpoint was in-hospital mortality within both the whole study population and the subset of AKI patients. The use of the renal replacement therapy (RRT) which represented the progression of AKI severity was also included as a secondary endpoint representing renal outcome. A restricted cubic splines model and Cox proportional hazards models were utilized to evaluate the association of TyG index with the risk of AKI in patients with HF in a critical condition. Kaplan-Meier survival analysis was employed to estimate primary and secondary endpoint disparities across groups differentiated by their TyG index.ResultsThis study included a total of 1,393 patients, with 59% being male. The incidence of AKI was 82.8%. Cox proportional hazards analyses revealed a significant association between TyG index and the incidence of AKI in critically ill patients with HF. The restricted cubic splines model illustrated the linear relationship between higher TyG index and increased risk of AKI in this specific patient population. Furthermore, the Kaplan-Meier survival analyses unveiled statistically significant differences in the use of RRT across the subset of AKI patients based on the quartiles of the TyG index.ConclusionsThe results highlight the TyG index as a robust and independent predictor of the incidence of AKI and poor renal outcome in patients with HF in a critical condition. However, further confirmation of causality necessitates larger prospective studies.

Urinary isomorphic red blood cells for the prediction of disease severity and renal outcomes in MPO-ANCA-associated vasculitis: a retrospective cohort study.

Hematuria is common in myeloperoxidaseanti-neutrophil cytoplasmic antibodyassociated vasculitis(ANCA-MPO). Previous studies have mainly focused on urinary dysmorphic red blood cells and few have reported the clinical significance of isomorphic urinaryred blood cells. Therefore, the main aim of this study was to assess the predictive yield of urinary isomorphic red blood cells for disease severity and renal outcomes in patients with ANCA-MPO associated vasculitis. A total of 191 patients with ANCA-MPOassociated vasculitiswith hematuria were retrospectively selectedand were divided into two groups (withisomorphic red blood cells versus dysmorphic red blood cells) according to the percentage of isomorphic red blood cells on urinary sediment analysis. Clinical, biological and pathological data at diagnosis were compared. Patients were followed up for a median of 25months and progression to end-stage kidneydisease and death were regarded as main outcome events. Additionally, univariate and multivariate Cox regression models were used to estimate the risk factors for end-stage kidneydisease. Out of 191 patients, 115 (60%) had ≥ 70% and 76 (40%) had < 30% urine isomorphic red blood cells. Compared with patients in the dysmorphic red blood cell group, patients in the isomorphic red blood cell group had a significantly lower estimated glomerular filtration rate(eGFR) [10.41mL/min (IQR 5.84-17.06) versus 12.53 (6.81-29.26); P = 0.026], higher Birmingham Vasculitis Activity Score [16 (IQR 12-18) versus 14 (10-18); P = 0.005] and more oftenreceived plasma exchange [40.0% versus 23.7% (P = 0.019)] at diagnosis. Kidney biopsies revealed a higher proportion of patients with glomerular basement membrane fracture in the isomorphic red blood cell group [46.3% versus 22.9% (P = 0.033)]. Furthermore, patients with predominant urinary isomorphic red blood cells were more likely to progress to end-stage kidney disease [63.5% versus 47.4% (P = 0.028)] and had a higher risk ofdeath [31.3% versus 19.7% (P = 0.077)]. The end-stage kidney disease-free survival was lower in patients in the isomorphic red blood cell group (P = 0.024). However, urine isomorphic red blood cells ≥ 70% could not predict the presence of end-stage kidney disease in multivariate Cox analysis. Myeloperoxidase-anti-neutrophil cytoplasmic antibodyassociated vasculitis patients with predominant urinary isomorphic red blood cells at diagnosis had more severe clinical manifestations and a higher risk of poor renal outcomes. In this respect, urinary isomorphic red blood cells could be viewed as a promising biomarker of ANCA_MPO vasculitisseverity and progression.

#3424 RENAL OUTCOMES IN THE ELDERLY WITH ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY-ASSOCIATED VASCULITIS: A NEW PREDICTION MODEL

Abstract Background and Aims Antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) is a type of necrotizing small vessel inflammatory disease, including alveolar hemorrhage and rapidly progressive glomerulonephritis. Elderly patients with antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) commonly experience renal impairment and poor prognosis. Based on the cohort of inpatients with AAV in Peking Union Medical College Hospital, this study aimed to analyze the clinical manifestations, diagnosis and treatment characteristics of elderly patients compared with non-elderly patients, and establish a risk scoring system for predicting composite renal outcomes in patients with AAV in elderly patients. Method This retrospective observational study included all AAV patients hospitalized in a single-center tertiary hospital in China between January 2013 and April 2022. Patients aged ≥ 65 years were defined as elderly and randomly divided into development and validation cohorts (2:1). Logistic regression analysis was performed in the development cohort to analyze risk factors. The scoring system was established accordingly and further validated in the validation cohort. Results A total of 1203 patients were enrolled in the study, among whom the elderly group accounted for 36% with a mean age of 71.4 ± 0.3 years. The elderly group had a worse prognosis, a higher mortality rate (8.9% vs. 3.5%, P &amp;lt; 0.001), a higher rate of end-stage renal disease (17.6% vs. 10.2%, P &amp;lt; 0.001), and worsening renal function (7.4% vs. 4.5%, P = 0.04). Logistic regression showed that age &amp;gt; 75 years, chronic heart disease, elevated serum creatine, and D-dimer values were risk factors for poor prognosis in patients with AAV. The development and validation cohorts in AAV patients produced area under the curve values of 0.823 (0.784–0.862) and 0.833 (0.777–0.888), respectively (Figure 1). When the risk score was ≥ 2 points, the risk of acquiring composite renal outcomes increased significantly with a sensitivity and specificity of 75.0% and 79.9%, respectively. Conclusion We established risk-scoring systems based on baseline clinical characteristics to predict composite renal outcomes in patients with AAV. Our results suggest that more attention should be paid to elderly patients who have severe renal impairment and active inflammation.

#6849 CLINICOPATHOLOGIC CHARACTERISTICS IN RENAL THROMBOTIC MICROANGIOPATHY

Abstract Background and Aims Thrombotic microangiopathy (TMA) is a life-threatening condition that can be caused on the background of various mechanisms, converging to a severe endotheliopathy that often affects the kidneys. Morphologic features of TMA on kidney biopsy have not been systematically studied. We studied the diagnostic and prognostic role of a kidney biopsy in patients with TMA, either linked to a coexisting condition (i.e., secondary TMA) or not (i.e., complement-mediated [C-]TMA). Method Patients with TMA on kidney biopsy and an enzymatic activity of ADAMTS13 &amp;gt;10% were recruited from the Limburg Renal Registry. C-TMA was defined as massive ex vivo C5b9 formation on the endothelium and/or rare variants in complement genes [1]; secondary TMA was defined as the presence of a coexisting condition and normal complement regulation. Kidney tissue sections were studied for activity and chronicity; also, C3d staining was performed. Results C-TMA and secondary TMA was diagnosed in 35 and 39 patients, respectively. The diagnosis TMA was based on a kidney biopsy in 52 (70%) out of 74 patients as systemic hemolysis, that is, microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, was lacking. Morphologic activity, such as, glomerular thrombosis and mesangiolysis, was not associated with MAHA (p = 0.116) and/or thrombocytopenia (p = 0.380). Morphologic activity, however, was associated with C-TMA, as was lower age and higher serum creatinine. C3d staining did not differentiate C-TMA from secondary TMA. A Mayo Clinic Chronicity Score (MCCS) of ≥4 was associated with an increased partial- (p = 0.023) and complete renal remission rate (p = 0.030), and decreased end-stage kidney disease (p = 0.050). Conclusions Only a small proportion of patients with TMA on kidney biopsy initially present with systemic hemolysis, suggesting an essential role of histologic examination to prevent underdiagnosing. Glomerular thrombosis and mesangiolysis were associated with C-TMA, however there is no role for staining of C3d in differentiating C-TMA from secondary TMA. An increased MCCS indicates worse renal outcome in patients with TMA.

#3701 MESANGIAL C3 DEPOSITION ASSOCIATES WITH CHRONIC LESIONS AND RENAL OUTCOME IN PATIENTS WITH IGA NEPHROPATHY

Abstract Background and Aims Mesangial C3 deposition is frequently observed in patients with IgA nephropathy (IgAN). We sought to investigate whether the extent of mesangial C3 deposition predicts long-term renal function. Method We conducted a retrospective, observational study that included all patients with biopsy-proven IgAN between 1999 and 2021 and a follow-up period of at least 12 months. All renal biopsy specimens were reviewed and scored according to the 2016 revised Oxford Classification by two independent pathologists. In addition, mesangial C3 deposits were assessed by immunofluorescence (IF) staining of C3 deposition and scored semi-quantitatively as: absent, mild (1+), moderate (2+) and intense (3+). The study composite endpoint was defined as doubling of serum creatinine or ESRD, whichever came first. Results 197 patients were followed for a median of 51.7 months (IQR:19.9-84.3 months). The mean eGFR and median 24-hour proteinuria were 54.4 ± 31.3 ml/min/1.73 m2 and 1.5 g/day (IQR: 0.8-3.35), respectively. 29.9% of the patients reached the composite endpoint. The percentage of patients with M1, E1, S1, T1 and T2 were 77.2%, 24.4%, 57%, 27.9% and 16.8%, respectively. 13.7% of patients showed crescents in less than 25% of glomeruli (C1), while 6.6% of them had over 25% of glomeruli involved (C2). In terms of mesangial C3 deposits, 7.7% had absent, 9.5% mild, 19.6% moderate and 63.1% intense IF staining. Compared to patients with mild-moderate or absent C3 staining on IF, those with intense C3 staining had more frequently M1 (83% vs. 73.5% vs. 38.5%, p = 0.04), S1 (64.2% vs. 49% vs. 30.8%, p = 0.03) and T1-2 (51.9% vs. 32.6% vs. 7.7%, p = 0.01). Similarly, the percentage of global glomerulosclerosis was significantly higher in patients with intense C3 staining (20.7% vs. 12.5% vs. 0%, p = 0.04). In terms of clinical variables, patients with intense C3 staining had a greater degree of proteinuria [1.8 (IQR: 0.9-3.6) vs. 1.2 (0.6-2.1) vs. 0.5 (IQR: 0.1-4.9), p = 0.04] and a tendency for a worse kidney function at baseline (52 ± 32 vs. 58 ± 32 vs. 66 ± 40 ml/min, p = 0.3). There was a tendency for patients with mesangial C3 deposits to have an increased serum IgA level, but the extent of deposits did not correlate with serum C3 level. Regarding the renal outcome, there was a significantly higher proportion of patients with intense C3 deposition to have a doubling of serum creatinine (23.6% vs. 12.2% vs. 0%, p = 0.05) and a tendency for a worse composite endpoint (35.8% vs. 22.4% vs. 23.1%, p = 0.1). Accordingly, the odds ratio for doubling of serum creatinine and for the composite endpoint in patients with intense C3 deposition were 2.88 (95%CI, 1.11-7.47, p = 0.02) and 1.91 (95%CI, 0.94-3.91, p = 0.07), respectively. Conclusion In our study, the extent of mesangial C3 deposition associated with clinical variables and chronic lesions of MESTC score. In addition, identification of intense C3 staining on IF could predict a worse renal outcome in patients with IgA nephropathy.

#5076 MONOCLONAL GAMMOPATHY IN C3 GLOMERULOPATHY: DOES THE BUCKET STOP THERE?

Abstract Background and Aims C3 glomerulopathy (C3G) is a rare diagnosis, characterized by dysregulation of the alternative pathway of complement, classically presenting in children and young adults. Recently, it has been reported the association between the production of a monoclonal protein and the development of C3G, affecting a larger age span. Method We report the case of a 53-year-old male patient, that attended the emergency department due to persistent holocranial headache. He was an IV drug abuser with a history of treated Hepatitis C infection and free lambda light chain monoclonal protein, being studied by the Haematology Department. On admission, he was hypertensive (187/98 mmHg), and labs showed an acute on chronic kidney disease (serum creatinine 2.35 mg/dL from a basal of 1.5 mg/dL) with an active urinary sediment (38 erythrocytes/field, with dysmorphia), a urinary protein/creatinine ratio of 626 mg/g, and C3 consumption (0.52 g/L). The patient was admitted, and a kidney biopsy was performed. Results Further lab results confirmed a serum IgG Lambda monoclonal protein. Autoantibodies screening (ANCAs, ANAs, Anti-GBM), ASLO and Rheumatoid Factor were negative. Cryoglobulinemia was detected, and the cryoprecipitate's immunofixation revealed monoclonal proteins IgG Lambda and IgM Kappa. HCV viral load was negative. Bone marrow biopsy revealed a small population (&amp;lt; 3%) of plasma cells with Lambda light chain restriction. Kidney biopsy's light microscopy showed increased mesangial matrix and cells, endocapillary hypercellularity, and some glomeruli with lobulated appearance. Five out of 15 glomeruli presented fibrocellular crescents. Immunofluorescence showed C3 dominant staining on capillary walls and in the mesangium, with absent IgG and light chain deposits. A presumptive diagnosis of C3 glomerulopathy was made and the patient was empirically started on corticosteroids (3 pulses of intravenous methylprednisolone, followed by oral prednisolone 1mg/Kg/day), which was followed by paraprotein-directed chemotherapy with bortezomib, cyclophosphamide and dexamethasone (VCD). The patient is currently on the third VCD cycle, presenting both renal and haematological responses: recovery of serum creatinine to basal levels (1.54 mg/dL), resolution of haematuria and proteinuria, normalisation of C3 levels. Serum immunofixation is currently negative for monoclonal protein, with normal serum immunoglobulin levels. Electron microscopy revealed electron-dense deposits in the mesangium, and mesangium-capillary transition, supporting the diagnosis of C3 glomerulonephritis. Genetic testing of complement-related genes revealed a rare missense variation of unknown significance (c.4855A&amp;gt;C) on the C3 gene, that has been previously reported in association with C3 glomerulopathy and atypical Haemolytic-Uremic syndrome. Conclusion This case represents a monoclonal gammopathy associated-C3 glomerulonephritis with a favourable response to paraprotein-directed chemotherapy. Although the association between monoclonal gammopathy and C3G rests on epidemiologic findings, experimental evidence suggests that several monoclonal proteins have complement dysregulation features, which may enhance alternate complement pathway activation. Our patient's response is in line with observational data that have shown improved renal outcomes in patients who achieve a haematological response following clone-directed chemotherapy, which further supports the role of monoclonal gammopathy in C3G pathogenesis [1]. Interestingly, the genetic variation identified in our patient might have provided a favourable genetic background for the development of C3G, which is thought to rely upon a complex interaction of triggering events, such as a monoclonal gammopathy, and underlying complement abnormalities, such as genetic variants in complement genes.

#2934 SGLT-2 INHIBITORS DELAY KIDNEY FAILURE PROGRESSION AND REDUCE NEED OF DIALYSIS IN CHRONIC KIDNEY DISEASE PATIENTS: A META-ANALYSIS

Abstract Background and Aims chronic kidney disease (CKD) is the main complication of type 2 diabetes mellitus (type 2 DM) with up to 7 million cases requiring dialysis therapy. The newest type 2 DM therapy, sodium-glucose co-transporter-2 inhibitor (SGLT-2 inhibitor), has developed into an attractive option for patients with comorbid CKD because of its effect on blood pressure and albuminuria, in addition to its effect on lowering blood sugar. Therefore, we conducted a systematic review and meta-analysis aimed at assessing the effect of SGLT-2 inhibitors in preventing the progression of renal failure and the need for dialysis in CKD patients with and without type 2 DM. Method We performed an analysis of randomized controlled trials of SGLT-2 inhibitors reporting renal outcomes in patients with and without type 2 DM. We searched the PUBMED, MEDLINE, and CENTRAL databases from baseline to August 2022 to identify suitable studies. The major outcome evaluated was the combination of a persistent increase in serum creatinine two times from baseline and the need for dialysis. Results Of the 2890 identified articles, ten studies were included in the inclusion criteria assessing the effect of using SGLT-2 inhibitors. Out of 76,312 participants, 1716 participants experienced a 2-fold increase in serum creatinine, and 647 participants required dialysis. The use of SGLT-2 inhibitors significantly reduced progressive renal failure and the need for dialysis in both patients with type 2 DM (RR: 0.65, 95% CI 0.60–0.71, p = 0.000) and patients without type 2 DM (RR: 0.59, 95% CI 0.46–0.77, p = 0.000). Subgroup analysis also showed that SGLT-2 inhibitors showed a significant effect in the group with eGFR &amp;gt; 60 ml/min (RR: 0.53, 95% CI 0.45-0.62, p = 0.000) and the group with eGFR 30- 60 ml/min (RR:0.66, 95% CI, 0.57-0.75, p = 0.000). Conclusion SGLT-2 inhibitors can significantly inhibit the progression of CKD and reduce the risk of needing dialysis in patients with and without type 2 DM. These effects were shown consistently across groups with varying baseline eGFR values.

#5127 COMBINED ACTIVITY AND CHRONICITY SCORE FOR PROGNOSTIC ASSESSMENT IN ANCA-ASSOCIATED VASCULITIS WITH GLOMERULONEPHRITIS

Abstract Background and Aims Previous studies have shown that chronic changes on kidney biopsy are useful for stratifying the risk of kidney failure in patients with AAV-GN. We aimed to evaluate the impact of inflammatory activity for the prediction of renal outcomes. Method A retrospective cohort study of MPO- or PR3-ANCA positive patients with AAV and active renal disease. Inflammatory activity was assessed by the Activity Index (AI): a ratio between the number of crescents and/or necrosis and the total number of glomeruli (in percent). We calculated the AI score: 0-5 = 0; 6-10 = 1; 11-15 = 2; 16-20 = 3; 21-25 = 4; 26-37.5 = 5; 37.6-50 = 6; 51-65 = 7; 66-80 = 8; 80-90 = 9; 90-100 = 10. Chronicity was evaluated with the Mayo Clinic Chronicity Score (MCCS). For the combined score, we summed the MCCS and the AI. Results Results. We analyzed 326 patients with kidney biopsies available to score. The biopsies had in median (IQR), 13 glomeruli (9-20), 4 crescents (2-6) and an AI of 28.6% (15.3-47.6). The population was classified according with the risk of progression to kidney failure (KF) in 3 classes as (i) low (0-6) – 114 (35.0%), (ii) intermediate (7-11) – 152 (46.6%), and (iii) high (≥12) – 60 (18.4%). Median eGFR at baseline correlated with the overall risk categories: 42.2 vs. 22.1 vs. 13.4 mL/min/1.73 m2, p&amp;lt;0.0001. The proportion of patients with eGFR&amp;lt; 30 mL/min/1.73 m2 was increased in patients classified as high: 88.3% vs. 66.4% vs. 36.0%, p&amp;lt;0.0001. Renal recovery was more frequent in patients at low risk of progression: 87.7% vs. 64.6% vs. 36.6%, p&amp;lt;0.0001, whereas kidney failure at 12 months and dialysis were more frequent in patients at higher risk (36.7% vs. 12.4% vs. 3.8%, p&amp;lt;0.0001; 35.6% vs. 13.0% vs. 2.9%, p&amp;lt;0.0001, respectively). The combination of AI with MCCS independently predicted the risk of KF at 12 months (HR 1.916, 95%CI 1.210 - 3.033, p = 0.006), particularly increased in patients classified as high risk (HR 3.124, 95%CI 1.224 – 7.970, p = 0.017) and in patients with PR3-ANCA (HR 1.896, 95%CI 1.012 - 3.551, p = 0.046) independently of eGFR at AAV-GN diagnosis and adjusted for severity of renal involvement and age. Conclusion The combined assessment of acute inflammatory activity and chronic changes on kidney histology independently predicted renal outcomes in patients with AAV-GN. The impact of the inflammatory activity is cumulative to the chronic changes.

#6399 ROLE OF THERAPEUTIC PLASMAPHERESIS IN PAUCI-IMMUNE VASCULITIS – A SINGLE CENTRE EXPERIENCE

Abstract Background and Aims The indication for plasmapheresis (PLF) in pauci-immune vasculitis (PIV) is controversial. This study aimed to characterize the population and renal outcome of patients with PIV undergoing PLF in a hospital in the north of Portugal. Method We conduct a retrospective cohort study of patients followed by a multidisciplinary team, from diagnosis to death or May/22. Two groups were defined: patients undergoing PLF (group A, GA) and not undergoing PLF (group B, GB). Demographic variables, comorbidities, serological subtype, clinical presentation, histological classification and therapeutic were evaluated. Recorded outcomes were death and ESRD (end-stage renal disease) (eGFR,15 ml/min per 1.73 m2, dialysis, or transplantation). Renal survival was estimated using the Kaplan-Meier analysis and differences between curves were evaluated using the log-rank test. Results A total of 72 patients, 26 (36.1%) in group A and 46 (63.9%) in group B were included. In both groups the most frequent serotype was myeloperoxidase ((MPO) (n = 23, GA; n = 38, GB)). In both groups, most patients were male (61.5% in GA and 56.5% in GB), with a mean age at admission of 64 (SD±11.5) and 66.5 years (SD±12.2) in GA and GB, respectively (p = 0.362). Most GA patients had pulmonary and renal involvement on admission (80.7%, n = 21), versus GB (36.9%, n = 17), p&amp;lt;0.05. Mean serum creatinine was superior in GA (6.74 mg/dl, SD ± 2.75) versus GB (3.82 mg/dl, SD±2.95), p&amp;lt;0.05. Twenty patients from GA (76.9%) and 7 from GB (15.2%) required dialysis upon admission, p&amp;lt;0.05. In both groups, almost all patients underwent induction immunosuppression with cyclophosphamide (mean cumulative dose of 4.4 grams (SD ± 2.6) and 5.9 grams (SD ± 2.7), in GA and GB, respectively) and azathioprine in the maintenance phase, with a rapid corticosteroid weaning scheme in both phases. Median follow-up time (months) of GA and GB was 11 (IQR [4.8-37.5]) and 58.5 (IQR [14.5-92]) months. Regarding renal prognosis, 9 of 20 patients in GA and 3 of 7 patients in GB who needed dialysis on admission, partial recover of renal function (p = 1.00). About 37% (n = 17) of patients of GB and 73% (n = 19) of patients of GA reached the composite renal outcome, with a median time of 0 (IQR 0 - 21.8) and 38.5 months (IQR 5.3-92), respectively. GA showed worse renal survival, with a mean of 30.9 months vs. 116.5 months in GB, p = 0.01. Renal survival at 2 years was 68.7% in GB and 24% at GA. Patients in both groups with admission serum creatinine ≥ 5.7 mg/dl had similar renal survival (GA 39.9 and GB 32 months, p = 0.714). Regarding the histological classification, 91.7% and 38.9% in GA and GB belonged to the crescentic class, (p = 0.009). Renal survival in the subgroup of patients with crescentic class was worse in GA (16.6±10.2 vs 83.3±16.1, p = 0.015). The analysis of the Renal Risk Score showed no statistically significant difference between the groups, and between patients with crescentic class in both groups, p = 0.274. Mortality and hospitalization rate due to infection were similar in both groups (p&amp;gt;0.05). Conclusion Patients undergoing PLF had a worse renal outcome, consistent with the higher proportion of patients with severe azotemia and requiring dialysis at admission, in a sample that was mostly ANCA MPO. As described in the literature, the experience of our centre did not demonstrate benefit in the addition of PLF, despite the limitations inherent to an observational, retrospective study and the modest sample size. A better knowledge of etiopathogenesis is essential for the optimization of the therapeutic strategy, together with the promotion of measures that allow timely referral, an early diagnosis and consequent improvement of renal prognosis.

#3521 ASSOCIATION BETWEEN NEPROLITHIASIS AND KIDNEY DISEASE PROGRESSION IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE PATIENTS: A PROSPECTIVE COHORT STUDY

Abstract Background and Aims Nephrolithiasis is a common complication in Autosomal dominant polycystic kidney disease (ADPKD) patients and is known to occur in up to 8% to 36% of the patients. A few in vitro and in vivo studies showed that kidney and ureter stone formation could accelerate renal disease progression in ADPKD. However, its association between nephrolithiasis and renal function deterioration remains unknown in ADPKD patients. Methods This is a study from single center prospective cohort called HOPE-PKD. A total of 410 study subjects with abdominal computed tomography (CT) scan within 1 year before the enrollment were analyzed. Study subjects were divided into two groups according to the CT results as follows: Patients with papillary calcification, calyceal stone, ureter stone, or renal stone were classified as a stone group (n = 80, 19.5%), and patients only with renal cyst calcification or without any stones in the kidney and ureter were classified as a no-stone group (n = 330, 80.5%). The primary outcome was defined as the initiation of renal replacement therapy due to end-stage renal disease. The secondary outcome was a composite outcome of a 50% decline in estimated glomerular filtration rate (eGFR), doubling serum creatinine from baseline, or the initiation of renal replacement therapy. The hazard ratios (HRs) and 95% confidence interval (95% CI) for the outcome were analyzed using multivariate Cox regression analysis. Results There was no difference in the baseline characteristics between the stone group and the no-stone group. During a median 5.18 [interquartile range 3.41 - 8.03] year of follow-up, the primary and secondary outcomes occurred in 51 (12.4%) and 96 (23.4%) patients, respectively. In the unadjusted Cox regression analysis, there was no significant difference in the survival analysis between the two groups. However, after adjusting possible confounding factors (age, sex, body mass index, eGFR, comorbidity of hypertension and diabetes, serum uric acid, phosphorous and calcium level, results of PKD1 and PKD2 gene analysis, and Mayo classification), the stone group showed an increased risk of the primary and secondary outcome of HR 2.84 (95% CI 1.26 - 6.38; p-value 0.012) and HR 1.83 (95% CI 1.03 - 3.27; p-value 0.041), respectively compared to the no-stone group (Figure 1). Conclusion This is the first prospective cohort study showing that nephrolithiasis is associated with poor renal outcomes in patients with APDKD. Further clinical studies of nephrolithiasis in ADPKD patients are warranted to improve renal outcomes.

Sodium-Glucose Co-Transporter 2 Inhibitors in Heart Failure-Current Evidence in Special Populations.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, originally used for diabetes mellitus, are gaining more popularity for other indications, owing to their positive cardiovascular and renal effects. SGLT2 inhibitors reduce heart failure (HF) hospitalization and improve cardiovascular outcomes in patients with type 2 diabetes. Later, SGLT2 inhibitors were evaluated in patients with HF with reduced ejection fraction (HFREF) and had beneficial effects independent of the presence of diabetes. Recently, reductions in cardiovascular outcomes were also observed in patients with HF with preserved ejection fraction (HFPEF). SGLT2 inhibitors also reduced renal outcomes in patients with chronic kidney disease. Overall, these drugs have an excellent safety profile with a negligible risk of genitourinary tract infections and ketoacidosis. In this review, we discuss the current data on SGLT2 inhibitors in special populations, including patients with acute myocardial infarction, acute HF, right ventricular (RV) failure, left ventricular assist device (LVAD), and type 1 diabetes. We also discuss the potential mechanisms behind the cardiovascular benefits of these medications.

Non-insulin-based insulin resistance indices for predicting all-cause mortality and renal outcomes in patients with stage 1-4 chronic kidney disease: another paradox.

Non-insulin-based insulin resistance (IR) indices serve as the indicators of metabolic syndrome (MetS) but have limited value for predicting clinical outcomes. Whether the obesity paradox affects the predictive value of these indicators in patients with chronic kidney disease (CKD) remains unknown. We investigated whether MetS and non-insulin-based IR indices can predict all-cause mortality and renal outcomes in a prospective observational study with stage 1-4 CKD Asians (N = 2,457). These IR indices were associated with MetS. A Cox regression model including body mass index (BMI) revealed an association between MetS and renal outcomes. Among the IR indices, only high triglyceride-glucose (TyG) index was associated with adverse renal outcomes: the hazard ratio of Q4 quartile of the TyG index was 1.38 (1.12-1.70). All-cause mortality was marginally associated with MetS but not high IR indices. Low TyG and TyG-BMI indices as well as low BMI and triglyceride were paradoxically associated with increased risks of clinical outcomes. The triglyceride-to-high-density lipoprotein cholesterol ratio and metabolic score for IR indices were not associated with clinical outcomes. In conclusion, MetS and TyG index predict renal outcome and obesity paradox affects the prediction of IR indices in patients with stage 1-4 CKD.

APOL1 and the risk of adverse renal outcomes in patients of African ancestry with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) disproportionately affects individuals of African ancestry (AA) compared to European ancestry (EA). In the general population, high risk (HR) variants in the apolipoprotein L1 (APOL1) gene increase the risk of renal and hypertensive disorders in individuals of AA. Since SLE is characterized by an interferon signature and APOL1 expression is driven by interferon, we examined the hypothesis that APOL1 HR genotypes predominantly drive higher rates of renal and hypertensive-related comorbidities observed in SLE patients of AA versus those of EA. We performed a retrospective cohort study in patients with SLE of EA and AA using a genetic biobank linked to de-identified electronic health records. APOL1 HR genotypes were defined as G1/G1, G2/G2, or G1/G2 and low risk (LR) genotypes as 1 or 0 copies of the G1 and G2 alleles. To identify renal and hypertensive-related disorders that differed in prevalence by ancestry, we used a phenome-wide association approach. We then used logistic regression to compare the prevalence of renal and hypertensive-related disorders in EA and AA patients, both including and excluding patients with the APOL1 HR genotype. In a sensitivity analysis, we examined the association of end stage renal disease secondary to lupus nephritis (LN-related ESRD) with ancestry and the APOL1 genotype. We studied 784 patients with SLE; 195 (24.9%) were of AA, of whom 27 (13.8%) had APOL1 HR genotypes. Eighteen renal and hypertensive-related phenotypes were more common in AA than EA patients (p-value ≤ 1.4E-4). All phenotypes remained significantly different after exclusion of patients with APOL1 HR genotypes, and most point odds ratios (ORs) decreased only slightly. Even among ORs with the greatest decrease, risk for AA patients without the APOL1 HR genotype remained significantly elevated compared to EA patients. In the sensitivity analysis, LN-related ESRD was more prevalent in SLE patients of AA versus EA and AA patients with the APOL1 HR genotype versus LR (p-value < .05 for both). The higher prevalence of renal and hypertensive disorders in SLE patients of AA compared to those of EA is not fully explained by the presence of APOL1 high risk variants.

Prognostic value of proteinuria monitoring in anti-neutrophil cytoplasmic antibody-associated vasculitis.

To determine the prognostic significance of proteinuria monitoring in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). We retrospectively analyzed the data of kidney biopsy-confirmed patients with AAV. Proteinuria was evaluated by a urine dipstick test. Poor renal outcome was defined as stage 4/5 chronic kidney disease (CKD) (estimated glomerular filtration rate < 30mL/min/1.73 m2). We enrolled 77 patients with a median follow-up duration of 36months (interquartile range, 18-79) in this study. Excluding 8 patients on dialysis at 6months, 59/69 (85.5%) achieved remission after induction therapy. Patients were then divided into two groups according to the presence of proteinuria at 6months after induction therapy (n = 29 with proteinuria, 40 without proteinuria). There was no significant difference in the rate of relapse or death according to the presence of proteinuria (p = 0.304 relapse, 0.401 death). In contrast, patients with proteinuria had significantly lower kidney function than those without proteinuria (41 vs. 53.5mL/min/1.73 m2, p = 0.003). Multivariate analysis revealed that eGFR values at 6months (hazard ratio [HR] 0.925; 95% CI 0.875-0.978, p = 0.006) and proteinuria at 6months (HR 4.613; 95% CI 1.230-17.298, p = 0.023) were significantly associated with stage 4/5 CKD. The presence of proteinuria at 6months after induction therapy and low renal function was significantly associated with a higher risk of stage 4/5 CKD in patients with AAV. Monitoring for proteinuria after induction therapy may help predict poor renal outcomes in patients with AAV.

A randomised-controlled trial (TARGET-C) of high vs. low target mean arterial pressure in patients with cirrhosis and septic shock

A high mean arterial pressure (MAP) target has been associated with improved renal outcomes in patients with cirrhosis, though it has not been studied in critically ill patients with cirrhosis and septic shock (CICs). We compared the efficacy of a high (80-85mmHg; H-MAP) vs. low (60-65; L-MAP) target MAP strategy in improving 28-day mortality in CICs. We performed open-label 1:1 randomisation of 150 CICs (H-MAP 75; L-MAP 75). The primary endpoint was 28-day mortality and secondary endpoints included reversal of shock, acute kidney injury (AKI) at day 5, the incidence of intradialytic hypotension (IDH), and adverse events. Endothelial markers were analysed in a subset of patients. The baseline characteristics were comparable. On intention-to-treat analysis, 28-day mortality (65% vs. 56%; p= 0.54), reversal of shock (47% vs. 53%; p= 0.41) and AKI development (45% vs. 31%;p= 0.06) were not different between the H-MAP and L-MAP groups, respectively. A lower incidence of IDH (12% vs. 48%; p <0.001) and higher adverse events necessitating protocol discontinuation (24% vs. 11%; p= 0.031) were noted in the H-MAP group. On per-protocol analysis (L-MAP 67; H-MAP 57), a significantly higher reversal of AKI (53% vs. 31%; p= 0.02) and a lower incidence of IDH (4% vs. 53%; p <0.001) were observed in the H-MAP group. Endothelial repair markers such as ADAMTS (2.11 ± 1.13 vs. 1.15 ± 0.48; p= 0.002) and angiopoietin-2 (74.08 ± 53.00 vs. 41.80 ± 15.95; p= 0.016) were higher in the H-MAP group. A higher MAP strategy does not confer a survival benefit in CICs, but improves tolerance to dialysis, lactate clearance and renal recovery. Higher adverse events indicate the need for better tools to evaluate target microcirculation pressures in CICs. Maintaining an appropriate organ perfusion pressure during sepsis is the ultimate goal of haemodynamic management. A higher mean arterial pressure (MAP) improves renal outcomes in patients with hepatorenal syndrome. Patients with cirrhosis and septic shock have severe circulatory disturbances, low MAP, and poor tissue perfusion. In these patients, targeting higher MAP vs. lower MAP does not confer any survival benefit but is associated with more adverse events. A higher target strategy was associated with better tolerance and lesser episodes of hypotension on dialysis. Patients who could achieve the higher target MAP, without the development of adverse events, had improved renal outcomes and better lactate clearance. Higher MAP was also associated with improvements in markers of endothelial function. A higher target MAP strategy, with close monitoring of adverse events, may be recommended for patients with cirrhosis and septic shock. NCT03145168.

Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors in Cardiovascular Disease and Chronic Kidney Disease.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to improve cardiovascular and renal outcomes in patients with established cardiovascular disease, chronic kidney disease (CKD), and heart failure (HF) with reduced or preserved ejection fraction. Clinical benefit has been substantiated in patients with and without type 2 diabetes (T2D). Consequently, SGLT2is have an increasingly important role in HF and CKD management that extends beyond T2D treatment. Their pleiotropic pharmacological effects underlying their cardiovascular and renal benefits are not completely understood but include significant effects beyond blood glucose reduction. SGLT2is inhibit the reabsorption of glucose and sodium in the proximal tubule which, in addition to lowering blood glucose, activates tubuloglomerular feedback, leading to reduced glomerular hydrostatic pressure and the mitigation of glomerular filtration rate loss. SGLT2is have diuretic and natriuretic effects, leading to decreased blood pressure, preload, and left ventricular (LV) filling pressure, and improvements in other surrogates of afterload. In HF, SGLT2is mitigate the risks of hyperkalemia and ventricular arrhythmia and improve LV dysfunction. SGLT2is also reduce sympathetic tone and uric acid levels, increase hemoglobin levels, and are postulated to have anti-inflammatory properties. This narrative review discusses the multifactorial and interrelated pharmacological mechanisms underlying the cardiovascular and renal benefits of SGLT2is.

Nexus between Periodontal Disease and Chronic Kidney Disease: A NarrativeReview

Background:Several decades of research have established the relationships between systemic diseases and periodontal diseases. Chronic kidney disease (CKD) is a chronic medical condition in which the homeostatic and emunctory activity of the kidneys is progressively declines. Periodontitis is a complex, polymicrobial disease that involves both the host and the environment. Tissue destruction is primarily associated with the host’s hyperresponsiveness, resulting in the release of inflammatory markers. Aim: This paper reviewed the evidence linking CKD, inflammatory markers, and periodontal disease and the effect of periodontal therapy on inflammatory markers and kidney function as well as dental parameters. Setting and Design: The sources of data were compiledand reviewed from MEDLINE, SCOPUS and Web of Sciences from 2010 to 2021. Result and Discussion: This review identifies biologically plausible bidirectional nexus between periodontitis and CKD. Periodontitis has emerged as non-traditional risk factor of CKD and vice versa. In addition, inflammatory markers are considered to play a role in the linkages between periodontitis and CKD. Recent study, has linked an increase in the production of inflammatory markers to a poorer renal outcome in patients with CKD. Periodontal therapy is effective in lowering the inflammatory markers levels and periodontal parameters as well as halting the progression of CKD. Conclusion : Understanding these links may help in identifying high-risk individuals and providing essential care at an early stage. Bangladesh Journal of Medical Science Vol. 22 No. 02 April’23 Page : 260-271

GLP-1 receptor agonist, liraglutide, protects podocytes from apoptosis in diabetic nephropathy by promoting white fat browning

Glucagon like peptide-1 receptor agonists (GLP-1RAs) belong to the class of incretin drugs. Incretin is a hormone secreted into blood by intestinal cells after food stimulation that induces insulin secretion. Liraglutide is a long-acting GLP-1RA that can reduce blood pressure, blood lipids, and inflammation. Previous studies showed that liraglutide can promote white fat browning and improve renal outcomes in patients with type 2 diabetes mellitus. However, no studies have linked white fat browning to kidney damage. The objective of this study was to investigate the effects of liraglutide-induced white fat browning on podocyte apoptosis in diabetic nephropathy. We also aimed to determine whether podocytes express glucagon like peptide-1 receptor (GLP-1R) and if liraglutide directly affects podocytes via GLP-1R. We assessed fat and renal function in db/db and wild-type mice and the effects of adipocyte conditioned medium on cultured podocytes. Liraglutide (400 mg/kg/d) was subcutaneously injected for 8 weeks. Liraglutide promoted white fat browning in vivo. During adipogenic differentiation of 3T3-L1 cells in vitro, liraglutide also upregulated expression of peroxisome proliferator-activated receptor γ coactivator-1 alpha (PGC1α) and uncoupling protein 1 (UCP1), which can induce white fat browning in vitro. Furthermore, we found that supernatant from 3T3-L1 cells stimulated by liraglutide reduced podocyte apoptosis. The inhibitory effect of liraglutide on apoptosis was eliminated by exogenous TNF-α. Finally, podocytes express GLP-1R. In vivo and in vitro studies showed that the apoptosis of podocytes in diabetic nephropathy may be related to the effect of liraglutide on promoting white lipid browning. Similarly, liraglutide may directly affect podocytes via GLP-1R.

SH3YL1 Protein Predicts Renal Outcomes in Patients with Type 2 Diabetes.

NADPH oxidase (NOX)-derived oxidative stress is an important factor in renal progression, with NOX4 being the predominant NOX in the kidney. Recently, Src homology 3 (SH3) domain-containing YSC84-like 1 (SH3YL1) was reported to be a regulator of NOX4. In this study, we tested whether the SH3YL1 protein could predict 3-year renal outcomes in patients with type 2 diabetes. A total of 131 patients with type 2 diabetes were enrolled in this study. Renal events were defined as a 15% decline in the estimated glomerular filtration rate (eGFR) from the baseline, the initiation of renal replacement therapy, or death during the 3 years. The levels of the urinary SH3YL1-to-creatinine ratio (USCR) were significantly different among the five stages of chronic kidney disease (CKD) and the three groups, based on albuminuria levels. The USCR levels showed a significant negative correlation with eGFR and a positive correlation with the urinary albumin-to-creatinine ratio (UACR). Plasma SH3YL1 levels were significantly correlated with UACR. The highest tertile group of USCR and plasma SH3YL1 had a significantly lower probability of renal event-free survival. Furthermore, the highest tertile group of USCR showed a significant association with the incidence of renal events after full adjustment: adjusted hazard ratio (4.636: 95% confidence interval, 1.416-15.181, p = 0.011). This study suggests that SH3YL1 is a new diagnostic biomarker for renal outcomes in patients with type 2 diabetes.

Long-term renal outcomes comparison between patients with chronic kidney disease and hepatorenal syndrome after living donor liver transplantation.

Hepatorenal syndrome (HRS) is a disastrous renal complication of advanced liver disease with a poor prognosis. Restoring normal liver function through liver transplantation (LT) is a standardized treatment with favorable short-term survival. However, the long-term renal outcomes in patients with HRS receiving living donor LT (LDLT) are controversial. This study aimed to investigate the prognostic impact of LDLT in patients with HRS. We reviewed adult patients who underwent LDLT between July 2008 and September 2017. Recipients were classified into 1) HRS type 1 (HRS1, N = 11), 2) HRS type 2 (HRS2, N = 19), 3) non-HRS recipients with pre-existing chronic kidney disease (CKD, N = 43), and 4) matched normal renal function (N = 67). Postoperative complications and 30-day surgical mortality were comparable among the HRS1, HRS2, CKD, and normal renal function groups. The 5-year survival rate was >90% and estimated glomerular filtration rate (eGFR) transiently improved and peaked at 4 weeks post-transplantation in patients with HRS. However, renal function deteriorated and resulted in CKD stage ≥ III in 72.7% of HRS1 and 78.9% of HRS2 patients (eGFR <60 ml/min/1.73 m2). The incidence of developing CKD and end-stage renal disease (ESRD) was similar between the HRS1, HRS2, and CKD groups, but significantly higher than that in the normal renal function group (both P < 0.001). In multivariate logistic regression, pre-LDLT eGFR <46.4 ml/min/1.73 m2 predicted the development of post-LDLT CKD stage ≥ III in patients with HRS (AUC = 0.807, 95% CI = 0.617-0.997, P = 0.011). LDLT provides a significant survival benefit for patients with HRS. However, the risk of CKD stage ≥ III and ESRD among patients with HRS was similar to that in pre-transplant CKD recipients. An early preventative renal-sparing strategy in patients with HRS is recommended.