Metabolic acidosis in chronic kidney disease: mere consequence or also culprit?

Metabolic acidosis is a frequent complication in non-transplant chronic kidney disease (CKD) and after kidney transplantation. It occurs when net endogenous acid production exceeds net acid excretion. While nephron loss with reduced ammoniagenesis is the main cause of acid retention in non-transplant CKD patients, additional pathophysiological mechanisms are likely inflicted in kidney transplant recipients. Functional tubular damage by calcineurin inhibitors seems to play a key role causing renal tubular acidosis. Notably, experimental and clinical studies over the past decades have provided evidence that metabolic acidosis may not only be a consequence of CKD but also a driver of disease. In metabolic acidosis, activation of hormonal systems and the complement system resulting in fibrosis have been described. Further studies of changes in renal metabolism will likely contribute to a deeper understanding of the pathophysiology of metabolic acidosis in CKD. While alkali supplementation in case of reduced serum bicarbonate < 22 mmol/l has been endorsed by CKD guidelines for many years to slow renal functional decline, among other considerations, beneficial effects and thresholds for treatment have lately been under intense debate. This review article discusses this topic in light of the most recent results of trials assessing the efficacy of dietary and pharmacological interventions in CKD and kidney transplant patients.

Temperature-Dependent, Site-Specific Rate Coefficients for the Reaction of OH (OD) with Methyl Formate Isotopologues via Experimental and Theoretical Studies.

Methyl esters are an important component of combustion and atmospheric systems. Reaction with the OH radical plays an important role in the removal of the simplest methyl ester, methyl formate (MF, CH3OCHO). In this paper, the overall rate coefficients for the reactions of OH and OD with MF isotopologues, studied under pseudo-first-order conditions, are reported using two different laser flash photolysis systems with the decay of OH monitored by laser-induced fluorescence. The room-temperature rate coefficient for OH + MF, (1.95 ± 0.34) × 10-13 cm3 molecule-1 s-1, is in good agreement with the literature. The rate coefficient exhibits curved Arrhenius behavior, and our results bridge the gap between previous low-temperature and shock tube studies. In combination with the literature, the rate coefficient for the reaction of OH with MF between 230 and 1400 K can be parametrized as kOH+MF = (3.2 × 10-13) × (T/300 K)2.3 × exp(-141.4 K/T) cm3 molecule-1 s-1 with an overall estimated uncertainty of ∼30%. The reactions of OD with MF isotopologues show a small enhancement (inverse secondary isotope effect) compared to the respective OH reactions. The reaction of OH/OD with MF shows a normal primary isotope effect, a decrease in the rate coefficient when MF is partially or fully deuterated. Experimental studies have been supported by ab initio calculations at the CCSD(T)-F12/aug-cc-pVTZ//M06-2X/6-31+G** level of theory. The calculated, zero-point-corrected, barrier heights for abstraction at the methyl and formate sites are 1.3 and 6.0 kJ mol-1, respectively, and the ab initio predictions of kinetic isotope effects are in agreement with experiment. Fitting the experimental isotopologue data refines these barriers to 0.9 ± 0.6 and 4.1 ± 0.9 kJ mol-1. The branching ratio is approximately 50:50 at 300 K. Between 300 and 500 K, abstraction via the higher-energy, higher-entropy formate transition state becomes more favored (60:40). However, experiment and calculations suggest that as the temperature increases further, with higher energy, less constrained conformers of the methyl transition state become more significant. The implications of the experimental and theoretical results for the mechanisms of MF atmospheric oxidation and low-temperature combustion are discussed.

Determinants of survival in patients on extracorporeal membrane oxygenation therapy due to severe covid-19.

BACKGROUND: Severe acute respiratory distress syndrome (ARDS) due to Coronavirus Disease-19 (COVID-19) is associated with high mortality. Although survival on mechanical circulatory support has improved, determinants for better prognosis are still unclear. Here, we report on the outcome of our patient population with the need for mechanical circulatory support due to severe COVID-19 (sCOVID-19) induced ARDS. METHODS: All patients treated with extracorporeal membrane oxygenation (ECMO) for severe ARDS due to sCOVID-19 were analysed. Patients > 18 years of age at the time of initiation of ECMO were included. Pre-existing comorbidities, complications during ECMO implantation, and ECMO runtime were reviewed. The latency to intubation, proning, tracheotomy, and ECMO implantation was analysed. Furthermore, the survival and non-survival population were compared to determine factors in favour of a better outcome. RESULTS: In total, 85 patients were treated with veno-venous membrane oxygenation (vv-ECMO) for severe ARDS in our medical centre. The patient population was predominantly male (83.5%) with a mean patient age of 54.9 years. A history of cardiovascular disease (p = .01), smoking (p < .05), need for vasopressor- (p < .05), and renal replacement therapy (p < .001) was associated with a worse prognosis. Overall survival was 50%. The survival population was significantly younger (p = .004), had a significantly higher body weight (p = .02) and body mass index (BMI) (p = .01). Furthermore, survival was significantly better when vv-ECMO was initiated within 48 h after admission (p < .001). CONCLUSIONS: Pre-existing cardiovascular disease, higher age, history of nicotine abuse, and development of renal failure are associated with poor outcome. Early start of vv-ECMO therapy may lead to better survival in sCOVID-19 patients, although complications during ECMO therapy are associated with a worse prognosis.

Relevance of deceased donor proteinuria for kidney transplantation: A comprehensive national cohort study.

PURPOSE: Proteinuria is frequent in patients with nephropathies and associated with progressive kidney disease and risk for end stage kidney disease. However, the relevance of deceased donor proteinuria on transplant outcome remains uncertain. In this nationwide cohort study, we evaluated the prevalence of proteinuria in deceased donor candidates and measured the impact on outcome after kidney transplantation. METHODS: Data from the Swiss Organ Allocation System and the Swiss Transplant Cohort Study were analyzed, comprising 1725 donors and 1516 recipients transplanted between 2008 and 2019. We correlated urine findings with donor characteristics and quantified the impact of proteinuria on allograft function at 12 months and survival. RESULTS: Proteinuria influenced allocation decisions in 4.5% of nonimmunological organ declines and was the leading cause for decline in 0.2% of cases. 74.1%, 51.4%, and 35.3% of donor candidates had a baseline proteinuria above 15, 30, and 50 mg protein/mmol urine creatinine, respectively. Proteinuria above 30 mg/mmol was associated with female donor sex, mechanical resuscitation, acute kidney injury, and time delay between ICU entry and urine sampling. Donor proteinuria was not associated with patient or allograft survival, nor allograft function at 12 months. CONCLUSION: We report a high prevalence of proteinuria in donor candidates, without evidence of a deleterious impact of proteinuria on graft function and/or survival. Therefore, low-level proteinuria should not be considered a limiting contraindication for kidney allocation in deceased donor transplant.

Key characteristics impacting survival of COVID-19 extracorporeal membrane oxygenation.

BACKGROUND: Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. METHODS: 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. RESULTS: Most patients were between 50 and 70 years of age. PaO2/FiO2 ratio prior to ECMO was 72 mmHg (IQR: 58-99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41-0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28-1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events. CONCLUSIONS: Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival. TRIAL REGISTRATION: Registered in the German Clinical Trials Register (study ID: DRKS00022964, retrospectively registered, September 7th 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022964 .

Different Acute Kidney Injury Patterns after Renal Ischemia Reperfusion Injury and Extracorporeal Membrane Oxygenation in Mice.

The use of extracorporeal membrane oxygenation (ECMO) is associated with acute kidney injury (AKI) in thoracic organ transplantation. However, multiple other factors contribute to AKI development after these procedures such as renal ischemia-reperfusion injury (IRI) due to hypo-perfusion of the kidney during surgery. In this study, we aimed to explore the kidney injury patterns in mouse models of ECMO and renal IRI. Kidneys of C57BL/6 mice were examined after moderate (35 min) and severe (45 min) unilateral transient renal pedicle clamping and 2 h of veno-venous ECMO. Renal injury markers, neutrophil infiltration, tubular transport function, pro-inflammatory cytokines, and renal heme oxygenase-1 (HO-1) expression were determined by immunofluorescence and qPCR. Both procedures caused AKI, but with different injury patterns. Severe neutrophil infiltration of the kidney was evident after renal IRI, but not following ECMO. Tubular transport function was severely impaired after renal IRI, but preserved in the ECMO group. Both procedures caused upregulation of pro-inflammatory cytokines in the renal tissue, but with different time kinetics. After ECMO, but not IRI, HO-1 was strongly induced in tubular cells indicating contact with hemolysis-derived proteins. After IRI, HO-1 was expressed on infiltrating myeloid cells in the tubulo-interstitial space. In conclusion, renal IRI and ECMO both caused AKI, but kidney damage after renal IRI was more pronounced including severe neutrophil infiltration and tubular transport impairment. Enhanced HO-1 expression in tubular cells after ECMO encourages limitation of hemolysis as a therapeutic approach to reduce ECMO-associated AKI.

Outcome of kidney transplantation from very senior donors in Switzerland - a national cohort study.

Kidney transplantation from older and marginal donors is effective to confront organ shortage. However, limitations after transplantation of kidneys from very marginal kidney donors remain unclear. We compared patient and graft outcome, achieved allograft function and quality of life of renal transplantations from Very Senior Donors (VSD, defined as donors aged 70 years and older) with Senior Donors (SD, aged 60-70 years) and Regular Donors (RD, aged younger than 60 years) in Switzerland. We evaluated the outcome of 1554 adult recipients of deceased donor kidney transplantations from 05/2008 to 12/2019; median follow-up was 4.7 years. Failure-free survival (freedom from graft loss or death), glomerular filtration rate (eGFR), and quality of life at 12 months were analyzed for RD (reference group, n = 940), SD (n = 404), and VSD (n = 210). Failure-free survival decreased with increasing donor age, mainly attributable to premature graft loss. Still, overall 5-year failure-free survival reached 83.1%, 81.0%, and 64.0% in the RD, SD, and VSD subgroups, respectively. eGFR 12 months post-transplantation was significantly higher in RD compared with SD and VSD. The acceptance rate of donor candidates for kidney TPL was 78% for the entire cohort (87% for RD, 79% for SD, and 56% for VSD). Deceased donor kidney transplantation from donors aged 70 years or older is associated with an inferior, yet acceptable failure-free outcome, with sustained quality of life.

Impact of unilateral diaphragm elevation on postoperative outcomes in bilateral lung transplantation - a retrospective single-center study.

This study evaluated the impact of unilateral diaphragm elevation following bilateral lung transplantation on postoperative course. Patient data for all lung transplantations performed at our institution between 01/2010 and 12/2019 were reviewed. Presence of right or left diaphragm elevation was retrospectively evaluated using serial chest X-rays performed while patients were standing and breathing spontaneously. Right elevation was defined by a > 40 mm difference between right and left diaphragmatic height. Left elevation was present if the left diaphragm was at the same height or higher than the right diaphragm. In total, 1093/1213 (90%) lung transplant recipients were included. Of these, 255 (23%) patients exhibited radiologic evidence of diaphragm elevation (right, 55%; left 45%; permanent, 62%). Postoperative course did not differ between groups. Forced expiratory volume in 1 second, forced vital capacity and total lung capacity were lower at 1-year follow-up in patients with permanent than in patients with transient or absent diaphragmatic elevation (P = 0.038, P < 0.001, P = 0.002, respectively). Graft survival did not differ between these groups (P = 0.597). Radiologic evidence of diaphragm elevation was found in 23% of our lung transplant recipients. While lung function tests were worse in patients with permanent elevation, diaphragm elevation did not have any relevant impact on outcomes.

Comparison of anticoagulation strategies for veno-venous ECMO support in acute respiratory failure.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) support in acute respiratory failure may be lifesaving, but bleeding and thromboembolic complications are common. The optimal anticoagulation strategy balancing these factors remains to be determined. This retrospective study compared two institutional anticoagulation management strategies focussing on oxygenator changes and both bleeding and thromboembolic events. METHODS: We conducted a retrospective observational cohort study between 04/2015 and 02/2020 in two ECMO referral centres in Germany in patients receiving veno-venous (VV)-ECMO support for acute respiratory failure for > 24 h. One centre routinely applied low-dose heparinization aiming for a partial thromboplastin time (PTT) of 35-40 s and the other routinely used a high-dose therapeutic heparinization strategy aiming for an activated clotting time (ACT) of 140-180 s. We assessed number of and time to ECMO oxygenator changes, 15-day freedom from oxygenator change, major bleeding events, thromboembolic events, 30-day ICU mortality, activated clotting time and partial thromboplastin time and administration of blood products. Primary outcome was the occurrence of oxygenator changes depending on heparinization strategy; main secondary outcomes were the occurrence of severe bleeding events and occurrence of thromboembolic events. The transfusion strategy was more liberal in the low-dose centre. RESULTS: Of 375 screened patients receiving VV-ECMO support, 218 were included in the analysis (117 high-dose group; 101 low-dose group). Disease severity measured by SAPS II score was 46 (IQR 36-57) versus 47 (IQR 37-55) and ECMO runtime was 8 (IQR 5-12) versus 11 (IQR 7-17) days (P = 0.003). There were 14 oxygenator changes in the high-dose group versus 48 in the low-dose group. Freedom from oxygenator change at 15 days was 73% versus 55% (adjusted HR 3.34 [95% confidence interval 1.2-9.4]; P = 0.023). Severe bleeding events occurred in 23 (19.7%) versus 14 (13.9%) patients (P = 0.256) and thromboembolic events occurred in 8 (6.8%) versus 19 (19%) patients (P = 0.007). Mortality at 30 days was 33.3% versus 30.7% (P = 0.11). CONCLUSIONS: In this retrospective study, ECMO management with high-dose heparinization was associated with lower rates of oxygenator changes and thromboembolic events when compared to a low-dose heparinization strategy. Prospective, randomized trials are needed to determine the optimal anticoagulation strategy in patients receiving ECMO support.

Improvement of renal function after transcatheter aortic valve replacement and its impact on survival.

BACKGROUND: Chronic kidney disease as well as acute kidney injury are associated with adverse outcomes after transcatheter aortic valve replacement (TAVR). However, little is known about the prognostic implications of an improvement in renal function after TAVR. METHODS: Renal improvement (RI) was defined as a decrease in postprocedural creatinine in µmol/l of ≥1% compared to its preprocedural baseline value. A propensity score representing the likelihood of RI was calculated to define patient groups which were comparable regarding potential confounders (age, sex, BMI, NYHA classification, STS score, log. EuroSCORE, history of atrial fibrillation/atrial flutter, pulmonary disease, previous stroke, CRP, creatinine, hsTNT and NT-proBNP). The cohort was stratified into 5 quintiles according to this propensity score and the survival time after TAVR was compared within each subgroup. RESULTS: Patients in quintile 5 (n = 93) had the highest likelihood for RI. They were characterized by higher creatinine, lower eGFR, higher NYHA class, higher NT-proBNP, being mostly female and having shorter overall survival time. Within quintile 5, patients without RI had significantly shorter survival compared to patients with RI (p = 0.002, HR = 0.32, 95% CI = [0.15-0.69]). There was no survival time difference between patients with and without RI in the whole cohort (p = 0.12) and in quintiles 1 to 4 (all p > 0.16). Analyses of specific subgroups showed that among patients with NYHA class IV, those with RI also had a significant survival time benefit (p < 0.001, HR = 0.15; 95%-CI = [0.05-0.44]) compared to patients without RI. CONCLUSIONS: We here describe a propensity score-derived specific subgroup of patients in which RI after TAVR correlated with a significant survival benefit.