Genetics of osteopontin in patients with chronic kidney disease: The German Chronic Kidney Disease study.

Osteopontin (OPN), encoded by SPP1, is a phosphorylated glycoprotein predominantly synthesized in kidney tissue. Increased OPN mRNA and protein expression correlates with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney disease. But its genetic underpinnings are incompletely understood. We therefore conducted a genome-wide association study (GWAS) of OPN in a European chronic kidney disease (CKD) population. Using data from participants of the German Chronic Kidney Disease (GCKD) study (N = 4,897), a GWAS (minor allele frequency [MAF]≥1%) and aggregated variant testing (AVT, MAF<1%) of ELISA-quantified serum OPN, adjusted for age, sex, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) was conducted. In the project, GCKD participants had a mean age of 60 years (SD 12), median eGFR of 46 mL/min/1.73m2 (p25: 37, p75: 57) and median UACR of 50 mg/g (p25: 9, p75: 383). GWAS revealed 3 loci (p<5.0E-08), two of which replicated in the population-based Young Finns Study (YFS) cohort (p<1.67E-03): rs10011284, upstream of SPP1 encoding the OPN protein and related to OPN production, and rs4253311, mapping into KLKB1 encoding prekallikrein (PK), which is processed to kallikrein (KAL) implicated through the kinin-kallikrein system (KKS) in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease. The SPP1 gene was also identified by AVT (p = 2.5E-8), comprising 7 splice-site and missense variants. Among others, downstream analyses revealed colocalization of the OPN association signal at SPP1 with expression in pancreas tissue, and at KLKB1 with various plasma proteins in trans, and with phenotypes (bone disorder, deep venous thrombosis) in human tissue. In summary, this GWAS of OPN levels revealed two replicated associations. The KLKB1 locus connects the function of OPN with PK, suggestive of possible further post-translation processing of OPN. Further studies are needed to elucidate the complex role of OPN within human (patho)physiology.

An intermediate-effect size variant in UMOD confers risk for chronic kidney disease.

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10-5 to 10-3. Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD.

Urinary CD4 + T Cells Predict Renal Relapse in ANCA-Associated Vasculitis.

SIGNIFICANCE STATEMENT: Early identification of patients at risk of renal flares in ANCA vasculitis is crucial. However, current clinical parameters have limitations in predicting renal relapse accurately. This study investigated the use of urinary CD4 + T lymphocytes as a predictive biomarker for renal flares in ANCA vasculitis. This study, including urine samples from 102 patients, found that the presence of urinary CD4 + T cells was a robust predictor of renal relapse within a 6-month time frame, with a sensitivity of 60% and a specificity of 97.8%. The diagnostic accuracy of urinary CD4 + T cells exceeded that of ANCA titers, proteinuria, and hematuria. Monitoring urinary CD4 + T lymphocytes could help assess the risk of future renal relapse, enabling early preventive measures and tailored treatment strategies. BACKGROUND: In ANCA-associated vasculitis, there is a lack of biomarkers for predicting renal relapse. Urinary T cells have been shown to differentiate active GN from remission in ANCA-associated vasculitis, but their predictive value for renal flares remains unknown. METHODS: The PRE-FLARED study was a prospective multicenter biomarker study including 102 individuals with ANCA-associated vasculitis in remission aimed to predict renal relapse by quantifying urinary CD4 + T-cell subsets using flow cytometry at baseline and monitoring clinical outcomes over a 6-month follow-up. RESULTS: Among the participants, ten experienced renal relapses, two had non-renal flares, and 90 remained in stable remission. The median baseline urinary CD4 + T-cell count was significantly higher in patients who relapsed compared with those in remission. Receiver operating characteristic curve analysis of urinary CD4 + T-cell counts showed an area under the curve value of 0.88 for predicting renal flares, outperforming ANCA titers, hematuria, and proteinuria. Using a cutoff of 490 CD4 + T cells per 100 ml urine, the sensitivity and specificity in identifying patients with future renal flares were 60% and 97.8%, respectively. In a post hoc analysis, combining urinary CD4 + T-cell counts with proteinase-3 ANCA levels suggested improved predictive performance in the PR3 + subgroup. In addition, the number of urinary CD4 + T cells showed a limited correlation with a decline in GFR and an increase in proteinuria over the follow-up period. CONCLUSIONS: This study concluded that urinary CD4 + T-cell counts could identify patients with ANCA-associated vasculitis at a substantial risk of renal relapse within 6 months. Combining these counts with ANCA levels further improved the prediction of relapse. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Urinary T Lymphocytes Predict Renal Flares in Patients With Inactive ANCA-associated Glomerulonephritis (PRE-FLARED), NCT04428398 .

Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).

Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter. CONCLUSIONS: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).

Use of Analog and Human Insulin in a European Hemodialysis Cohort With Type 2 Diabetes: Associations With Mortality, Hospitalization, MACE, and Hypoglycemia.

RATIONALE & OBJECTIVE: Poor glycemic control may contribute to the high mortality rate in patients with type 2 diabetes receiving hemodialysis. Insulin type may influence glycemic control, and its choice may be an opportunity to improve outcomes. This study assessed whether treatment with analog insulin compared with human insulin is associated with different outcomes in people with type 2 diabetes and kidney failure receiving hemodialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: People in the Analyzing Data, Recognizing Excellence and Optimizing Outcomes (AROii) study with kidney failure commencing hemodialysis and type 2 diabetes being treated with insulin within 288 dialysis facilities between 2007 and 2009 across 7 European countries. Study participants were followed for 3 years. People with type 1 diabetes were excluded using an established administrative data algorithm. EXPOSURE: Treatment with an insulin analog or human insulin. OUTCOME: All-cause mortality, major adverse cardiovascular events (MACE), all-cause hospitalization, and confirmed hypoglycemia (blood glucose<3.0mmol/L sampled during hemodialysis). ANALYTICAL APPROACH: Inverse probability weighted Cox proportional hazards models to estimate hazard ratios for analog insulin compared with human insulin. RESULTS: There were 713 insulin analog and 733 human insulin users. Significant variation in insulin type by country was observed. Comparing analog with human insulin at 3 years, the percentage of patients experiencing end points and adjusted hazard ratios (AHR) were 22.0% versus 31.4% (AHR, 0.808 [95% CI, 0.66-0.99], P=0.04) for all-cause mortality, 26.8% versus 35.9% (AHR, 0.817 [95% CI, 0.68-0.98], P=0.03) for MACE, and 58.2% versus 75.0% (AHR, 0.757 [95% CI, 0.67-0.86], P<0.001) for hospitalization. Hypoglycemia was comparable between insulin types at 14.1% versus 15.0% (AHR, 1.169 [95% CI, 0.80-1.72], P=0.4). Consistent strength and direction of the associations were observed across sensitivity analyses. LIMITATIONS: Residual confounding, lack of more detailed glycemia data. CONCLUSIONS: In this large multinational cohort of people with type 2 diabetes and kidney failure receiving maintenance hemodialysis, treatment with analog insulins was associated with better clinical outcomes when compared with human insulin. PLAIN-LANGUAGE SUMMARY: People with diabetes who are receiving dialysis for kidney failure are at high risk of cardiovascular disease and death. This study uses information from 1,446 people with kidney failure from 7 European countries who are receiving dialysis, have type 2 diabetes, and are prescribed either insulin identical to that made in the body (human insulin) or insulins with engineered extra features (insulin analog). After 3 years, fewer participants receiving analog insulins had died, had been admitted to the hospital, or had a cardiovascular event (heart attack, stroke, heart failure, or peripheral vascular disease). These findings suggest that analog insulins should be further explored as a treatment leading to better outcomes for people with diabetes on dialysis.

Associations of Urine and Plasma Metabolites with Kidney Failure and Death in a CKD Cohort.

RATIONALE & OBJECTIVE: Biomarkers that enable better identification of persons with chronic kidney disease (CKD) who are at higher risk for disease progression and adverse events are needed. This study sought to identify urine and plasma metabolites associated with progression of kidney disease. STUDY DESIGN: Prospective metabolome-wide association study. SETTING & PARTICIPANTS: Persons with CKD enrolled in the German CKD Study (GCKD) with metabolite measurements; with external validation within the Atherosclerosis Risk in Communities Study. EXPOSURES: 1,513 urine and 1,416 plasma metabolites (Metabolon, Inc.) measured at study entry using untargeted mass spectrometry. OUTCOMES: Main endpoints were kidney failure (KF), and a composite endpoint of KF, eGFR <15 mL/min/1.73m2, or 40% decline in eGFR (CKE). Death from any cause was a secondary endpoint. After a median of 6.5 years follow-up, 500 persons experienced KF, 1,083 experienced CKE and 680 died. ANALYTICAL APPROACH: Time-to-event analyses using multivariable proportional hazard regression models in a discovery-replication design, with external validation. RESULTS: 5,088 GCKD participants were included in analyses of urine metabolites and 5,144 in analyses of plasma metabolites. Among 182 unique metabolites, 30 were significantly associated with KF, 49 with CKE, and 163 with death. The strongest association with KF was observed for plasma hydroxyasparagine (hazard ratio: 1.95, 95% confidence interval: 1.68-2.25). An unnamed metabolite measured in plasma and urine was significantly associated with KF, CKE, and death. External validation of the identified associations of metabolites with KF or CKE revealed direction-consistency for 88% of observed associations. Selected associations of 18 metabolites with study outcomes have not been previously reported. LIMITATIONS: Use of observational data and semi-quantitative metabolite measurements at a single time point. CONCLUSIONS: The observed associations between metabolites and KF, CKE or death in persons with CKD confirmed previously reported findings and also revealed several associations not previously described. These findings warrant confirmatory research in other study cohorts.

Apolipoprotein A-IV concentrations and cancer in a large cohort of chronic kidney disease patients: results from the GCKD study.

BACKGROUND: Chronic kidney disease (CKD) is highly connected to inflammation and oxidative stress. Both favour the development of cancer in CKD patients. Serum apolipoprotein A-IV (apoA-IV) concentrations are influenced by kidney function and are an early marker of kidney impairment. Besides others, it has antioxidant and anti-inflammatory properties. Proteomic studies and small case-control studies identified low apoA-IV as a biomarker for various forms of cancer; however, prospective studies are lacking. We therefore investigated whether serum apoA-IV is associated with cancer in the German Chronic Kidney Disease (GCKD) study. METHODS: These analyses include 5039 Caucasian patients from the prospective GCKD cohort study followed for 6.5 years. Main inclusion criteria were an eGFR of 30-60 mL/min/1.73m2 or an eGFR > 60 mL/min/1.73m2 in the presence of overt proteinuria. RESULTS: Mean apoA-IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dL (median 27.6 mg/dL). 615 patients had a history of cancer before the enrolment into the study. ApoA-IV concentrations above the median were associated with a lower odds for a history of cancer (OR = 0.79, p = 0.02 when adjusted age, sex, smoking, diabetes, BMI, albuminuria, statin intake, and eGFRcreatinine). During follow-up 368 patients developed an incident cancer event and those with apoA-IV above the median had a lower risk (HR = 0.72, 95%CI 0.57-0.90, P = 0.004). Finally, 62 patients died from such an incident cancer event and each 10 mg/dL higher apoA-IV concentrations were associated with a lower risk for fatal cancer (HR = 0.62, 95%CI 0.44-0.88, P = 0.007). CONCLUSIONS: Our data indicate an association of high apoA-IV concentrations with reduced frequencies of a history of cancer as well as incident fatal and non-fatal cancer events in a large cohort of patients with CKD.

Plasma NGAL levels in stable kidney transplant recipients and the risk of allograft loss.

BACKGROUND: The objective of this study was to investigate the utility of neutrophil gelatinase-associated lipocalin (NGAL) and calprotectin (CPT) to predict long-term graft survival in stable kidney transplant recipients (KTR). METHODS: A total of 709 stable outpatient KTR were enrolled >2 months post-transplant. The utility of plasma and urinary NGAL (pNGAL, uNGAL) and plasma and urinary CPT at enrollment to predict death-censored graft loss was evaluated during a 58-month follow-up. RESULTS: Among biomarkers, pNGAL showed the best predictive ability for graft loss and was the only biomarker with an area under the curve (AUC) > 0.7 for graft loss within 5 years. Patients with graft loss within 5 years (n = 49) had a median pNGAL of 304 [interquartile range (IQR) 235-358] versus 182 (IQR 128-246) ng/mL with surviving grafts (P < .001). Time-dependent receiver operating characteristic analyses at 58 months indicated an AUC for pNGAL of 0.795, serum creatinine-based Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (eGFR) had an AUC of 0.866. pNGAL added to a model based on conventional risk factors for graft loss with death as competing risk (age, transplant age, presence of donor-specific antibodies, presence of proteinuria, history of delayed graft function) had a strong independent association with graft loss {subdistribution hazard ratio (sHR) for binary log-transformed pNGAL [log2(pNGAL)] 3.4, 95% confidence interval (CI) 2.24-5.15, P < .0001}. This association was substantially attenuated when eGFR was added to the model [sHR for log2(pNGAL) 1.63, 95% CI 0.92-2.88, P = .095]. Category-free net reclassification improvement of a risk model including log2(pNGAL) in addition to conventional risk factors and eGFR was 54.3% (95% CI 9.2%-99.3%) but C-statistic did not improve significantly. CONCLUSIONS: pNGAL was an independent predictor of renal allograft loss in stable KTR from one transplant center but did not show consistent added value when compared with baseline predictors including the conventional marker eGFR. Future studies in larger cohorts are warranted.

Interactive exploration of adverse events and multimorbidity in CKD.

BACKGROUND AND HYPOTHESIS: Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality, and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study. METHODS: The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60 mL/min/1.73m2 and an overt proteinuria. Cardio-, cerebro- and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology. RESULTS: Over a median of 6.5 years, 10 271 events occurred in total and 680 participants (13.0%) died while 2947 participants (56.5%) experienced any event. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology, and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney), and 66.0 (infection). Participants with diabetic kidney disease and men were more prone to experiencing events. CONCLUSION: This comprehensive explorative tool to visualize adverse events (https://gckd.diz.uk-erlangen.de/), their combination, mortality, and multimorbidity among persons with CKD may manifest as a valuable resource for patient care, identification of high-risk groups, health services, and public health policy planning.

Validation of risk scores for prediction of severe pneumonia in kidney transplant recipients hospitalized with community-acquired pneumonia.

PURPOSE: Risk scores for community-acquired pneumonia (CAP) are widely used for standardized assessment in immunocompetent patients and to identify patients at risk for severe pneumonia and death. In immunocompromised patients, the prognostic value of pneumonia-specific risk scores seems to be reduced, but evidence is limited. The value of different pneumonia risk scores in kidney transplant recipients (KTR) is not known. METHODS: Therefore, we retrospectively analyzed 310 first CAP episodes after kidney transplantation in 310 KTR. We assessed clinical outcomes and validated eight different risk scores (CRB-65, CURB-65, DS-CRB-65, qSOFA, SOFA, PSI, IDSA/ATS minor criteria, NEWS-2) for the prognosis of severe pneumonia and in-hospital mortality. Risk scores were assessed up to 48 h after admission, but always before an endpoint occurred. Multiple imputation was performed to handle missing values. RESULTS: In total, 16 out of 310 patients (5.2%) died, and 48 (15.5%) developed severe pneumonia. Based on ROC analysis, sequential organ failure assessment (SOFA) and national early warning score 2 (NEWS-2) performed best, predicting severe pneumonia with AUC of 0.823 (0.747-0.880) and 0.784 (0.691-0.855), respectively. CONCLUSION: SOFA and NEWS-2 are best suited to identify KTR at risk for the development of severe CAP. In contrast to immunocompetent patients, CRB-65 should not be used to guide outpatient treatment in KTR, since there is a 7% risk for the development of severe pneumonia even in patients with a score of zero.

Standard vs. carbone dioxide adapted kidney replacement therapy in hypercapnic ARDS patients: a randomized controlled pilot trial (BigBIC).

BACKGROUND: Current continuous kidney replacement therapy (CKRT) protocols ignore physiological renal compensation for hypercapnia. This study aimed to explore feasibility, safety, and clinical benefits of pCO2-adapted CKRT for hypercapnic acute respiratory distress syndrome (ARDS) patients with indication for CKRT. METHODS: We enrolled mechanically ventilated hypercapnic ARDS patients (pCO2 > 7.33 kPa) receiving regional citrate anticoagulation (RCA) based CKRT in a prospective, randomized-controlled pilot-study across five intensive care units at the Charité-Universitätsmedizin Berlin, Germany. Patients were randomly assigned 1:1 to the control group with bicarbonate targeted to 24 mmol/l or pCO2-adapted-CKRT with target bicarbonate corresponding to physiological renal compensation. Study duration was six days. Primary outcome was bicarbonate after 72 h. Secondary endpoints included safety and clinical endpoints. Endpoints were assessed in all patients receiving treatment. RESULTS: From September 2021 to May 2023 40 patients (80% male) were enrolled. 19 patients were randomized to the control group, 21 patients were randomized to pCO2-adapted-CKRT. Five patients were excluded before receiving treatment: three in the control group (consent withdrawal, lack of inclusion criteria fulfillment (n = 2)) and two in the intervention group (lack of inclusion criteria fulfillment, sudden unexpected death) and were therefore not included in the analysis. Median plasma bicarbonate 72 h after randomization was significantly higher in the intervention group (30.70 mmol/l (IQR 29.48; 31.93)) than in the control group (26.40 mmol/l (IQR 25.63; 26.88); p < 0.0001). More patients in the intervention group received lung protective ventilation defined as tidal volume < 8 ml/kg predicted body weight. Thirty-day mortality was 10/16 (63%) in the control group vs. 8/19 (42%) in the intervention group (p = 0.26). CONCLUSION: Tailoring CKRT to physiological renal compensation of respiratory acidosis appears feasible and safe with the potential to improve patient care in hypercapnic ARDS. TRIAL REGISTRATION: The trial was registered in the German Clinical Trials Register (DRKS00026177) on September 9, 2021 and is now closed.

Spot urinary sodium in CKD patients: correlation with 24h-excretion and evaluation of commonly used prediction equations.

BACKGROUND: Salt intake in CKD patients can affect cardiovascular risk and kidney disease progression. Twenty-four hour (24h) urine collections are often used to investigate salt metabolism but are cumbersome to perform. We assessed urinary sodium (U-Na) concentration in spot urine samples and investigated the correlation with 24h U-Na excretion and concentration in CKD patients under nephrological care. Further, we studied the role of CKD stage and diuretics and evaluated the performance of commonly used formulas for the prediction of 24h U-Na excretion from spot urine samples. METHODS: One hundred eight patients of the German Chronic Kidney Disease (GCKD) study were included. Each participant collected a 24h urine and two spot urine samples within the same period. The first spot urine sample (AM) was part of the second morning urine. The second urine sample was collected before dinner (PM). Patients were advised to take their medication as usual without changing dietary habits. U-Na concentrations in the two spot urine samples and their average ((AM + PM)/2) were correlated with U-Na concentration and total Na excretion in the 24h urine collections. Correlations were subsequently studied after stratification by CKD stage and diuretic intake. The usefulness of three commonly applied equations to estimate 24h U-Na excretion from spot urine samples (Kawasaki, Tanaka and Intersalt) was determined using Bland-Altman plots, analyses of sensitivity, specificity, as well as positive (PPV) and negative predictive values (NPV). RESULTS: Participants (42 women, 66 men) were on average (± SD) 62.2 (± 11.9) years old, with a mean serum creatinine of 1.6 (± 0.5) mg/dl. 95% had arterial hypertension, 37% diabetes mellitus and 55% were on diuretics. The best correlation with 24h U-Na total excretion was found for the PM spot U-Na sample. We also found strong correlations when comparing spot and 24h urine U-Na concentration. Correction of spot U-Na for U-creatinine did not improve strength of correlations. Neither CKD stage, nor intake of diuretics had significant impact on these correlations. All examined formulas revealed a significant mean bias. The lowest mean bias and the strongest correlation between estimated and measured U-Na excretion in 24h were obtained using the Tanaka-formula. Also, application of the Tanaka-formula with PM U-Na provided best sensitivity, specificity, PPV and NPV to estimate U-Na excretion > 4g/d corresponding to a salt consumption > 10g/d. CONCLUSION: U-Na concentration of spot urine samples correlated with 24h U-Na excretion especially when PM spot U-Na was used. However, correlation coefficients were relatively low. Neither CKD stage nor intake of diuretics appeared to have an influence on these correlations. There was a significant bias for all tested formulas with the Tanaka-formula providing the strongest correlation with measured 24h U-Na excretion. In summary, using spot urine samples together with the Tanaka-formula in epidemiological studies appears feasible to determine associations between approximate salt intake and outcomes in CKD patients. However, the usefulness of spot-urine samples to guide and monitor salt consumption in individual patients remains limited.

Identifying individuals at risk of needing CKD associated medications in a European kidney disease cohort.

BACKGROUND: The consequences of chronic kidney disease (CKD) can be addressed with a range of pharmacotherapies primarily prescribed by nephrologists. More accurate information regarding future CKD-related pharmacotherapy requirements could guide clinical decisions including follow-up frequency. METHODS: Following assignment to derivation and validation groups (2,1), variables predicting individually future use of vitamin D receptor agonists (VDRA), phosphate binders, erythropoiesis stimulating agents (ESAs) and iron were identified using logistic regression in a prospective cohort study containing demography, comorbidity, hospitalization, laboratory, and mortality data in patients with CKD stage G4/G5 across six European countries. Discriminative ability was measured using C-statistics, and predicted probability of medication use used to inform follow-up frequency. RESULTS: A total of 2196 patients were included in the analysis. During a median follow-up of 735 days 648 initiated hemodialysis and 1548 did not. Combinations of age, diabetes status and iPTH, calcium, hemoglobin and serum albumin levels predicted the use of ESA, iron, phosphate binder or VDRA, with C-statistics of 0.70, 0.64, 0.73 and 0.63 in derivation cohorts respectively. Model performance in validation cohorts were similar. Sixteen percent of patients were predicted to have a likelihood of receiving any of these medications of less than 20%. CONCLUSIONS: In a multi-country CKD cohort, prediction of ESA and phosphate binder use over a two-year period can be made based on patient characteristics with the potential to reduce frequency of follow-up in individuals with low risk for requiring these medications.

The Costs of Anonymization: Case Study Using Clinical Data.

BACKGROUND: Sharing data from clinical studies can accelerate scientific progress, improve transparency, and increase the potential for innovation and collaboration. However, privacy concerns remain a barrier to data sharing. Certain concerns, such as reidentification risk, can be addressed through the application of anonymization algorithms, whereby data are altered so that it is no longer reasonably related to a person. Yet, such alterations have the potential to influence the data set's statistical properties, such that the privacy-utility trade-off must be considered. This has been studied in theory, but evidence based on real-world individual-level clinical data is rare, and anonymization has not broadly been adopted in clinical practice. OBJECTIVE: The goal of this study is to contribute to a better understanding of anonymization in the real world by comprehensively evaluating the privacy-utility trade-off of differently anonymized data using data and scientific results from the German Chronic Kidney Disease (GCKD) study. METHODS: The GCKD data set extracted for this study consists of 5217 records and 70 variables. A 2-step procedure was followed to determine which variables constituted reidentification risks. To capture a large portion of the risk-utility space, we decided on risk thresholds ranging from 0.02 to 1. The data were then transformed via generalization and suppression, and the anonymization process was varied using a generic and a use case-specific configuration. To assess the utility of the anonymized GCKD data, general-purpose metrics (ie, data granularity and entropy), as well as use case-specific metrics (ie, reproducibility), were applied. Reproducibility was assessed by measuring the overlap of the 95% CI lengths between anonymized and original results. RESULTS: Reproducibility measured by 95% CI overlap was higher than utility obtained from general-purpose metrics. For example, granularity varied between 68.2% and 87.6%, and entropy varied between 25.5% and 46.2%, whereas the average 95% CI overlap was above 90% for all risk thresholds applied. A nonoverlapping 95% CI was detected in 6 estimates across all analyses, but the overwhelming majority of estimates exhibited an overlap over 50%. The use case-specific configuration outperformed the generic one in terms of actual utility (ie, reproducibility) at the same level of privacy. CONCLUSIONS: Our results illustrate the challenges that anonymization faces when aiming to support multiple likely and possibly competing uses, while use case-specific anonymization can provide greater utility. This aspect should be taken into account when evaluating the associated costs of anonymized data and attempting to maintain sufficiently high levels of privacy for anonymized data. TRIAL REGISTRATION: German Clinical Trials Register DRKS00003971; https://drks.de/search/en/trial/DRKS00003971. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1093/ndt/gfr456.

Intra- and Interobserver Study Investigating the Adapted EFSUMB Bosniak Cyst Categorization Proposed for Contrast-Enhanced Ultrasound (CEUS) in 2020.

BACKGROUND: To investigate the inter- and intraobserver variability in comparison to an expert gold standard of the new and modified renal cyst Bosniak classification proposed for contrast-enhanced ultrasound findings (CEUS) by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) in 2020. MATERIALS AND METHODS: 84 CEUS examinations for the evaluation of renal cysts were evaluated retrospectively by six readers with different levels of ultrasound expertise using the modified Bosniak classification proposed for CEUS. All cases were anonymized, and each case was rated twice in randomized order. The consensus reading of two experts served as the gold standard, to which all other readers were compared. Statistical analysis was performed using Cohen's weighted kappa tests, where appropriate. RESULTS: Intraobserver variability showed substantial to almost perfect agreement (lowest kappa κ=0.74; highest kappa κ=0.94), with expert level observers achieving the best results. Comparison to the gold standard was almost perfect for experts (highest kappa κ=0.95) and lower for beginner and intermediate level readers still achieving mostly substantial agreement (lowest kappa κ=0.59). Confidence of rating was highest for Bosniak classes I and IV and lowest for classes IIF and III. CONCLUSION: Categorization of cystic renal lesions based on the Bosniak classification proposed by the EFSUMB in 2020 showed very good reproducibility. While even less experienced observers achieved mostly substantial agreement, training remains a major factor for better diagnostic performance.

Successful Desensitization with Imlifidase and Daratumumab in a Highly Immunized, Crossmatch Positive, Blood Group-Incompatible Living-Donor Re-Transplant Recipient with Systemic Lupus Erythematosus and Antiphospholipid Syndrome.

Introduction: The transplantation of highly sensitized patients remains a major obstacle. Immunized patients wait longer for a transplant if not prioritized, and if transplanted, their transplant outcome is worse. Case Presentation: We report a successful AB0- and HLA-incompatible living donor kidney transplantation in a 35-year-old female patient with systemic lupus erythematosus (SLE) and antiphospholipid syndrome. The patient had a positive T- and B-cell complement-dependent cytotoxicity (CDC) crossmatch and previous graft loss due to renal vein thrombosis. We treated the patient with intravenous immunoglobulins, rituximab, horse anti-thymocyte globulin, daratumumab, and imlifidase, besides standard immunosuppression. All IgG antibodies were sensitive to imlifidase treatment. Besides donor-specific HLA antibodies, anti-dsDNA antibodies and antiphospholipid antibodies were cleaved. The patient initially had delayed graft function. Two kidney biopsies (day 7 and day 14) revealed acute tubular necrosis without signs of HLA antibody-mediated rejection. On posttransplant day 30, hemodialysis was stopped, and creatinine levels declined over the next weeks to a baseline creatinine of about 1.7 mg/dL after 12 months. Conclusion: In this case, a novel multimodal treatment strategy including daratumumab and imlifidase enabled successful kidney transplantation for a highly immunized patient with antiphospholipid antibodies.

Novel anemia therapies in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Anemia is common in patients with chronic kidney disease and is associated with a high burden of morbidity and adverse clinical outcomes. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline for the diagnosis and management of anemia in chronic kidney disease. Since then, new data from studies assessing established and emerging therapies for the treatment of anemia and iron deficiency have become available. Beginning in 2019, KDIGO planned 2 Controversies Conferences to review the new evidence and its potential impact on the management of anemia in clinical practice. Here, we report on the second of these conferences held virtually in December 2021, which focused on a new class of agents-the hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs). This report provides a review of the consensus points and controversies from this second conference and highlights areas that warrant prioritization for future research.

Trends and perspectives for improving quality of chronic kidney disease care: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Chronic kidney disease (CKD) affects over 850 million people globally, and the need to prevent its development and progression is urgent. During the past decade, new perspectives have arisen related to the quality and precision of care for CKD, owing to the development of new tools and interventions for CKD diagnosis and management. New biomarkers, imaging methods, artificial intelligence techniques, and approaches to organizing and delivering healthcare may help clinicians recognize CKD, determine its etiology, assess the dominant mechanisms at given time points, and identify patients at high risk for progression or related events. As opportunities to apply the concepts of precision medicine for CKD identification and management continue to be developed, an ongoing discussion of the potential implications for care delivery is required. The 2022 KDIGO Controversies Conference on Improving CKD Quality of Care: Trends and Perspectives examined and discussed best practices for improving the precision of CKD diagnosis and prognosis, managing the complications of CKD, enhancing the safety of care, and maximizing patient quality of life. Existing tools and interventions currently available for the diagnosis and treatment of CKD were identified, with discussion of current barriers to their implementation and strategies for improving the quality of care delivered for CKD. Key knowledge gaps and areas for research were also identified.

Altered increase in STAT1 expression and phosphorylation in severe COVID-19.

The interferon pathway, a key antiviral defense mechanism, is being considered as a therapeutic target in COVID-19. Both, substitution of interferon and JAK/STAT inhibition to limit cytokine storms have been proposed. However, little is known about possible abnormalities in STAT signaling in immune cells during SARS-CoV-2 infection. We investigated downstream targets of interferon signaling, including STAT1, STAT2, pSTAT1 and 2, and IRF1, 7 and 9 by flow cytometry in 30 patients with COVID-19, 17 with mild, and 13 with severe infection. We report upregulation of STAT1 and IRF9 in mild and severe COVID-19 cases, which correlated with the IFN-signature assessed by Siglec-1 (CD169) expression on peripheral monocytes. Interestingly, Siglec-1 and STAT1 in CD14+ monocytes and plasmablasts showed lower expression among severe cases compared to mild cases. Contrary to the baseline STAT1 expression, the phosphorylation of STAT1 was enhanced in severe COVID-19 cases, indicating a dysbalanced JAK/STAT signaling that fails to induce transcription of interferon stimulated response elements (ISRE). This abnormality persisted after IFN-α and IFN-γ stimulation of PBMCs from patients with severe COVID-19. Data suggest impaired STAT1 transcriptional upregulation among severely infected patients may represent a potential predictive biomarker and would allow stratification of patients for certain interferon-pathway targeted treatments.