Urinary Kidney Injury Biomarkers Are Associated with Ischemia-Reperfusion Injury Severity in Kidney Allograft Recipients.

BACKGROUND: We explored the potential of emerging and conventional urinary kidney injury biomarkers in recipients of living donor (LD) or donation after circulatory death (DCD) kidney transplantation, patients with chronic kidney disease (CKD), and individuals from the general population. METHODS: Urine samples from kidney allograft recipients with mild (LD; n = 199) or severe (DCD; n = 71) ischemia-reperfusion injury (IRI) were analyzed for neutrophil gelatinase-associated lipocalin (NGAL), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases 2 (TIMP2), kidney injury molecule-1 (KIM-1), chemokine C-X-C motif (CXCL9), solute carrier family 22 member 2 (SLC22A2), nephrin, and uromodulin (UMOD) by quantitative multiplex LC-MS/MS analysis. The fold-change in biomarker levels was determined in mild and severe IRI and in patients with CKD stage 1-2 (n = 127) or stage ≥3 (n = 132) in comparison to the general population (n = 1438). Relationships between the biomarkers and total protein, ß2-microglobulin (B2M), creatinine, and osmolality were assessed. RESULTS: NGAL, IGFBP7, TIMP2, KIM-1, CXCL9, and UMOD were quantifiable, whereas nephrin and SLC22A2 were below the limit of detection. Kidney injury biomarkers were increased up to 6.2-fold in allograft recipients with mild IRI and 8.3-fold in recipients with severe IRI, compared to the reference population, with the strongest response observed for NGAL and B2M. In CKD stage 1-2, B2M, NGAL, IGFBP7, TIMP2, KIM-1, UMOD, and CXCL9 were not altered, but in individuals with CKD stage ≥3, B2M, NGAL, and KIM-1 were increased up to 1.3-fold. IGFBP7, TIMP2, NGAL, and CXCL9 were strongly correlated (all r ≥ 0.8); correlations with B2M and TP were smaller (all r ≤ 0.6). CONCLUSIONS: IRI, but not stable CKD, was associated with increased urinary levels of kidney injury biomarkers determined by LC-MS/MS. Absolute and multiplexed protein quantitation by LC-MS/MS is an effective strategy for biomarker panel evaluation for translation toward the clinical laboratory.

Clinical and patient-reported trajectories at end-of-life in older patients with advanced CKD.

BACKGROUND: We explore longitudinal trajectories of clinical indicators, patient-reported outcomes, and hospitalizations, in the years preceding death in a population of older patients with advanced chronic kidney disease (CKD). METHODS: The EQUAL study is a European observational prospective cohort study with an incident eGFR <20 ml/min per 1.73 m2 and ≥65 years of age. The evolution of each clinical indicator was explored using generalized additive models during the 4 years preceding death. RESULTS: We included 661 decedents with a median time to death of 2.0 years (IQR 0.9-3.2). During the years preceding death, eGFR, Subjective Global Assessment score, and blood pressure declined, with accelerations seen at 6 months preceding death. Serum hemoglobin, hematocrit, cholesterol, calcium, albumin, and sodium values declined slowly during follow-up, with accelerations observed between 6 and 12 months preceding death. Physical and mental quality of life declined linearly throughout follow-up. The number of reported symptoms was stable up to 2 years prior to death, with an acceleration observed at 1 year prior to death. The rate of hospitalization was stable at around one hospitalization per person year, increasing exponentially at 6 months preceding death. CONCLUSIONS: We identified clinically relevant physiological accelerations in patient trajectories that began ∼6 to 12 months prior to death, which are likely multifactorial in nature, but correlate with a surge in hospitalizations. Further research should focus on how to effectively use this knowledge to inform patient and family expectations, to benefit the planning of (end-of-life) care, and to establish clinical alert systems.

Serum Potassium and Risk of Death or Kidney Replacement Therapy in Older People With CKD Stages 4-5: Eight-Year Follow-up.

RATIONALE & OBJECTIVE: Hypokalemia may accelerate kidney function decline. Both hypo- and hyperkalemia can cause sudden cardiac death. However, little is known about the relationship between serum potassium and death or the occurrence of kidney failure requiring replacement therapy (KRT). We investigated this relationship in older people with chronic kidney disease (CKD) stage 4-5. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: We followed 1,714 patients (≥65 years old) from the European Quality (EQUAL) study for 8 years from their first estimated glomerular filtration rate (eGFR)<20mL/min/1.73m2 measurement. EXPOSURE: Serum potassium was measured every 3 to 6 months and categorized as≤3.5,>3.5-≤4.0,>4.0-≤4.5,>4.5-≤5.0 (reference),>5.0-≤5.5, >5.5-≤6.0, and>6.0mmol/L. OUTCOME: The combined outcome death before KRT or start of KRT. ANALYTICAL APPROACH: The association between categorical and continuous time-varying potassium and death or KRT start was examined using Cox proportional hazards and restricted cubic spline analyses, adjusted for age, sex, diabetes, cardiovascular disease, renin-angiotensin-aldosterone system (RAAS) inhibition, eGFR, and subjective global assessment (SGA). RESULTS: At baseline, 66% of participants were men, 42% had diabetes, 47% cardiovascular disease, and 54% used RAAS inhibitors. Their mean age was 76±7 (SD) years, mean eGFR was 17±5 (SD) mL/min/1.73m2, and mean SGA was 6.0±1.0 (SD). Over 8 years, 414 (24%) died before starting KRT, and 595 (35%) started KRT. Adjusted hazard ratios for death or KRT according to the potassium categories were 1.6 (95% CI, 1.1-2.3), 1.4 (95% CI, 1.1-1.7), 1.1 (95% CI, 1.0-1.4), 1 (reference), 1.1 (95% CI, 0.9-1.4), 1.8 (95% CI, 1.4-2.3), and 2.2 (95% CI, 1.5-3.3). Hazard ratios were lowest at a potassium of about 4.9mmol/L. LIMITATIONS: Shorter intervals between potassium measurements would have allowed for more precise estimations. CONCLUSIONS: We observed a U-shaped relationship between serum potassium and death or KRT start among patients with incident CKD 4-5, with a nadir risk at a potassium level of 4.9mmol/L. These findings underscore the potential importance of preventing both high and low potassium in patients with CKD 4-5. PLAIN-LANGUAGE SUMMARY: Abnormal potassium blood levels may increase the risk of death or kidney function decline, especially in older people with chronic kidney disease (CKD). We studied 1,714 patients aged≥65 years with advanced CKD from the European Quality (EQUAL) study and followed them for 8 years. We found that both low and high levels of potassium were associated with an increased risk of death or start of kidney replacement therapy, with the lowest risk observed at a potassium level of 4.9 mmol/L. In patients with CKD, the focus is often on preventing high blood potassium. However, this relatively high optimum potassium level stresses the potential importance of also preventing low potassium levels in older patients with advanced CKD.

Association between CKD-MBD and mortality in older patients with advanced CKD-results from the EQUAL study.

BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication of CKD; it is associated with higher mortality in dialysis patients, while its impact in non-dialysis patients remains mostly unknown. We investigated the associations between parathyroid hormone (PTH), phosphate and calcium (and their interactions), and all-cause, cardiovascular (CV) and non-CV mortality in older non-dialysis patients with advanced CKD. METHODS: We used data from the European Quality study, which includes patients aged ≥65 years with estimated glomerular filtration rate ≤20 mL/min/1.73 m2 from six European countries. Sequentially adjusted Cox models were used to assess the association between baseline and time-dependent CKD-MBD biomarkers and all-cause, CV and non-CV mortality. Effect modification between biomarkers was also assessed. RESULTS: In 1294 patients, the prevalence of CKD-MBD at baseline was 94%. Both PTH [adjusted hazard ratio (aHR) 1.12, 95% confidence interval (CI) 1.03-1.23, P = .01] and phosphate (aHR 1.35, 95% CI 1.00-1.84, P = .05), but not calcium (aHR 1.11, 95% CI 0.57-2.17, P = .76), were associated with all-cause mortality. Calcium was not independently associated with mortality, but modified the effect of phosphate, with the highest mortality risk found in patients with both hypercalcemia and hyperphosphatemia. PTH level was associated with CV mortality, but not with non-CV mortality, whereas phosphate was associated with both CV and non-CV mortality in most models. CONCLUSIONS: CKD-MBD is very common in older non-dialysis patients with advanced CKD. PTH and phosphate are independently associated with all-cause mortality in this population. While PTH level is only associated with CV mortality, phosphate seems to be associated with both CV and non-CV mortality.

Effect of residual kidney function and dialysis adequacy on chronic pruritus in dialysis patients.

BACKGROUND: Chronic kidney disease-associated pruritus (CKD-aP) is common in dialysis patients, and is associated with lower quality of life and increased risk of death. We investigated the association between residual estimated glomerular filtration rate (eGFR), dialysis adequacy or serum phosphate level and CKD-aP in incident dialysis patients. METHODS: A total of 1256 incident hemodialysis (HD) and 670 peritoneal dialysis (PD) patients (>18 years) from the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) study were included (1997-2007) and followed until death, transplantation or a maximum of 10 years. CKD-aP was measured using a single item of the Kidney Disease Quality of Life Instrument-36. The associations were studied by logistic and linear regression analyses, adjusted for potential baseline confounders. RESULTS: At baseline mean (standard deviation) age was 60 (16) years, 62% were men and median (interquartile range) residual eGFR was 3.4 (1.7; 5.3) mL/min/1.73 m2. The prevalence of CKD-aP (∼70%) was similar in HD and PD. It was observed that 12 months after starting dialysis (after multivariable adjustment) each 1 mL/min/1.73 m2 higher residual eGFR, one unit higher total weekly Kt/V, or 1 mmol/L lower serum phosphate level was associated with lower burden of CKD-aP in HD and PD patients of -0.05 (95% CI -0.09; -0.02) and -0.09 (95% CI -0.13; -0.05), -0.15 (95% CI -0.26; -0.05) and -0.35 (95% CI -0.54; -0.16), and of -0.34 (95%CI: -0.51; -0.17) and -0.45 (95%CI: -0.71; -0.19), respectively. We found no association between dialysis Kt/V and CKD-aP. CONCLUSIONS: Higher residual eGFR and lower serum phosphate level, but not the dialysis dose, were related with lower burden of CKD-aP in dialysis patients.

Symptom Burden before and after Dialysis Initiation in Older Patients.

BACKGROUND AND OBJECTIVES: For older patients with kidney failure, lowering symptom burden may be more important than prolonging life. Dialysis initiation may affect individual kidney failure-related symptoms differently, but the change in symptoms before and after start of dialysis has not been studied. Therefore, we investigated the course of total and individual symptom number and burden before and after starting dialysis in older patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The European Quality (EQUAL) study is an ongoing, prospective, multicenter study in patients ≥65 years with an incident eGFR ≤20 ml/min per 1.73 m2. Using the dialysis symptom index (DSI), 30 symptoms were assessed every 3-6 months between 2012 and 2021. Scores for symptom number range from zero to 30 and, for burden, from zero to 150, with higher scores indicating more severity. Using mixed effects models, we studied symptoms during the year preceding and the year after dialysis initiation. RESULTS: We included 456 incident patients on dialysis who filled out at least one DSI during the year before or after dialysis. At dialysis initiation, mean (SD) participant age was 76 (6) years, 75% were men, mean (SD) eGFR was 8 (3) ml/min per 1.73 m2, 44% had diabetes, and 46% had cardiovascular disease. In the year before dialysis initiation, symptom number increased +3.6 (95% confidence interval [95% CI], +2.5 to +4.6) and symptom burden increased +13.3 (95% CI, +9.5 to +17.0). In the year after, symptom number changed -0.9 (95% CI, -3.4 to +1.5) and burden decreased -5.9 (95% CI, -14.9 to -3.0). At dialysis initiation, "fatigue," "decreased interest in sex," and "difficulty becoming sexually aroused" had the highest prevalence of 81%, 69%, and 68%, respectively, with a burden of 2.7, 2.4, and 2.3, respectively. "Fatigue" somewhat improved after dialysis initiation, whereas the prevalence and burden of sexual symptoms further increased. CONCLUSIONS: Symptom burden worsened considerably before and stabilized after dialysis initiation. "Fatigue," "decreased interest in sex," and "difficulty becoming sexually aroused" were considered most burdensome, of which only "fatigue" somewhat improved after dialysis initiation.

Quality of Life before and after the Start of Dialysis in Older Patients.

BACKGROUND AND OBJECTIVES: In older people with kidney failure, improving health-related quality of life is often more important than solely prolonging life. However, little is known about the effect of dialysis initiation on health-related quality of life in older patients. Therefore, we investigated the evolution of health-related quality of life before and after starting dialysis in older patients with kidney failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The European Quality study is an ongoing prospective, multicenter study in patients aged ≥65 years with an incident eGFR ≤20 ml/min per 1.73 m2. Between April 2012 and December 2021, health-related quality of life was assessed every 3-6 months using the 36-item Short-Form Health Survey (SF-36), providing a mental component summary (MCS) and a physical component summary (PCS). Scores range from zero to 100, with higher scores indicating better health-related quality of life. With linear mixed models, we explored the course of health-related quality of life during the year preceding and following dialysis initiation. RESULTS: In total, 457 patients starting dialysis were included who filled out at least one SF-36 during follow-up. At dialysis initiation, mean ± SD age was 76±6 years, eGFR was 8±3 ml/min per 1.73 m2, 75% were men, 9% smoked, 45% had diabetes, and 46% had cardiovascular disease. Median (interquartile range) MCS was 53 (38-73), and median PCS was 39 (27-58). During the year preceding dialysis, estimated mean change in MCS was -13 (95% confidence interval, -17 to -9), and in PCS, it was -11 (95% confidence interval, -15 to -7). In the year following dialysis, estimated mean change in MCS was +2 (95% confidence interval, -7 to +11), and in PCS, it was -2 (95% confidence interval, -11 to +7). Health-related quality-of-life patterns were similar for most mental (mental health, role emotional, social functioning, vitality) and physical domains (physical functioning, bodily pain, role physical). CONCLUSIONS: Patients experienced a clinically relevant decline of both mental and physical health-related quality of life before dialysis initiation, which stabilized thereafter. These results may help inform older patients with kidney failure who decided to start dialysis.

Health-Related Quality-of-Life Trajectories over Time in Older Men and Women with Advanced Chronic Kidney Disease.

BACKGROUND AND OBJECTIVES: The effect of sex on longitudinal health-related quality of life remains unknown in CKD. Here we assess differences in the sex-specific evolution of health-related quality of life in older men and women with advanced CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The European Quality Study on Treatment in Advanced Chronic Kidney Disease is a European observational prospective cohort study in referred patients with CKD and an incident eGFR<20 ml/min per 1.73 m2 who are ≥65 years of age not on dialysis. Health-related quality of life was measured using the 36-Item Short Form Survey at 3- to 6-month intervals between April 2012 and September 2020, providing Physical Component Summary and Mental Component Summary scores. Trajectories were modeled by sex using linear mixed models, and sex differences in health-related quality-of-life slope were explored. RESULTS: We included 5345 health-related quality-of-life measurements in 1421 participants. At baseline, women had considerably lower mean Physical Component Summary (42) and Mental Component Summary (60) compared with men (Physical Component Summary: 55; Mental Component Summary: 69; P<0.001). However, during follow-up, Physical Component Summary and Mental Component Summary scores declined approximately twice as fast in men (Physical Component Summary: 2.5 per year; 95% confidence interval, 1.8 to 3.1; Mental Component Summary: 2.7 per year; 95% confidence interval, 2.0 to 3.4) compared with in women (Physical Component Summary: 1.1 per year; 95% confidence interval, 0.1 to 2.0; Mental Component Summary: 1.6 per year; 95% confidence interval, 0.7 to 2.6). This difference was partly attenuated after adjusting for important covariates, notably eGFR decline. Higher serum phosphate, lower hemoglobin, and the presence of preexisting diabetes were associated with lower Physical Component Summary and Mental Component Summary scores in men but to a lesser extent in women. CONCLUSIONS: Among older men and women with advanced CKD, women had lower health-related quality of life at baseline, but men experienced a more rapid decline in health-related quality of life over time.

Serum Potassium and Mortality Risk in Hemodialysis Patients: A Cohort Study.

RATIONALE & OBJECTIVE: Both hypo- and hyperkalemia can cause fatal cardiac arrhythmias. Although predialysis serum potassium level is a known modifiable risk factor for death in patients receiving hemodialysis, especially for hypokalemia, this risk may be underestimated. Therefore, we investigated the relationship between predialysis serum potassium level and death in incident hemodialysis patients and whether there is an optimum level. STUDY DESIGN: Prospective multicenter cohort study. SETTING & PARTICIPANTS: 1,117 incident hemodialysis patients (aged >18 years) from the Netherlands Cooperative Study on the Adequacy of Dialysis-2 study were included and followed from their first hemodialysis treatment until death, transplantation, switch to peritoneal dialysis, or a maximum of 10 years. EXPOSURE: Predialysis serum potassium levels were obtained every 6 months and divided into 6 categories: ≤4.0 mmol/L, >4.0 mmol/L to ≤4.5 mmol/L, >4.5 mmol/L to ≤5.0 mmol/L, >5.0 mmol/L to ≤5.5 mmol/L (reference), >5.5 mmol/L to ≤6.0 mmol/L, and >6.0 mmol/L. OUTCOMES: 6-month all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards and restricted cubic spline analyses with time-dependent predialysis serum potassium levels were used to calculate the adjusted HRs for death. RESULTS: At baseline, the mean age of the patients was 63 years (standard deviation, 14 years), 58% were men, 26% smoked, 24% had diabetes, 32% had cardiovascular disease, the mean serum potassium level was 5.0 mmol/L (standard deviation, 0.8 mmol/L), 7% had a low subjective global assessment score, and the median residual kidney function was 3.5 mL/min/1.73 m2 (IQR, 1.4-4.8 mL/min/1.73 m2). During the 10-year follow-up, 555 (50%) deaths were observed. Multivariable adjusted HRs for death according to the 6 potassium categories were as follows: 1.42 (95% CI, 1.01-1.99), 1.09 (95% CI, 0.82-1.45), 1.21 (95% CI, 0.94-1.56), 1 (reference), 0.95 (95% CI, 0.71-1.28), and 1.32 (95% CI, 0.97-1.81). LIMITATIONS: Shorter intervals between potassium measurements would have allowed for more precise mortality risk estimations. CONCLUSIONS: We found a U-shaped relationship between serum potassium level and death in incident hemodialysis patients. A low predialysis serum potassium level was associated with a 1.4-fold stronger risk of death than the optimal level of approximately 5.1 mmol/L. These results may imply the cautious use of potassium-lowering therapy and a potassium-restricted diet in patients receiving hemodialysis.

Acute kidney injury and kidney replacement therapy in COVID-19: a systematic review and meta-analysis.

BACKGROUND: Acute kidney injury (AKI) can affect hospitalized patients with coronavirus disease 2019 (COVID-19), with estimates ranging between 0.5% and 40%. We performed a systematic review and meta-analysis of studies reporting incidence, mortality and risk factors for AKI in hospitalized COVID-19 patients. METHODS: We systematically searched 11 electronic databases until 29 May 2020 for studies in English reporting original data on AKI and kidney replacement therapy (KRT) in hospitalized COVID-19 patients. Incidences of AKI and KRT and risk ratios for mortality associated with AKI were pooled using generalized linear mixed and random-effects models. Potential risk factors for AKI were assessed using meta-regression. Incidences were stratified by geographic location and disease severity. RESULTS: A total of 3042 articles were identified, of which 142 studies were included, with 49 048 hospitalized COVID-19 patients including 5152 AKI events. The risk of bias of included studies was generally low. The pooled incidence of AKI was 28.6% [95% confidence interval (CI) 19.8-39.5] among hospitalized COVID-19 patients from the USA and Europe (20 studies) and 5.5% (95% CI 4.1-7.4) among patients from China (62 studies), whereas the pooled incidence of KRT was 7.7% (95% CI 5.1-11.4; 18 studies) and 2.2% (95% CI 1.5-3.3; 52 studies), respectively. Among patients admitted to the intensive care unit, the incidence of KRT was 20.6% (95% CI 15.7-26.7; 38 studies). Meta-regression analyses showed that age, male sex, cardiovascular disease, diabetes mellitus, hypertension and chronic kidney disease were associated with the occurrence of AKI; in itself, AKI was associated with an increased risk of mortality, with a pooled risk ratio of 4.6 (95% CI 3.3-6.5). CONCLUSIONS: AKI and KRT are common events in hospitalized COVID-19 patients, with estimates varying across geographic locations. Additional studies are needed to better understand the underlying mechanisms and optimal treatment of AKI in these patients.

The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus.

OBJECTIVE: In systemic lupus erythematosus (SLE) patients, excessive formation of neutrophil extracellular traps (NETs) is observed and their degradation is impaired. In vitro, immune complexes (ICx) trigger NET formation while NET-derived DNA is a postulated autoantigen for anti-nuclear autoantibodies (ANAs), found in SLE. Based on these self-perpetuating mechanisms in SLE, this study investigates whether interfering with ICx formation using a combination of rituximab (RTX) and belimumab (BLM) could decrease NET formation and ameliorate disease. METHODS: A phase 2A, open-label, single arm proof-of-concept study was performed wherein 16 SLE patients with severe, refractory disease were treated with a combination of CD20-mediated B-cell depletion with rituximab and sustained inhibition of B-cell activating factor BlyS with belimumab. Besides safety, the study's endpoints were chosen to address the concept of autoantibodies in relation to excessive NET formation. RESULTS: We demonstrated a surge of BlyS levels upon RTX-mediated B-cell depletion which was abrogated by subsequent BLM treatment. As such, therapeutic intervention with RTX + BLM led to specific reductions in ANAs and regression of excessive NET formation. RTX + BLM appeared to be safe and achieved clinically significant responses: low lupus disease activity state was achieved in 10 patients, renal responses in 11 patients and concomitant immunosuppressive medication was tapered in 14 out of the 16 patients. CONCLUSIONS: This study provides novel insights into clinical beneficence of reducing excessive NET formation in SLE by therapeutic targeting ANA production with RTX + BLM. Altogether putting forward a new treatment concept that specifically ameliorates underlying SLE pathophysiology. TRIAL REGISTRATION: ClinicalTrials.gov NCT02284984.