Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. METHODS: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. RESULTS: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. CONCLUSIONS: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.

Risk factors for infection and mortality among hemodialysis patients during COVID-19 pandemic.

PURPOSE: The aim of this study was to evaluate risk factors for COVID-19 infection and mortality and to document if any relation exists between 25 (OH) Vitamin D and COVID-19 infection. METHODS: This retrospective study evaluated 151 HD patients. Patients infected with COVID-19 were compared to patients without the infection. Risk factors for intensive care unit (ICU) stay and mortality were analyzed. Deceased infected patients were also compared to patients who died due to other causes. RESULTS: The mean age of all HD patients was 57.15 ± 15.73 years and 51.7% were male. The mean 25 (OH) Vitamin D level of all patients was 16.48 ± 8.45 ng/ml. Thirty-five infected patients were significantly older, had a higher Charlson comorbidity index (CCI) score. They also had a higher number of patients with diabetic nephropathy, cerebrovascular accident (CVA) and coronary heart disease (CHD). Patients who needed to stay in ICU had higher CCI score, a higher number of patients with diabetic nephropathy, pulmonary diseases and had statistically significantly higher CRP levels. Deceased infected patients were significantly older, had higher CCI scores and lower PTH than survived infected patients. Deceased infected patients had lower PTH, but had significantly lower leukocyte, lymphocyte counts and urea levels at admission when compared to patients who died due to other causes. Patients with poor prognosis had lower neutrophil and lymphocyte counts before infection and at admission; respectively. 25 (OH) Vitamin D level was not related to the risk of COVID-19 infection, ICU stay or mortality. CONCLUSION: Older age, higher CCI scores, diabetic nephropathy, CHD, CVA, pulmonary diseases, and lower neutrophil and lymphocyte counts were found as poor prognostic factors. The comparisons yielded no significant finding for 25 (OH) Vitamin D, acetylsalicylic acid, erythropoietin, intravenous iron, ACEI, ARBs, and dialysis adequacy parameters.

End-stage kidney disease and COVID-19 in an urban safety-net hospital in Boston, Massachusetts.

INTRODUCTION: End-stage kidney disease (ESKD) patients are at a high risk for Coronavirus Disease 2019 (COVID-19). In this study, we compared characteristics and outcomes of ESKD and non-ESKD patients admitted with COVID-19 to a large safety-net hospital. METHODS: We evaluated 759 adults (45 with ESKD) hospitalized with COVID-19 in Spring of 2020. We examined clinical characteristics, laboratory measures and clinical outcomes. Logistic regression analyses were performed to investigate the associations between ESKD status and outcomes. RESULTS: 73% of ESKD and 47% of non-ESKD patients identified as Black (p = 0.002). ESKD patients were older and had higher rates of comorbidities. Admission ferritin was approximately 6-fold higher in ESKD patients. During hospitalization, the rise in white blood cell count, lactate dehydrogenase, ferritin and C-reactive protein, and the decrease in platelet count and serum albumin were all significantly greater in ESKD patients. The in-hospital mortality was higher for ESKD [18% vs. 10%; multivariable adjusted odds ratio 1.5 (95% CI, 0.48-4.70)], but this did not reach statistical significance. CONCLUSIONS: Among hospitalized COVID-19 patients, ESKD patients had more co-morbidities and more robust inflammatory response than non-ESKD patients. The odds ratio point estimate for death was higher in ESKD patients, but the difference did not reach statistical significance.

Dialysis circuit clotting in critically ill patients with COVID-19 infection.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) infection has been associated with a hypercoagulable state with increased reports of thrombotic events. Acute kidney injury requiring dialysis is common in critically ill patients and circuit clotting compromises efficacy of treatment. This study aims to analyze the circuit life and circuit clotting during continuous kidney replacement therapy (CKRT) and intermittent hemodialysis in patients with and without COVID-19. METHODS: This is a single-center, retrospective cohort study in critically ill patients undergoing CKRT or intermittent hemodialysis between 1 February 2020 to 22 May 2020. Patients in the intensive care unit (ICU) with COVID-19 infection and contemporary controls who tested negative were included. Co-primary outcomes were functional circuit life for patients on CKRT and all circuit clotting events for patients on CKRT and/or intermittent hemodialysis. RESULTS: Seventy CKRT circuits and 32 intermittent hemodialysis sessions for 12 COVID-19 cases and 22 CKRT circuits and 18 intermittent hemodialysis sessions for 15 controls were analyzed. CKRT circuit clotting was more common in the COVID-19 group compared to the control group (64% vs 36%, p = 0.02), despite higher anticoagulation use in the COVID-19 group (41% vs 14%, p = 0.02). Functional CKRT circuit life was similar in COVID-19 patients and controls (median 11 vs 12 h, p = 0.69). On Cox regression analysis, circuit clotting was similar with hazard ratio (HR) 1.90 [95% confidence interval (CI): 0.89-4.04]; however, clotting was increased in COVID-19 patients after adjustment for anticoagulation use (HR: 3.31 [95% CI 1.49-7.33]). In patients with COVID-19, CKRT circuits with anticoagulation had a longer circuit life compared to CKRT circuits without anticoagulation (median 22 versus 7 h respectively, p <  0.001). Circuit clotting was similar in both groups undergoing intermittent hemodialysis. CONCLUSION: Dialysis clotting amongst COVID-19 patients is increased despite more anticoagulation use and the hazard for clotting is greater especially after adjusting for anticoagulation use. Circuit life was suboptimal in COVID-19 patients on circuits without anticoagulation and therefore routine use of anticoagulation amongst COVID-19 patients should be considered whenever possible.

The COVID-19 Epidemic: Management and Outcomes of Hemodialysis and Peritoneal Dialysis Patients in Stockholm, Sweden.

BACKGROUND: The COVID-19 outbreak has been associated with a high morbidity, mortality, and a risk of long-term sequelae, and patients with severe COVID-19 are at increased risk of acute kidney injury. CKD patients are at high risk of being exposed to COVID-19 and suffer complications and poor outcome. In Sweden, mitigation strategies did not include lockdown. During March-April of 2020, wide-spread infection occurred in Stockholm. METHODS: Management and outcomes in forty hemodialysis (HD) patients and 4 peritoneal dialysis (PD) patients, with symptomatic COVID-19 in greater Stockholm during March and April of 2020 are reported. RESULTS: Twenty-four HD patients (60%) required medical care and hospitalization, whereas 16 patients (40%) were treated at home. Nine patients died (mortality rate of 22.5%), of whom 8 were men. The median age in non-survivors (78 years) was significantly higher than in survivors (p = 0.003). The median time in dialysis (11.5 years) was also significantly longer in non-survivors (p = 0.01). C-reactive protein (CRP) at diagnosis in 7 of non-survivors (median 213 mg/L, range 86-329 mg/L) was significantly higher than the CRP in 25 survivors (median 87 mg/L, range 1-328 mg/L) (p = 0.0003). Maximum CRP also indicated poorer outcome among hospitalized patients (p = 0.0004). The gender imbalance was striking with only men dying apart from 1 elderly woman. Only 4 PD patients were hospitalized with symptomatic COVID-19. One patient died, 2 were discharged, and 1 was treated at the intensive care unit and survived. CONCLUSION: HD patients >70 years were reported with longer dialysis vintage, higher CRP, and males were at an increased risk of dying from COVID-19, whereas those <70 years seemed to have a milder disease. Mitigation strategies to reduce rates of infection in high-risk populations remain essential. Follow-up focusing on long-term prognosis for extrapulmonary manifestations is likely to be important also in dialysis patients.

Longitudinal proteomic profiling of dialysis patients with COVID-19 reveals markers of severity and predictors of death.

End-stage kidney disease (ESKD) patients are at high risk of severe COVID-19. We measured 436 circulating proteins in serial blood samples from hospitalised and non-hospitalised ESKD patients with COVID-19 (n = 256 samples from 55 patients). Comparison to 51 non-infected patients revealed 221 differentially expressed proteins, with consistent results in a separate subcohort of 46 COVID-19 patients. Two hundred and three proteins were associated with clinical severity, including IL6, markers of monocyte recruitment (e.g. CCL2, CCL7), neutrophil activation (e.g. proteinase-3), and epithelial injury (e.g. KRT19). Machine-learning identified predictors of severity including IL18BP, CTSD, GDF15, and KRT19. Survival analysis with joint models revealed 69 predictors of death. Longitudinal modelling with linear mixed models uncovered 32 proteins displaying different temporal profiles in severe versus non-severe disease, including integrins and adhesion molecules. These data implicate epithelial damage, innate immune activation, and leucocyte-endothelial interactions in the pathology of severe COVID-19 and provide a resource for identifying drug targets.

COVID-19 varies from a mild illness in some people to fatal disease in others. Patients with severe disease tend to be older and have underlying medical problems. People with kidney failure have a particularly high risk of developing severe or fatal COVID-19. Patients with severe COVID-19 have high levels of inflammation, causing damage to tissues around the body. Many drugs that target inflammation have already been developed for other diseases. Therefore, to repurpose existing drugs or design new treatments, it is important to determine which proteins drive inflammation in COVID-19. Here, Gisby, Clarke, Medjeral-Thomas et al. measured 436 proteins in the blood of patients with kidney failure and compared the levels between patients who had COVID-19 to those who did not. This revealed that patients with COVID-19 had increased levels of hundreds of proteins involved in inflammation and tissue injury. Using a combination of statistical and machine learning analyses, Gisby et al. probed the data for proteins that might predict a more severe disease progression. In total, over 200 proteins were linked to disease severity, and 69 with increased risk of death. Tracking how levels of blood proteins changed over time revealed further differences between mild and severe disease. Comparing this data with a similar study of COVID-19 in people without kidney failure showed many similarities. This suggests that the findings may apply to COVID-19 patients more generally. Identifying the proteins that are a cause of severe COVID-19 ­ rather than just correlated with it ­ is an important next step that could help to select new drugs for severe COVID-19.

Dynamic assessment of interleukin-6 during hemodialysis and mortality in coronavirus disease-19.

The impact of the newly discovered severe acute respiratory syndrome coronavirus 2 causing coronavirus disease-19 (COVID-19) in hemodialysis patients remains poorly characterized. Some hemodialysis techniques reduce systemic inflammation but their impact on COVID-19 has not been addressed. The aim of this prospective study was to evaluate factors associated with mortality in COVID-19 hemodialysis patients, including the impact of reducing interleukin-6 using a cytokine adsorbent filter. This is a prospective single-center study including 16 hemodialysis patients with COVID-19. All were dialyzed using a polymethyl methacrylate (PMMA) filter. Interleukin-6 levels were obtained before and after the first admission hemodialysis session and at 1 week. Baseline comorbidities, laboratory values, chest X-ray, and treatments were recorded and compared between survivors and non-survivors. Out of 16 patients (13 males, mean age 72 ± 15 years), 4 (25%) died. Factors associated with mortality were dialysis vintage (P = 0.01), chest X-ray infiltrates (P = 0.032), serum C-reactive protein (P = 0.05), and lactate dehydrogenase (P = 0.02) at 1 week, oxygen therapy requirement (P = 0.02) and anticoagulation (P < 0.01). At admission, non-survivors had higher predialysis and postdialysis interleukin-6 levels (P = 0.02 for both) and did not present the reduction of interleukin-6 levels during the dialysis session with PMMA filter that was observed in survivors (survivors vs. non-survivors: 25.0 [17.5-53.2]% vs. -2.8 [-109.4-12.8]% reduction, P = 0.04). A positive balance of interleukin-6 during the admission dialysis was associated with mortality (P = 0.008). In conclusion, in hemodialysis COVID-19 patients, a positive interleukin-6 balance during the admission hemodialysis session was associated with higher mortality.

The risk factors associated with COVID-19-Related death among patients with end-stage renal disease.

BACKGROUND: The extent to which patients with End-stage renal disease (ESRD) are at a higher risk of COVID-19-related death is still unclear. Therefore, the aim of this study was to identify the ESRD patients at increased risk of COVID-19 -related death and its associated factors. METHODS: This retrospective cohort study was conducted on 74 patients with ESRD and 446 patients without ESRD hospitalized for COVID-19 in Alborz province, Iran, from Feb 20 2020 to Apr 26 2020. Data on demographic factors, medical history, Covid-19- related symptoms, and blood tests were obtained from the medical records of patients with confirmed COVID-19. We fitted univariable and multivariable Cox regression models to assess the association of underlying condition ESRD with the COVID-19 in-hospital mortality. Results were presented as crude and adjusted Hazard Ratios (HRs) and 95% confidence intervals (CIs). In the ESRD subgroup, demographic factors, medical history, symptoms, and blood parameters on the admission of survivors were compared with non-survivors to identify factors that might predict a high risk of mortality. RESULTS: COVID-19 patients with ESRD had in-hospital mortality of 37.8% compared to 11.9% for those without ESRD (P value < 0.001). After adjusting for confounding factors, age, sex, and comorbidities, ESRD patients were more likely to experience in-hospital mortality compared to non-ESRD patients (Adjusted HR (95% CI): 2.59 (1.55-4.32)). The Log-rank test revealed that there was a significant difference between the ESRD and non-ESRD groups in terms of the survival distribution (χ2 (1) = 21.18, P-value < 0.001). In the ESRD subgroup, compared to survivors, non-survivors were older, and more likely to present with lack of consciousness or O2 saturation less than 93%; they also had lower lymphocyte but higher neutrophil counts and AST concentration at the presentation (all p -values < 0.05). CONCLUSIONS: Our findings suggested that the presence of ESRD would be regarded as an important risk factor for mortality in COVID-19 patients, especially in those who are older than age 65 years and presented with a lack of consciousness or O2 saturation less than 93%.

Clinical features and outcome of maintenance hemodialysis patients with COVID-19 from a tertiary nephrology care center in Romania.

BACKGROUND: There is limited information about the clinical characteristics, treatment and outcome of maintenance hemodialysis patients with COVID-19. Moreover, regional differences are also conceivable since the extend and severity of outbreaks varied among countries. METHODS: In this retrospective, observational, single-center study, we analyzed the clinical course and outcomes of 37 maintenance hemodialysis patients (median age 64 years, 51% men) hospitalized with COVID-19 from 24 March to 22 May 2020 as confirmed by real-time PCR. RESULTS: The most common symptoms at admission were fatigue (51%), fever (43%), dyspnea (38%) and cough (35%). There were 59% mild/moderate patients and 41% severe/critical patients. Patients in the severe/critical group had a significantly higher atherosclerotic burden since diabetic kidney disease and vascular nephropathies were the most common primary kidney diseases and eighty percent of them had coronary heart disease. Also, Charlson comorbidity score was higher in this group. At admission chest X-ray, 46% had ground-glass abnormalities. Overall, 60% patients received hydroxychloroquine, 22% lopinavir-ritonavir, 11% tocilizumab, 24% systemic glucocorticoids, and 54% received prophylactic anticoagulation. Seven (19%) patients died during hospitalization and 30 were discharged. The main causes of death were cardiovascular (5 patients) and respiratory distress syndrome (2 patients). In Cox regression analysis, lower oxygen saturation, anemia and hypoalbuminemia at admission were associated with increased mortality. CONCLUSIONS: In conclusion, we observed a high mortality rate among maintenance hemodialysis patients hospitalized for COVID-19. Anemia, lower serum albumin and lower basal oxygen saturation at admission were factors associated with poor prognosis.

Safely reducing haemodialysis frequency during the COVID-19 pandemic.

BACKGROUND: Patients undergoing haemodialysis (HD) are at higher risk of developing worse outcomes if they contract COVID-19. In our renal service we reduced HD frequency from thrice to twice-weekly in selected patients with the primary aim of reducing COVID 19 exposure and transmission between HD patients. METHODS: Dialysis unit nephrologists identified 166 suitable patients (38.4% of our HD population) to temporarily convert to twice-weekly haemodialysis immediately prior to the peak of the COVID-19 pandemic in our area. Changes in pre-dialysis weight, systolic blood pressure (SBP) and biochemistry were recorded weekly throughout the 4-week project. Hyperkalaemic patients (serum potassium > 6.0 mmol/L) were treated with a potassium binder, sodium bicarbonate and received responsive dietary advice. RESULTS: There were 12 deaths (5 due to COVID-19) in the HD population, 6 of which were in the twice weekly HD group; no deaths were definitively associated with change of dialysis protocol. A further 19 patients were either hospitalised and/or developed COVID-19 and thus transferred back to thrice weekly dialysis as per protocol. 113 (68.1%) were still receiving twice-weekly HD by the end of the 4-week project. Indications for transfer back to thrice weekly were; fluid overload (19), persistent hyperkalaemia (4), patient request (4) and compliance (1). There were statistically significant increases in SBP and pre-dialysis potassium during the project. CONCLUSIONS: Short term conversion of a large but selected HD population to twice-weekly dialysis sessions was possible and safe. This approach could help mitigate COVID-19 transmission amongst dialysis patients in centres with similar organisational pressures.

Sudden Cardiac Death in Haemodialysis Patients under Hydroxychloroquine Treatment for COVID-19: A Report of Two Cases.

Hydroxychloroquine (HQ) has been used for the treatment of novel coronavirus disease (COVID-19) even though there is no clear evidence for its effectiveness yet. In contrary, HQ has major side effects like QTc prolongation and subsequent development of ventricular arrhythmias. Such side effects may possess additional risks on end-stage renal disease (ESRD) patients who have higher cardiovascular risks than general population. We herein present 2 cases of sudden cardiac death in 2 ESRD patients with COVID-19 for whom a treatment regimen including HQ was preferred. Both patients were clinically stable at the time of arrest. Death could not be attributed to worsening of the COVID-19 since the patients' clinical picture and laboratory values were improving. The cardiac events coincided with the end of routine haemodialysis sessions of both patients. Electrocardiography controls upon admission and on the 24 and 48 h of treatment showed normal QTc intervals. Potential risks contributing to sudden cardiac death during HQ treatment of ESRD patients are discussed.

Impact of first-wave COronaVIrus disease 2019 infection in patients on haemoDIALysis in Alsace: the observational COVIDIAL study.

BACKGROUND: There are only scarce data regarding the presentation, incidence, severity and outcomes of coronavirus disease 2019 (COVID-19) in patients undergoing long-term haemodialysis (HD). A prospective observational study was conducted in eight HD facilities in Alsace, France, to identify clinical characteristics of HD patients with COVID-19 and to assess the determinants of the risk of death. METHODS: All HD patients tested positive for COVID-19 from 5 March to 28 April 2020 were included. Collected data included patient characteristics, clinical features at diagnosis, laboratory data, treatments and outcomes. RESULTS: Among 1346 HD patients, 123 tested positive for COVID-19. Patients had a median age of 77 years (interquartile range 66-83), with a high number of comorbidities (3.2 ± 1.6 per patient). Symptoms were compatible in 63% of patients. Asthenia (77%), diarrhoea (34%) and anorexia (32%) were frequent at diagnosis. The delay between the onset of symptoms and diagnosis, death or complete recovery was 2 (0-5), 7 (4-11) and 32 (26.5-35) days, respectively. Treatment, including lopinavir/ritonavir, hydroxychloroquine and corticosteroids, was administered in 23% of patients. The median C-reactive protein (CRP) and lymphocyte count at diagnosis was 55 mg/L (IQR 25-106) and 690 Ly/µL (IQR 450-960), respectively. The case fatality rate was 24% and determinants associated with the risk of death were body temperature {hazard ratio [HR] 1.96 [95% confidence interval (CI) 1.11-3.44]; P = 0.02} and CRP at diagnosis [HR 1.01 (95% CI 1.005-1.017); P < 0.0001]. CONCLUSIONS: HD patients were found to be at high risk of developing COVID-19 and exhibited a high rate of mortality. While patients presented severe forms of the disease, they often displayed atypical symptoms, with the CRP level being highly associated with the risk of death.

2019 Novel coronavirus disease (COVID-19) in hemodialysis patients: A report of two cases.

OBJECTIVE: To analyze the diagnosis and treatment of patients with chronic renal failure complicated with novel coronavirus pneumonia, and to evaluate the effect of blood purification technology on the treatment and prognosis of such patients. METHODS: Two COVID-19 cases undergoing hemodialysis with chronic renal failure were retrospectively analysed in our hospital. RESULTS: Two COVID-19 patients were admitted to hospital due to cough, with or without fever. Laboratory tests showed decreased lymphocyte count, elevated PCT, IL-10, IL-6, TNF-α, IL-2R, high-sensitivity cardiac troponin I, NT-proBNP, creatinine, and urea nitrogen. Chest CT scan showed multiple blurred plaques and patchy shadows in both patients. Two patients received continuous venovenous hemodiafiltration (CVVHDF) every other day for 4-6 h everytime, in addition to the standard treatment. After CVVHDF, not only cytokines were reduced, but also liver function and cardiac function significantly improved. Both patients did not develop severe pneumonia. They were discharged on March 1, 2020 when meeting the discharge criteria. CONCLUSION: Two COVID-19 patients on maintenance hemodialysis discharged after a month of hospitalization. The removal of cytokines through blood purification technology may be beneficial for the recovery of COVID-19 patients.