Renin-Angiotensin System Blockers and the Risk of COVID-19-Related Mortality in Patients with Kidney Failure

Background: There is concern about potential deleterious effects of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) in patients with COVID-19. Patients with kidney failure, who often use ACEi/ARB, are at higher risk of more severe COVID-19. However, there are no data available on the association of ACEi/ARB use with COVID-19 severity in this population. Methods: Data were retrieved from the ERACODA database of kidney transplant and dialysis patients affected by COVID-19, between February 1 and October 1 2020, and had information on 28-day mortality. Cox proportional-hazards regression was used to calculate hazard ratios (HRs) for the relation between ACEi/ARB use and 28-day mortality risk. Additionally, we studied the association of ACEi/ARB discontinuation with 28-day mortality. Results: We evaluated 1,511 patients, 459 kidney transplant recipients and 1,052 dialysis patients. At COVID-19 diagnosis, 189 (41%) of the transplant and 288 (27%) of the dialysis patients were on ACEi/ARB. In transplant, 88 (19%) and in dialysis patients 244 (23%) died within 28 days of initial presentation. In transplant and dialysis patients, there was no association between ACEi/ARB use and 28-day mortality in both crude and adjusted models (adjusted HR=1.12, 95%CI: 0.69-1.83 in transplant; 1.04, 95%CI: 0.73-1.47 in dialysis patients). Among transplant recipients, ACEi/ARB discontinuation was associated with higher mortality risk after adjustment for demographics and comorbidities, but the association was no longer statistically significant after adjustment for COVID-19 severity (adjusted HR=1.36, 95%CI: 0.40-4.58). Among dialysis patients, ACEi/ARB discontinuation was not associated with mortality in any model. Similar results were obtained across subgroups when ACEi and ARB were studied separately and when other outcomes for COVID-19 severity were studied e.g., hospital admission, intensive care unit admission or need for ventilator support. Conclusions: Amongst kidney transplant and dialysis patients with COVID-19, there was no significant association of ACEi/ARB use or ACEi/ARB discontinuation with mortality.

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Impaired immune response to SARS-CoV-2 vaccination in dialysis patients and in kidney transplant recipients

Kidney360 ◽

10.34067/kid.0003512021 ◽

2021 ◽

pp. 10.34067/KID.0003512021

Author(s):

Thilo Kolb ◽

Svenja Fischer ◽

Lisa Müller ◽

Nadine Lübke ◽

Jonas Hillebrandt ◽

...

Keyword(s):

Immune Responses ◽

Kidney Transplant ◽

Kidney Failure ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Dialysis Patients ◽

Specific Antibodies ◽

Neutralization Capacity

Background: Kidney failure patients on dialysis or after renal transplantation have a high risk for severe COVID-19 infection and vaccination against SARS-CoV-2 is the only expedient prophylaxis. Generally, immune responses are attenuated in kidney failure patients, however, systematic analyses of immune responses to SARS-CoV-2 vaccination in dialysis patients and in kidney transplant recipients (KTR) are still missing. Methods: In this prospective multicentric cohort study, antibody responses COVID-19 mRNA vaccines (BNT162b2; Biontech/Pfizer or mRNA-1273; Moderna) were measured in 32 dialysis patients and in 28 KTRs. SARS-CoV-2-specific antibodies and neutralization capacity were evaluated and compared to controls (n=78) in a similar age-range. Results: After the first vaccination, SARS-CoV-2-specific antibodies were nearly undetectable in kidney failure patients. After the second vaccination, 93% of the controls and 88% of dialysis patients but only 37% of KTRs developed SARS-CoV-2-specific IgG above cut-off. Moreover, mean IgG levels were significantly lower in KTRs (54±93 BAU/ml) compared to dialysis patients (503±481 BAU/ml, p<0.01). Both KTRs as well as dialysis patients had significantly lower IgG levels compared to controls (1992±2485 BAU/ml; p<0.001 and p<0.01). Importantly, compared to controls, neutralizing antibody titers were significantly lower in KTRs and dialysis patients. After the second vaccination, 76% of KTRs did not show any neutralization capacity against SARS-CoV-2 suggesting impaired seroprotection. Conclusions: Kidney failure patients show a significantly weaker antibody response compared to controls. Most strikingly, only one out four KTRs developed neutralizing antibodies against SARS-CoV-2 after two doses of vaccine. These data suggest that vaccination strategies need modification in immune transplant and dialysis patients.

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Physical activity and risk of cardiovascular events and all-cause mortality among kidney transplant recipients

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa038 ◽

2020 ◽

Vol 35 (8) ◽

pp. 1436-1443

Author(s):

Augustine W Kang ◽

Andrew G Bostom ◽

Hongseok Kim ◽

Charles B Eaton ◽

Reginald Gohh ◽

...

Keyword(s):

Physical Activity ◽

Kidney Transplant ◽

Proportional Hazards ◽

Controlled Trial ◽

Cox Proportional Hazards ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Cvd Risk ◽

All Cause Mortality ◽

Cvd Mortality

Abstract Background Insufficient physical activity (PA) may increase the risk of all-cause mortality and cardiovascular disease (CVD) morbidity and mortality among kidney transplant recipients (KTRs), but limited research is available. We examine the relationship between PA and the development of CVD events, CVD death and all-cause mortality among KTRs. Methods A total of 3050 KTRs enrolled in an international homocysteine-lowering randomized controlled trial were examined (38% female; mean age 51.8 ± 9.4 years; 75% white; 20% with prevalent CVD). PA was measured at baseline using a modified Yale Physical Activity Survey, divided into tertiles (T1, T2 and T3) from lowest to highest PA. Kaplan–Meier survival curves were used to graph the risk of events; Cox proportional hazards regression models examined the association of baseline PA levels with CVD events (e.g. stroke, myocardial infarction), CVD mortality and all-cause mortality over time. Results Participants were followed up to 2500 days (mean 3.7 ± 1.6 years). The cohort experienced 426 CVD events and 357 deaths. Fully adjusted models revealed that, compared to the lowest tertile of PA, the highest tertile experienced a significantly lower risk of CVD events {hazard ratio [HR] 0.76 [95% confidence interval (CI) 0.59–0.98]}, CVD mortality [HR 0.58 (95% CI 0.35–0.96)] and all-cause mortality [HR 0.76 (95% CI 0.59–0.98)]. Results were similar in unadjusted models. Conclusions PA was associated with a reduced risk of CVD events and all-cause mortality among KTRs. These observed associations in a large, international sample, even when controlling for traditional CVD risk factors, indicate the potential importance of PA in reducing CVD and death among KTRs.

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Plasma Vitamin C and Cancer Mortality in Kidney Transplant Recipients

Journal of Clinical Medicine ◽

10.3390/jcm8122064 ◽

2019 ◽

Vol 8 (12) ◽

pp. 2064 ◽

Cited By ~ 4

Author(s):

Tomás A. Gacitúa ◽

Camilo G. Sotomayor ◽

Dion Groothof ◽

Michele F. Eisenga ◽

Robert A. Pol ◽

...

Keyword(s):

Vitamin C ◽

Kidney Transplant ◽

Cardiovascular Mortality ◽

Cancer Mortality ◽

Proportional Hazards ◽

Smoking Status ◽

Cox Proportional Hazards ◽

Plasma Vitamin ◽

Transplant Recipients ◽

Kidney Transplant Recipients

There is a changing trend in mortality causes in kidney transplant recipients (KTR), with a decline in deaths due to cardiovascular causes along with a relative increase in cancer mortality rates. Vitamin C, a well-known antioxidant with anti-inflammatory and immune system enhancement properties, could offer protection against cancer. We aimed to investigate the association of plasma vitamin C with long-term cancer mortality in a cohort of stable outpatient KTR without history of malignancies other than cured skin cancer. Primary and secondary endpoints were cancer and cardiovascular mortality, respectively. We included 598 KTR (mean age 51 ± 12 years old, 55% male). Mean (SD) plasma vitamin C was 44 ± 20 μmol/L. At a median follow-up of 7.0 (IQR, 6.2–7.5) years, 131 patients died, of which 24% deaths were due to cancer. In Cox proportional hazards regression analyses, vitamin C was inversely associated with cancer mortality (HR 0.50; 95%CI 0.34–0.74; p < 0.001), independent of potential confounders, including age, smoking status and immunosuppressive therapy. In secondary analyses, vitamin C was not associated with cardiovascular mortality (HR 1.16; 95%CI 0.83–1.62; p = 0.40). In conclusion, plasma vitamin C is inversely associated with cancer mortality risk in KTR. These findings underscore that relatively low circulating plasma vitamin C may be a meaningful as yet overlooked modifiable risk factor of cancer mortality in KTR.

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Local Angiotensin-Converting Enzyme 2 Gene Expression in Kidney Allografts Is Not Affected by Renin-Angiotensin-Aldosterone Inhibitors

Kidney & Blood Pressure Research ◽

10.1159/000513710 ◽

2021 ◽

Vol 46 (2) ◽

pp. 245-249

Author(s):

Monika Cahova ◽

Martin Kveton ◽

Vojtech Petr ◽

David Funda ◽

Helena Dankova ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Kidney Transplant ◽

Converting Enzyme ◽

Transplant Recipients ◽

Angiotensin Ii Receptor ◽

Kidney Transplant Recipients ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Receptor Blockers

Background: Preclinical studies suggested that pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) by ACE inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) may increase local angiotensin-converting enzyme 2 (ACE2) expression. Methods: In this study, we evaluated the effect of ACEi or ARB treatment on expression of ACE2, ACE, and AGTR1 in 3-month protocol kidney allograft biopsies of stable patients using RT-qPCR (n = 48). Protein ACE2 expression was assessed using immunohistochemistry from paraffin sections. Results: The therapy with RAAS blockers was not associated with increased ACE2, ACE, or ATGR1 expression in kidney allografts and also ACE2 protein immunohistochemistry did not reveal differences among groups. Conclusions: ACEis or ARBs in kidney transplant recipients do not affect local ACE2 expression. This observation supports long-term RAAS treatment in kidney transplant recipients, despite acute complications such as COVID-19 where ACE2 serves as the entry protein for infection.

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FC 028COVID-19 RELATED MORTALITY IN KIDNEY TRANSPLANT AND DIALYSIS PATIENTS: A COMPARATIVE, PROSPECTIVE REGISTRY BASED STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab145.004 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Alexandre Candellier ◽

Eric Jean Goffin ◽

Priya Vart ◽

Marlies Noordzij ◽

Miha Arnol ◽

...

Keyword(s):

Kidney Transplantation ◽

Replacement Therapy ◽

Kidney Transplant ◽

Hemodialysis Patients ◽

Cox Proportional Hazards ◽

Elderly Subjects ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Kidney Replacement Therapy ◽

Adjusted Model

Abstract Background and Aims Studies examining kidney failure patients with COVID-19 reported higher mortality in hemodialysis patients than in kidney transplant recipients. However, hemodialysis patients are often older and have more comorbidities. This study investigated the association of type of kidney replacement therapy with COVID-19 severity adjusting for differences in characteristics. Method Data were retrieved from the European Renal Association COVID-19 Database (ERACODA), which includes kidney replacement therapy patients diagnosed with COVID-19 from all over Europe. We included all kidney transplant recipients and hemodialysis patients who presented between February 1st and December 1st 2020 and had complete information reason for COVID-19 screening and vital status at day 28. The diagnosis of COVID-19 was made based on a PCR of a nasal or pharyngeal swab specimens and/or COVID-19 compatible findings on a lung CT scan. The association of kidney transplantation or hemodialysis with 28-day mortality was examined using Cox proportional-hazards regression models adjusted for age, sex, frailty and comorbidities. Additionally, this association was investigated in the subsets of patients that were screened because of symptoms or have had routine screening. Results A total of 1,670 patients (496 functional kidney transplant recipients and 1,174 hemodialysis patients) were examined. 16.9% of kidney transplant recipients and 23.9% of hemodialysis patients died within 28 days of presentation. In an unadjusted model, the risk of 28-day mortality was 33% lower in kidney transplant recipients compared with hemodialysis patients (hazard ratio (HR): 0.67, 95% CI: 0.52, 0.85). However, in an age, sex and frailty adjusted model, the risk of 28-day mortality was 29% higher in kidney transplant recipients (HR=1.29, 95% CI: 1.00, 1.68), whereas in a fully adjusted model the risk was even 43% higher (HR=1.43, 95% CI: 1.06, 1.93). This association in patients who were screened because of symptoms (n=1,145) was similar (fully adjusted model HR=1.46, 95% CI: 1.05, 2.04). Results were similar when other endpoints were studied (e.g. risk for hospitalization, ICU admission or mortality beyond 28 days) as well as across subgroups. Only age was found to interact significantly, suggesting that the increased mortality risk associated with kidney transplantation was especially present in elderly subjects. Conclusion In this study, kidney transplant recipients had a greater risk of a more severe course of COVID-19 compared with hemodialysis patients when adjusted for age, sex and comorbidities.

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Mineralocorticoid receptor blockade with spironolactone has no direct effect on plasma IL-17A and injury markers in urine from kidney transplant patients

AJP Renal Physiology ◽

10.1152/ajprenal.00104.2021 ◽

2021 ◽

Author(s):

Sai Sindhu Thangaraj ◽

Helle Charlotte Thiesson ◽

Per Svenningsen ◽

Jane Stubbe ◽

Yaseelan Palarasah ◽

...

Keyword(s):

Kidney Transplant ◽

Mineralocorticoid Receptor ◽

Enzyme Inhibitor ◽

Plasma Concentrations ◽

Transplant Recipients ◽

Angiotensin Ii Receptor ◽

Kidney Transplant Recipients ◽

Double Blind ◽

Plasma Aldosterone Concentration ◽

Increased Risk

Kidney transplantation is associated with increased risk of cardiovascular morbidity. Interleukin-17A (IL-17A) mediates kidney injury. Aldosterone promotes T-helper-17 (Th-17) lymphocyte differentiation and IL-17A production through the mineralocorticoid receptor (MR). In this exploratory, post-hoc substudy, it was hypothesized that 1-year intervention with the MR antagonist spironolactone lowers IL-17A and related cytokines and reduces epithelial injury in kidney transplant recipients. Plasma and urine samples were obtained from kidney transplant recipients from a double-blind randomized clinical trial testing spironolactone (n=39) versus placebo (n=41). Plasma concentrations of cytokines IFN-γ, IL-17A, TNF-α, IL-6, IL-1β, and IL-10 were determined before and after 1-year treatment. Urine calbindin, clusterin, KIM-1, osteoactivin, TFF3, and VEGF/creatinine ratios were analyzed. Blood pressure and plasma aldosterone concentration at inclusion did not relate to plasma cytokines and injury markers. None of the cytokines changed in plasma after spironolactone intervention. Plasma IL-17A increased in the placebo group. Spironolactone induced an increase in plasma K+ (0.4 ± 0.4 mmol/L). This increase did not correlate with plasma IL-17A or urine calbindin and TFF3 changes. Ongoing treatment at inclusion with angiotensin-converting-enzyme inhibitor and/or angiotensin II receptor blockers was not associated with changed levels of IL-17A and injury markers and had no effect on the response to spironolactone. Urinary calbindin and TFF3 decreased in the spironolactone group with no difference in between-group analyses. In conclusion, irrespective of ongoing ANGII inhibition, spironolactone has no effect on plasma IL-17A and related cytokines or urinary injury markers in kidney transplant recipients.

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