Cyclosporine and COVID‐19: Risk or favorable? Poulsen, Nadia Nicholine; Brunn, Albrecht; Hornum, Mads ...
American journal of transplantation,
November 2020, Letnik:
20, Številka:
11
Journal Article
Recenzirano
Odprti dostop
The coronavirus disease 2019 (COVID‐19) pandemic is declared a global health emergency. COVID‐19 is triggered by a novel coronavirus: severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). ...Baseline characteristics of admitted patients with COVID‐19 show that adiposity, diabetes, and hypertension are risk factors for developing severe disease, but so far immunosuppressed patients who are listed as high‐risk patients have not been more susceptible to severe COVID‐19 than the rest of the population. Multiple clinical trials are currently being conducted, which may identify more drugs that can lower mortality, morbidity, and burden on the society. Several independent studies have convincingly shown that cyclosporine inhibit replication of several different coronaviruses in vitro. The cyclosporine‐analog alisporivir has recently been shown to inhibit SARS‐CoV‐2 in vitro. These findings are intriguing, although there is no clinical evidence for a protective effect to reduce the likelihood of severe COVID‐19 or to treat the immune storm or acute respiratory distress syndrome (ARDS) that often causes severe morbidity. Here, we review the putative link between COVID‐19 and cyclosporine, while we await more robust clinical data.
This review examines possible effects of cyclosporine on SARS‐CoV‐2 replication and the host immune response, challenging the current dogma that cyclosporine is associated with an increased risk of severe COVID‐19.
Objective Acute pancreatitis is the most dreaded complication of ERCP. Two studies have shown a significant effect of glyceryl nitrate (GN) in preventing post-ERCP pancreatitis (PEP). We wanted to ...evaluate this promising effect in a larger study with a realistically precalculated incidence of PEP. Design/Patients A randomized, double-blind, placebo-controlled multicenter study including patients from 14 European centers was performed. A total of 820 patients were entered; 806 were randomized. Intervention The active drug was transdermal GN (Discotrine/Minitran, 3M Pharma) 15 mg/24 hours; placebo (PL) was an identical-looking patch applied before ERCP. A total of 401 patients received GN; 405 received PL. Results Forty-seven patients had PEP (5.8%), 18 (4.5%) in the GN group and 29 (7.1%) in the PL group. The relative risk reduction of PEP in the GN group of 36% (95% CI, 11%-65%) compared with the PL group was not statistically significant ( P = .11). Thirteen had mild pancreatitis (4 in the GN group, 9 in the PL group), 26 had moderate pancreatitis (9 in the GN group, 17 in the PL group), and 8 had severe pancreatitis (5 in the GN group, 3 in the PL group). Headache ( P < .001) and hypotension ( P = .006) were more common in the GN group. Significant variables predictive of PEP were not having biliary stones extracted; hypotension after ERCP; morphine, propofol, glucagon, and general anesthesia during the procedure; or no sufentanil during the procedure. Conclusions The trial showed no statistically significant preventive effect of GN on PEP. Because of a considerable risk of a type II error, an effect of GN may have been overlooked. ( ClinicalTrials.gov ID: NCT00121901.)
Neutrophil gelatinase associated lipocalin (NGAL) is a biomarker of kidney injury. We examined plasma levels of NGAL in a cohort of 57 kidney allograft recipients (Tx group, 39 ± 13 years), a uraemic ...group of 40 patients remaining on the waiting list (47 ± 11 years) and a control group of 14 healthy subjects matched for age, sex and body mass index (BMI). The kidney graft recipients were studied at baseline before transplantation and 3 and 12 months after transplantation and the uraemic group at baseline and after 12 months.
NGAL was measured using a validated in-house Time-Resolved Immuno-flourometric assay (TRIFMA). Repeated measurements differed by < 10% and mean values were used for statistical analyses. Spearman rank order correlation analysis and the Kruskal-Wallis non-parametric test were used to evaluate the association of NGAL concentrations with clinical parameters.
Plasma NGAL levels before transplantation in the Tx and uraemic groups were significantly higher than in the healthy controls (1,251 μg/L, 1,478 μg/L vs. 163 μg/L, p < 0.0001). In the Tx group NGAL concentrations were associated with serum creatinine (R = 0.51, p < 0.0001), duration of end-stage renal failure (R = 0.41, p = 0.002) and leukocyte count (R = 0.29, p < 0.026). At 3 and 12 months plasma NGAL concentrations declined to 223 μg/L and 243 μg/L, respectively and were associated with homocysteine (R = 0.39, p = 0.0051 and R = 0.47, p = 0.0007).
Plasma NGAL is a novel marker of kidney function, which correlates to duration of end-stage renal failure (ESRD) and serum creatinine in uraemic patients awaiting kidney transplantation. Plasma NGAL is associated with homocysteine in transplanted patients. The prognostic value of these findings requires further studies.
Abstract
Chronic kidney disease (CKD) in patients with diabetes mellitus (DM) is a major problem of public health. Currently, many of these patients experience progression of cardiovascular and renal ...disease, even when receiving optimal treatment. In previous years, several new drug classes for the treatment of type 2 DM have emerged, including inhibitors of renal sodium–glucose co-transporter-2 (SGLT-2) and glucagon-like peptide-1 (GLP-1) receptor agonists. Apart from reducing glycaemia, these classes were reported to have other beneficial effects for the cardiovascular and renal systems, such as weight loss and blood pressure reduction. Most importantly, in contrast to all previous studies with anti-diabetic agents, a series of recent randomized, placebo-controlled outcome trials showed that SGLT-2 inhibitors and GLP-1 receptor agonists are able to reduce cardiovascular events and all-cause mortality, as well as progression of renal disease, in patients with type 2 DM. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of SGLT-2 inhibitors and GLP-1 analogues, analyses the potential mechanisms involved in these actions and discusses their place in the treatment of patients with CKD and DM.
Abstract
Background and Aims
In order to improve renal and cardiovascular outcome in patients with chronic kidney disease (CKD), it is important to identify patients with CKD in early stages of the ...disease. Given the asymptomatic nature of early-stage CKD, the majority of the CKD patients are living with an unrecognized condition. There is limited knowledge about the Danish prevalence of CKD stage 1-4. Moreover, previous studies have shown association between CKD and low socio-economic status. This study aims to increase the insights into prevalence and risk factors of CKD in a population living in a part of Denmark where income and life expectancy is below the national average.
Method
Data was derived from The Lolland-Falster Health Study (LOFUS) which is a population and household-based prospective cohort study at Lolland-Falster, a mixed rural-provincial area in Denmark. Data was obtained between 2016 and 2020 from questionnaires, clinical- and paraclinical evaluation. CKD was defined according to KDIGO classification (single test) as urinary albumin-to-creatinine ratio (UACR) >30 mg/g and/or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Univariate and multiple logistic regression models were used to evaluate potential risk factors for CKD.
Results
The study included 16,142 adult individuals. Characteristics of the population are reported in Table 1. The median age was 58.6 years (IQR 44.7-68.6) and 53% of the population were women. The overall CKD prevalence was 17.7% and was higher in women than in men (19.2% versus 16.0%, p-value < 0.001). Of the 2856 participants with CKD, 71.1% had CKD based on elevated UACR, 19.0% had CKD based on reduced eGFR and 9.9% had CKD based on reduced eGFR combined with elevated UACR. Among the participants with CKD, 31.8% had CKD stage 1, 39.2% had stage 2, 28.0% stage 3, and 1.1% had CKD stage 4-5. Less than 2% (n = 207) of the total population had a self-reported kidney-related diagnosis which correspond to only 4.5% of the individuals with CKD identified in the study. Among those with CKD stage 3-5, more than 27% did not report any kidney-related diagnosis. In univariate analyses, female sex (OR 1.25, 95% CI 1.15 – 1.35), age above 55 years (OR 3.55, 95% CI 3.01 – 4.20), BMI > 25 kg/m2 (OR 1.02, 95% CI 1.02 – 1.03), diabetes (OR 3.38, 95% CI 2.89 – 3.95), hypertension (OR 3.34, 95% CI 3.06 – 3.65), cardiovascular disease (OR 2.28, 95% CI 1.86 – 2.79) and current or former smoking (OR 1.27, 95% CI 1.17 – 1.39) were all risk factors for CKD. In a multiple regression analysis, all risk factors but BMI were independent risk factors for CKD.
Conclusion
CKD is common in the LOFUS cohort with a prevalence of nearly 18%. Less than 5% are aware of their condition and therefore our data indicate a high rate of unrecognized CKD. Comorbidities such as hypertension, diabetes, and cardiovascular disease are strongly associated with CKD. In contrast to earlier findings, overweight and obesity did not seem to increase the risk of CKD in our study, when adjusted for other comorbidities. Our findings could be used to develop strategies for early identification of CKD patients, particularly in populations living in socio-economically disadvantaged areas.
Abstract
Background and Aims
Fluid overload is a major challenge in haemodialysis (HD) patients and might cause hypervolaemia. We speculated that HD patients reaching dry weight could have undetected ...hypervolaemia and low haemoglobin concentration (Hb) due to haemodilution.
Method
The study included HD patients (n = 22) and matched healthy controls (n = 22). Blood volume, plasma volume, red blood cell volume, and total haemoglobin mass (Hb mass) were determined using a carbon monoxide (CO)-rebreathing method in HD patients reaching dry weight and controls. Blood volume measurements were also obtained by a dual-isotope labelling technique in a subgroup for validation purposes.
Results
Blood volume was higher in 16 out of the 22 HD patients compared to controls. In the HD group, the median blood volume was 89.3 mL/kg (interquartile range (IQR) 76.7–95.4 mL/kg) and was higher than in the control group (79.9 mL/kg (IQR 70.4–88.0 mL/kg); P < 0.037) (Table 1). The median plasma volume was 54.7 mL/kg (IQR 47.1–61.0 mL/kg) and 44.0 mL/kg (IQR 38.7–49.5 mL/kg) in the HD and control groups, respectively (P < 0.001). Hb was lower in HD patients (P<0.001), whereas no difference in total Hb mass was observed between groups (P = 0.11). Changes in Hb levels during and after dialysis were observed in the HD group and is shown in Fig. 1. A correlation was found between blood volume measured by the CO-rebreathing test and the dual-isotope labelling technique in the control group (r = 0.83, P = 0.015), but not the HD group (r = 0.25, P = 0.60).
Conclusion
The HD group had increased blood volume at dry weight due to high plasma volume, indicating a hypervolaemic state. The total Hb mass was similar between HD patients and controls, unlike Hb, which emphasizes that Hb is an inaccurate marker of anaemia among HD patients.
Background
The significance of chronic kidney disease on susceptibility to COVID‐19 and subsequent outcomes remains unaddressed.
Objective
To investigate the association of estimated glomerular ...filtration rate (eGFR) on risk of contracting COVID‐19 and subsequent adverse outcomes.
Methods
Rates of hospital‐diagnosed COVID‐19 were compared across strata of eGFR based on conditional logistic regression using a nested case–control framework with 1:4 matching of patients diagnosed with COVID‐19 with controls from the Danish general population on age, gender, diabetes and hypertension. Risk of subsequent severe COVID‐19 or death was assessed in a cohort study with comparisons across strata of eGFR based on adjusted Cox regression models with G‐computation of results to determine 60‐day risk standardized to the distribution of risk factors in the sample.
Results
Estimated glomerular filtration rate was inversely associated with rate of hospital‐diagnosed COVID‐19: eGFR 61–90 mL/min/1.73m2 HR 1.13 (95% CI 1.03–1.25), P = 0.011; eGFR 46–60 mL/min/1.73m2 HR 1.26 (95% CI 1.06–1.50), P = 0.008; eGFR 31–45 mL/min/1.73m2 HR 1.68 (95% CI 1.34–2.11), P < 0.001; and eGFR ≤ 30 mL/min/1.73m2 3.33 (95% CI 2.50–4.42), P < 0.001 (eGFR > 90 mL/min/1.73m2 as reference), and renal impairment was associated with progressive increase in standardized 60‐day risk of death or severe COVID‐19; eGFR > 90 mL/min/1.73m2 13.9% (95% CI 9.7–15.0); eGFR 90–61 mL/min/1.73m2 16.1% (95% CI 14.5–17.7); eGFR 46–60 mL/min/1.73m2 17.8% (95% CI 14.7–21.2); eGFR 31–45 mL/min/1.73m2 22.6% (95% CI 18.2–26.2); and eGFR ≤ 30 mL/min/1.73m2 23.6% (95% CI 18.1–29.1).
Conclusions
Renal insufficiency was associated with progressive increase in both rate of hospital‐diagnosed COVID‐19 and subsequent risk of adverse outcomes. Results underscore a possible vulnerability associated with impaired renal function in relation to COVID‐19.
Following transplantation (TX) of both renal and non-renal organs, a large proportion of patients have renal dysfunction. There are multiple causes for this. Chronic nephrotoxicity and high doses of ...calcineurin inhibitors are important factors. Preoperative and perioperative factors like hypertension, hypotension, drugs and infections may play a causative role as well. Organ-specific causes include hepatorenal syndrome, cirrhosis, low cardiac function, low respiratory function and diabetes developed both before and after TX. It is important to be able to perform precise and valid measurements or estimates of renal function in these patients, in order to accurately and safely dose immunosuppressive medication and perform and adjust the treatment and prophylaxis of renal dysfunction. This is a short overview and discussion of relevant studies and possible caveats of estimated glomerular filtration rate methods for use in renal and non-renal TX.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a kidney protective effect in patients with diabetic kidney disease. Several mechanisms have been proposed, but why precisely SGLT2 inhibition ...has a kidney protective effect is incompletely understood. Clinical trials using SGLT2 inhibitors have found them to induce a rapid weight loss likely due to loss of sodium and subsequently fluid. While SGLT2 inhibitors are reported to increase hematocrit, it remains unknown whether the natriuretic and aquaretic effect reduces patient's blood volume and whether this could partly explain its kidney protective effects. A blood volume reduction could induce several beneficial effects with reduction in arterial and venous blood pressure as two central mechanisms. The aim of this paper was to review current techniques for assessing patient blood volume that could enhance our understanding of SGLT2 inhibitors' physiological effects.
Changes induced by SGLT2 inhibitors on erythrocyte volume and plasma volume can be assessed by tracer dilution techniques that include radioisotopes, indocyanine green (ICG) dye, or carbon monoxide (CO). Techniques with radioisotopes can provide direct estimates of both erythrocyte volume and plasma volume but are cumbersome procedures and the radiation exposure is a limitation for repeated measures in clinical studies. Methods more suitable for repeated assessment of erythrocyte and plasma volume include dilution of injected ICG dye or dilution of inhaled CO. ICG dye requires higher precision with timed blood samples and provides only a direct estimate of plasma volume wherefrom erythrocyte volume is estimated. Inhalation of CO is a time-effective and automated method that provides measure of the total hemoglobin mass wherefrom erythrocyte and plasma volumes are estimated.
A kidney protective effect has been observed in clinical trials with SGLT2 inhibitors, but the underlying mechanisms are not fully understood. Significant weight loss within weeks has been reported in the SGLT2 inhibitor trials and could be related to a reduction in blood volume secondary to increased natriuresis and aquaresis. Alterations in blood volume compartments can be quantified by tracer dilution techniques and further improve our understanding of kidney protection from SGLT2 inhibitors.
Abstract
Background and Aims
Although the global prevalence of advanced diabetic kidney disease is increasing, the optimum glycemic target remains uncertain. Specifically, data pertaining to the ...association of hemoglobin A1c (HbA1c) level with micro- and macrovascular outcomes in patients with advanced diabetic kidney disease remain inconclusive. We examined the association between HbA1c levels and complications in patients with diabetes and chronic kidney disease (CKD) stage 4 and 5.
Method
In a Danish nationwide registry-based retrospective cohort study, we included persons ≥18 years of age with diabetes, an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 and a concurrent measured HbA1c between 2010 and 2022. Complications were categorized as 1) major adverse cardiovascular events (MACE) defined as a composite endpoint of acute myocardial infarction, stroke, and all-cause mortality; 2) microvascular complications defined as a composite endpoint of diabetic retinopathy, major lower extremity amputation, and start of dialysis; 3) hospitalization with hypoglycemia. Multiple outcome-specific Cox regressions stratified by HbA1c levels were performed to calculate the 1-year risk of complications standardized to the distribution of risk factors of all patients in the sample. The analyses regarding the risk of hypoglycemia were further stratified according to insulin treatment at baseline.
Results
In total, 34,046 patients were included. The median age was 76.2 (IQR 69.1-82.7) years and 54.6% were men. The median eGFR and HbA1c level was 26.4 (IQR 21.9-28.5) mL/min/1.73m2 and 53 (IQR 46-63) mmol/mol, respectively. Figure 1 depicts the 1-year risks of MACE and microvascular complications stratified by HbA1c level. We found a U-shaped association between HbA1c level and MACE where patients with an HbA1c level between 45-50 mmol/mol had the lowest risk. The risk increased significantly with an HbA1c level below 45 mmol/mol or above 65 mmol/mol compared with 45-50 mmol/mol (P<0.001). The risk of microvascular complications was lowest at an HbA1c level between 35-40 mmol/mol. The risk increased significantly with increasing levels of HbA1c above 50 mmol/mol compared with 35-40 mmol/mol (P<0.05). The 1-year risks of hospitalization with hypoglycemia stratified according to HbA1c level and insulin treatment are illustrated in Figure 2. For both groups, the risk was lowest at an HbA1c level between 30-40 mmol/mol and increased with increasing HbA1c levels.
Conclusion
In patients with diabetes and CKD stage 4 and 5, HbA1c levels >65 mmol/mol and <45 mmol/mol were associated with an increased risk of MACE, whereas HbA1c levels >50 mmol/mol were associated with a higher risk of microvascular complications. Our findings suggest that appropriate glycemic control can reduce adverse outcomes in patients with advanced CKD without increasing the risk of hypoglycemia, but also suggest that intensive glycemic control (HbA1c <45 mmol/mol) might be associated with an increased risk of MACE.
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