Home dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Home dialysis modalities (home hemodialysis [HD] and peritoneal dialysis [PD]) are associated with greater patient autonomy and treatment satisfaction compared with in-center modalities, yet the level of home-dialysis use worldwide is low. Reasons for limited utilization are context-dependent, informed by local resources, dialysis costs, access to healthcare, health system policies, provider bias or preferences, cultural beliefs, individual lifestyle concerns, potential care-partner time, and financial burdens. In May 2021, KDIGO (Kidney Disease: Improving Global Outcomes) convened a controversies conference on home dialysis, focusing on how modality choice and distribution are determined and strategies to expand home-dialysis use. Participants recognized that expanding use of home dialysis within a given health system requires alignment of policy, fiscal resources, organizational structure, provider incentives, and accountability. Clinical outcomes across all dialysis modalities are largely similar, but for specific clinical measures, one modality may have advantages over another. Therefore, choice among available modalities is preference-sensitive, with consideration of quality of life, life goals, clinical characteristics, family or care-partner support, and living environment. Ideally, individuals, their care-partners, and their healthcare teams will employ shared decision-making in assessing initial and subsequent kidney failure treatment options. To meet this goal, iterative, high-quality education and support for healthcare professionals, patients, and care-partners are priorities. Everyone who faces dialysis should have access to home therapy. Facilitating universal access to home dialysis and expanding utilization requires alignment of policy considerations and resources at the dialysis-center level, with clear leadership from informed and motivated clinical teams.

Review of the present features and the infection control challenges of COVID-19 pandemic in dialysis facilities.

The COVID-19 has swept the world causing suffering, death, loss, and massive economy damage. The dialysis population is vulnerable and the dialysis facility is critical in maintaining operations and avoiding disease transmission. The present information regarding the clinical features of COVID-19 infection in the dialysis population was collected, and the useful measures of COVID-19 infection prevention and infection control in the dialysis facilities were summarized. Leadership, education, preparedness, management, and recovery phase were determined to be the critical procedures. It is hoped this updated interim review might provide information for medical professionals to take proactive action to best prepare and mitigate damage when facing the COVID-19 pandemic challenge.

Effect of remdesivir on adverse kidney outcomes in hospitalized patients with COVID-19 and impaired kidney function.

BACKGROUND: Chronic kidney disease (CKD) is an important risk factor for mortality from COVID-19. Remdesivir has been shown to shorten time to recovery in patients with severe COVID-19. However, exclusion of patients with severe kidney function impairment in clinical trials has led to concerns about kidney safety of remdesivir in patients with pre-existing kidney disease. METHODS: Retrospective propensity score matched cohort study of hospitalized patients with COVID-19 admitted with estimated glomerular filtration rate (eGFR) between 15 - 60 mL/min/1.73m2. Remdesivir-treated patients were 1:1 matched to historical comparators admitted during the first wave of COVID-19 (between March-April 2020) prior to emergency use authorization of remdesivir using propensity scores accounting for factors predicting treatment assignment. Dependent outcomes included in-hospital peak creatinine, incidence of doubling of creatine, rate of kidney replacement therapy initiation and eGFR among surviving patients at day 90. RESULTS: 175 remdesivir-treated patients were 1:1 matched to untreated historical comparators. Mean age was 74.1 (SD 12.8), 56.9% were male, 59% patients were white, and the majority (83.1%) had at least one co-morbidity. There were no statistically significant differences in peak creatinine during hospitalization (2.3mg/dL vs. 2.5 mg/dL, P = 0.34), incidence of doubling of creatinine (10.3% vs. 13.1%, P = 0.48), and rate of kidney replacement therapy initiation (4.6% vs. 6.3%, P = 0.49) in remdesivir-treated patients versus matched untreated historical comparators, respectively. Among surviving patients, there was no difference of the average eGFR at day 90 (54.7 ± 20.0 mL/min/1.73m2 for remdesivir-treated patients vs. 51.7 ± 19.5 mL/min/1.73m2 for untreated comparators, P = 0.41). CONCLUSIONS: Remdesivir use in patients with impaired kidney function (eGFR between 15 - 60 mL/min/1.73m2) who present to the hospital with COVID-19 is not associated with increased risk of adverse kidney outcomes.

Leveraging Prior Healthy Participant Pharmacokinetic Data to Evaluate the Impact of Renal and Hepatic Impairment on Ritlecitinib Pharmacokinetics.

Ritlecitinib is a selective, covalent, irreversible inhibitor of Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinases. Pharmacokinetics and safety of ritlecitinib in participants with hepatic (Study 1) or renal (Study 2) impairment were to be characterized from two phase I studies. Due to a study pause caused by the COVID-19 pandemic, the study 2 healthy participant (HP) cohort was not recruited; however, the demography of the severe renal impairment cohort closely matched the study 1 HP cohort. We present results from each study and two innovative approaches to utilizing available HP data as reference data for study 2: a statistical approach using analysis of variance and an in silico simulation of an HP cohort created using a population pharmacokinetics (POPPK) model derived from several ritlecitinib studies. For study 1, the observed area under the curve for 24-h dosing interval and maximum plasma concentration for HPs and their observed geometric mean ratios (participants with moderate hepatic impairment vs HPs) were within 90% prediction intervals from the POPPK simulation-based approach, thereby validating the latter approach. When applied to study 2, both the statistical and POPPK simulation approaches demonstrated that patients with renal impairment would not require ritlecitinib dose modification. In both phase I studies, ritlecitinib was generally safe and well tolerated. These analyses represent a new methodology for generating reference HP cohorts in special population studies for drugs in development with well-characterized pharmacokinetics in HPs and adequate POPPK models. TRIAL REGISTRATION: ClinicalTrials.gov NCT04037865 , NCT04016077 , NCT02309827 , NCT02684760 , and NCT02969044 .

Thrombocytopenia, anasarca, and renal insufficiency as severe and rare complications of Hodgkin lymphoma: a case report.

BACKGROUND: Patients with Hodgkin lymphoma exhibit various clinical presentations. Needle biopsy of the lymph nodes is a minimally invasive procedure and a useful diagnostic method for malignant lymphomas. However, at times it is difficult to differentiate malignant lymphomas from reactive lymph node changes using a small amount of biopsy material. CASE PRESENTATION: A 77-year-old Japanese man was referred to the emergency department of our hospital owing to high fever and disturbance of consciousness. We diagnosed sepsis due to an acute biliary tract infection because he presented with Charcot's triad-fever, jaundice, and right-sided abdominal pain. However, he did not respond well to antimicrobial therapy and his high fever persisted. Considering the swelling of the right cervical, mediastinal, and intraperitoneal lymph nodes and splenomegaly detected on computed tomography, a differential diagnosis of malignant lymphoma was needed. Hence, we performed a needle biopsy of the right cervical lymph node; however, the amount of sample obtained was insufficient in establishing a definitive diagnosis of malignant lymphoma. Furthermore, during hospitalization, the patient developed thrombocytopenia, anasarca, and renal insufficiency. These symptoms seemed to be the typical signs of the thrombocytopenia, anasarca, fever, reticulin fibrosis or renal insufficiency, and organomegaly syndrome. Next, an external incisional mass biopsy of the right cervical lymph node was performed, which helped identify Hodgkin and Reed-Sternberg cells. Collectively, we established a definitive diagnosis of Hodgkin lymphoma with lymphoma-associated hemophagocytic syndrome. CONCLUSIONS: This case highlights the importance of performing an external incisional mass biopsy of the lymph nodes for the early diagnosis and treatment, if malignant lymphoma is strongly suspected.

Growing a peritoneal dialysis program in Palestine from zero to 178 patients in 5 years: a single-center experience.

INTRODUCTION: Kidney failure is rapidly rising in Palestine, as the number of patients receiving maintenance dialysis has quadrupled in the last 15 years. In this study, we share an overview of our experience growing a peritoneal dialysis (PD) program from zero to 178 patients in 5 years at An-Najah National University Hospital in Palestine, presenting some challenges and ways to overcome them. METHODS: This was a single-center retrospective study of patients treated with PD from November 2016 to December 2021. Demographic and clinical data were obtained for each patient. In addition, PD discontinuation, peritonitis, and mortality rates were calculated and presented as the primary patient outcomes. RESULTS: A total of 158 patients were eligible for the study. The mean age was 51.8 ± 16.4 years, and 53.8% of patients were male. Diabetic nephropathy was the most common cause of kidney failure. 63 episodes of peritonitis were diagnosed in 48 patients (30.4%) for a rate of 1 episode/ 38.2 patient-months (0.31 episodes/ patient-years). 20 patients had their PD treatment discontinued, mainly due to psychosocial reasons and infectious and mechanical complications. Death was the fate of 27 patients, with cardiovascular disease and COVID-19 being the two main causes. CONCLUSION: The outcomes of this experience proved favorable and showed that PD could serve as a viable option for kidney failure patients in Palestine. Moreover, this study can serve as an example for other places where circumstances are challenging to take the initiative of starting their PD programs.

Diffuse proliferative glomerulonephritis in a patient with COVID-19 infection.

COVID-19 primarily presents with respiratory involvement. Extrapulmonary manifestations as the sole manifestation also occur although rare. The kidney, being one of the organs with the greatest number of ACE receptors, is usually reported as part of multiorgan involvement. We report an early adolescent boy who presented with nephrotic-nephritic syndrome with severe kidney dysfunction from COVID-19 infection. He had low C3 and undetected antineutrophil cytoplasmic antibodies, antinuclear antibody and antistreptolysin O. Kidney biopsy revealed findings consistent with diffuse proliferative glomerulonephritis with a focal glomerular crescent formation and thin basement nephropathy. Due to the rapidly progressive deterioration of kidney function, he was given pulse methylprednisolone therapy followed by oral prednisone. Complete recovery was documented 12 weeks after the onset of post-infectious glomerulonephritis. The possible pathogenesis of glomerulonephritis in a patient with COVID-19, its differential diagnosis and treatment are discussed.

Spontaneous pneumomediastinum in a COVID-19 patient after renal transplantation: a case report and literature review (preprint)

Background: Spontaneous pneumomediastinum is a rare complication in COVID-19. Severe pneumonia complicated with pneumomediastinum after renal transplantation is rarely reported. Here we report a case of pneumomediastinum before invasive mechanical ventilation (IMV) in a COVID-19 patient with long-term immunosuppressive therapy after renal transplantation. Case presentation: A 57-year-old man was admitted to our center with the main complaint of “fever and dyspnea for 5 days”. His past medical history was notable for renal transplantation and with long-term immunosuppressive and anti-rejection therapy. We made the diagnosis as COVID-19 pneumonia (severe type). We managed the patient with high flow nasal cannulae (HFNC), oral dexamethasone, broad-spectrum antibiotic, prophylactic anticoagulation, and anti-viral therapy with reduced dose of azvudine due to severe renal insufficiency. During hospitalization, the patient suffered from several times of aggravation of dyspnea. First bedside chest X-ray showed suspicious pneumomediastinum and subcutaneous emphysema, and the gas in the mediastinum gradually increased. The patient’s status deteriorated rapidly, we performed urgent trachea intubation and mechanical ventilation with low tidal volume lung-protective model and performed mediastinal decompression by suprasternal drainage. Despite our active rescue efforts, the patient still died of severe infection and multiple organ failure. Conclusions: In conclusion, we are the first to report spontaneous pneumomediastinum in a renal transplant recipient with severe COVID-19 pneumonia. This case reminds us that pneumomediastinum is a severe complication and a poor prognostic factor of COVID-19 pneumonia, especially when it occurred without positive pressure ventilation and in immunocompromised patients.

Decreased serum vitamin D level as a prognostic marker in patients with COVID-19 (preprint)

Background: The corona virus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2, is still localized outbreak and has resulted in a high rate of infection and severe disease in older patients with comorbidities. The vitamin D status of the population has been found to be an important factor that could influence outcome of COVID-19. However, whether vitamin D can lessen the symptoms or severity of COVID-19 still remains controversial. Methods: A total of 719 patients with confirmed COVID-19 were enrolled retrospectively in this study from April 13 to June 6, 2022 at Shanghai Forth People's Hospital. The circulating levels of 25(OH)D3, inflammatory factors, and clinical parameters were assayed. Time to viral RNA clearance (TVRC), classification and prognosis of COVID-19 were used to evaluate the severity of COVID-19 infection. Results: The median age was 76 years (interquartile range, IQR, 64.5-84.6), 44.1% of patients were male, and the TVRC was 11 days (IQR, 7-16) in this population. The median level of 25(OH)D3 was 27.15 (IQR, 19.31-38.89) nmol/L. Patients with lower serum 25(OH)D3 had prolonged time to viral clearance, more obvious inflammatory response, more severe respiratory symptoms and higher risks of impaired hepatic and renal function. Multiple regression analyses revealed that serum 25(OH)D3 level was negatively associated with TVRC independently. ROC curve showed the serum vitamin D level could predict the severity classification and prognosis of COVID-19 significantly.Conclusions: Serum 25(OH)D3 level is independently associated with the severity of COVID-19 in elderly, and it could be used as a predictor of the severity of COVID-19. In addition, supplementation with vitamin D might provide beneficial effects in old patients with COVID-19.

A Variant Mutation in the gene encoding Mitochondrial Seryl-tRNA Synthetase Cause HUPRA Syndrome with Atypical Presentation-A Case Report (preprint)

Background Hyperuricemia, pulmonary hypertension, renal failure, and alkaline intoxication syndrome (HUPRA syndrome) is a rare autosomal recessive mitochondrial disease with prevalence of less than one in a million. Due to mutations in the mitochondrial SARS enzyme encoding seryl-tRNA synthetase on chromosome 19 (19q13.2). Case–Diagnosis/Treatment We investigated two Palestinian girls from the same village presented with progressive renal failure in infancy were diagnosed with this multisystemic disease. presented with atypical clinical manifestations of HUPRA syndrome include leukopenia, anemia, salt wasting resulting in hyponatremia and hypochloremia, renal failure with elevated blood lactate, marked hyperuricemia, hypercholesterolemia and hypertriglyceridemia but  without  pulmonary hypertension or alkaline intoxication that distinguish them from the rest of the usual cases, instead they showed acidosis in routine follow up. By using single exome sequencing analysis, we identified a two homozygous pathogenic mutation c.1175A>G (p.D392G), c.1169A>G (D390G) in SARS2 gene. This sequence identified a new variant mutation of HUPRA syndrome c.1175A>G (p.D392G) with atypical presentation, that will be added to the literature. Conclusion SARS2 gene with pathogenic homozygous mutation variants were detected in our two patients c.1175A>G (p.D392G), c.1169A>G (D390G) in exon 13, with atypical clinical manifestations of HUPRA syndrome, expanding the spectrum of SARS2 pathogenic variants with its characteristic findings, describing the differences in clinical manifestations between homozygous and compound heterozygous mutations.

Growing a Peritoneal Dialysis Program in Palestine from Zero to 178 Patients in 5 Years: A Single-Center Experience (preprint)

Introduction: Kidney failure is rapidly rising in Palestine, as the number of patients receiving maintenance dialysis has quadrupled in the last 15 years. In this study, we share an overview of our experience growing a peritoneal dialysis (PD) program from zero to 178 patients in five years at An-Najah National University Hospital in Palestine, presenting some challenges and ways to overcome them. Methods: This was a single-center retrospective study of patients treated with PD from November 2016 to December 2021. Demographic and clinical data were obtained for each patient. In addition, PD discontinuation, peritonitis, and mortality rates were calculated and presented as the primary patient outcomes. Results: A total of 158 patients were eligible for the study. The mean age was 51.8 ± 16.4 years, and 53.8% of patients were male. Diabetic nephropathy was the most common cause of kidney failure. Sixty-three episodes of peritonitis were diagnosed in 48 patients (30.4%) for a rate of 1 episode/ 38.2 patient-months (0.31 episodes/ patient-years). Twenty patients had their PD treatment discontinued, mainly due to psychosocial reasons and infectious and mechanical complications. Death was the fate of 27 patients, with cardiovascular disease and COVID-19 being the two main causes. Conclusion: The outcomes of this experience proved favorable and showed that PD could serve as a viable option for kidney failure patients in Palestine. Moreover, this study can serve as an example for other places where circumstances are challenging to take the initiative of starting their PD programs.

Cytokine and Chemokine Retention Profile in COVID-19 Patients with Chronic Kidney Disease.

Chronic kidney disease (CKD) patients are more susceptible to infections compared to the general population. SARS-CoV-2 virus pathology is characterized by a cytokine storm responsible for the systemic inflammation typical of the COVID-19 disease. Since CKD patients have a reduced renal clearance, we decided to investigate whether they accumulate harmful mediators during the COVID-19 disease. We conducted a retrospective study on 77 COVID-19 hospitalized subjects in the acute phase of the illness. Thirteen different cytokines were assessed in plasma collected upon hospitalization. The patients were divided into three groups according to their estimated glomerular filtration rate, eGFR < 30 (n = 23), 30 < eGFR < 60 (n = 33), eGFR > 60 mL/min (n = 21). We found that Tumor Necrosis Factor α and its receptors I and II, Interleukin-7, Leukemia Inhibitory Factor, FAS receptor, Chitinase 3-like I, and the Vascular Endothelial Growth Factor showed an increased accumulation that negatively correlate with eGFR. Moreover, non-survivor patients with an impaired kidney function have significantly more elevated levels of the same mediators. In conclusion, there is a tendency in COVID-19 ESRD patients to accumulate harmful cytokines. The accumulation seems to associate with mortality outcomes and may be due to reduced clearance but also to increased biosynthesis in most severe cases.

Reduction in Serum Magnesium Levels and Renal Function Are Associated with Increased Mortality in Obese COVID-19 Patients.

Several studies provide evidence that obesity is a significant risk factor for adverse outcomes in coronavirus disease 2019 (COVID-19). Altered renal function and disturbances in magnesium levels have been reported to play important pathophysiological roles in COVID-19. However, the relationship between obesity, renal function, circulating magnesium levels, and mortality in patients with COVID-19 remains unclear. In this retrospective cohort study, we characterized 390 hospitalized patients with COVID-19 that were categorized according to their body mass index (BMI). Patients were clinically characterized and biochemical parameters, renal function, and electrolyte markers measured upon admission. We found that in patients who died, BMI was associated with reduced estimated glomerular filtration rate (eGFR, Rho: -0.251, p = 0.001) and serum magnesium levels (Rho: -0.308, p < 0.0001). Multiple linear regression analyses showed that death was significantly associated with obesity (p = 0.001). The Cox model for obese patients showed that magnesium levels were associated with increased risk of death (hazard ratio: 0.213, 95% confidence interval: 0.077 to 0.586, p = 0.003). Thus, reduced renal function and lower magnesium levels were associated with increased mortality in obese COVID-19 patients. These results suggest that assessment of kidney function, including magnesium levels, may assist in developing effective treatment strategies to reduce mortality among obese COVID-19 patients.

Impaired kidney function biomarkers and risk of severe COVID-19: Analysis of population-based cohort data.

BACKGROUND: Patients with impaired kidney function were found at a high risk of COVID-19 hospitalization and mortality in many observational, cross-sectional, and hospital-based studies, but evidence from large-scale prospective cohorts has been lacking. We aimed to examine the association of kidney function-related biomarkers and their genetic predisposition with the risk of developing severe COVID-19 in population-based data. METHODS: We analyzed data from UK Biobank to examine the prospective association of abnormal kidney function biomarkers with severe COVID-19, defined by laboratory-confirmed COVID-19 hospitalizations. Using genotype data, we constructed polygenic risk scores (PRS) to represent an individual's overall genetic risk for these biomarkers. We also identified tipping points where the risk of severe COVID-19 began to increase significantly for each biomarker. RESULTS: Of the 502,506 adults, 1650 (0.32%) were identified as severe COVID-19, before August 12, 2020. High levels of cystatin C (OR: 1.3; 95% CI: 1.2-1.5; FDR = 1.5 × 10-5 ), serum creatinine (OR: 1.7; 95% CI: 1.3-2.1; p = 3.5 × 10-4 ; FDR = 3.5 × 10-4 ), microalbuminuria (OR: 1.4; 95% CI: 1.2-1.6; FDR = 4 × 10-4 ), and UACR (urinary albumin creatinine ratio; OR: 1.4; 95% CI: 1.2-1.6; p = 3.5 × 10-4 ; FDR = 3.5 × 10-4 ) were found significantly associated with severe COVID-19. Individuals with top 10% of PRS for elevated cystatin C, urate, and microalbuminuria had 28% to 43% higher risks of severe COVID-19 than individuals with bottom 30% PRS (p < 0.05). Tipping-point analyses further supported that severe COVID-19 could occur even when the values of cystatin C, urate (male), and microalbuminuria were within their normal value ranges (OR >1.1, p < 0.05). CONCLUSIONS: Findings from this study might point to new directions for clinicians and policymakers in optimizing risk-stratification among patients based on polygenic risk estimation and tipping points of kidney function markers. Our results call for further investigation to develop a better strategy to prevent severe COVID-19 outcomes among patients with genetic predisposition to impaired kidney function. These findings could provide a new tool for clinicians and policymakers in the future especially if we need to live with COVID-19 for a long time.

The effect of vitamin D and magnesium supplementation on clinical symptoms, and serum inflammatory and oxidative stress markers in patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial (preprint)

Objectives: This study aims to evaluate the effect of vitamin D and magnesium supplementation on clinical symptoms and serum inflammatory and oxidative stress markers in patients with COVID-19. Trial design: This study is a 4-arm randomized, double-blind, placebo-controlled clinical trial with a factorial design and the intervention period is 3 weeks. Participants: This study is conducted on COVID-19 patients admitted to the Shahid Mohammadi hospital in Bandar Abbas, Iran who be eligible for inclusion in the study. Patients are included only if they meet all of the following criteria: 1) aged from 18 to 65 years old, 2) confirmation of COVID-19 by RT-PCR test, 3) completing informed consent, 4) passing less than 48 hours since the patient's hospitalization, 5) no skin or gastrointestinal allergies due to taking multivitamin supplements, vitamin D, and magnesium, 6) having more than 30 breaths per minute and less than 93% oxygen saturation in room air and sea level. Patients are excluded if they have any of the following conditions: 1) pregnancy or lactation, 2) take a daily multivitamin or take a vitamin D or magnesium supplement in the last month, 3) participating in other clinical trials, 4) renal failure or dialysis, severe liver disease or cirrhosis, 5) known diagnosis of hypercalcemia, 6) discharging from the hospital less than 24 hours after the start of the intervention, 7) history of kidney stones in the last year, 8) transfer the patient to the ICU, 9) baseline vitamin D levels above 80 ng/ml, 9) baseline magnesium levels above 2.6 mg/dl. Intervention and comparator: Participants will be randomly allocated to one of the four following groups: A) Vitamin D (two 50,000 IU capsules at the beginning of the study, two 50,000 IU capsules on the 4th day, one 50,000 IU capsule on the 11th day, and one 50,000 IU capsule on the 17th day) and magnesium supplement (300 mg/day). B) Vitamin D capsule and magnesium placebo. C) Magnesium supplement and vitamin D placebo. D) Vitamin D placebo and magnesium placebo. Main outcomes: Clinical symptoms (fever, dry cough, shortness of breath, headache, myalgia, oxygen saturation, and mortality) and laboratory markers (CRP, MDA, TAC, WBC, neutrophils count, lymphocytes count, ratio of neutrophils to lymphocytes, levels of 25 hydroxyvitamin D and magnesium) Randomization: A computer-generated block randomization list is used for randomization. Blinding (masking): Investigators and patients are blinded to group allocation and treatment. A double-blind design is achieved using matched placebos. Numbers to be randomized (sample size): A total of 104 eligible patients are randomized into four groups of 26 subjects (1:1:1:1 allocation ratio). Discussion With the rapid prevalence of COVID-19 in recent years, more attention has been paid to effective dietary supplementation to improve clinical symptoms and biochemical parameters in these patients. To our knowledge, this is the first study to evaluate the effects of vitamin D supplementation in combination with magnesium or alone with respect to this infectious disease. The findings of the current RCT will provide evidence regarding the effectiveness of dietary supplementation strategies to improve COVID-19 outcomes. Trial Status: Ethical approval of the first version of the study protocol was obtained from the medical ethics committee of Hormozgan University of Medical Sciences, Bandar Abbas, Iran on May 30th, 2021 (IR.HUMS.REC.1400.085). Currently, the recruitment phase is ongoing since August 23th, 2021 and is anticipated to be complete by the end of August 2022. Trial registration: The study protocol was registered in the Iranian Registry of Clinical Trials (https://www.irct.ir; IRCT20210702051763N1) on August 14th, 2021. https://www.irct.ir/trial/57413 Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Baclofen Withdrawal-Induced Psychosis in the Setting of Renal Insufficiency.

Baclofen is used to treat muscle spasticity, acting at GABA B receptors in the central nervous system. The abrupt cessation of baclofen causes baclofen withdrawal-induced psychosis. The risk is exacerbated if the patient has renal insufficiency or if the drug has been taken for a long time at high doses. Gradual tapering of baclofen usually does not produce symptomatic adverse effects. However, abrupt termination of the drug, especially in an inpatient hospital setting, can lead to symptoms such as increased spasticity, agitation, confusion, hallucinations, and seizures. We present a case of a patient who initially presented with seizures and experienced hallucinations after abrupt cessation of the medication. She had baseline chronic kidney disease but presented with acute worsening of her renal function. Impaired renal function decreases baclofen clearance and causes increased concentration of baclofen in circulation. This put the patient at higher risk of developing baclofen withdrawal, even at a lower dose.

Vaccination in patients with kidney failure: lessons from COVID-19.

Infection is the second leading cause of death in patients with chronic kidney disease (CKD). Adequate humoral (antibody) and cellular (T cell-driven) immunity are required to minimize pathogen entry and promote pathogen clearance to enable infection control. Vaccination can generate cellular and humoral immunity against specific pathogens and is used to prevent many life-threatening infectious diseases. However, vaccination efficacy is diminished in patients with CKD. Premature ageing of the immune system and chronic systemic low-grade inflammation are the main causes of immune alteration in these patients. In the case of SARS-CoV-2 infection, COVID-19 can have considerable detrimental effects in patients with CKD, especially in those with kidney failure. COVID-19 prevention through successful vaccination is therefore paramount in this vulnerable population. Although patients receiving dialysis have seroconversion rates comparable to those of patients with normal kidney function, most kidney transplant recipients could not generate humoral immunity after two doses of the COVID-19 vaccine. Importantly, some patients who were not able to produce antibodies still had a detectable vaccine-specific T cell response, which might be sufficient to prevent severe COVID-19. Correlates of protection against SARS-CoV-2 have not been established for patients with kidney failure, but they are urgently needed to enable personalized vaccination regimens.

Pharmacokinetics of nirmatrelvir and ritonavir in COVID-19 patients with end stage renal disease on intermittent haemodialysis (preprint)

Background: Nirmatrelvir/ritonavir is an effective therapy against SARS-CoV-2. Patients with end-stage renal disease (ESRD) are at high risk for severe COVID-19 and show impaired vaccine responses underlining the importance of antiviral therapy. However, use of nirmatrelvir/ritonavir is not recommended in these patients due to lack of clinical and pharmacokinetic data. Objective: To investigate pharmacokinetics and hepatic tolerance of nirmatrelvir/ritonavir in patients with ESRD and haemodialysis (HD). Patients and methods: Four patients diagnosed with SARS-CoV-2 infection received nirmatrelvir/ritonavir 150/100mg twice daily as recommended for renal impairment; HD ran in two- to three-day intervals. Plasma and serum samples were drawn before and after each HD during the 5-day treatment and for ensuing 3-5 days. Results: Median peak levels of nirmatrelvir obtained two hours after medication pre-HD in three patients were 7745ng/mL on day 3 and 6653ng/mL on day 5; median post-HD levels (C6h) declined to 5765ng/mL (74%) and 5521ng/mL (83%), on days 3 and 5 of treatment, respectively. Three days after end of treatment, median levels were 365ng/mL pre-HD and 30ng/mL post-HD. Measurements of the fourth patient, six hours after drug intake pre-HD showed nirmatrelvir-levels of 3704ng/mL on treatment day 3 which fell to 2308ng/mL post-HD, at one hour before intake of the next dose (Cmin). Conclusion: Use of nirmatrelvir/ritonavir in patients with ESRD results in high nirmatrelvir blood concentrations, which are still within the range known from patients without renal failure. No accumulation of nirmatrelvir took place and levels declined to zero within few days after end of treatment.