Nirmatrelvir/ritonavir treatment in SARS-CoV-2 positive kidney transplant recipients - a case series with four patients.

BACKGROUND: Despite vaccination coronavirus disease 2019 (COVID-19)-associated mortality caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains high in kidney transplant recipients. Nirmatrelvir is a protease inhibitor with activity against SARS-CoV-2. Nirmatrelvir reduces the risk for mortality and hospitalization, which is approved for treating adults at risk for severe disease. Nirmatrelvir is metabolized by the cytochrome P-450 (CYP) 3A4 isozyme CYP3A4 and is therefore co-administered with the irreversible CYP3A4 inhibitor ritonavir, which results in a drug interaction with tacrolimus. A limited number of patients with nirmatrelvir/ritonavir and tacrolimus therapy after kidney transplantation have been reported to date. It has been reported that tacrolimus was paused during the five-day nirmatrelvir/ritonavir therapy and subtherapeutic tacrolimus levels were observed after finishing nirmatrelvir/ritonavir in two patients. Therefore, optimization of tacrolimus dosing is urgently needed in transplant recipients receiving nirmatrelvir/ritonavir treatment. CASE PRESENTATION: Here, we present our first-hand experience with four patients receiving tacrolimus therapy following kidney transplantation and nirmatrelvir/ritonavir therapy due to COVID-19. Tacrolimus was paused during nirmatrelvir/ritonavir therapy in all patients, which resulted in stable therapeutic tacrolimus levels. Tacrolimus was continued directly after finishing nirmatrelvir/ritonavir to avoid subtherapeutic levels in the first patient treated. This patient received his usual tacrolimus maintenance dose, which resulted in toxic levels. Based on this observation, tacrolimus therapy was continued 24 h after finishing nirmatrelvir/ritonavir treatment at a reduced dose in the subsequent patients. In these patients, therapeutic to supratherapeutic tacrolimus levels were observed despite the therapeutic break and dose reduction. DISCUSSION AND CONCLUSIONS: Based on altered CYP3A4 metabolism, tacrolimus levels have to be closely monitored after treatment with nirmatrelvir/ritonavir. Our study suggests that tacrolimus treatment should be paused during nirmatrelvir/ritonavir medication and be continued 24 h after completing nirmatrelvir/ritonavir therapy at a reduced dose and under close monitoring. Based on the limited number of patients in this study, results must be interpreted with caution.

Clinical covariates influencing clinical outcomes in primary membranous nephropathy.

BACKGROUND: Primary membranous nephropathy (PMN) frequently causes nephrotic syndrome and declining kidney function. Disease progression is likely modulated by patient-specific and therapy-associated factors awaiting characterization. These cofactors may facilitate identification of risk groups and could result in more individualized therapy recommendations. METHODS: In this single-center retrospective observational study, we analyze the effect of patient-specific and therapy-associated covariates on proteinuria, hypoalbuminemia, and estimated glomerular filtration rate (eGFR) in 74 patients diagnosed with antibody positive PMN and nephrotic-range proteinuria (urine-protein-creatinine-ratio [UPCR] ≥ 3.5 g/g), treated at the University of Freiburg Medical Center between January 2000 - November 2022. The primary endpoint was defined as time to proteinuria / serum-albumin response (UPCR ≤ 0.5 g/g or serum-albumin ≥ 3.5 g/dl), the secondary endpoint as time to permanent eGFR decline (≥ 40% relative to baseline). RESULTS: The primary endpoint was reached after 167 days. The secondary endpoint was reached after 2413 days. Multivariate time-to-event analyses showed significantly faster proteinuria / serum-albumin response for higher serum-albumin levels (HR 2.7 [95% CI: 1.5 - 4.8]) and cyclophosphamide treatment (HR 3.6 [95% CI: 1.3 - 10.3]). eGFR decline was significantly faster in subjects with old age at baseline (HR 1.04 [95% CI: 1 - 1.1]). CONCLUSION: High serum-albumin levels, and treatment with cyclophosphamide are associated with faster proteinuria reduction and/or serum-albumin normalization. Old age constitutes a risk factor for eGFR decline in subjects with PMN.

Integration of sustained low-efficiency dialysis into extracorporeal membrane oxygenation circuit in critically ill COVID-19 patients: A feasibility study.

BACKGROUND: Severe COVID-19 can necessitate multiple organ support including veno-venous extracorporeal membrane oxygenation (vvECMO) and renal replacement therapy. The therapy can be complicated by venous thromboembolism due to COVID-19-related hypercoagulability, thus restricting vascular access beyond the vvECMO cannula. Although continuous renal replacement therapy can be performed via a vvECMO circuit, studies addressing sustained low-efficiency dialysis (SLED) integration into vvECMO circuits are scarce. Here we address the lack of evidence by evaluating feasibility of SLED integration into vvECMO circuits. METHODS: Retrospective cohort study on nine critically ill COVID-19 patients, treated with integrated ECMO-SLED on a single intensive care unit at a tertiary healthcare facility between December 2020 and November 2021. The SLED circuits were established between the accessory arterial oxygenator outlets of a double-oxygenator vvECMO setup. Data on filter survival, quality of dialysis, and volume management were collected and compared with an internal control group receiving single SLED. RESULTS: This study demonstrates general feasibility of SLED integration into existing vvECMO circuits. Filter lifespans of ECMO-SLED compared with single SLED are significantly prolonged (median 18.3 h vs. 10.3 h, p < 0.01). ECMO-SLED treatment is furthermore able to sufficiently normalize creatinine, blood urea nitrogen, and serum sodium, and allows for adequate ultrafiltration rates. CONCLUSIONS: We can show that ECMO-SLED is practical, safe, results in adequate dialysis quality and enables sufficient electrolyte and volume management. Our data indicate that SLED devices can serve as potential alternative to continuous-veno-venous-hemodialysis for integration in vvECMO circuits.

Descendo-bifemoral bypass grafting and renal artery revascularization to treat complex obliterative arteriopathy.

OBJECTIVES: Our goal was to describe a new standardized approach in patients with extensive obliterative arteriopathy aimed at distal revascularization and surgical kidney recruitment via descendo-bifemoral bypass grafting and renal artery revascularization. METHODS: Three patients with Leriche's syndrome and either a compromised single kidney or unilateral significant renal artery stenosis were treated with a standardized surgical approach, restoration of distal perfusion via descendo-bifemoral bypass with synchronous ( n = 2) left-sided renal artery revascularization or metachronous ( n = 1) right-sided renal artery revascularization. RESULTS: The intended surgical aim was achieved successfully in all 3 cases. All patients showed a decline in serum creatinine levels. One patient who needed substitution therapy was free from dialysis 3 months after surgery. Additionally, blood pressure management was substantially reduced because uncontrolled peak systolic episodes were no longer observed and pharmacotherapeutic agents could be partially withdrawn. CONCLUSIONS: Distal revascularization and surgical kidney recruitment via descendo-bifemoral bypass and renal artery revascularization is a promising option to treat complex obliterative arteriopathy.

Successful Management of Calciphylaxis in a Kidney Transplant Patient: Case Report.

UNLABELLED: Calciphylaxis is a rare and often fatal condition mostly associated with end-stage renal disease. The pathophysiology remains elusive and treatment options are scarce. We present a rare case of severe calciphylaxis after kidney transplantation in a patient with persistent hyperparathyroidism. CASE DESCRIPTION: A 78-year-old man with a history of end-stage renal disease developed edema and ulcerations on both lower limbs 14 months after kidney transplantation while receiving an mammalian target of rapamycin inhibitor to manage polyoma virus-associated nephropathy. Skin biopsies taken from the ulcerations confirmed calciphylaxis. A multimodal treatment regimen combining medical (calcium-free phosphate binders, cinacalcet, paricalcitol, sodium thiosulfate, antibiotic treatment) and surgical treatments (debridement and autologous skin transplantation) ultimately resulted in successful wound healing. DISCUSSION: We describe a case of severe calciphylaxis in a nonuremic patient after kidney transplantation. Rapid diagnosis by skin biopsy and an aggressive multimodal therapy regimen followed by long-term oral sodium thiosulfate treatment were crucial factors for a favorable outcome.