Eglė Ašakienė

BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.

The coronavirus (COVID-19) pandemic is evolving very quickly and has affected healthcare systems worldwide. Many uncertainties remain about transplantation from a SARS-CoV-2-positive donor as only a few cases have been reported. Here, we present the successful transplantation of 2 kidneys from a 52-year-old male donor with active (2 weeks of COVID-19-like symptoms and positive nasopharyngeal swab SARS-CoV-2 polymerase chain reaction on the day of organ recovery) SARS-CoV-2 disease. The immediate postoperative course of both recipients was uneventful. This case emphasizes that patients with SARS-CoV-2 may be safe organ donors.

The purpose of this study was to evaluate the incidence of delayed graft function and its impact on the antigraft response after cadaver kidney transplantation. The analysis is based on 183 consecutive cadaver kidney transplantations performed in Vilnius University Hospital Santariskiu klinikos from January 2000 to December 2004. Delayed graft function occurred in 21.3% (39/183) of kidney transplantations. The frequency and severity of acute rejection episodes in recipients during first three months after transplantation and graft survival rate at one and two years were evaluated. Group 1 consisted of 39 patients with delayed graft function and group 2 (control group) of 144 patients with graft function immediately after transplantation. The maintenance immunosuppressive therapy consisted of cyclosporine, mycophenolate mofetil/azathioprine and prednisolone. The proportion of patients treated with monoclonal antibodies was similar in both groups (35.9% vs. 33.3%). Actuarial graft survival was estimated by the modified Kaplan-Meier method, graft loss was censored for death of recipient with functioning transplant and other causes of loss not related to rejection. There were no significant differences in the age of recipients (42.3+/-11.3 vs. 39.4+/-14.1), as well as in HLA matching (2.2/6 M vs. 2.2/6 M), in the number retransplanted patients (10.3% vs. 10.4%) and in highly sensitized patients (plasma renin activity >50.0%) (5.1% vs. 4.8%) between those groups. Significant differences were observed in donors over 50 year (33.3% vs. 18.7%; p<0.05), in cold ischemic time over 20 h (53.8 vs. 32.6%, respectively). The occurrence of acute rejection episodes was higher in group 1 than in group 2 (69.2% (27/39) vs. 34.7% (50/144); chi2=14.9945, p<0.05). Graft survival was 88.5%, 84.3% at one year and two years in group 1 and 94.7%, 93.8% at one year and two years in group 2 (ns). Donor age >50, cerebral vascular disease as cause of donor death, and cold ischemic time >20 h are the main risk factors for delayed graft function. Delayed graft function is a risk factor for acute rejection episodes, but it has no impact on graft loss due to immunological reason at one and two years. These data may serve for tailoring immunosuppressive protocols.

Our case series showed that eculizumab is efficacious and safe in treating thrombotic microangiopathy, as well as it has positive effects on quality of life. Further extensive studies are required to develop unified treatment guidelines.

A 66-year-old woman with a history of arterial hypertension was admitted to the emergency department (ED) due to disorientation. She reported a severe headache, nausea, vomiting in the evening prior the admission; her blood pressure (BP) when the ambulance arrived was 220/100 mmHg. During admission, BP was 158/91 mmHg, pulse 95 beats/minute, oxygen saturation 88% on room air, body temperature 36.6°C. The urine examination showed that urine protein was 3+, red blood cell count 10 mg/L. The whole blood cell analysis revealed neutrophilic leukocytosis, thrombocytopenia (Table). There was 1 schistocyte seen in the peripheral blood smear. The serum creatinine and urea values were raised (Table) with elevated level of D-dimers (1690 mcg/L (&lt; 250 mcg/L)). Head CT showed no signs of hemorrhage or ischemia. Ceftriaxone, ampicillin, and acyclovir were initiated for suspected neuro-infection, she also underwent transfusion with 4 units of platelets due to thrombocytopenia. Patients GCS fell from 11 to 9 over 13 hours, therefore she was transferred to the intensive care unit (ICU). Cerebrospinal fluid analysis showed cytosis 15 cells/mcL (predominance of lymphocytes) and protein level of 1,073 g/L; PCR panel for the most common bacterial and viral meningitis agents came back negative. On day 2, lactate dehydrogenase level was raised at 3086 U/L (125–243 U/L), haptoglobin was &lt; 0.08 g/L (0.3–2.0 g/L) and Coombs test was negative. Due to worsening renal function (Table) hemodialysis was initiated. The differential diagnosis included thrombotic thrombocytopenic purpura, atypical hemolytic-uremic syndrome (HUS), secondary thrombotic microangiopathy (TMA), immune thrombocytopenic purpura (ITP) and disseminated intravascular coagulation (DIC). ADAMTS-13, CH50, SC5b-9 levels were tested (0.53 TV/ml (0.40–1.50 TV/ml), 60 U Eq/ml (55–75 U Eq/ml), 4689 ng/ml (200–325 ng/ml), respectively). The patient started on plasmapheresis. On day 3, fundoscopy showed cotton wool spots (ischemia) with hemorrhages and soft exudates next to the optic nerve disc; intravenous methylprednisolone pulse therapy was administered (1 g daily for three days followed by oral methylprednisolone 32 mg daily). Renal biopsy on day 5 revealed active TMA damaging the glomeruli and acute tubular necrosis. After 15 days in the ICU, she remained hypertensive and anuric despite given treatment. Moreover, pulmonary edema occurred on day 15. Malignant hypertension (MH) is characterized by severe hypertension and multi-organ ischemic complications. It can cause TMA and the overall presentation may imitate primary TMA. The approach of renal TMA in MH remains challenging. Herein, we reported a case of MHT with biopsy-proven TMA in the kidney.