A Head-to-head Comparison of De Novo Sirolimus or Everolimus Plus Reduced-dose Tacrolimus in Kidney Transplant Recipients: A Prospective and Randomized Trial.

BACKGROUND: Mammalian target of rapamycin inhibitors (mTORi), sirolimus (SRL) and everolimus (EVR), have distinct pharmacokinetic/pharmacodynamics properties. There are no studies comparing the efficacy and safety of de novo use of SRL versus EVR in combination with reduced-dose calcineurin inhibitor. METHODS: This single-center prospective, randomized study included first kidney transplant recipients receiving a single 3 mg/kg antithymocyte globulin dose, tacrolimus, and prednisone, without cytomegalovirus (CMV) pharmacological prophylaxis. Patients were randomized into 3 groups: SRL, EVR, or mycophenolate sodium (MPS). Doses of SRL and EVR were adjusted to maintain whole blood concentrations between 4 and 8 ng/mL. The primary endpoint was the 12-mo incidence of the first CMV infection/disease. RESULTS: There were 266 patients (SRL, n = 86; EVR, n = 90; MPS, n = 90). The incidence of the first CMV event was lower in the mTORi versus MPS groups (10.5% versus 7.8% versus 43.3%, P < 0.0001). There were no differences in the incidence of BK polyomavirus viremia (8.2% versus 10.1% versus 15.1%, P = 0.360). There were no differences in survival-free from treatment failure (87.8% versus 88.8% versus 93.3%, P = 0.421) and incidence of donor-specific antibodies. At 12 mo, there were no differences in kidney function (75 ± 23 versus 78 ± 24 versus 77 ± 24 mL/min/1.73 m 2 , P = 0.736), proteinuria, and histology in protocol biopsies. Treatment discontinuation was higher among patients receiving SRL or EVR (18.6% versus 15.6% versus 6.7%, P = 0.054). CONCLUSIONS: De novo use of SRL or EVR, targeting similar therapeutic blood concentrations, shows comparable efficacy and safety. The reduced incidence of CMV infection/disease and distinct safety profile of mTORi versus mycophenolate were confirmed in this study.

Two-Hit Kidney Allograft Injury by SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) has been associated with acute kidney injury in kidney transplant recipients by several mechanisms. The authors report a case of acute kidney allograft dysfunction in a 48-year-old patient who presented in the emergency room with anasarca and nephrotic syndrome close after mild COVID-19 and no other clinical condition. Histopathology of the allograft biopsy revealed two distinct and simultaneous kidney lesions, collapsing glomerulopathy and thrombotic microangiopathy. Renal function persistently deteriorated, and definitive dialysis was initiated. After excluding other plausible causes for the findings, this case strengthens the hypothesis that the kidney allograft is also a target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The influence of the antithymocyte globulin dose on clinical outcomes of patients undergoing kidney retransplantation.

Optimizing antithymocyte globulin (rATG) dosage is critical for high immunological risk patients undergoing a repeat kidney transplant. This natural retrospective cohort study compared clinical outcomes of two successive cohorts of consecutive recipients of retransplants receiving 5 x 1 mg/kg (rATG-5, n = 100) or a single 3 mg/kg (rATG-3, n = 110) dose of rATG induction therapy. All patients had negative complement-dependent cytotoxicity crossmatch and no anti-HLA A, B, DR donor-specific antibodies (DSA). The primary endpoint was efficacy failure (first biopsy-proven acute rejection, graft loss, or death) at 12 months. There was no difference in the cumulative incidence of efficacy failure (18.0% vs. 21.8%, HR = 1.22, 95% CI 0.66-2.25), respectively. There were no differences in 3-years freedom from biopsy proven acute rejection, and patient, graft, and death-censored graft survivals. There were no differences in the incidence of surgical complications (25.0% vs. 18.2%; p 0.151), early hospital readmission (27.8% vs. 29.5%; p = 0.877) and CMV infections (49% vs. 40%; p = 0.190). There were also no differences in the incidence (59.6% vs. 58.7%, p = 0.897) and duration of delayed graft function but a stable difference in estimate glomerular filtration rate was observed from month 1 (54.7±28.8 vs. 44.1±25.3 ml/min/1.73 m2, p = 0.005) to month 36 (51.1±27.7 vs. 42.5±24.5, p = 0.019). Mean urinary protein concentration (month 36: 0.38±0.81 vs. 0.70±2.40 g/ml, p = 0.008) and mean chronic glomerular Banff score in for cause biopsies (months 4-36: 0.0±0.0 vs. 0.04±0.26, p = 0.044) were higher in the rATG-3 group. This cohort analysis did not detect differences in the incidence of efficacy failure and in safety outcomes at 12 months among recipients of kidney retransplants without A, B, and DR DSA, receiving induction therapy with a single 3 mg/kg rATG dose or the traditional 5 mg/kg rATG.

Prospective randomized study comparing everolimus and mycophenolate sodium in de novo kidney transplant recipients from expanded criteria deceased donor.

The optimal immunosuppressive regimen for recipients of expanded criteria donor (ECD) kidneys has not been identified. In this single-center study, 171 recipients of ECD kidney transplants were randomized to receive antithymocyte globulin induction, and delayed introduction of reduced dose tacrolimus, prednisone and everolimus (r-ATG/EVR, n = 88), or mycophenolate (r-ATG/MPS, n = 83). No cytomegalovirus (CMV) pharmacological prophylaxis was used. The primary endpoint was the incidence of CMV infection/disease at 12 months. Secondary endpoints included treatment failure [first biopsy-proven acute rejection (BPAR), graft loss, or death] and safety. Patients treated with EVR showed a 89% risk reduction (13.6 vs. 71.6%; HR 0.11, 95% CI 0.06-0.220, P < 0.001) in the incidence of first CMV infection/disease. Incidences of BPAR (16% vs. 5%, P = 0.021), graft loss (11% vs. 1%, P = 0.008), death (10% vs. 1%, P = 0.013), and treatment discontinuation (40% vs. 28%, P = 0.12) were higher in the r-ATG/EVR, leading to premature study termination. Mean glomerular filtration rate was lower in r-ATG/EVR (31.8 ± 18.8 vs. 42.6 ± 14.9, P < 0.001). In recipients of ECD kidney transplants receiving no CMV pharmacological prophylaxis, the use of everolimus was associated with higher treatment failure compared with mycophenolate despite the significant reduction in the incidence of CMV infection/disease (ClinicalTrials.gov.NCT01895049).

Diagnostic accuracy of immunofluorescence versus immunoperoxidase staining to distinguish immune complex-mediated glomerulonephritis and C3 dominant glomerulopathy.

AIMS: The technique used for classification of membranoproliferative glomerulonephritis (MPGN) has been changed from an electron microscopy-based to an immunofluorescence (IF)-based semiquantitative technique with immunoperoxidase (IP) staining as a backup option when IF is not possible. Since data on that matter is lacking, our aims were to study the interobserver variability, the correlation and the reclassification of MPGN based on these two techniques. METHODS AND RESULTS: We retrospectively analysed cases of type 1 MPGN. We repeated IF staining and performed IP staining for IgG, kappa, lambda, C3c and C4d in 35 renal biopsies, among which 19 biopsies had matched IP and IF samples. We observed substantial to near-perfect agreement among the seven observers for both IF and IP (W coefficients from 0.66 for IF lambda to 0.89 for IF C4d). Of the 19 cases with matched IP and IF samples, five (26%) turned out to have different diagnoses on IF and on IP. Also, the ability of C4d to discriminate immune complex-mediated glomerulonephritis (ICGN) from C3 glomerulopathy (C3G) was poor, with areas under the curve of 0.44 [95% confidence interval (CI) 0.24-0.63] and 0.66 (95% CI 0.50-0.81) for the receiver operating characteristic curves of IF and IP respectively. Limitations include the fact that no clinical data regarding complement activation were available. CONCLUSION: The diagnosis of ICGN versus C3GN depends on the immunochemical technique used. Also, the use of C4d failed to discriminate ICGN from C3G in our study. Further validation studies are required to avoid misdiagnosis based on kidney biopsy.

Acquired cystic kidney disease in allograft with long-standing poor function.

Acquired Cystic Kidney Disease (ACKD) is regarded as a common late condition of end stage renal damage and expresses its most important features when associated with long term hemodialysis. ACKD is also widely known as a premalignant lesion. Its occurrence in chronically rejected renal allografts is rare and its frequency and behavior in this setting are not well known. Herein we report a case of ACKD in a long standing nonfunctional allograft (215 months) which is not associated with malignancy and briefly review the related literature.

Acquired cystic kidney disease in allograft with long-standing poor function / Doença renal cística adquirida em um enxerto cronicamente disfuncional

Abstract Acquired Cystic Kidney Disease (ACKD) is regarded as a common late condition of end stage renal damage and expresses its most important features when associated with long term hemodialysis. ACKD is also widely known as a premalignant lesion. Its occurrence in chronically rejected renal allografts is rare and its frequency and behavior in this setting are not well known. Herein we report a case of ACKD in a long standing nonfunctional allograft (215 months) which is not associated with malignancy and briefly review the related literature.

Resumo A doença renal cística adquirida (ACKD) é considerada uma condição tardia relacionada à doença renal crônica terminal e manifesta-se de modo mais evidente no contexto de hemodiálise de longo prazo. ACKD é amplamente reconhecida como lesão pré-maligna. Sua ocorrência em enxertos renais cronicamente rejeitados é rara, de modo que a frequência e o comportamento da entidade nesse cenário não estão bem documentados. Relatamos a ocorrência de ACKD em um aloenxerto renal não funcionante sem malignidade após 215 meses de transplante e brevemente revisamos a literatura relacionada.

Donor-Specific Anti-Human Leukocyte Antigens Antibodies, Acute Rejection, Renal Function, and Histology in Kidney Transplant Recipients Receiving Tacrolimus and Everolimus.

BACKGROUND: This analysis compared efficacy, renal function, and histology in kidney transplant recipients receiving tacrolimus (TAC) combined with everolimus (EVR) or mycophenolate (MPS). METHODS: This was a retrospective analysis from a randomized trial in kidney transplant recipients who received a single 3 mg/kg dose of rabbit antithymocyte globulin (r-ATG), TAC, EVR, and prednisone (PRED; r-ATG/EVR, n = 85), basiliximab (BAS), TAC, EVR, and PRED (BAS/EVR, n = 102) or BAS, TAC, MPS, and PRED (BAS/MPS, n = 101). We evaluated the incidence of de novo donor-specific anti-human leukocyte antigens antibodies (DSA) and histology on protocol biopsies at 12 months, and the incidence of acute rejection, estimated glomerular filtration rate (eGFR) and proteinuria at 36 months. RESULTS: At 12 months, there were no differences in de novo DSA (6.4 vs. 3.4 vs. 5.5%) or in subclinical inflammation (2.0 vs. 4.8 vs. 10.2%), interstitial fibrosis/tubular atrophy (57.1 vs. 58.5 vs. 53.8%) and C4d deposition (2.0 vs. 7.3 vs. 2.6%). At 36 months, there were no differences in the incidence of treatment failure (19.0 vs. 27.7 vs. 27.7%, p = 0.186), first biopsy-proven acute rejection (9.5 vs. 21.8 vs. 16.8%, p = 0.073), and urine protein/creatinine ratios (0.53 ± 1.05 vs. 0.62 ± 0.75 vs. 0.71 ± 1.24). eGFR was lower in the BAS/EVR compared to that in the BAS/MPS group (53.4 ± 20.9 vs. 50.8 ± 19.5 vs. 60.7 ± 21.2 mL/min/1.73 m2, p = 0.017) but comparable using a sensitive analysis (49.5 ± 23 vs. 47.5 ± 22.6 vs. 53.6 ± 27.8 mL/min/1.73 m2, p = 0.207). CONCLUSION: In this cohort, the use of EVR and reduced TAC concentrations were associated with comparable efficacy, renal function, and histological parameters compared to the standard-of-care immunosuppressive regimen.