The incidence of acute humoral rejection (AHR) in renal allograft biopsies has been difficult to determine because widely accepted diagnostic criteria have not been established. C4d deposition in peritubular capillaries (PTC) of renal allografts has been proposed as a useful marker for AHR. This study was designed to test the relative value of C4d staining, histology, and serology in the diagnosis of AHR. Of 232 consecutive kidney transplants performed at a single institution from July 1995 to July 1999, all patients (n = 67) who developed acute rejection within the first 3 mo and had a renal biopsy with available frozen tissue at acute rejection onset, as well as posttransplant sera within 30 d of the biopsy, were included in this study. Hematoxylin and eosin and periodic acid-Schiff stained sections were scored for glomerular, vascular, and tubulointerstitial pathology. C4d staining of cryostat sections was done by a sensitive three-layer immunofluorescence method. Donor-specific antibodies (DSA) were detected in posttransplant recipient sera using antihuman-globulin–enhanced T cell and B cell cytotoxicity assays and/or flow cytometry. Widespread C4d staining in PTC was present in 30% (20 of 67) of all acute rejection biopsies. The initial histologic diagnoses of the C4d⁺ acute rejection cases were as follows: AHR only, 30%; acute cellular rejection (ACR) and AHR, 45%; ACR (CCTT types 1 or 2) alone, 15%; and acute tubular injury (ATI), 10%. The distinguishing morphologic features in C4d⁺versus C4d⁻ acute rejection cases included the following: neutrophils in PTC, 65% versus 9%; neutrophilic glomerulitis, 55% versus 4%; neutrophilic tubulitis, 55% versus 9%; severe ATI, 75% versus 9%; and fibrinoid necrosis in glomeruli, 20% versus 0%, or arteries, 25% versus 0%; all P < 0.01. Mononuclear cell tubulitis was more common in the C4d⁻ group (70% versus 100%; P < 0.01). No significant difference between C4d⁺ and C4d⁻ acute rejection was noted for endarteritis, 25% versus 32%; interstitial inflammation (mean % cortex), 27.2 ± 27% versus 38 ± 21%; interstitial hemorrhage, 25% versus 15%; or infarcts, 5% versus 2%. DSA were present in 90% (18 of 20) of the C4d⁺ cases compared with 2% (1 of 47) in the C4d⁻ acute rejection cases (P < 0.001). The pathology of the C4d⁺ but DSA⁻ cases was not distinguishable from the C4d⁺, DSA⁺ cases. The C4d⁺ DSA⁻ cases may be due to non-HLA antibodies or subthreshold levels of DSA. The sensitivity of C4d staining is 95% in the diagnosis of AHR compared with the donor-specific antibody test (90%). Overall, eight grafts were lost to acute rejection in the first year, of which 75% (6 of 8) had AHR. The 1-yr graft failure rate was 27% (4 of 15) for those AHR cases with only capillary neutrophils versus 40% (2 of 5) for those who also had fibrinoid necrosis of arteries. In comparison, the 1-yr graft failure rates were 3% and 7%, respectively, in ACR 1 (Banff/CCTT type 1) and ACR 2 (Banff/CCTT type 2) C4d⁻ groups. A substantial fraction (30%) of biopsy-confirmed acute rejection episodes have a component of AHR as judged by C4d staining; most (90%), but not all, have detectable DSA. AHR may be overlooked in the presence of ACR or ATI by histology or negative serology, arguing for routine C4d staining of renal allograft biopsies. Because AHR has a distinct therapy and prognosis, we propose that it should be classified separately from ACR, with further sub-classification into AHR 1 (neutrophilic capillary involvement) and AHR 2 (arterial fibrinoid necrosis).

Acute rejection (AR) associated with de novo production of donor-specific antibodies (DSA) is a clinicopathological entity that carries a poor prognosis (acute humoral rejection, AHR). The aim of this study was to determine the incidence and clinical characteristics of AHR in renal allograft recipients, and to further analyze the antibodies involved. During a 4-year period, 232 renal transplants (Tx) were performed at our institution. Assays for DSA included T and B cell cytotoxic and/or flow cytometric cross-matches and cytotoxic antibody screens (PRA). C4d complement staining was performed on frozen biopsy tissue. A total of 81 patients (35%) suffered at least one episode of AR within the first 3 months: 51 had steroid-insensitive AR whereas the remaining 30 had steroid-sensitive AR. No DSA were found in patients with steroid-sensitive AR. In contrast, circulating DSA were found in 19/51 patients (37%) with steroid-insensitive AR, and widespread C4d deposits in peritubular capillaries were present in 18 of these 19 (95%). In at least three cases, antibodies were against donor HLA class II antigens. DSA were not found in the remaining 32 patients but C4d staining was positive in 2 of 32. The DSA/C4d positive (n=18) and DSA/C4d negative (n=30) groups differed in pre-Tx PRA levels, percentage of re-Tx patients, refractoriness to antilymphocyte therapy, and outcome. Plasmapheresis and tacrolimus-mycophenolate mofetil rescue reversed rejection in 9 of 10 recipients with refractory AHR. More than one-third of the patients with steroid-insensitive AR had evidence of AHR, often resistant to antilymphocyte therapy. Most cases (95%) with DSA at the time of rejection had widespread C4d deposits in peritubular capillaries, suggesting a pathogenic role of the circulating alloantibody. Combined DSA testing and C4d staining provides a useful approach for the early diagnosis of AHR, a condition that often necessitates a more intensive therapeutic rescue regimen.

We report the nationwide experience with solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients diagnosed with coronavirus disease 2019 (COVID-19) in Spain until 13 July 2020. We compiled information for 778 (423 kidney, 113 HSCT, 110 liver, 69 heart, 54 lung, 8 pancreas, 1 multivisceral) recipients. Median age at diagnosis was 61 years (interquartile range [IQR]: 52-70), and 66% were male. The incidence of COVID-19 in SOT recipients was two-fold higher compared to the Spanish general population. The median interval from transplantation was 59 months (IQR: 18-131). Infection was hospital-acquired in 13% of cases. No donor-derived COVID-19 was suspected. Most patients (89%) were admitted to the hospital. Therapies included hydroxychloroquine (84%), azithromycin (53%), protease inhibitors (37%), and interferon-β (5%), whereas immunomodulation was based on corticosteroids (41%) and tocilizumab (21%). Adjustment of immunosuppression was performed in 85% of patients. At the time of analysis, complete follow-up was available from 652 patients. Acute respiratory distress syndrome occurred in 35% of patients. Ultimately, 174 (27%) patients died. In univariate analysis, risk factors for death were lung transplantation (odds ratio [OR]: 2.5; 95% CI: 1.4-4.6), age >60 years (OR: 3.7; 95% CI: 2.5-5.5), and hospital-acquired COVID-19 (OR: 3.0; 95% CI: 1.9-4.9).

The safety and efficacy of early steroid withdrawal or avoidance in patients receiving a kidney transplant (KT) are controversial. We performed a systematic review and a meta-analysis of the randomized controlled studies about steroid avoidance or withdrawal after a few days in patients receiving a KT and treated with antibody induction and cyclosporine (CsA) or tacrolimus (Tac) plus mycophenolate mofetil (MMF) (nine available studies and 1934 participants). Death and graft loss (including or excluding death with function) were similar in steroid avoidance and control patients, with no differences between CsA and Tac studies. After steroid avoidance, acute rejection was more frequent than conventional steroid use in CsA trials [risk ratios (RR) 1.59, 95% confidence intervals (95% CI) 1.01–2.49] but not when Tac was used (RR 1.06, 95% CI 0.79–1.42). Steroid avoidance was associated with less frequent new-onset diabetes mellitus, but this decrease was only evident with CsA (RR 0.54, 95% CI 0.30–0.98), whereas this difference was not significant analysing Tac studies (RR 0.75, 95% CI 0.32–1.77). Despite this trend, the corresponding interaction tests were not statistically significant (P = 0.140 and P = 0.535, for acute rejection and new-onset diabetes mellitus, respectively). Serum creatinine, creatinine clearance, mean blood pressure, serum cholesterol and serum triglycerides were similar in both groups. Steroid avoidance or early withdrawal within the first 2 weeks is safe in KT recipients receiving induction with anti-interleukin-2 receptor antibodies or thymoglobulin and a drug regimen based on calcineurin inhibitor and MMF. However, the real benefits remain unclear.

Kidney transplantation from deceased donors aged 65 years or older is associated with suboptimal patient and graft survival. In large registries, survival is longer after kidney transplantation than when remaining on dialysis. However, whether recipients of these old grafts survive longer than their dialysis counterparts is unknown. We retrospectively assessed the outcomes of 5,230 recipients of first deceased donor grafts transplanted during the period of 1990 to 2010 in Catalonia, 915 of whom received grafts from donors 65 years or older. In a match-pair analysis, we aimed to pair each of 915 eligible cases with one control (1:1 ratio). Each pair had the same characteristics at the time of entering dialysis program: age, sex, primary renal disease, period of dialysis onset, and cardiovascular comorbidities. We found 823 pairs. Patient survival of 823 recipients of elderly donors was significantly higher than that of their 823 matched dialysis waitlisted nontransplanted partners (91.6%, 74.5%, and 55.5% vs. 88.8%, 44.2%, and 18.1%, respectively at 1, 5, and 10 years; P<0.001). The probability of death after the first year was similar (8.1% transplant vs 10.3% dialysis; P=0.137); however, analyzing the whole period, the adjusted proportional risk of death was 2.66 (95% confidence interval, 2.21-3.20) times higher for patients remaining on dialysis than for transplanted patients (P<0.001). Our study demonstrates that despite the fact that kidney transplantation from elderly deceased donors is associated with reduced graft and patient survival, their paired counterpart patients remaining on dialysis have a risk of death 2.66 times higher.