The outcome of SARS-CoV2 infection in patients who have received a kidney allograft and are being treated with immunosuppression is unclear. We describe 20 kidney transplant recipients (median age 59 ...years inter quartile range 51-64 years, median age of transplant 13 years 9-20 years, baseline eGFR 36.5 23-47.5) with SARS-CoV2 induced pneumonia. At admission, all had immunosuppression withdrawn and were started on methylprednisolone 16 mg/day, all but one was commenced on antiviral therapy and hydroxychloroquine with doses adjusted for kidney function. At baseline, all patients presented fever but only one complained of difficulty in breathing. Half of patients showed chest radiographic evidence of bilateral infiltrates while the other half showed unilateral changes or no infiltrates. During a median follow-up of seven days, 87% experienced a radiological progression and among those 73% required escalation of oxygen therapy. Six patients developed acute kidney injury with one requiring hemodialysis. Six of 12 patients were treated with tocilizumab, a humanized monoclonal antibody to the IL-6 receptor. Overall, five kidney transplant recipients died after a median period of 15 days 15-19 from symptom onset. These preliminary findings describe a rapid clinical deterioration associated with chest radiographic deterioration and escalating oxygen requirement in renal transplant recipients with SARS-Cov2 pneumonia. Thus, in this limited cohort of long-term kidney transplant patients, SARS-CoV-2 induced pneumonia is characterized by high risk of progression and significant mortality.
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease (COVID-19), is a major pandemic challenging health care systems around the world. The optimal ...management of patients infected with COVID-19 is still unclear, although the consensus is moving toward the need of a biphasic approach. During the first phase of the disease (from onset of the symptoms up to 7–10 days) viral-induced effects are prominent, with the opportunity to institute antiviral therapy. In the second inflammatory phase of the disease, immunosuppressive strategies (for example with glucocorticoids or anticytokine drugs) may be considered. This latter stage is characterized by the development of progressive lung involvement with increasing oxygen requirements and occasionally signs of the hemophagocytic syndrome. The management of the disease in patients with kidney disease is even more challenging, especially in those who are immunosuppressed or with severe comorbidities. Here we present the therapeutic approach used in Brescia (Italy) for managing patients infected with COVID-19 who underwent kidney transplantation and are receiving hemodialysis. Furthermore, we provide some clinical and physiopathological background, as well as preliminary outcome data of our cohort, to better clarify the pathogenesis of the disease and clinical management.
Background. Chronic kidney disease patients who are resistant to erythropoietin (EPO) treatment may suffer from malnutrition and/or inflammation. Methods. In a cross-sectional study of haemodialysis ...patients, we investigated the relationship between the natural logarithm of the weekly EPO dose normalized for post-dialysis body weight and outcome measures of nutrition and/or inflammation BMI, albumin and C reactive protein (CRP) by means of multiple linear regression analysis. On the basis of the decile distribution of weekly EPO doses, we also evaluated four groups of patients: untreated, hyper-responders, normo-responders and hypo-responders. Results. Six hundred and seventy-seven adult haemodialysis patients were recruited from five Italian centres. BMI and albumin were lower in the hypo-responders than in the other groups (21.3±3.8 vs 24.4±4.7 kg/m2, P<0.001; and 3.8±0.6 vs 4.1±0.4 g/dl, P<0.001), whereas the median CRP level was higher (1.9 vs 0.8 mg/dl, P = 0.004). The median weekly EPO dose ranged from 30 IU/kg/week in the hyper-responsive group to 263 IU/kg/week in the hypo-responsive group. Transferrin saturation linearly decreased from the hyper- to hypo-responsive group (37±15 to 25±10%, P = 0.003), without any differences in transferrin levels. Ferritin levels were lower in the hypo-responsive than in the other patients (median 318 vs 445 ng/ml, P = 0.01). At multiple linear regression analysis, haemoglobin, BMI, albumin, CRP and serum iron levels were independently associated with the natural logarithm of the weekly EPO dose (R2 = 0.22). Conclusions. Our findings support a clear association between EPO responsiveness and nutritional and inflammation variables in haemodialysis patients; iron deficiency is still a major cause of hypo-responsiveness.
The SARS-CoV-2 epidemic is pressuring healthcare systems worldwide. Disease outcomes in certain subgroups of patients are still scarce, and data are needed. Therefore, we describe here the experience ...of four dialysis centers of the Brescia Renal COVID Task Force. During March 2020, within an overall population of 643 hemodialysis patients, SARS-CoV-2 RNA positivity was detected in 94 (15%). At disease diagnosis, 37 of the 94 (39%) patients (group 1) were managed on an outpatient basis, whereas the remaining 57 (61%) (group 2) required hospitalization. Choices regarding management strategy were made based on disease severity. In group 1, 41% received antivirals and 76% hydroxychloroquine. Eight percent died and 5% developed acute respiratory distress syndrome (ARDS). In group 2, 79% received antivirals and 77% hydroxychloroquine. Forty two percent died and 79% developed ARDS. Overall mortality rate for the entire cohort was 29%. History of ischemic cardiac disease, fever, older age (over age 70), and dyspnea at presentation were associated with the risk of developing ARDS, whereas fever, cough and a C-reactive protein higher than 50 mg/l at disease presentation were associated with the risk of death. Thus, in our population of hemodialysis patients with SARS-CoV-2 infection, we documented a wide range of disease severity. The risk of ARDS and death is significant for patients requiring hospital admission at disease diagnosis.
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The outcome of kidney transplant patients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is still unclear. Here we describe the clinical characteristics, disease outcome, ...and risk factors for acute respiratory distress syndrome (ARDS) and death of a cohort of 53 kidney transplant patients with coronavirus disease 2019 (COVID‐19). Eight of 53 have been handled as outpatients because of mild disease, on average with immunosuppression reduction and the addition of hydroxychloroquine and azithromycin; no patients required admission, developed ARDS, or died. Because of severe symptoms, 45/53 required admission: this cohort has been managed with immunosuppression withdrawal, methylprednisolone 16 mg/d, hydroxychloroquine, and antiviral drugs. Dexamethasone and tocilizumab were considered in case of ARDS. About 33% of the patients developed acute kidney injury, 60% ARDS, and 33% died. In this group, thrombocytopenia was associated to ARDS whereas lymphopenia at the baseline, higher D‐dimer, and lack of C‐reactive protein reduction were associated with risk of death. In the overall population, dyspnea was associated with the risk of ARDS and age older than 60 years and dyspnea were associated with the risk of death with only a trend toward an increased risk of death for patients on tacrolimus. In conclusion, SARS‐CoV‐2 infection may have a variable outcome in renal transplant patients, with higher risk of ARDS and death in the ones requiring admission.
Findings from an Italian cohort of kidney transplant patients with COVID‐19 support heterogenous disease courses with higher risks of acute respiratory distress syndrome and death in the subgroup with severe disease.
Abstract
Background and Aims
In renal transplant field, the progressive increase both of donor and recipient age has led further challenges in patient management. In this setting, the personalization ...of immunosuppressive therapies (IT) has been strongly suggested. We have investigated renal histology at 12 months after transplantation to assess whether surveillance biopsies (SB) could be considered an additional tool to further improve management of immunosuppression.
Method
Monocentric retrospective analysis of SB performed 12 months post-transplant (Tx) between 2009-2018. For each SB were collected recipient and donor demographic data, HLA mismatch, induction and maintenance IT, DGF, cold ischemia time, PRA, DSA and nDSA, previous episodes of acute rejection (AR), serum creatinine (Cr) at the time of SB and 1, 3 and 5 years later, histological score according to Banff classification in force at the time of SB. Statistics included comparison between groups and Cox regression.
Results
We analyzed 209 SB in as many pts, most of them at low immunological risk (first Tx in 94.3%, PRA <30% in 88%, DSA at time of Tx in 5.4%). All pts received induction therapy; maintenance IT included calcineurine inhibitors in 97%, mycophenolate mofetil in 49%, mTOR inhibitors in 30%, azathioprine in 10% and corticosteroids in 33%.
SB showed normal histology in only 26.3% of cases. There were no differences in renal function between normal and pathological biopsies (Cr 1.40 vs 1.46 mg/dl, p=NS). Major histologic findings, isolated or associated with each other Fig. 1, were vascular lesions (VL, 40%), IFTA (33%) and inflammatory lesions (IL, 32%).
VL correlated with donor age (OR 1.07, p<0.001), whereas IFTA with both donor age (OR 1.03, p=0.04) and DGF (OR 1.07, p=0.04). IFTA was the only histological pattern associated with a lower renal function (Cr 1.58 vs 1.39 mg/dl, p=0.016). IL included interstitial infiltrates (14.8% of specimens), tubulitis (9.6%), glomerulitis (19.6%) and capillaritis (ptc, 13.9%). Both glomerulitis and capillaritis were associated with the presence of DSA, both at Tx (OR 4.35, p=0.037) and at biopsy (OR 5.45, p<0.001).
All types of lesions were found to be related with previous AR (VL with OR 3.08, p= 0.003, IFTA with OR 2.15, p=0.04, IL with OR 4.71, p<0.001) and to be more frequent in the last 5 year biopsies, according to an older donor age (59.5 vs. 52.3 ys, p< 0.001) and a lower HLA-matching (mismatch AB >2: 50.5% vs 32%, p=0.045).
Indipendent histological variables that predicted a worsening of renal function were glomerulitis/capillaritis (HR 6.996, P<0.001) and VL (HR 2.229, p=0.038).
Conclusion
Our data confirm that stable renal function does not exclude the presence of subclinical histological lesions, even in patients at low immunological risk. Abnormal findings are present in 73.7% of our SB. Glomerulitis/capillaritis and VL can affected renal function, so their recognition should be considered for immunosuppression optimization. Patients with previous AR are at higher risk for all types of histologic lesions and may require a closer monitoring.
Figure:
Abstract
Background and Aims
Efficacy of acute rejection (AR) therapy has always been evaluated based upon improvement of renal function. On the contrary, the degree of histological lesion (HL) ...regression has rarely been considered for this purpose.
The main goal of this study was to evaluate the percentage of failures in HLs regression after treatment aimed at both “subclinical” and “clinical” AR. Treatment efficacy was therefore evaluated with control renal biopsies (CBs) performed 30-60 days after anti-rejection therapy. In addition, the correlation between graft function and histological data was assessed. The results of treatment for “subclinical" and "clinical” AR were considered separately.
Method
Real-time ultrasound-guided CBs were performed in an outpatient setting using 16G tru-cut needles. The HLs considered were: interstitial inflammation (i), tubulitis (t), glomerulitis (g), arteritis (v), capillaritis (ptc). Each lesion was graded from 0 to 3 (sec Banff 2013-2017). For this study, only HLs with a score ≥2 were considered. Therapy failure was determined both by the percentage of patients (pts) with persistence of HLs and by the change of HLs score after treatment, in the control biopsies. Anti-rejection therapy varied according to AR type and severity. In patients failing AR therapy, serum creatinine was evaluated before and after the treatment.
Results
111 BCs were performed after treatment either for subclinical (n = 47) or for clinical (n = 64) AR. Before therapy, HLs (with score ≥2) present in subclinical and clinical AR were: i: 23% and 52%; t: 30% and 30%; g: 34% and 41%; ptc: 11% and 28%; v: 15% and 19%.
After therapy, in the setting of subclinical AR, HLs were still present with a range between 29% (v) and 81% (g) with stable or improved histological score. In this scenario, renal function resulted stable and satisfactory (Tab 1).
In the case of clinical AR, the persistence of histological lesions ranged from 25% (v) to 92% (g), also with stable or improved histological scores. In this case, therapy was always followed by an improvement in renal function (Tab 2).
Conclusion
After AR therapy, only the morphological data obtained with histological analysis can disclose failures of anti-rejection therapy, both in presence of subclinical and clinical AR.
The high rate of treatment failure may explain the correlation between AR and worse graft survival.
Our results could lead us to consider the need for a more aggressive anti-rejection treatment.
Control renal biopsies after AR therapy should always be considered on clinical grounds.
Figure:
: The aim of this retrospective study was to assess the impact of steroid therapy on cardiovascular disease (CVD) and patient mortality, in 486 on‐CsA renal transplant recipients, with a follow‐up ...of 9.5 ± 4.3 yr. Two hundred and one patients had their steroids permanently withdrawn at sixth month after transplantation (G1); 285 patients did not (G2) as they were unable (acute rejection after suspension) or unsuitable (because of clinical criteria or immunosuppressive protocols). The CVD considered were coronary artery disease diagnosed by angiography and myocardial infarction. G1 and G2 patients were well‐matched regarding CVD risk factors, except for age (G1: 44 ± 14 yr; G2: 40 ± 12 yr; p < 0.003), incidence of male (G1: 62%; G2: 72%, p < 0.02) incidence of acute rejection (G1: 39%; G2: 83%, p < 0.0001). Both CVD and deaths occurring during the first year of transplantation were excluded from the analysis. At 20 yr, the cumulative probability of developing a CVD, was 3.8% in G1; 23.8% in G2 (p < 0.0005). Patient survival rate was 95% in G1; 62% in G2 (p < 0.003). Mortality caused by CVD was higher in G2 (4.2% vs. 0.5%; p < 0.03). The Cox analysis identified in steroid therapy the main independent risk factors for both CVD (hazard ratio 9.56 p < 0.0001) and patient mortality (hazard ratio 5.99, p < 0.0001). At 10th and 15th year after transplantation, the mean‐daily dose of steroids was 4.2 mg.
In the long‐term, steroid therapy, even in low‐doses, increases significantly both the rate of CVD and patient mortality. This retrospective study suggests that steroid‐free regime should always be recommended for the prevention of post‐transplant CVD. This relevant statement should be followed by a long‐term prospective study.
: Background: Sirolimus (SRL) can increase the risk of wound complications. In this study, we investigated the impact of steroids when added to SRL, in this side effect.
Methods: One hundred and ...forty‐eight patients entered prospective studies comparing early (fifth day) with late (sixth month) steroid withdrawal. All patients were on SRL, added either to Tacrolimus (n = 56) or to cyclosporine (n = 97). At 15th day after transplantation, 68 patients were on steroids (On‐St group) and 80 were not (Off‐St group). Wound complications considered were as follows: dehiscence, lymphocele, wound leakage, hematoma and seromas. Risk factors under analysis were as follows: body mass index, diabetes, rejection, creatininemia, length of dialysis before transplantation, recipient age, being on steroids at 15th day, SRL levels.
Results: The overall incidence of wound complications was significantly lower in Off‐St group than in On‐St group: 18.8% vs. 45.6%, respectively (p < 0.0004). In detail, lymphocele: 5.0% vs. 32.3% (p < 0.0001); dehiscence 0% vs. 10.3% (p < 0.009), leakage 6.2% vs. 8.8% (p = NS), seromas 1.4% vs. 7.5% (NS). At multivariate analysis, the addition of steroids to SRL increases 4.2‐fold the risk for wound complications.
Conclusions: Early steroid withdrawal is effective in preventing both the incidence and the severity of wound‐healing complications because of SRL regime, even when started with a loading dose.
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