Validation of a noninvasive prognostic signature for allograft failure following BK virus associated nephropathy.

Identifying kidney transplant recipients at risk for graft failure following BK virus nephropathy (BKVN) may allow personalization of therapy. We have reported that a noninvasive composite signature of urinary cell level of plasminogen activator inhibitor-1(PAI-1) mRNA and serum creatinine level, measured at the time of BKVN diagnosis, is prognostic of graft failure. In this investigation, we determined whether the composite signature is prognostic of graft failure in an independent cohort of 25 patients with BKVN. Of the 25 patients, 8 developed graft failure and 17 did not. We measured urinary cell levels of PAI-1 mRNA, 18S rRNA, and BKV VP1 mRNA at the time of BKVN diagnosis and evaluated clinical parameters including Banff pathology scores, acute rejection, and graft function. The area under the receiver operating characteristic curve for the noninvasive composite signature was 0.95 (P < .001) for prognosticating graft failure. The previously reported threshold of -0.858 predicted graft failure with a sensitivity of 75% and a specificity of 94%. Our current study validates the use of composite signature and the threshold of -0.858 to identify those at risk for graft failure following BKVN diagnosis, and supports future studies utilizing the composite signature score to personalize treatment of BKVN.

Kidney allograft recipients, immunosuppression, and coronavirus disease-2019: a report of consecutive cases from a New York City transplant center.

BACKGROUND: Kidney graft recipients receiving immunosuppressive therapy may be at heightened risk for coronavirus disease 2019 (Covid-19) and adverse outcomes. It is therefore important to characterize the clinical course and outcome of Covid-19 in this population and identify safe therapeutic strategies. METHODS: We performed a retrospective chart review of 73 adult kidney graft recipients evaluated for Covid-19 from 13 March to 20 April 2020. Primary outcomes included recovery from symptoms, acute kidney injury, graft failure and case fatality rate. RESULTS: Of the 73 patients screened, 54 tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-39 with moderate to severe symptoms requiring hospital admission and 15 with mild symptoms managed in the ambulatory setting. Hospitalized patients were more likely to be male, of Hispanic ethnicity and to have cardiovascular disease. In the hospitalized group, tacrolimus dosage was reduced in 46% of patients and mycophenolate mofetil (MMF) therapy was stopped in 61% of patients. None of the ambulatory patients had tacrolimus reduction or discontinuation of MMF. Azithromycin or doxycycline was prescribed at a similar rate among hospitalized and ambulatory patients (38% versus 40%). Hydroxychloroquine was prescribed in 79% of hospitalized patients. Graft failure requiring hemodialysis occurred in 3 of 39 hospitalized patients (8%) and 7 patients died, resulting in a case fatality rate of 13% among Covid-19-positive patients and 18% among hospitalized Covid-19-positive patients. CONCLUSIONS: Data from our study suggest that a strategy of systematic triage to outpatient or inpatient care, early management of concurrent bacterial infections and judicious adjustment of immunosuppressive drugs rather than cessation is feasible in kidney transplant recipients with Covid-19.

Clinical and pathological comparisons of adnexal torsion between pregnant and non-pregnant women.

AIM: We evaluated and compared the clinical and pathological differences between pregnant and non-pregnant women with adnexal torsion. METHODS: We retrospectively reviewed 239 women with adnexal torsion from January 2006 to December 2015 in a tertiary hospital. The clinical and pathological differences between pregnant and non-pregnant women who underwent surgery for adnexal torsion were analyzed. RESULTS: The most common pathologies were corpus luteum cysts in pregnant women and dermoid cysts in non-pregnant women. Eight of the pregnant women (24.2%) had a history of exogenous ovarian stimulation, and their episodes were only caused by corpus luteum or a stimulated ovary. In pregnant women, 72.7% of the torsion occurred before the 14th week of gestation. CONCLUSION: The common pathology causing adnexal torsion was different, depending on the pregnancy status. Exogenous ovarian stimulation increases the risk of adnexal torsion, and the majority of episodes occurred in the first trimester in pregnant women.

Kidney allograft failure in the steroid-free immunosuppression era: A matched case-control study.

We studied the causes and predictors of death-censored kidney allograft failure among 1670 kidney recipients transplanted at our center in the corticosteroid-free maintenance immunosuppression era. As of January 1, 2012, we identified 137 recipients with allograft failure; 130 of them (cases) were matched 1-1 for recipient age, calendar year of transplant, and donor type with 130 recipients with functioning grafts (controls). Median time to allograft failure was 29 months (interquartile range: 18-51). Physician-validated and biopsy-confirmed categories of allograft failure were as follows: acute rejection (21%), glomerular disease (19%), transplant glomerulopathy (13%), interstitial fibrosis tubular atrophy (10%), and polyomavirus-associated nephropathy (7%). Graft failures were attributed to medical conditions in 21% and remained unresolved in 9%. Donor race, donor age, human leukocyte antigen mismatches, serum creatinine, urinary protein, acute cellular rejection, acute antibody-mediated rejection, BK viremia, and CMV viremia were associated with allograft failure. Independent predictors of allograft failure were acute cellular rejection (odds ratio: 18.31, 95% confidence interval: 5.28-63.45) and urine protein ≥1 g/d within the first year post-transplantation (5.85, 2.37-14.45). Serum creatinine ≤1.5 mg/dL within the first year post-transplantation reduced the odds (0.29, 0.13-0.64) of allograft failure. Our study has identified modifiable risk factors to reduce the burden of allograft failure.

Messenger RNA for FOXP3 in the urine of renal-allograft recipients.

BACKGROUND: The outcome of renal transplantation after an episode of acute rejection is difficult to predict, even with an allograft biopsy. METHODS: We studied urine specimens from 36 subjects with acute rejection, 18 subjects with chronic allograft nephropathy, and 29 subjects with normal biopsy results. Levels of messenger RNA (mRNA) for FOXP3, a specification and functional factor for regulatory T lymphocytes, and mRNA for CD25, CD3epsilon, perforin, and 18S ribosomal RNA (rRNA) were measured with a kinetic, quantitative polymerase-chain-reaction assay. We examined associations of mRNA levels with acute rejection, rejection reversal, and graft failure. RESULTS: The log-transformed mean (+/-SE) ratio of FOXP3 mRNA copies to 18S ribosomal RNA copies was higher in urine from the group with acute rejection (3.8+/-0.5) than in the group with chronic allograft nephropathy (1.3+/-0.7) or the group with normal biopsy results (1.6+/-0.4) (P<0.001 by the Kruskal-Wallis test). FOXP3 mRNA levels were inversely correlated with serum creatinine levels measured at the time of biopsy in the acute-rejection group (Spearman's correlation coefficient = -0.38, P=0.02) but not in the group with chronic allograft nephropathy or the group with normal biopsy results. Analyses of receiver-operating-characteristic curves demonstrated that reversal of acute rejection can be predicted with 90 percent sensitivity and 73 percent specificity with use of the optimal identified cutoff for FOXP3 mRNA of 3.46 (P=0.001). FOXP3 mRNA levels identified subjects at risk for graft failure within six months after the incident episode of acute rejection (relative risk for the lowest third of FOXP3 mRNA levels, 6; P=0.02). None of the other mRNA levels were predictive of reversal of acute rejection or graft failure. CONCLUSIONS: Measurement of FOXP3 mRNA in urine may offer a noninvasive means of improving the prediction of outcome of acute rejection of renal transplants.

In-Hospital Cardiovascular Complications After Pancreas Transplantation in the United States from 2003 to 2012.

Large database studies detailing the risk of perioperative cardiovascular complications after pancreas transplant has been limited, perhaps because these outcomes are not captured by transplant registries. Greater data on the incidence and risks of such outcomes could provide additional insight for referring physicians and inform potential recipients of their risk. We performed a serial, cross-sectional analysis of the National Inpatient Sample, the largest publicly available inpatient database in the United States, to assess for the risk of cardiovascular complications after pancreas transplants in the United States from 2003 to 2012 (n = 13,399). Using multivariable logistic regression models, the risk of cardiovascular outcomes after simultaneous pancreas-kidney transplants (SPK) was compared with solitary pancreas transplants (pancreas after kidney and pancreas transplant alone [PAK + PTA]). The unadjusted prevalence of in-hospital cardiovascular complications was higher in SPK than PAK + PTA (5.5% vs 3.7%, p <0.001). After multivariable adjustment, SPK remained associated with significantly higher odds of any cardiovascular complication (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.21 to 1.80, p = 0.01), and particularly stroke (OR 13.41, 95% CI 4.78 to 37.63, p <0.001), compared with PAK + PTA. However, there was no difference in perioperative mortality (OR 0.78, 95% CI 0.54 to 1.12, p = 0.18). In conclusion, these findings highlight the association between uremia and stroke in pancreas transplant patients, as well as the need for improved preoperative cardiac risk assessment and perioperative management, especially in those who underwent SPK.

Circulating levels of 25-hydroxyvitamin D and acute cellular rejection in kidney allograft recipients.

BACKGROUND: Vitamin D, in addition to its established role in bone metabolism, may regulate the immune system and affect the outcome of allografts. METHODS: We identified 351 kidney allograft recipients who had serum levels of 25-hydroxyvitamin D (25[OH]D) measured within the first 30 days of transplantation. We evaluated the relationship between the circulating levels of 25(OH)D and acute cellular rejection (ACR), cytomegalovirus (CMV) disease, BK virus nephropathy, and kidney graft function. RESULTS: Vitamin D deficiency (circulating levels of 25[OH]D ≤20 ng/mL, defined using The Endocrine Society Clinical Practice 2011 Guideline) was observed in 216 (61.5%) of 351 kidney graft recipients. Vitamin D deficiency was more frequent in female recipients (P=0.007, Fisher exact test) and African American recipients (P<0.001) and was less frequent in preemptive kidney graft recipients (P=0.002). Biopsy-confirmed ACR was more frequent in the vitamin D-deficient group than in the sufficient group (10.2% vs. 3.7%, P=0.04). By multivariable Cox regression analysis, vitamin D deficiency was an independent risk factor for ACR (hazard ratio=3.3, P=0.02). Vitamin D deficiency was not associated with CMV disease, BK virus nephropathy, or kidney allograft function at 1 year. 1,25-Dihydroxyvitamin D3 supplementation initiated within the first 90 days of transplantation was associated with a lesser incidence of ACR compared to no treatment with 1,25-dihydroxyvitamin D3 (5.1% vs. 13.0%, P=0.099). CONCLUSIONS: Vitamin D deficiency is an independent risk factor for development of ACR within the first year of kidney transplantation and 1,25-dihydroxyvitamin D3 supplementation may help reduce the occurrence of ACR in the vitamin D-deficient group.

Early corticosteroid withdrawal in recipients of renal allografts: a single-center report of ethnically diverse recipients and recipients of marginal deceased-donor kidneys.

BACKGROUND: Candidacy for kidney transplantation is being progressively liberalized, and the safety and efficacy of early withdrawal of corticosteroids in high-risk patients have not been fully characterized. METHODS: We analyzed the safety and efficacy of an early corticosteroid withdrawal regimen of rabbit antithymocyte globulin induction, tacrolimus, mycophenolate mofetil, and steroid withdrawal by day 5 after transplantation in our study cohort of 634 kidney transplant recipients that included 27% African American and 18% Hispanic recipients. Fifty-five percent of the recipients were recipients of deceased-donor kidneys, and 46% of deceased-donor kidneys were kidneys from expanded criteria donors. RESULTS: Kaplan-Meier patient survival at 1, 3, and 5 years after transplantation was 98.6%, 94.6%, and 90.2%, and death-censored graft survival was 96.2%, 91.9%, and 87.6%, respectively. During a mean follow-up of 57 months, 89.3% of patients remained off of corticosteroids, and the incidence of acute rejection including subclinical rejection identified by protocol biopsy was 12.0%. Multivariable analysis identified age older than 60 years as protective against (P=0.01) and the African American ethnicity as a risk factor for (P=0.03) rejection. Delayed graft function (P<0.0001), rejection (P<0.0001), and transplant panel reactive antibody 20% or more (P=0.03) were risk factors for graft loss. Opportunistic infections included viral in 15.3%, fungal in 1.6%, and parasitic in 0.6% of the patients. Posttransplantation malignancy occurred in 9.1% of patients. CONCLUSIONS: An early corticosteroid withdrawal regimen of rabbit antithymocyte globulin induction, tacrolimus, and mycophenolate mofetil is associated with excellent patient and kidney graft survival in an ethnically diverse population with risk factors for poor outcomes.