Kidney transplant recipients after nonrenal solid organ transplantation show low alloreactivity but an increased risk of infection

The number of kidney transplant recipients (KTRs) after nonrenal solid organ transplantation (SOT) has increased to almost 5%. Knowledge on patient and allograft outcomes, infections, and alloreactivity, however, remains scarce. We studied 40 KTRs after nonrenal SOT. Seven hundred and twenty primary KTRs and 119 repeat KTRs were used for comparison. Samples were collected pretransplantation, at +1, +2, and +3 months post‐transplantation. Alloreactive and CMV‐specific T cells were measured by interferon‐γ ELISPOT assay. Patient survival in KTRs after SOT, primary and repeat KTRs was comparable. While death‐censored allograft survival was comparable between KTRs after SOT and primary KTRs, KTRs after SOT showed superior 5‐year death‐censored allograft survival of 92.5% compared to 81.2% in repeat KTRs. Interestingly, KTRs after SOT show less preformed panel‐reactive antibodies, frequencies of alloreactive T cells, and acute rejections compared to repeat KTRs. KTRs after SOT, however, show higher incidences of EBV viremia and PTLD, sepsis, and death from sepsis. Impaired CMV‐specific cellular immunity was associated with more CMV replication compared to repeat KTRs. Our results suggest comparable patient and allograft outcomes in KTRs after SOT and primary KTRs. The observed low alloreactivity may contribute to excellent allograft outcomes. Caution should be taken in KTRs after SOT regarding infectious complications due to overimmunosuppression.     

Renal disease in recipients of nonrenal solid organ transplantation

Worldwide, more than 250,000 individuals who have received a liver, heart, lung, or intestinal transplant are living longer. Twenty percent to 25% of these recipients experience perioperative acute renal failure, with 10% to 15% requiring renal replacement therapy. Chronic kidney disease (CKD) is also highly prevalent, affecting 30% to 50% of the nonrenal organ transplant population with an annual end-stage renal disease risk of 1.5% to 2.0%. Both acute renal failure and CKD contribute to increased morbidity and premature mortality. The dominant causative factor for renal disorders seen in nonrenal transplant recipients are the calcineurin inhibitors (CNI) and rapamycin analogues, which singly or in combination lead to a variety of nephrotoxic injury. However, 25% to 30% of nonrenal transplant recipients with CKD have other conditions such as hypertension, focal segmental glomerulosclerosis, diabetes mellitus, and hepatitis C infection as the principal underlying cause. Management strategies for renal disease in the nonrenal transplant recipients include the following: (1) delayed introduction of CNI after graft implantation, (2) withdrawal or minimization of long-term CNI therapy, (3) timely use of an appropriate dialysis modality, and (4) expeditious introduction of supportive measures such as anemia management, phosphate binding therapy, and dietary modification. Compared with maintenance dialysis, kidney transplantation reduces long-term mortality by 60% to 70% in nonrenal transplant recipients with end-stage renal disease.     

BK virus in solid organ transplant recipients: an emerging syndrome.

BK virus is a human polyomavirus associated with a range of clinical presentations from asymptomatic viruria with pyuria to ureteral ulceration with ureteral stenosis in renal transplant patients or hemorrhagic cystitis in bone marrow transplant recipients. Infection of renal allografts has been associated with diminished graft function in some individuals. Fortunately, however, the majority of patients with BK virus infections are asymptomatic. The type, duration, and intensity of immunosuppression are major contributors to susceptibility to the activation of BK virus infection. Histopathology is required for the demonstration of renal parenchymal involvement; urine cytology and viral polymerase chain reaction methods are useful adjunctive diagnostic tools. Current, treatment of immunosuppressed patients with polyomavirus viruria is largely supportive and directed toward minimizing immunosuppression. Improved diagnostic tools and antiviral therapies are needed for polyomavirus infections.     

BK virus infection in kidney transplant recipients

INTRODUCTION: Nephropathy associated with the polyomavirus type BK virus (BKV) has emerged as a cause of allograft failure linked to immunosuppressive regimens containing tacrolimus or mycophenolate mofetil (MMF). The outcome in BKV nephropathy is generally unfavorable, namely 50% of patients lose graft function. We herein report nine cases of BKV nephropathy after kidney transplantation. METHODS: From October 1998 to May 2003, 138 of 169 consecutive kidney transplant patients received tacrolimus-based immunosuppression, and 31 received cyclosporine-based immunosuppression. Additionally, 88.2% of the patients received mycophenolate mofetil (MMF). The diagnosis of BK infection was made by the presence of decoy cells in the urine and by allograft biopsy. RESULTS: There were nine cases of BKV nephropathy in kidney transplant recipients, an incidence of 5.3%. All patients with BKV nephropathy received tacrolimus, MMF, and steroids. The median time to diagnosis of BKV infection was 7.8 months after transplantation. All patients experienced an elevated serum creatinine, which stabilized or decreased in seven patients with altered or decreased immunosuppression. After a mean follow-up of 11.1 months, 2 (22.2%) of nine patients lost the graft. CONCLUSION: Because BKV nephropathy is a rare but serious complication after kidney transplantation, it should be included in the clinical differential of transplant dysfunction. In the absence of documented antiviral treatment, early diagnosis and judicious use of immunosuppressive agents is indicated to minimize the occurrence of BKV infection.     

The prevalence of BK polyomavirus infection in outpatient kidney transplant recipients followed in a single center

Abstract: Background: BK polyomavirus (BKV) infection has emerged as an important cause of renal allograft loss. There is no proven therapy, and much basic clinical information is still lacking. Methods: We serially enrolled 95 outpatient renal transplant recipients (43% of whom were African American) in a single center cross‐sectional screening study to determine the prevalence of BKV infection by whole blood polymerase chain reaction, and the prevalence of decoy cells by urinalysis and cytology. We also investigated the demographic and clinical factors associated with BKV infection, and the performance of urinalysis for decoy cells as a screening test for BKV infection. Results: The point prevalence of active BKV viremia was 7.4%. When subjects without active viremia but with a history of viremia and/or nephropathy were included, the overall prevalence was 15.8%. Urinary decoy cells were common, present in 50% of subjects at study entry. Urinalysis for decoy cells as a screen for BKV viremia had a sensitivity of 86%, specificity of 52%, positive predictive value of 13% and negative predictive value of 98%. Conclusions: Decoy cells on urinalysis were the only factor independently associated with an increased risk of BKV infection on multivariate analysis. Although associated with BKV infection on univariate analysis, thymoglobulin, mycophenolate mofetil, and tacrolimus use were not independently associated with BKV infection on multivariate analysis, neither were history of acute rejection, gender, race, nor cause of end‐stage renal disease.     

Hypertension in solid organ transplant recipients

Hypertension (HT) is one of the most frequent complications of solid organ transplantation; about 70-90% of this population have high blood pressure or require antihypertensive therapy. Abnormal blood pressure is a potent non-immunological risk factor directly related to patient and graft survival. The etiology of hypertension after orthotopic heart transplantation is multifactorial and varies depending on the time following transplantation. In the early period after transplantation, hypertension is generally related to intravascular volume expansion and persistently increased systemic vascular resistance. Other factors predominant in kidney allograft recipients include: donor age, donor familial history of hypertension, transplant renal artery stenosis, graft function, the recurrence or de novo appearance of glomerulonephritis in transplanted kidney, and post-biopsy arteriovenous fistula. In liver and heart transplantation, hypertension is mainly due to impaired kidney function, with all its consequences. Another contributing factor is immunosuppressive regimen based on calcineurin inhibitors and steroids. The management of post-transplant hypertension usually requests non-pharmacological and pharmacological treatment. In this review, the pathogenesis and treatment of post-transplant hypertension in solid organ transplantation is presented.     

Diagnosis and management of BK polyomavirus interstitial nephritis in renal transplant recipients

BACKGROUND: Interstitial nephritis caused by BK polyomavirus is a recognized complication of renal transplantation. A study of renal transplant recipients at Duke University Medical Center was undertaken to evaluate diagnostic modalities and assess clinical outcomes in transplant polyomavirus infections. METHODS: Polyomavirus nephritis was identified in 6 of 240 patients who received renal transplants between January 1996 and June 1998 and an additional patient who underwent transplantation in 1995. The clinical records of these seven patients were reviewed, as were all renal biopsy and nephrectomy specimens. Electron microscopy (EM) was performed on negatively stained urine samples from 6 patients with polyomavirus infection and 23 patients with other diagnoses. RESULTS: Patients with polyomavirus infection shared several clinical features, including ureteral obstruction (5/7 patients), lymphocele (3/7), bacterial urinary tract infection (3/7), hematuria (3/7), cytomegalovirus infection (3/7), and immunosuppression with mycophenolate mofetil (6/7). All patients experienced elevations in serum creatinine, which stabilized or decreased in four patients with altered or decreased immunosuppression. The diagnosis of polyomavirus infection was established by renal biopsy and EM of urine in five patients, by biopsy alone in one, and by EM alone in one. Sequential examinations of urine by EM were used to monitor the course of infection in six patients. CONCLUSIONS: Interstitial nephritis due to BK polyomavirus occurred in 2.5% of patients receiving renal transplants at our center since 1996. Polyomavirus infection can cause transplant dysfunction and graft loss, but progression of the infection can frequently be abrogated with alterations in immunosuppressive therapy. Both renal biopsy and EM of urine samples are useful in the diagnosis and monitoring of polyomavirus infections.     

Humoral response to natural influenza infection in solid organ transplant recipients

The humoral immune response of transplant recipients to influenza vaccination has been studied in detail. In contrast, the hemagglutinin inhibiting (HI) antibody response evoked by natural influenza infection and its impact on viral kinetics is unknown. In this prospective, multicenter, cohort study of natural influenza infection in transplant recipients, we measured HI antibody titers at presentation and 4 weeks later. Serial nasopharyngeal viral loads were determined using a quantitative influenza A polymerase chain reaction (PCR). We analyzed 196 transplant recipients with influenza infection. In the cohort of organ transplant patients with influenza A (n = 116), seropositivity rates for strain‐specific antibodies were 44.0% (95% confidence interval [CI] 31.5‐53.2%) at diagnosis and 64.7% (95% CI 55.4‐72.9%) 4 weeks postinfection. Seroconversion was observed in 32.8% (95% CI 24.7‐41.9%) of the cases. Lung transplant recipients were more likely to seroconvert (P = .002) and vaccine recipients were less likely to seroconvert (P = .024). A subset of patients (n = 30) who were unresponsive to prior vaccination were also unresponsive to natural infection. There was no correlation between viral kinetics and antibody response. This study provides novel data on the seroresponse to influenza infection in transplant patients and its relationship to a number of parameters including a prior vaccination status, virologic measures, and clinical variables.     

Polyomavirus BK infection in Greek renal transplant recipients

BK polyoma virus associated nephropathy is increasingly recognized as an important cause of allograft dysfunction among renal transplant recipients. Herein we present the cases of two renal transplant recipients who developed progressive functional deterioration suspicious for BK polyoma virus involvement. One patient had been treated with mycophenolate mofetil (MMF), cyclosporine (CsA), and prednisolone (P), and the second patient with tacrolimus (Tac), MMF, and (P). Using quantitative real-time polymerase chain reactions for BK virus DNA, we monitored the content of BK virus in the blood to evaluate disease progression. The high BK virus load initially detected in the blood samples from these patients decreased in the patient who received MMF, CsA, and P after the reduction of immunosuppression, but not in the patient who was treated with Tac, MMF and P. In contrast to previous reports, our patients had not received treatment with anti-lymphocyte globulin (ALG) or monoclonal anti-CD3 antibody (OKT3) after transplantation. It is concluded that even in the absence of vigorous antirejection treatment, immunosuppressive therapy based on Tac and MMF may carry the risk of BK virus-associated nephropathy. Because BK virus specific antiviral therapy is not available, its course may be monitored by measuring the viral load in blood.     

Genitourinary malignancies in solid organ transplant recipients

Malignancy is a recognized complication of transplantation. Genitourinary cancers are the second most common tumors in transplant recipients with prostate cancer and renal cell carcinoma the most common. Unlike the more common skin malignancies, genitourinary tumors have a significant impact on both graft and patient survival. Surgical and radiation treatments need to consider the location of heterotopic transplants and administration of chemotherapy may need alteration in light of immunosuppression being used. The major genitourinary malignancies and their management will be reviewed in this article with emphasis on the concerns that arise in a transplant recipient.     

Low molecular weight heparin dosing and monitoring in solid organ transplant recipients

Anti‐Xa monitoring for low molecular weight heparin (LMWH) is currently recommended in obese, renally impaired, and pregnant patients. Substantial evidence indicates that solid organ transplant (SOT) patients are at an increased risk of renal impairment, thus representing a population at risk of LMWH accumulation. The purpose of this study was to review our experience with LMWH dosing and monitoring in a cohort of transplant recipients. This was a retrospective, single‐center review of 96 SOT patients receiving enoxaparin treatment and anti‐Xa monitoring. The percent of patients with supratherapeutic anti‐Xas (>1 IU/mL) was determined, as was the relationship between enoxaparin dosages and anti‐Xa levels and bleeding. The cohort had a mean age of 62 yr and creatinine clearance of 59 mL/min and was primarily lung transplant recipients (73%). The mean enoxaparin dose was 0.82 mg/kg, which resulted in a mean anti‐Xa level of 0.98 IU/mL. Despite the reduced enoxaparin dose, 44% of patients experienced a supratherapeutic anti‐Xa level. Patients with supratherapeutic anti‐Xas had higher doses than those within the therapeutic range (0.89 mg/kg vs. 0.77 mg/kg; p = 0.002). No major bleeds occurred. Supratherapeutic anti‐Xa levels are common in transplant patients receiving enoxaparin therapy. Empirically reduced dosing of enoxaparin and monitoring may warrant consideration in this population.     

Clinical and immunologic aspects of cytomegalovirus infection in solid organ transplant recipients

Primary cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in recipients after solid organ transplantation (SOT). Widespread and prolonged use of antiviral drugs has changed the natural course of CMV disease by delaying its onset and causing drug resistance. CMV induces a strong cellular immune response, even in immunosuppressed patients, and has developed strategies to evade this immune surveillance. This review summarizes challenges in managing CMV infection in transplant recipients and highlights current insights in the cellular immune response against CMV.     

肾移植受者BK病毒的感染特点

Objective To investigate the characteristics of BK virus (BKV) infection in renal transplant recipients. Methods A total of 243 renal recipients from our clinic within 48 months after transplantation were enrolled as the trial group and 82 healthy people as the control group. Urine and peripheral blood samples of these two groups were harvested for urinary sediment BKV cytology by Decoy cell counting and BKV DNA by real-time PCR. Results The positive rates of urinary Decoy cell, BKV viruria and viremia were 35.4%, 36.6% and 16.9% in trial group, and 4.9%, 20.7% and 2.9% in control group, respectively. In trial group, the medians of urinary Decoy cell, urinary BKV and peripheral blood BKV were 6/10 HPF, 1.00×104 copy/ml and 6.87×103 copy/ml respectively, while in control group, they were 2/10 HPF, 1.10×104 copy/ml and 2.24×1(3 copy/ml. Compared with the healthy people, the positive rates and the levels of BKV DNA in urine and peripheral blood of recipients were significantly higher. The amount of urinary Decoy cells was positively correlated to urinary BKV load (r=0.636, P＜0.01). Conclusions BKV replication is easier to happen in renal recipients as compared to healthy people. Counting of urinary Decoy cells is convenient, useful and sensitive to evaluate BK viruria and viremia in renaltransplant recipients. BKV DNA detection in urine and peripheral blood can be used to screen the evidence of BK reaction in order to prevent irreversible graft damage by BKV.[ Key words ] Kidney transplantation; BK virus; Kidney diseases; Decoy cells