BK virus nephropathy: a pediatric nephrologist's perspective

Polyomavirus (BK)–associated nephropathy (BKVN) is now recognized as significant problem in pediatric renal transplants that may lead to progressive allograft dysfunction. BKVN was first recognized in 1999 in adult renal transplant recipients, and most data have been obtained from this patient population. Today, there is an increasing number of publications pertaining to children with BKVN that allows for a selective analysis of the pediatric population. Most early pediatric publications were predominantly cases reports. However, several retrospective and prospective studies are now available that provide important insights with respect to the incidence of BKVN in the pediatric transplant population, the efficacy of treatment strategies, and the risk factors for developing BKVN. This review analyzes several of the most significant studies that address these issues.     

Polyoma virus BK and renal dysfunction in a transplanted population

INTRODUCTION: Reactivation of polyoma virus BK (BKV) is increasingly recognized as a cause of severe renal-allograft dysfunction. The aim of the present study was to evaluate prevalence of BKV infection and activity in a population of kidney (KT) and liver (LT) transplant patients and search for a possible correlation with renal dysfunction. METHODS: We studied 118 patients for BKV viruria and, when present, for BKV viremia. We also assessed HCV status. RESULTS: Among 16 patients with BKV viruria (5 LT and 11 KT), eight showed BKV viremia (one LT and seven KT). Among BKV viruria-positive patients, three LT recipients were HCV-positive. All LT BKV viruria-positive patients showed normal renal function with a mean serum creatinine (sCr) blood level of 0.9 mg% and a mean blood urea nitrogen (BUN) value of about 36 mg%. The mean transplant age was 2.5 years. In contrast, KT BKV viruria-positive patients showed impaired renal function which was slightly worse in patients who also displayed BKV viremia, namely, a mean sCr blood level 1.7 mg% and a mean BUN value about 80 mg%. The mean transplant age was 7 years. CONCLUSION: Based on these findings, it seems that BKV viruria in renal allograft recipients may be associated with viremia and related to nephropathy that may lead to allograft rejection. The study will be completed with a 2-year follow-up of positive patients to assess the possible relationship between BKV active infection and eventual decrease of renal function and loss of transplanted organ.     

BK virus nephropathy in renal transplant recipients

BK virus nephropathy (BKVN) occurs in up to 10% of renal transplant recipients and can result in graft loss. The reactivation of BK virus in renal transplant recipients is largely asymptomatic, and routine surveillance especially in the first 12–24 months after transplant is necessary for early recognition and intervention. Reduced immunosuppression and anti‐viral treatment in the early stages may be effective in stopping BK virus replication. Urinary decoy cells, although highly specific, lack sensitivity to diagnose BKVN. Transplant biopsy remains the gold standard to diagnose BKVN, good surrogate markers for surveillance using quantitative urinary decoy cells, urinary SV40 T immunochemical staining or polyoma virus‐Haufen bodies are offered by recent studies. Advanced BKVN results in severe tubulo‐interstitial damage and graft failure. Retransplantation after BKVN is associated with good outcomes. Newer treatment modalities are emerging.     

Favorable outcome of crescentic IgA nephropathy associated with methicillin-resistant Staphylococcus aureus infection

Dominant or codominant IgA deposits in the setting of proliferative glomerulonephritis usually indicate IgA nephropathy, Henoch-Sch?nlein purpura nephritis, or, sometimes, lupus nephritis. However, a new type of poststaphylococcal glomerulonephritis with predominantly IgA deposition has been increasingly reported. Herein, we report an unusual case of rapidly progressive glomerulonephritis following methicillin-resistant Staphylococcus aureus infection. Renal biopsy showed crescentic IgA nephropathy. The renal function improved after eradication of infection and administration of immunosuppressive therapy. Although the limited data support the use of immunosuppressive agents in this setting, one must proceed with caution. We suggest that immunosuppressive therapy should only be an option if the underlying infection has definitely been well controlled while the renal disease still progresses.     

Native kidney BK virus nephropathy associated with chronic lymphocytic leukaemia

BK virus nephropathy (BKVN) is a well-recognized complication of renal transplantation. Several cases of native kidney BKVN following other solid organ or bone marrow transplants have been reported. We describe a patient with chronic lymphocytic leukaemia who presented with deteriorating renal function with no history of solid organ or bone marrow transplantation. Renal biopsy demonstrated tubular injury characteristic of viral infection, confirmed as BK virus by immunohistochemistry and elevated serum BK viral titres. Treatment with leflunomide reduced serum viral titres and stabilized renal function. This is the first biopsy-proven case of native kidney BKVN in a patient with no previous transplantation history.     

BK virus nephropathy in renal transplant patients in London

BACKGROUND: BK nephropathy (BKN) is an important cause of renal transplant dysfunction, believed to be associated with higher levels of immunosuppression. We assessed the experience of BKN in renal transplant patients in the London region. METHODS: All six London transplant centers participated and case notes of patients with BKN in 2004 to 2005 were reviewed. RESULTS: There were 17 cases of BKN, giving an incidence of 2.1%. Median time to diagnosis was 9 months. Median baseline creatinine rose from 150 to 196 mumol/L. At diagnosis, 16 patients were on tacrolimus, 15 on mycophenolate mofetil, and 10 on triple therapy with tacrolimus, mycophenolate mofetil, and prednisolone. Management of BKN involved reducing immunosuppression; cidofovir was used in two patients and methylprednisolone in five for acute rejection. Median follow-up time was 29.2 months. Creatinine returned to baseline in four patients, remained elevated in 12 and one patient lost his graft. The new median baseline creatinine was 216 mumol/L. Eight patients underwent repeat biopsies of which four became negative for BKV and three subsequently cleared the virus on blood and urine polymerase chain reaction and urine decoy cells. Overall, eight patients cleared the virus. None of age, sex, viral load, or biopsy characteristics (Banff ct score, Drachenberg grade, and number of BKV positive cells) were associated with poorer outcome when patients with increase in creatinine of less than 30% (n=7) or more than 30% (n=10) from baseline were compared. CONCLUSION: The incidence of BKN in this study is comparable with previous studies, with more favorable outcomes. It supports the association of BKN with potent immunosuppression.     

Iga nephropathy, antineutrophil cytoplasmic antibodies and crescentic glomerulonephritis in a patient with the Hermansky-Pudlak syndrome

Hermansky-Pudlak syndrome is an uncommon cause of renal dysfunction. Because of the risk of bleeding in this condition, few patients have undergone a renal biopsy. Renal dysfunction has been attributed to the deposition of ceroid pigment in the tubules and interstitial fibrosis. We report a case with renal biopsy findings of ceroid deposition and interstitial fibrosis, but also of mesangial IgA deposition, crescentic glomerulonephritis, and an interstitial lymphocytic infiltrate. Furthermore, perinuclear antineutrophil cytoplasmic antibodies of the IgG subclass were detected in a blood sample. It is well known that ceroid pigment in this syndrome accumulates in monocytes, macrophages and T lymphocytes and it has been suggested that this may affect their function. We suggest that this novel combination of renal changes might be explained on the basis of alterations in immune mechanisms in the Hermansky-Pudlak syndrome.     

Native kidney BK virus nephropathy associated with acute lymphocytic leukemia

Background

Polyoma BK virus nephropathy is a common complication after renal transplantation and is rarely seen in non-renal transplant recipients. There are only a couple of case reports of BK virus nephropathy in native kidneys in non-transplant patients, including a recent report of a 73-year-old patient with chronic lymphatic leukemia. A variety of treatment options, including leflunomide and cidofovir, were reported in these patients.

Case diagnosis/treatment

Here we report the case of a 10-year-old boy with acute lymphatic leukemia who presented with non-oliguric hypertensive acute kidney injury at the 12th maintenance cycle of his chemotherapy. The workup supported the clear diagnosis of BK virus nephropathy with tubulointerstitial changes, and the patient responded favorably to intravenous immunoglobulin therapy.

Conclusions

Pediatric nephrologists need to consider BK virus nephropathy as a differential diagnosis of acute kidney injury in immunocompromised non-transplant patients.     

BK virus nephropathy: Clinical experience in a university hospital in Japan

Objectives: To review the medical records of patients with BK virus nephropathy (BKVN) following kidney transplantation in our institution. Methods: We screened patients for decoy cells using urine cytology, assessed serum creatinine levels, and conducted a graft biopsy, as well as assessed the presence of plasma BK virus DNA by quantitative real‐time polymerase chain reaction. The treatment of BKVN was based on the decreased use of immunosuppressants. Results: Overall, six male patients were studied (mean age 40.8 years, range 18–58; mean donor age 45.2 years, range 15–67). A positive urine cytology screen led to the subsequent detection of plasma BK virus DNA in the five patients with urine cytology results positive for decoy cells. In the four patients in whom plasma BK virus DNA was detected, a maximum value of DNA of ≥10 000 copies/mL was observed. Time elapsed from transplantation to BKVN diagnosis ranged from 3 to 62 months. Although the two cadaver grafts were lost, the loss was not due to any effects directly associated with BKVN. The other four grafts are still functioning with a mean creatinine level of 1.8 mg/dL. Most of the patients with BKVN were regarded as being in a state of heightened immunosuppression. BK virus transition to blood was prevented in one patient. Conclusions: Early diagnosis of BKV infection with reduction of immunosuppression may potentially counter BK viremia and retard progression of BKV nephropathy. Decoy cell screening by urine cytology as well as plasma BK virus DNA screening should be considered in addition to the required graft biopsy in kidney transplant recipients, particularly in those with impaired graft function.     

Proteomic analysis of urine in kidney transplant patients with BK virus nephropathy

The differentiation of BK virus-associated renal allograft nephropathy (BKVAN) from acute allograft rejection (AR) in renal transplant recipients is an important clinical problem because the treatment can be diametrically opposite for the two conditions. The aim of this discovery-phase biomarker development study was to examine feasibility of developing a noninvasive method to differentiate BKVAN from AR. Surface-enhanced laser desorption/ionization (SELDI) time-of-flight mass spectrometry analysis was used to compare proteomic profiles of urine samples of 21 patients with BKVAN, 28 patients with AR (Banff Ia to IIb), and 29 patients with stable graft function. SELDI analysis showed proteomic profiles that were significantly different in the BKVAN group versus the AR and stable transplant groups. Peaks that corresponded to m/z values of 5.872, 11.311, 11.929, 12.727, and 13.349 kD were significantly higher in patients with BKVAN. Bioinformatics analyses allowed distinction of profiles of patients with BKVAN from patients with AR and stable patients. SELDI profiles also showed a high degree of reproducibility. Proteomic analysis of urine may offer a noninvasive way to differentiate BKVAN from AR in clinical practice. The identification of individual proteomic peaks can improve further the clinical utility of this screening method.     

BK virus nephropathy in renal transplant recipients in Kuwait: a preliminary report

INTRODUCTION: BK virus nephropathy (BKVN) is a significant cause of graft loss among renal transplant recipients. The treatment outcomes of BKVN have been variably reported in the literature. PATIENTS AND METHODS: We prospectively investigated BKV infection and BKVN among a population of renal transplant recipients with suspected BKV infection. The 42 subjects who all had acute allograft dysfunction, were categorized in three groups: those with clinical, laboratory, and histological findings that did not suggest acute rejection, drug toxicity, or obstruction (group 1, n = 24); those with findings that suggested probable acute cellular rejection but did not respond to antirejection treatment (group 2, n = 10); and those whose renal histology suggested BKVN (group 3, n = 8). Polymerase chain reaction analysis was done to detect BKV DNA in urine and blood samples from each subject. BKV DNA was detected in 19 (45%) urine samples with 11 of these subjects (26.1% of total) having BK viremia as well. RESULTS: No evidence of BKVN was detected histologically in seven subjects with isolated BK viruria, while the others proved to be JC virus infections. Among the 11 subjects with BK viremia, eight had BKVN based on renal histology at the time of diagnosis with BKV infection, while the other three subsequently developed histological features of BKVN. BKVN developed after 5.3 +/- 2.5 (2 to 44) months after transplantation. The serum creatinine at time of BKVN diagnosis was 158.9 +/- 58 (87 to 285) micromol/L. All subjects were initially treated with a 50% reduction in immunosuppressive drug doses. Further decreases in immunosuppression were performed in all patients with close monitoring of renal function. All subjects were followed up for a of 18.2 +/- 5 (12 to 26) months. Two grafts were lost not due to BKVN, and one patient was lost to follow-up during this period. The latest serum creatinine in eight recipients is 113 + 20 (81 to 138) micromol/L, which is better than the renal function at diagnosis. CONCLUSION: The prevalence of BKVN in suspected BKV infection was 26%. Although the study period was short (30 months), BK viremia strongly correlated with BKVN, which seemed to be successfully treated with reduction in immunosuppression.     

BK virus nephropathy in a patient with ABO-incompatible renal transplantation

Abstract:  A 43-year-old woman with end-stage renal disease originating from IgA nephropathy entered chronic haemodialysis therapy. She then received an ABO-incompatible living related renal transplantation. Initial immunosuppression consisted of azathioprine, methylprednisolone and tacrolimus. At 155 days after transplantation, the azathioprine was changed to mycophenolate mofetil for continuous graft dysfunction. Furthermore, a total of three courses of anti-rejection therapy was given. At 665 days after transplantation, diagnosis of BK-virus nephropathy was made by immunohistochemical analysis and viral DNA assay. Therefore the immunosuppression therapy was reduced for graft dysfunction. All five renal biopsy specimens were examined retrospectively in order to determine when the BK virus nephropathy had developed. The expressions of SV40 large T antigens were detected from the third (117 days) to the fifth (665 days) biopsies, with increasing numbers of SV40 large T antigen positive cells. In addition, many cells contained inclusion bodies which were already present in the urinary sediment for 3 months post-transplantation. Although it is difficult to make a diagnosis of early stage of BKVN, we have to consider with caution if urinary cells with inclusion body are seen. Awareness of BKVN at the earliest opportunity is important in order to avoid over-immunosuppression.     

Combination of Leflunomide and Everolimus for treatment of BK virus nephropathy

BK nephropathy (BKN) is a common cause of graft dysfunction following kidney transplantation. Minimization of immunosuppressive therapy remains the first line of therapy, but this may lead to rejection and graft loss. In some cases, despite lowering immunosuppression, BK infection can persist, leading to chronic damage and kidney failure. Currently, there is no specific anti‐BK viral therapy. Recent in vitro experiments have demonstrated a reduction in BK viral replication when infected cells are treated with the combination of Leflunomide and Everolimus. This study aims to explore the effect of this drugs combination on viral clearance and graft function in patients with persistent disease despite reduction in immunosuppression. We treated three patients with combination Leflunomide and Everolimus. Data on medical history, biochemical parameters and viral loads were collected. Significant improvement in viral loads was observed in two cases with resolution of viremia in another (Table 1). Two recipients had preserved allograft function. The remaining graft was lost because of combination of obstruction and BKN. No adverse reactions such as bone marrow toxicity were observed. Combination of Leflunomide and Everolimus is safe and should be considered as a rescue therapy in treatment of BKN, especially in those who fail to clear this infection despite reduction of immunosuppressive therapy.     

A single-center experience with BK virus nephropathy

BACKGROUND: BK virus nephropathy has an increasing role in renal transplant dysfunction, since new, highly potent immunosuppressive drugs have been introduced into therapy following renal transplantation. Diagnosis of acute impairment of renal transplant function is complicated by difficulty in differentiating BK virus nephropathy from acute rejection. PATIENTS AND METHODS: We retrospectively described the findings and therapeutic approaches of 6 consecutive patients with BK virus nephropathy in our transplantation center (75 - 80 transplantations/ year). BK virus nephropathy was classified according to Drachenberg et al. [2004]. RESULTS: We observed an incidence rate of < 1% for BK nephropathy in our center. Four patients had a pattern B whereas 2 patients revealed a pattern C of BK virus nephropathy. Focal C4d-positive staining of peritubular capillaries were found in 2 of the 6 cases. For earlier detection of BK nephropathy, a diagnostic algorithm for each patient after renal transplantation was established. Urine was continuously monitored by cytology for decoy cells and PCR for BK virus DNA. If PCR was also positive for the BK virus in plasma, biopsy of the renal allograft was performed. Thereby diagnosis could be confirmed sooner. For treatment of BK nephropathy in our center, we reduced immunosuppressive agents and initiated a virustatic treatment with cidofovir in the first 3 cases. However, results were not satisfactory and two allografts were lost. We then reconsidered our therapeutic approach and switched the immunosuppressive treatment to leflunomide with consistent low dose steroids. We use therapeutic drug monitoring for leflunomide and aim at a target level of 40 - 100 microg/ml. We lost no allograft with BK nephropathy since using this therapeutic approach. CONCLUSION: In our center, leflunomide therapy, but not cidofovir, was effective in patients with BK virus nephropathy of the renal allograft.