Low-dose Cidofovir Research Articles

A randomized, placebo-controlled, dose-escalation phase I/II multicenter trial of low-dose cidofovir for BK polyomavirus nephropathy.

BK polyomavirus-associated nephropathy (BKPyVAN) is an important cause of allograft dysfunction and failure in kidney transplant recipients (KTRs) and there are no proven effective treatments. Case reports and in vitro data support the potential activity of cidofovir against BK polyomavirus (BKPyV). We report the results of a phase I/II, double-blind, placebo-controlled randomized dose-escalation trial of cidofovir in KTRs with biopsy-confirmed BKPyVAN and estimated glomerular filtration rate ≥30mL/min. Intravenous cidofovir (0.25mg/kg/dose or 0.5mg/kg/dose) or placebo was administered on days 0, 7, 21, and 35, with final follow-up through day 49. The trial was prematurely discontinued due to slow accrual after 22 KTRs had completed the study. Cidofovir was safe and tolerated at the doses and duration studied. The proportion of subjects with any adverse event (AE) was similar between groups (9/14 [64%] in the combined cidofovir dose groups and 6/8 [75%] in the placebo group); 84% of AEs were mild. BKPyV DNAemia reduction by day 49 was similar between groups (>1 log10 reduction in (2/9 [22.2%] of 0.25mg/kg group, 1/5 [20%] of 0.5mg/kg group, and 2/8 [25%] of placebo group). These preliminary results indicate that low-dose cidofovir was safe and tolerated but had no significant BKPyV-specific antiviral effect in KTRs with BKPyVAN.

Combination therapy of low-dose cidofovir and leflunomide in a kidney transplant recipient with BK virus nephropathy: a case report

Combination therapy of low-dose cidofovir and leflunomide in a kidney transplant recipient with BK virus nephropathy: a case report

Low-dose cidofovir and conversion to mTOR-based immunosuppression in polyomavirus-associated nephropathy.

Polyomavirus-associated nephropathy (PVAN) remains a relevant complication following kidney transplantation with allograft loss rates of up to 50%. Reduction in overall immunosuppression is a cornerstone of therapy, whereas no specific antiviral regimen has shown conclusive benefit to date. The present case series demonstrates the efficacy of a dual therapeutic approach with low-dose cidofovir and conversion to mTOR-based immunosuppression in PVAN. Patients with biopsy-proven PVAN having received low-dose cidofovir (0.25mg/kg) according to the Tübingen Cidofovir Protocol and been converted to mTOR-based immunosuppression were analyzed retrospectively. Twenty-three patients with a median follow-up of 2.24 [IQR 1.55-5.01] years were included in the analysis. Median time to PVAN diagnosis was 268 [IQR 153-869] days after transplantation. Polyomavirus clearance from plasma was achieved in 78% of patients after a median of 118 [IQR 76-293] days. Of the 23 patients, nine patients (39%) lost their allograft function during follow-up, but only three of these (13%) due to PVAN. Fourteen patients (61%) stabilized or improved allograft function. The cidofovir protocol allowed for specific antiviral therapy without adverse nephrotoxicity, even in patients with low allograft function. Low-dose cidofovir and conversion to mTOR-based immunosuppression allow for effective virus clearance and preservation of allograft function in a high proportion of patients with PVAN and progressive allograft dysfunction and may prolong allograft survival in these patients.

BK virus-induced severe hemorrhagic cystitis in non-transplant oncology patients: A case series

Hemorrhagic cystitis is often a serious condition in cancer patients and can be life threatening despite aggressive treatment measures. The condition may be secondary to infections, radiation or chemotherapy. Oxazaphosphorine alkylating agents, such as cyclophosphamide and ifosfamide, are the most frequent causes of chemotherapy-induced HC in cancer patients. Only a few cases of BK virus-associated hemorrhagic cystitis in non-transplant cancer patients have been reported worldwide. Here, we report two cases of BK-induced HC in non-transplant oncology patients; one patient died due to multi-system failure of unknown etiology, and the other patient was treated successfully with low-dose cidofovir.

Treatment of BK virus-associated hemorrhagic cystitis with low-dose intravenous cidofovir in patients undergoing allogeneic hematopoietic cell transplantation.

Background/AimsBK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC) in recipients of hematopoietic stem cell transplantation (HSCT). Cidofovir has been used at higher doses (3 to 5 mg/kg/wk) with probenecid prophylaxis; however, cidofovir may result in nephrotoxicity or cytopenia at high doses.MethodsAllogeneic HSCT recipients with BKV-associated HC are treated with 1 mg/kg intravenous cidofovir weekly at our institution. A microbiological response was defined as at least a one log reduction in urinary BKV viral load, and a clinical response was defined as improvement in symptoms and stability or reduction in cystitis grade.ResultsEight patients received a median of 4 weekly (range, 2 to 11) doses of cidofovir. HC occurred a median 69 days (range, 16 to 311) after allogeneic HSCT. A clinical response was detected in 7/8 patients (86%), and 4/5 (80%) had a measurable microbiological response. One patient died of uncontrolled graft-versus-host disease; therefore, we could not measure the clinical response to HC treatment. One microbiological non-responder had a stable BKV viral load with clinical improvement. Only three patients showed transient grade 2 serum creatinine toxicities, which resolved after completion of concomitant calcineurin inhibitor treatment.ConclusionsWeekly intravenous low-dose cidofovir without probenecid appears to be a safe and effective treatment option for patients with BKV-associated HC.

Effect of Low Dose Cidofovir in Kidney Transplant Recipients with Polyomavirus Associated Nephropathy

Background: Polyomavirus associated nephropathy (PVAN) is an important cause of graft dysfunction and graft failure in current era of immunosuppressant. First treatment is early reduction of immunosuppressant, but the rate of graft failure is still high. And there is no consensus on its management. Cidofovir, antiviral drug for cytomegalovirus, is thought to have therapeutic effect for polyomavirus, but the benefits are still controversial. Patients and methods: We treated Biopsy proven PVAN patients between 2008˜2010 in single center. All patients were treated with a reduction of their original immunosuppressive medications. 15 patients agreed to receive low-dose cidofovir (0.25 mg/kg) every 2 weeks for a total of eight doses. Result: They received mean 7.5 times (3˜14) of cidofovir with mean dose of 2.9 mg/kg (1.0˜6.5mg/kg). Mean serum creatinine level increased from 2.4mg/dl, at the start of cidofovir to 2.6 mg/dl, at the end of cidofovir. Mean BKV blood PCR reduced from 6.5 logs to 5.9 logs. There was no adverse effect of cidofovir. After 6 month of treatment, renal function was improved in 7 patients compared to at the time of initial cidofovir use. During 2.7 years of follow up there was no rejection episode but one graft failure due to chronic allograft nephropathy. Dose of cidofovir, time interval between diagnosis of PVAN and cidofovir treatment, initial BKV blood PCR level, and initial creatinine were not associated with clinical outcome. Conclusion: Adverse effect of low dose cidofovir is uncommon and low dose cidofovir therapy in PVAN patients seems to be beneficial in addition to reduction of immunosuppressant. But this small series of cidofovir use does did not prove that cidofovir in addition to immunosuppressant reduction is better than immunosuppressant reduction alone. These findings warrant a randomized controlled prospective study in order to asses the clinical value of adjuvant low-dose cidofovir.

Pharmacokinetics of low‐dose cidofovir in kidney transplant recipients with BK virus infection

BK virus (BKV) infection in kidney transplant recipients is associated with progressive graft dysfunction and graft loss. Cidofovir, an antiviral agent with known nephrotoxicity, has been used in low doses to treat BKV infections. However, the systemic exposure and disposition of the low-dose cidofovir regimen are not known in kidney transplant recipients. We investigated the pharmacokinetics (PK) of low-dose cidofovir (0.24 - 0.62 mg/kg) both without and with oral probenecid in 9 transplant patients with persistent BK viremia without nephropathy in a crossover design. The mean estimated glomerular filtration rate (eGFR) of the study participants was 46.2 mL/min/1.73 m(2) (range: 17-75 mL/min/1.73 m(2) ). The contribution of active renal secretion to cidofovir total body clearance was assessed by evaluating the effect of probenecid on cidofovir PK. Maximum cidofovir plasma concentrations, which averaged approximately 1 μg/mL, were significantly below the 36 μg/mL 50% effective concentration in vitro for cidofovir against BKV. The plasma concentration of cidofovir declined with an overall disposition half-life of 5.1 ± 3.5 and 5.3 ± 2.9 h in the absence and in the presence of probenecid, respectively (P > 0.05). Cidofovir clearance and eGFR were linearly related irrespective of probenecid administration (r(2) = 0.8 without probenecid; r(2) = 0.7 with probenecid). This relationship allows for the prediction of systemic cidofovir exposure in individual patients and may be utilized to evaluate exposure-response relationships to optimize the cidofovir dosing regimen for BKV infection.

Cidofovir Therapy for Adenovirus Pneumonia in an AIDS Patient on HAART: A Case Report

Introduction: Adenovirus infections are associated with significant morbidity and mortality among immunocompromised hosts. Adenovirus pneumonia is a rare and often fatal disease in patients with AIDS. Case Report: We report a case of a 28-year-old woman with advanced HIV/AIDS, who developed pneumonia four weeks after initiation of highly active antiretroviral therapy (HAART). Despite empiric antibiotics, the patient developed worsening hypoxemia and progressive pneumonia on chest x-ray. Culture data from a bronchoalveolar lavage (BAL) was negative for bacteria, fungi, pneumocystis jirovecii, but was positive for adenovirus detected by PCR. After transfer to a tertiary care hospital intensive care unit, a repeat BAL confirmed the presence of adenovirus by immunohistochemical staining. Tissue samples sent for histopathology revealed smudge cells. Serum adenovirus viral load was 1.6 × 105 copies/mL. Intravenous cidofovir, 1 mg/kg/day, was initiated and scheduled three times a week. The patient exhibited remarkable improvement and was discharged to home in stable condition after four doses of cidofovir treatment. Discussion: Prior to our case, the few published accounts of HIV patients with adenovirus pneumonia treated with cidofovir have all resulted in death. Our case is distinct from these cases by the lack of concomitant pulmonary infection and the initiation of HAART prior to presentation. Conclusion: To our knowledge, we present the first case of adenovirus pneumonia in a patient with AIDS successfully treated with cidofovir. Our case suggests that limited and low dose cidofovir may be an efficacious approach to treat adenovirus pneumonia among HIV patients, especially those established on HAART.

BK polyomavirus nephropathy complicated with acute T‐cell‐mediated rejection in a kidney transplant recipient: a case report

We present a case of severe BK polyomavirus nephropathy (BKVN) complicated with persistent acute T-cell-mediated rejection (ATMR) that progressed to allograft failure. A 54-yr-old man received a living donor kidney transplant from his wife. Approximately four months after transplantation, the patient's serum creatinine (SCr) increased from a baseline value of 1.5-2.4 mg/dL. A histological analysis showed BKVN, and the SV40 antigen was detected in the tubular nuclei. The doses of immunosuppressants were reduced, and immunoglobulin was administered intravenously. The SCr increased further, to 5.3 mg/dL, and a second renal biopsy revealed the presence of severe ATMR. Antirejection treatment was performed, and low-dose cidofovir was started. The SCr decreased, to 3 mg/dL, and BK virus antigen in the serum and urine samples became negative at the time of hospital discharge. However, the histological findings subsequently showed gradually progressive interstitial fibrosis and tubular atrophy, and the SCr increased gradually. Two years after the transplantation, the patient resumed hemodialysis. BK polyomavirus nephropathy is usually treated with a reduction in immunosuppressant therapy, although in some patients, the reduction in immunosuppressants induces a subsequent exacerbation of acute rejection and results in progressive graft failure, which suggests difficulty in treating BKVN after kidney transplantation.

How I treat adenovirus in hematopoietic stem cell transplant recipients

AbstractAdenovirus (AdV) infections are very common in the general pediatric population. The delayed clearance in young persons imposes a threat to immunocompromised patients after hematopoietic stem cell transplantation (HSCT), who can reactivate the virus, resulting in life-threatening disseminated disease. Although a definitive cure requires adequate immune reconstitution, 2 approaches appear to be feasible and effective to improve the outcomes of AdV infections. Strict monitoring with AdV quantitative polymerase chain reaction followed by preemptive treatment with low-dose (1 mg/kg) cidofovir 3 times a week, is effective in most cases to bridge the severely immunocompromised period shortly after HSCT, with acceptable toxicity rates. For centers who have the access, AdV-specific cytotoxic T cells can be the other important cornerstone of anti-AdV therapy with promising results so far. Methods to positively influence the reconstitution of the immune system after HSCT and optimizing new and currently available cellular immunotherapies will make HSCT safer against the threat of AdV infection/reactivation and associated disease.

Low-dose cidofovir in the treatment of symptomatic BK virus infection in patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis of an algorithmic approach

BK virus (BKV) reactivation occurs in 50% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Standardized antiviral management of BKV infection has not been established. In order to develop a uniform guideline, a treatment algorithm for the management of symptomatic BKV replication was implemented for our allo-HSCT population. This is a retrospective analysis of patients treated according to the protocol between January 2008 and January 2009. Eighteen patients developed symptomatic BKV replication a median of 43 days after allo-HSCT. All patients had BK viruria and 12 patients had BK viremia in addition to viruria. Patients with isolated viruria were treated with intravenous (IV) low-dose cidofovir (0.5-1mg/kg IV weekly) until symptom resolution. In patients with BK viremia, therapy was continued until virological clearance was achieved in the blood. Four patients also received intravesical instillation of cidofovir per physician discretion. Thirteen of 18 (72%) patients with viruria and 8 of 12 (75%) patients with viremia responded to treatment. Three patients developed transient renal dysfunction. Low-dose cidofovir is safe and effective in allo-HSCT recipients. In absence of randomized prospective data, an institutional algorithmic protocol removes variance in practice pattern and derives data that may be used for research and improved patient care.

Meet the expert: microbiology case presentation

A 64-year-old man underwent an orthotopic liver transplant in October 2008 for end-stage cirrhosis secondary to hepatitis C virus (HCV) infection. His HCV infection (genotype 1A) had previously been unresponsive to treatment with pegylated-interferon-α and ribavirin. He suffered an episode of mild acute rejection 6 days post-operatively, which was responsive to steroids, and his subsequent immunosuppressive regime consisted of cyclos-porine and prednisone. Given that there was cytomegalovirus (CMV) serostatus mismatch (D+/R-), he was also given prophylactic valganciclovir for 12 weeks post-operatively. One week after discontinuation of valganciclovir, he developed malaise, anorexia, spiking fevers and dyspnoea. He was admitted to hospital, and was profoundly hypoxic, with bilateral chest infiltrates. He was commenced on iv ganciclovir, pending CMV levels. However, his CMV viral load was undetectable, as was his Epstein-Barr virus (EBV) viral load and no CMV was detected in a bronchoalveolar lavage specimen. However, his white blood cells and plasma were strongly positive for human herpes virus-6 (HHV-6), as was his broncho-alveolar lavage specimen and a diagnosis of HHV-6 pneumonitis was made. He was treated with 2 weeks of iv ganciclovir, and 2 months of valganciclovir, and made a good clinical response. One month after discontinuation of his valganciclovir, he developed worsening graft dysfunction, fevers and diarrhoea. A liver biopsy revealed recurrent HCV infection, and his CMV viral load was elevated. He was again commenced on ganciclovir, although after one week there was no clinical response, and his high CMV viraemia remained unchanged. A molecular and clinical diagnosis of ganciclovir resistance was made, and he received 2 weeks of foscarnet therapy, to which he responded, although this was discontinued due to renal impairment and neurotoxicity. He was commenced on low-dose cidofovir for 3 months, and during this time also developed a CMV IgG response. He has remained free of HHV-6 or CMV-related disease for 6 months to date. This case posed several management and diagnostic dilemmas: •the role of HHV-6 as a true pathogen given that it can reactivate in many transplant recipients; •duration of prophylactic therapy in CMV mismatch patients; •development of ganciclovir resistance and toxicity of second-line agents. A 64-year-old man underwent an orthotopic liver transplant in October 2008 for end-stage cirrhosis secondary to hepatitis C virus (HCV) infection. His HCV infection (genotype 1A) had previously been unresponsive to treatment with pegylated-interferon-α and ribavirin. He suffered an episode of mild acute rejection 6 days post-operatively, which was responsive to steroids, and his subsequent immunosuppressive regime consisted of cyclos-porine and prednisone. Given that there was cytomegalovirus (CMV) serostatus mismatch (D+/R-), he was also given prophylactic valganciclovir for 12 weeks post-operatively. One week after discontinuation of valganciclovir, he developed malaise, anorexia, spiking fevers and dyspnoea. He was admitted to hospital, and was profoundly hypoxic, with bilateral chest infiltrates. He was commenced on iv ganciclovir, pending CMV levels. However, his CMV viral load was undetectable, as was his Epstein-Barr virus (EBV) viral load and no CMV was detected in a bronchoalveolar lavage specimen. However, his white blood cells and plasma were strongly positive for human herpes virus-6 (HHV-6), as was his broncho-alveolar lavage specimen and a diagnosis of HHV-6 pneumonitis was made. He was treated with 2 weeks of iv ganciclovir, and 2 months of valganciclovir, and made a good clinical response. One month after discontinuation of his valganciclovir, he developed worsening graft dysfunction, fevers and diarrhoea. A liver biopsy revealed recurrent HCV infection, and his CMV viral load was elevated. He was again commenced on ganciclovir, although after one week there was no clinical response, and his high CMV viraemia remained unchanged. A molecular and clinical diagnosis of ganciclovir resistance was made, and he received 2 weeks of foscarnet therapy, to which he responded, although this was discontinued due to renal impairment and neurotoxicity. He was commenced on low-dose cidofovir for 3 months, and during this time also developed a CMV IgG response. He has remained free of HHV-6 or CMV-related disease for 6 months to date. This case posed several management and diagnostic dilemmas: •the role of HHV-6 as a true pathogen given that it can reactivate in many transplant recipients; •duration of prophylactic therapy in CMV mismatch patients; •development of ganciclovir resistance and toxicity of second-line agents.

Low-dose Cidofovir for the Treatment of Polyomavirus-Associated Nephropathy: Two Case Reports and Review of the Literature

Polyomavirus-associated nephropathy (PVAN) is a serious complication and cause of graft loss in kidney transplant recipients. In the absence of specific antiviral drugs, early detection of the disease and reduction of immunosuppressive regimen is the cornerstone of therapy. Cidofovir, a nucleoside analogue, has been found to inhibit BK virus (BKV) replication in vitro and has been proposed as treatment of refractory PVAN at low doses; however, its efficacy has never been demonstrated in randomized controlled trials. Cidofovir therapy (0.5 mg/kg at a 2-week interval for eight consecutive doses) was initiated in two patients with biopsy-proven PVAN and persistent BKV DNA viraemia (> or = 10,000 copies/ml despite sustained reduction of the immunosuppressive regimen). In addition to these two case reports, we performed a critical review of the literature on the use of cidofovir in PVAN. No significant decrease of BKV viral load in blood was observed during cidofovir therapy and in follow-up of the two patients treated with cidofovir. Our literature review identified 21 publications reporting the use of cidofovir for the treatment of PVAN. All were case reports or small series. The efficacy of cidofovir therapy could not be assessed in 17 of these publications because of lack of data or concomitant reduction of immunosuppressive regimen. The four remaining publications were case reports. In vitro and clinical data to support the efficacy of cidofovir in the treatment of PVAN are currently lacking. More promising compounds should be identified for further clinical studies.

The effect of low-dose cidofovir on the long-term outcome of polyomavirus-associated nephropathy in renal transplant recipients

Polyomavirus-associated nephropathy (PVAN) has an unfavourable impact on graft survival. The cornerstone of therapy is early reduction of immunosuppressive medications; however, the rate of graft failure is still high. Antiviral drugs, such as cidofovir, are thought to have therapeutic effects, but the benefits of cidofovir in retarding the deterioration of PVAN are still a controversial issue. Fourteen renal kidney recipients were diagnosed to have biopsy-proven PVAN between 2001 and 2006 in Chung-Shan Medical University Center with nearly 600 renal transplant recipients. After the diagnosis of PVAN, all patients were treated with a reduction of their original immunosuppressive medications with/without converting tacrolimus to cyclosporine. Eight of the 14 patients agreed to receive low-dose cidofovir (0.5 mg/kg) every 2 weeks for a total of six doses. During 30 +/- 18 months of follow-up, three (37%) patients in the cidofovir-treated and three (50%) patients in the non-cidofovir-treated group experienced graft loss (P = 0.64). The rejection rate before PVAN diagnosis or other baseline characteristics of the patients between two groups were not significantly different. The long-term survival rate to graft loss and major graft functional decline with Kaplan-Meier analysis between the two groups were not significantly different (P = 0.898 and P = 0.243). In all demographic and clinical characteristics, we found that there was a tendency towards long-term major graft functional decline in the patients with acute rejection prior to PVAN diagnosis (P = 0.04). We concluded that (1) there was no obvious effect of low-dose cidofovir on long-term graft survival in patients with PVAN, and (2) acute rejection prior to PVAN diagnosis was a potential risk factor for poorer long-term graft outcome.

Absence of BK Viremia Clearance after Low-dose Cidofovir Therapy in Kidney Transplant Recipients with BK Virus Associated Nephropathy

Absence of BK Viremia Clearance after Low-dose Cidofovir Therapy in Kidney Transplant Recipients with BK Virus Associated Nephropathy

Biopsy-proven adenoviral diarrhea responding to low-dose cidofovir

We present a case of diarrhea secondary to biopsy-proven adenovirus (ADV) infection after autologous peripheral hematopoietic stem cell transplant for multiple myeloma. The patient had a negative plasma polymerase chain reaction for ADV and a dramatic clinical response to low-dose cidofovir. To our knowledge, this is the first report in an adult hematopoietic stem cell recipient of the use of low-dose cidofovir to treat proven ADV gastrointestinal infection.

Low-dose cidofovir treatment of BK virus-associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant

In recipients of hematopoietic stem cell transplants (HSCTs), BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC). In our institution, HSCT recipients with BKV-associated HC are treated with 1 mg/kg of cidofovir weekly. We identified HSCT recipients with BKV-associated HC, treated with weekly cidofovir. Microbiological response was defined as at least a one log reduction in urinary BKV viral load; clinical response was defined as improvement in symptoms and stability or reduction in the grade of cystitis. Nineteen allogeneic HSCT patients received a mean of 4.5 weekly doses of cidofovir. HC occurred at a mean of 68.7 days after transplant. A clinical response was detected in 16/19 (84%) patients, and 9/19 (47%) had a measurable microbiological response (8/10 nonresponders had a BKV viral load above the upper limit of the assay before treatment). Fourteen out of nineteen (74%) patients had no significant increase in serum creatinine. Five patients with renal dysfunction resolved after completion of the therapy and removal of other nephrotoxic agents. We conclude that weekly low-dose cidofovir appears to be a safe treatment option for BKV-associated HC. Although the efficacy of low-dose cidofovir is not proven, a prospective trial is warranted.

Kidney Transplant Function and Histological Clearance of Virus Following Diagnosis of Polyomavirus-Associated Nephropathy (PVAN)

Polyomavirus-associated nephropathy (PVAN) is managed by reduced immunosuppression with or without antiviral therapy. Data from 55 patients with biopsy-proven PVAN were analyzed for adverse outcomes and influence of baseline variables and interventions. During 20+/-11 months follow-up, the frequencies of graft loss, major and any functional decline were 15%, 24% and 38%, respectively. Repeat biopsies were performed in 45 patients with persistent PVAN in 47%. Low-dose cidofovir, IVIG and cyclosporine conversion were used in 55%, 20% and 55% of patients. No single intervention was associated with improved outcome. Of the variables examined, only degree of interstitial fibrosis at diagnosis was associated with kidney function decline. In contrast, donor source, interstitial fibrosis, proportion of BKV positive tubules and plasma viral load at diagnosis were all associated with failure of histological viral clearance. This retrospective, nonrandomized analysis suggests that: (i) Graft loss within 2 years of PVAN diagnosis is now uncommon, but ongoing functional decline and persistent infection occur frequently. (ii) Low-dose cidofovir, IVIG and conversion to cyclosporine do not abrogate adverse outcomes following diagnosis. (iii) Fibrosis at the time of diagnosis predicts subsequent functional decline. Further elucidation of the natural history of PVAN and its response to individual interventions will require prospective clinical trials.

Intermediate‐dose cidofovir without probenecid in the treatment of BK virus allograft nephropathy

BK virus allograft nephropathy (BKVAN) is a rising complication in kidney transplant recipients. Reducing immunosuppression has been the initial form of therapy in most cases, but is not always associated with improvement in graft function. Anti-viral therapy with low-dose cidofovir (0.25-0.42 mg/kg/dose) has been used successfully in some patients, but dose-related nephrotoxicity has limited its use. We present our experience with 3 kidney transplant recipients diagnosed with BKVAN who received intermediate-dose cidofovir (0.75-1.0 mg/kg/dose) without probenecid, and without concomitant nephrotoxicity. Three female patients, ages 8, 19 and 20 yr, presented with elevated serum creatinine (SCr) values, BK virus stain positive on renal biopsy and high plasma BK viral loads. As a result of viral loads being >2 million copies/ml in two patients and a lack of response to reduction in immunosuppression in the third, we initiated therapy with low-dose cidofovir. Because of persistent positive BK stain and positive plasma viral load, we then administered intermediate-dose cidofovir, without probenecid, for several subsequent doses (seven to 15 infusions till date). All patients tolerated the intermediate-dose cidofovir with no significant rise in SCr during the course of the infusions. The most recent SCr values in all three patients were improved from those at the initial diagnosis of BKVAN. All three patients showed a marked drop in BK viral loads when on intermediate-dose cidofovir, with complete clearing of viremia in two patients. In our experience, intermediate-dose cidofovir without probenecid, used judiciously, is not associated with additional nephrotoxicity and may provide an additional alternative for treatment.

Adjuvant Low‐Dose Cidofovir Therapy for BK Polyomavirus Interstitial Nephritis in Renal Transplant Recipients

BK virus interstitial nephritis (BKVIN) is a serious complication after kidney grafting, necessitating drastic reduction of immunosuppressive therapy in order to enable viral clearance. Despite these measures, progressive graft dysfunction and graft loss occur in the majority of recipients. We diagnosed BKVIN in 21 recipients grafted between 1998 and 2004. Eight of 21 patients were treated with weekly, adjuvant low-dose cidofovir in addition to reduction of immunosuppressive therapy. BKVIN caused irreversible deterioration of graft function in all patients but renal function stabilized after antiviral treatment (creatinine clearance: 51.8-32 mL/min; p=0.001) and no graft loss occurred in cidofovir-treated recipients during 24.8 (8-41) months follow-up. Peak serum cidofovir concentrations were dose-dependent and attained approximately one-tenth of thein vitroEC50 for cidofovir against BK-virus, while pre-treatment with probenecid did not alter peak serum concentrations nor affected the incidence of nephrotoxicity. In fact, no cidofovir-related renal toxicity occurred; few patients had minor transient side effects (nausea, skin rash). In contrast, 9 of 13 patient who received no adjuvant cidofovir therapy lost their graft after median 8 (4-40) months. In this selected group of recipients with BKVIN, the use of adjuvant low-dose cidofovir therapy resulted in prolonged graft survival and stabilized graft function.