valganciclovir and Kidney-Failure--Chronic

Cytomegalovirus (CMV), human herpes virus (HHV)-6, and HHV-7 are ubiquitous β-herpesviruses that can cause opportunistic infection and disease in kidney transplant recipients. Active CMV infection and disease are associated with acute allograft failure and death, and HHV-6 and HHV-7 replication are associated with CMV disease. CMV prevention strategies are used commonly after kidney transplantation, and include prophylaxis with antiviral medications and preemptive treatment upon the detection of asymptomatic viral replication in blood. Both approaches decrease CMV disease and allograft rejection, but CMV prophylaxis is preferred for high-risk patients because it is easy to administer and may be more effective in real-world settings. CMV disease commonly occurs even with current preventive strategies, whereas HHV-6 and HHV-7 diseases are rare. The clinical manifestations of CMV, HHV-6, and HHV-7 are nonspecific, and laboratory confirmation is essential to establishing diagnoses. Although nucleic acid testing has supplanted other diagnostic modalities given its high sensitivity and specificity, histopathologic examination sometimes is necessary to identify disease definitively. Ganciclovir and valganciclovir are the treatments of choice for CMV and HHV-6, and foscarnet can be used to treat HHV-7. Treatment duration should be informed by the initial severity of disease, and subsequent clinical and virologic responses.

Topics: Antiviral Agents; Cytomegalovirus Infections; Ganciclovir; Graft Rejection; Herpesvirus 6, Human; Herpesvirus 7, Human; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Roseolovirus Infections; Valganciclovir

A supplemental dose is often necessary after hemodialysis depending on the amount of drug removed by hemodialysis. However, there are different methods of estimating this amount, and most methods ignore drug rebound after hemodialysis. In this report we present a new area under the concentration curve (AUC)-based method that provides an estimate of the drug fraction removed by hemodialysis including drug rebound.. Valganciclovir, the oral prodrug of ganciclovir, was administered to 6 patients with end-stage renal disease. Hemodialysis was performed after 32 h. The fraction of ganciclovir removed by hemodialysis was estimated using the new AUC-based method, a classical method (using the slope on and off hemodialysis), the back-extrapolation method, and a reference model (a two-compartment model with zero-order input and first-order elimination).. The AUC-based method and the back-extrapolation method provided accurate estimates of the fraction of ganciclovir removed by hemodialysis (47 +/- 6 and 46 +/- 5%, respectively) compared to the reference model (49 +/- 3%). The classical method, which does not account for the rebound of ganciclovir concentrations after hemodialysis, overestimated the removed fraction by 9% (58 +/- 3%).. The new AUC-based method and the back-extrapolation method accurately estimate the drug fraction removed by hemodialysis for drugs with a rebound after hemodialysis. The AUC-based method is more robust and as efficient compared to the back-extrapolation method.

Topics: Adult; Antiviral Agents; Ganciclovir; Humans; Kidney Failure, Chronic; Middle Aged; Models, Biological; Renal Dialysis; Valganciclovir

Valganciclovir is the oral prodrug of ganciclovir. The pharmacokinetics of valganciclovir in patients with renal impairment is not known. Furthermore, it is not known whether there are any pharmacokinetic differences between patients who are positive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) and healthy subjects.. A total of 44 patients were included-18 with mild, medium, or severe renal impairment; 6 with end-stage renal disease who were on long-term hemodialysis; 8 HIV/CMV-positive patients with normal renal function; and 12 healthy subjects serving as controls. Valganciclovir and ganciclovir serum concentrations were measured after oral administration of 900 mg of valganciclovir. Pharmacokinetic parameters were estimated by means of noncompartmental and compartmental methods.. After oral administration of the prodrug valganciclovir, ganciclovir bioavailability was 60% and ganciclovir concentrations were higher (maximum concentration [C(max)], 8.5 microg/mL versus 5.8 microg/mL) and appeared later (time to maximum concentration [T(max)], 4.3 versus 2.0 hours) in patients with severe renal impairment compared with healthy subjects. The elimination half-life (t(1/2)) of ganciclovir was longer in patients with renal failure (t(1/2) of 68.1 hours in patients with end-stage renal disease compared with 3.5 hours in healthy subjects). Ganciclovir clearance was correlated with creatinine clearance (r = 0.975). Hemodialysis removed 50% of ganciclovir. We observed no differences in pharmacokinetics between HIV/CMV-positive patients and healthy subjects. A 2-compartment model with zero-order input and first-order elimination proved to be the most appropriate model for ganciclovir after oral administration of valganciclovir.. The dosage of valganciclovir has to be adjusted to the degree of renal impairment. Dosage adjustment is not necessary for HIV/CMV-positive patients.

Topics: Administration, Oral; Adult; Aged; AIDS-Related Opportunistic Infections; Antiviral Agents; Biological Availability; Cytomegalovirus Infections; Drug Administration Schedule; Female; Ganciclovir; HIV Infections; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prodrugs; Renal Dialysis; Valganciclovir

Cytomegalovirus is the most common viral infection in organ transplant recipients that usually affects the brain, lungs, liver, and gastrointestinal tract. Renal involvement of Cytomegalovirus (CMV) is otherwise rare. We present six cases of biopsy-proven CMV renal infection. Five out of the six patients had detectable CMV viremia. Kidney biopsy revealed glomerulopathy in four cases and tubulointerstitial involvement in two cases. All patients exhibited decline in renal function at the onset of infection. Four out of six patients had improvement of renal function following treatment of CMV disease. To date, this is the largest case series of pure biopsy-proven CMV renal infection described in a single center.

Topics: Adolescent; Adult; Allografts; Antiviral Agents; Biopsy; Cytomegalovirus; Cytomegalovirus Infections; Humans; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Transplant Recipients; Treatment Outcome; Valganciclovir

Polyomavirus BK (BKV) is the cause of polyomavirus-associated nephropathy resulting in premature graft loss. There are limited data regarding the role of cytomegalovirus (CMV) infection and its prevention in developing BKV viremia and PVAN. In a prospective study, we analyzed 207 consecutive renal transplant recipients previously enrolled in 2 randomized trials evaluating different CMV prevention regimens with routine screening for BKV and CMV. Of these, 59 received valganciclovir and 100 valacyclovir prophylaxis; 48 patients were managed by preemptive therapy. At 3 years, the incidence of BKV viremia and PVAN was 28% and 5%, respectively. CMV DNAemia developed in 55% and CMV disease in 6%. Both BKV viremia (42% vs 23% vs 21%, P = .006) and PVAN (12% vs 2% vs 2%, P = .011) were increased in patients treated with valganciclovir prophylaxis compared to valacyclovir and preemptive therapy. Using multivariate Cox proportional hazard regression, valganciclovir prophylaxis was independent predictor of BKV viremia (hazard ratio [HR] = 2.38, P = .002) and PVAN (HR = 4.73, P = .026). In contrast, the risk of subsequent BKV viremia was lower in patients with antecedent CMV DNAemia (HR = 0.50, P = .018). These data suggest valganciclovir prophylaxis may be associated with increased risk of BKV viremia and PVAN. CMV DNAemia did not represent a risk for BKV.

Topics: Adult; BK Virus; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Polyomavirus Infections; Premedication; Proportional Hazards Models; Prospective Studies; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome; Tumor Virus Infections; Valacyclovir; Valganciclovir; Viremia

Topics: Antibiotic Prophylaxis; Biopsy; Child; Epstein-Barr Virus Infections; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymph Nodes; Lymphadenopathy; Male; Nephrotic Syndrome; Postoperative Complications; Valganciclovir

To clarify whether cytomegalovirus (CMV) infection can affect the results of living related donor kidney transplantation.. A study group included 17 (7.27%) patients (10 men and 7 women; 8 children and 9 adults) aged 3 to 51 years who had developed resistant CMV infection. For comparative analysis, a control group was formed from 113 patients (61 men and 52 women; 40 children and 73 adults) aged 1 to 61 years, whose CMV polymerase chain reaction (PCR) had always been negative, i.e. CMV DNA was absent. The duration of CMV infection episodes was 44 to 232 days.. The patients were given valganciclovir in a dose of 450 mg/day. CMV PCR was negative in all the patients at the end of therapy. None of the patients died; one graft was lost. In the control (negative CMV PCR) group, 6 grafts were lost in 113 patients lost and 4 patients died. Statistical analysis showed that the results of related donor kidney transplantation were virtually equal.. Suppression of resistant CMV infection can be achieved with the longer use of valganciclovir or its higher dose. CMV infection fails to affect the results of related donor kidney transplantation.. Цель исследования. Выяснить влияет ли цитомегаловирусная инфекция (ЦМФИ) на результаты операции пересадки почки от живых родственных доноров. Материалы и методы. В основную группу включили 17 (7,27%) пациентов (возраст от 3 лет до 51 года; 10 мужчин и 7 женщин, 8 детей и 9 взрослых), у которых развилась резистентная ЦМВИ. Для сравнительного анализа сформирована контрольная группа из 113 (возраст от 1 до 61 года; 61 мужчина и 52 женщины, 40 детей и 73 взрослых), у которых ЦМВ-ПЦР всегда была отрицательной, т.е. отсутствовала ДНК ЦМВ. Продолжительность эпизодов ЦМВИ составила от 44 до 232 дней. Результаты. Больным назначали вальганцикловир в дозе 450 мг/сут. В конце курса терапии у всех пациентов полимеразная цепная реакция (ПЦР) ЦМВ была отрицательной. Ни один больной не умер, потерян один трансплантат. Среди 113 больных контрольной группы (ЦМВ-ПЦР отрицательная) потеряны 6 трансплантатов и умерли 4 больных. Статистический анализ показал, что результаты операции пересадки родственных почек были практически одинаковыми. Заключение. Преодоление резистентной ЦМВИ достигается увеличением длительности применения вальганцикловира или повышением его дозы. ЦМВИ не влияет на результаты пересадки родственных почек.

Topics: Adolescent; Antiviral Agents; Child, Preschool; Cytomegalovirus; Cytomegalovirus Infections; Disease Resistance; DNA, Viral; Dose-Response Relationship, Drug; Female; Ganciclovir; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Russia; Time Factors; Transplantation, Homologous; Treatment Outcome; Valganciclovir

Skin grafting has been evolving as an important application in reconstructive surgery. Mixed reports about the survival of allogeneic and xenogeneic keratinocytes require further substantiation to determine the role of these cells in wound healing.. Rabbit and rat skins were recovered and cultured in vitro. Full-thickness wounds were created on the dorsum of rabbits (2 cm × 2 cm; n = 4). Cultured epithelial autograft, allograft, and xenograft cells were sprayed onto 3 freshly created wounds, with 1 wound acting as a control. The wounds were monitored every 2 days for 4 weeks. After 4 weeks, the rabbits were killed; skin biopsies were taken from each healed wound and stained with hematoxylin and eosin, and epidermal thickness was measured.. All examined grafts showed favorable healing outcomes because the wounds appeared similar to normal skin upon healing. The only observed significant difference was the thickness of the epidermis layer, which was thinner in the xenograft (P = .002) than the autograft or allograft. Morphologic evaluation of the skin surface showed that the rat skin was thinner than the rabbit skin. The graft that achieved the best result was the autograft because the thickness was similar to and mimicked normal skin.. All 3 grafts (autograft, allograft, and xenograft) have the potential to reconstitute epithelial defects. This approach can overcome the limitation of autologous skin donor sites, especially in burn cases.

Topics: Adult; Allografts; Antiviral Agents; Biopsy; Cytomegalovirus Infections; Female; Ganciclovir; Gastritis; Humans; Immunocompromised Host; Immunohistochemistry; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Opportunistic Infections; Risk Factors; Time Factors; Treatment Outcome; Valganciclovir

We compared the effectiveness of lower-dose (LD) (450 mg/day for 6 months) to standard-dose (SD) (900 mg/day for 6 months) valganciclovir (VGCV) prophylaxis for prevention of cytomegalovirus (CMV) infection and disease in high-risk CMV donor-positive/recipient-negative (D+/R-) kidney recipients.. We performed a single-center, retrospective cohort study, in a 750-bed academic medical center, involving a total of 90 evaluable CMV high-risk kidney recipients. All patients were retrospectively followed from day of transplantation to November 1, 2012, or to the development of CMV infection or disease, death, or loss to follow-up. CMV screening was only done if suggestive symptoms or abnormal laboratory values were present. Our immunosuppressive protocol otherwise did not differ between periods.. In total, 45 consecutive eligible patients initiated SD prophylaxis in the 22 months before the institutional protocol change regarding CMV prophylaxis. One patient developed CMV infection in the setting of non-adherence. In the 16 months after the protocol update, 45 consecutive eligible patients receiving LD prophylaxis were evaluated: 6 developed CMV infection while receiving prophylaxis (P = 0.11). Ganciclovir (GCV)-resistant infection was confirmed in 1 patient in the LD prophylaxis group. Late-onset CMV infection or disease occurred in 11 patients (24%) in the SD group and in 12 patients (27%) in the LD group (P = 0.86). More patients in the SD group developed leukopenia (75% vs. 44%, P < 0.01). During the study period, no significant differences were seen between the groups in mean mg/kg exposure to rabbit anti-thymocyte globulin induction courses, mean tacrolimus troughs, number of rejection episodes, mean estimated renal function, graft survival, or patient survival. Overall mean follow-up (± standard deviation) was 357 days (± 53) in the SD group and 320 days (± 103) in the LD group (P = 0.03).. Breakthrough CMV infection while receiving VGCV prophylaxis occurred more often after the institutional protocol revision to LD VGCV prophylaxis. Given our concern for increased risk of breakthrough infection and GCV resistance when prophylaxis is under-dosed, our institutional protocols were revised back to SD prophylaxis for all CMV D+/R- kidney transplant recipients.

Topics: Academic Medical Centers; Adult; Allografts; Antiviral Agents; Cohort Studies; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Resistance, Viral; Female; Ganciclovir; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Valganciclovir

BACKGROUND.: We have shown that high-dose intravenous immune globulin (IVIG; 2 g/kg x2 doses)+rituximab (1 g x2 doses) was effective in lowering anti-human leukocyte antigen (HLA) antibodies and improving rates of transplantation. The aim of this report was to evaluate the efficacy of IVIG+rituximab on reduction of anti-HLA antibodies to a level that was permissive for living donor (LD) or deceased donor (DD) transplantation without incurring the risk of antibody-mediated rejection and immediate graft loss. METHODS.: From July 2006 to February 2009, 76 HLA-sensitized (HS) patients who met strict sensitization criteria received kidney transplants after desensitization using IVIG 2 g/kg (days 1 and 30)+rituximab (1 g, day 15). Parameters evaluated included rates of transplantation, previous transplants, panel reactive antibodies, donor specific antibody, crossmatches (CMXs), patient and graft survival, acute rejection, serum creatinines, and infections. RESULTS.: Seventy-six HS CMX treated patients (31 LD/45 DD) were transplanted. For LD and DD recipients, significant reductions were seen in T-cell flow cytometry CMXs from pretreatment (T cell 183.5+/-98.4 mean channel shifts (MCS) for LD and 162.8+/-41 MCS for DD) to time of transplant (T cell 68.2+/-58 MCS for LD [P<0.00006] and 125+/-49 for DD [P=0.05]), respectively. Time on wait list for DD recipients was reduced from 95+/-46 months to 4.2+/-4.5 months after treatment. Twenty-eight patients (37%) experienced acute rejection (29% C4d/8% C4d). Patient and graft survival up to 24 months was 95% and 84%, respectively. The mean serum creatinines, at 12 and 24 months were 1.5+/-1.1 and 1.3+/-0.3 mg/dL, respectively. Viral infections were seen in six patients. CONCLUSIONS.: IVIG and rituximab seems to offer significant benefits in reduction of anti-HLA antibodies allowing improved rates of transplantation for HS patients, especially those awaiting DD, with acceptable antibody-mediated rejection and survival rates at 24 months.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antiviral Agents; Autoantibodies; Desensitization, Immunologic; Drug Therapy, Combination; Female; Flow Cytometry; Ganciclovir; Graft Rejection; Graft Survival; Histocompatibility Testing; HLA Antigens; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Rituximab; Survival Rate; T-Lymphocytes; Valganciclovir; Virus Diseases

We followed up 550 primary kidney transplant recipients in an observational retrospective cohort to evaluate the impact of three consecutive cytomegalovirus (CMV) prevention strategies. In period 1 (1996-2000; n = 190), no anti-CMV prophylaxis was given; in period 2 (2000-2004; n = 173), 6-month valacyclovir was given and in period 3 (>2004; n = 187), 6-month valganciclovir was given. Cytomegalovirus disease significantly decreased from 33.2% in period 1 to 13.9% in period 2 and to 8.6% in period 3; onset was significantly prolonged with valganciclovir (228 days) compared with valacyclovir (93 days) and with no prophylaxis (33 days). After Cox regression adjustments, both valganciclovir and valacyclovir were similarly protective factors for CMV disease. Cytomegalovirus diseases encountered in both valacyclovir and valganciclovir groups were primary infections (79.2 and 93.8% respectively) as compared with a significant low number (39.7%) in the nonprophylaxis group. Two cases of valganciclovir resistance were recorded in the valganciclovir group and no resistance was seen with valacyclovir. A significantly reduced incidence of other herpes viruses was only observed with valganciclovir. Valganciclovir was better tolerated than valacyclovir and this long-term prophylaxis was applicable to 85% of patients. Longer follow-up of valganciclovir or valacyclovir prophylaxis is still required to appreciate its impact on graft and patient survivals, as well as other indirect effects, in the mycophenolate mofetil and calcineurin inhibitor immunosuppressive era.

Topics: Acyclovir; Antiviral Agents; Cytomegalovirus Infections; Female; Follow-Up Studies; Ganciclovir; Graft Survival; Humans; Incidence; Injections, Intravenous; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prodrugs; Retrospective Studies; Survival Rate; Time Factors; Treatment Outcome; Valacyclovir; Valganciclovir; Valine

Valganciclovir is an l-valyl ester pro-drug of ganciclovir that was initially used to treat cytomegalovirus (CMV)-associated retinitis in patients with human immunodeficiency virus. Currently, it is also indicated for the prevention of CMV disease in solid-organ transplantation. It is primarily eliminated via the kidneys through glomerular filtration and tubular secretion. Decreased renal function results in decreased drug clearance. Valganciclovir has been reported to cause usually mild to moderate hematologic adverse effects such as leukopenia, neutropenia, anemia, thrombocytopenia, and pancytopenia. Severe and fatal bone marrow depression has been described in 1 adult patient. Herein, we describe the cases of 4 patients with end-stage renal disease who underwent cadaveric renal transplantation and received valganciclovir prophylaxis for CMV at a standard dose of 900 mg/d despite persistant renal failure. This therapy resulted in severe bone marrow failure after 18 to 20 days in all 4 patients, with fatal infections in 2 patients. This report demonstrates the in vivo pharmacodynamics of valganciclovir overdose in terms of hematotoxicity in the setting of renal impairment. Valganciclovir, as its derivative ganciclovir, should be used cautiously in patients with renal impairment.

Topics: Adult; Antilymphocyte Serum; Antiviral Agents; Biopsy; Bone Marrow; Cadaver; Female; Ganciclovir; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; T-Lymphocytes; Tissue Donors; Valganciclovir

Topics: ABO Blood-Group System; Antiviral Agents; Blood Group Incompatibility; Boronic Acids; Bortezomib; Cytomegalovirus Infections; Doxorubicin; Ganciclovir; Hemagglutinins; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multiple Myeloma; Protease Inhibitors; Pyrazines; Valganciclovir

Cytomegalovirus is an important viral pathogen in the kidney transplant population. Reports of direct cytopathic effects of cytomegalovirus in the kidney allograft are infrequent, with the majority of earlier reports highlighting tubulointerstitial involvement. We report a 58-year-old man who presented with an acute decrease in kidney allograft function 3 months posttransplantation. At presentation, both cytomegalovirus and polyomavirus blood polymerase chain reaction results were positive. Biopsy showed predominant glomerular endothelial involvement by cytomegalovirus with positive immunohistochemistry results. Polyomavirus was not detected in the biopsy specimen. He was treated with oral valganciclovir and a decrease in immunosuppression. He had a complete response, with clearance of viremia and return of allograft function to baseline. Recent reports of glomerular involvement may reflect changing practices in antiviral chemoprophylaxis and immunosuppressive regimen. Oral valganciclovir may have a role in the treatment of patients with mild viremia with tissue-invasive kidney disease.

Topics: Administration, Oral; Biopsy, Needle; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Ganciclovir; Glomerulonephritis; Graft Survival; Humans; Immunohistochemistry; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Risk Assessment; Severity of Illness Index; Tissue Donors; Transplantation, Homologous; Valganciclovir