Retrospective Evaluation of Cystatin C as a Measure of Renal Function in Pediatric Hematopoietic Stem Cell Transplant Patients Receiving Foscarnet for Cytomegalovirus Reactivation.

BACKGROUND: Cytomegalovirus (CMV) infection following allogeneic hematopoietic cell transplantation has considerable morbidity and mortality, and foscarnet is a treatment option that requires renal dose adjustment. Serum creatinine (SCr)-based estimated glomerular filtration rate (eGFR) equations are used to estimate renal function for patients receiving foscarnet, but cystatin C (cysC) has been shown as a possible alternative. Data examining cysC-based eGFR in this population is sparse. Our primary objective was to evaluate outcomes of patients treated with foscarnet dosed utilizing cysC-based eGFR versus SCr-based eGFR. METHODS: We analyzed patients on the transplantation and cellular therapies service at Memorial Sloan Kettering Kids from January 2011 to September 2021 who received allogeneic hematopoietic cell transplantation and ≥14 days of foscarnet for CMV infection. Patients with cysC-based eGFR were compared to a historical cohort of patients who only had SCr-based eGFR. Outcomes included time to CMV clearance, death or change in anti-CMV therapy. Cumulative incidence curves and cause-specific hazards model were used for analysis. RESULTS: In 61 analyzed patients, no differences were found between the cohorts in cumulative incidence of change in anti-CMV therapy ( P = 0.17) or death ( P = 0.69). After adjustment for multiple confounders, patients in the SCr cohort seemed to have a higher chance of CMV clearance compared with the cysC cohort, but the difference was not statistically significant (hazard ratio = 2.42, P = 0.089). Patients who received corticosteroids appeared to have lower incidence of CMV clearance ( P = 0.056). CONCLUSIONS: We did not find differences in outcomes when dosing foscarnet using cysC versus SCr for treatment of CMV infection.

Foscarnet-Induced Penile Ulceration.

This case report describes an uncircumcised male individual with tender perimeatal erythema and ulceration extending to the right glans.

Long-term use of foscarnet is associated with an increased incidence of acute kidney injury in hematopoietic stem cell transplant patients: A retrospective observational study.

BACKGROUND: Foscarnet is an important drug for the treatment of cytomegalovirus infection in patients undergoing hematopoietic stem cell transplantation (HSCT). Foscarnet is often discontinued because of the development of acute kidney injury (AKI). Thus, the identification of factors leading to the development of AKI is beneficial. This study aimed to investigate the incidence of AKI and the factors influencing AKI development in HSCT patients treated with foscarnet. METHODS: This was a retrospective observational study. Patients who underwent HSCT and received foscarnet at the Department of Hematology, Osaka City University Hospital, were identified from medical records. The patients were classified into AKI and non-AKI groups, and the risk factors associated with AKI were evaluated. For continuous variables, receiver-operating characteristic (ROC) curve analysis was used to calculate the optimal cutoff value. RESULTS: Thirty-five patients (47 cases) were assigned to the AKI (51.1%, 24/47) and non-AKI groups (48.9%, 23/47). The AKI group had a significantly longer foscarnet administration period than the non-AKI group (p = 0.049). The appropriate cutoff value for the foscarnet administration period using the ROC curve was 27 days. The incidence of AKI was significantly higher in cases who received foscarnet for more than 27 days (11/14, 78.6%) compared to those who received less than 27 days (13/33, 39.4%) (odds ratio: 5.64, 95% confidence interval 1.32-24.2, p = 0.024). CONCLUSION: The incidence of AKI was 51.1% in HSCT patients treated with foscarnet, and foscarnet administration for more than 27 days may be associated with the incidence of AKI.

Phosphate Overload Stimulates Inflammatory Reaction via PiT-1 and Induces Vascular Calcification in Uremia.

OBJECTIVE: Vascular calcification (VC) is an important risk factor for cardiovascular disease in maintenance hemodialysis (MHD) patients. Hyperphosphatemia and microinflammation statement are known major contributors to the development of VC; however, the mechanisms are unknown. The aims of this study were to explore the risk factors of VC in MHD patients and to explore whether high phosphate could increase the secretion of inflammatory cytokines via PiT-1 in monocytes. METHODS: A cross-sectional study was conducted on 65 MHD patients to assess the relevance of coronary artery calcification (CAC), inflammatory factors, serum phosphate, and sodium-dependent phosphate cotransporter (NPT) mRNA expression of peripheral blood mononuclear cells (PBMCs). Multivariate logistic regression analysis was used to analyze the predictors of CAC. The calcification effects of high phosphate (HP), TNF-α, and supernatants of healthy human monocytes treated with HP were further evaluated in cultured HASMCs. RESULTS: Diabetes, longer dialysis vintage, higher serum TNF-α levels, and PiT-1 mRNA expression of PBMCs) were independent risk factors of CAC in MHD patients. The mRNA levels of PiT-1 in PBMCs were positively correlated with serum phosphate, CAC scores, and Pit-2 mRNA levels of PBMCs. The expressions of TNF-α, IL-6, and PiT-1 in human monocytes were significantly increased in a dose-dependent manner after treatment with HP, which was subsequently inhibited by NPT antagonist phosphonoformic acid. Neither TNF-α alone nor supernatants of monocytes stimulated with HP promoted the expression of osteopontin and Runt-related transcription factor 2 (Runx2) or caused mineralization in human aortic smooth muscle cells, but combined with HP intervention, the calcification effects were markedly increased in human aortic smooth muscle cells and ameliorated by phosphonoformic acid treatment. CONCLUSION: Hyperphosphatemia directly increased the synthesis and secretion of TNF-α by monocytes may via PiT-1 pathway, resulting in elevated systemic inflammatory response, which may further aggravate VC induced by phosphate overload in MHD patients.

Glomerular and tubulointerstitial foscarnet nephropathy of kidney allograft with emphasis on ultrastructural findings: A case report.

INTRODUCTION: Foscarnet (trisodium phosphonoformate hexahydrate) is standard treatment for ganciclovir-resistant cytomegalovirus (CMV) infections. In the kidney, foscarnet-induced injury may be attributed to reversible tubulointerstitial lesions, but foscarnet crystals have also been observed within glomerular capillaries, suggesting that foscarnet can lead to glomerular lesions such as crescentic glomerulonephritis. We present biopsy and autopsy findings of foscarnet induced nephropathy in a transplanted kidney, with a particular emphasis on the histopathology and electron micrographic peculiarities of drug crystal deposits. CASE PRESENTATION: A 72-year-old Caucasian male patient with a deceased donor kidney was treated with several foscarnet applications due to ganciclovir-resistant CMV infection. Transplant kidney biopsy revealed massive glomerular crystalline precipitates, resulting in crescentic glomerulonephritis and tubular damage. The last foscarnet application was complicated with several infections and kidney graft failure. Autopsy revealed multi-organ damage due to foscarnet crystal precipitations associated with systemic CMV and fungal infection. On autopsy of kidney specimens, we succeeded in preserving the rectangular flat plate-like foscarnet crystals in stacks detected by transmission electron microscopy (TEM) after 100% alcohol fixation. The chemical composition of the crystals was confirmed by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. CONCLUSION: Transplant kidney biopsy remains the gold standard in distinguishing between foscarnet crystalline glomerular and/or tubulointerstitial lesions, and various forms of rejection and other causes of impaired renal function in transplant kidney.

Relationship between renal dysfunction and electrolyte abnormalities in hematopoietic stem cell transplant patients treated with foscarnet.

This study aimed to investigate the relationship between renal dysfunction and electrolyte abnormalities, which are adverse events of foscarnet used for cytomegalovirus infection. Of the Ninety hematopoietic stem cell transplantation patients, 32 who met the selection criteria were enrolled in this retrospective study. The study patients were divided into two groups according to whether they developed renal dysfunction. The incidences of hypocalcemia, hypokalemia, and hypomagnesemia with an increase of grade 2 or higher in the renal dysfunction group were 45.5%, 18.2%, and 27.3%, respectively. Additionally, in the renal dysfunction group, a significant correlation was observed between creatinine and calcium (r = -0.458, p = 0.0244) and between creatinine and potassium (r = -0.520, p = 0.0092). This study shows that renal dysfunction and electrolyte abnormalities may be closely related in HSCT patients receiving foscarnet; thus, it is a report that may contribute to the safety of continuous foscarnet treatment.

Continuous-Infusion Foscarnet Facilitates Administration in Hematopoietic Stem Cell Transplantation Patients.

Infections due to herpesviruses resistant to first-line antivirals remains an ever-present and serious complication in recipients of hematopoietic cell transplantation (HCT) and other cellular therapies. Foscarnet is the most common therapy for patients who have resistant herpesvirus infections or intolerable cytopenias due to ganciclovir or valganciclovir; however, the widespread use of foscarnet is limited by its associated nephrotoxicity and challenges in administration. In the earliest published small case series investigating the optimal infusion modality, patients with acquired immunodeficiency syndrome (AIDS) due to the human immunodeficiency virus (HIV) received either continuous infusion or intermittent dosing of foscarnet. Moreover, there was no standardization of hydration strategies to minimize side effects. Eventually, intermittent foscarnet infusions became the standard of care; however, the true impact of hydration and infusion duration on nephrotoxicity has not been adequately studied, and the reports of foscarnet administration in HCT patients has been limited primarily to intermittent infusions. In this report, we characterize the administration of foscarnet as a 24-hour continuous infusion in both the inpatient and outpatient settings compared with intermittent infusion in HCT recipients. This retrospective, single-center, observational study at Stanford University Medical Center assessed HCT recipients who received foscarnet between January 2009 and May 2019. Twenty-eight of 45 patients (62.2%) who received continuous-infusion foscarnet experienced an acute kidney injury (AKI) as defined by the Kidney Disease Improving Global Outcomes classification, compared with 39 of 62 patients (62.9%) who received conventional infusion (P = .94). The average duration of outpatient antiviral days for the continuous infusion group was 9 days (range, 0 to 121 days), compared with 6.3 days (range, 0 to 70 days) in the intermittent infusion group (P = .54). Our findings suggest that foscarnet given as a continuous infusion or as an intermittent infusion have similar rates of adverse reactions, most notably similar rates of AKI. Administering foscarnet as a continuous infusion is a feasible option to facilitate outpatient treatment.

Recommended foscarnet dose is not associated with improved outcomes in cytomegalovirus salvage therapy.

BACKGROUND: Cytomegalovirus (CMV) infection causes significant morbidity and mortality in transplant recipients. Ganciclovir and valganciclovir have proven efficacy but are limited by resistance and toxicity, whereas foscarnet typically retains activity when CMV has become resistant to other antivirals. Foscarnet dosing used in practice may be discordant with what is recommended in product labeling, as the result of an unconventional dosing nomogram or prescriber preference; however, it is unknown how discordant foscarnet dosing affects outcomes. OBJECTIVE: Our purpose was to characterize the relationship between initial foscarnet dosing intensity (relative to product labeling) and key effectiveness and safety endpoints. STUDY DESIGN: This single-center, retrospective study included immunosuppressed adults with CMV viremia who received foscarnet between January 2012-July 2017. Subjects were divided into low dose (LD) and non-low dose (NLD) groups, according to foscarnet dose intensity. The primary endpoint was time-to-CMV eradication. Secondary endpoints included time-to-CMV clearance, acute kidney injury, hematologic toxicity, and mortality. RESULTS: Of 87 subjects, 38 met inclusion. Primary immunosuppression reasons were solid organ (63%) or hematopoietic cell transplant (29%). Seventeen and 21 subjects were in the LD and NLD groups, respectively. Median time-to-CMV eradication was 17 days (LD group) versus 13 days (NLD group), p = 0.823. Median time-to-CMV clearance was also non-significant (p = 0.505). There was no association between initial foscarnet dosing intensity and acute kidney injury, hematologic toxicity, or mortality (24% in both groups). CONCLUSIONS: These findings suggest outcomes may be sensitive to other factors and underscore the need for further studies to improve understanding of foscarnet dosing in immunosuppressed patients.

Presentación atípica de infección por virus de herpes simple tipo II (VHS II) refractaria a tratamiento con aciclovir en 2 pacientes hematológicos / Atypical Presentation of Herpes Simplex Virus Type 2 Infection Refractory to Treatment With Aciclovir in 2 Hematologic Patients

Las infecciones por virus herpes presentan una frecuencia no desdeñable en pacientes hematológicos. El primer caso corresponde a una paciente con leucemia linfática crónica con un herpes genital extenso refractario a aciclovir, con respuesta parcial a foscarnet que hubo que suspender por efectos secundarios sistémicos. El segundo caso es el de una paciente con un linfoma de Hodgkin folicular que presentaba un herpes hipertrófico refractario a tratamiento con aciclovir, que respondió a cidofovir intralesional e imiquimod tópico. Los pacientes hematológicos, al igual que otros enfermos inmunodeprimidos, pueden presentar manifestaciones atípicas de infección por virus herpes, así como resistencia a los tratamientos que actúan por medio de la timidina quinasa viral. Esto hace necesario tener una alta sospecha clínica para poder alcanzar un diagnóstico precoz, y conocer los diferentes tratamientos alternativos disponibles

Herpesvirus infections are not uncommon in hematologic patients. Our first patient, diagnosed with chronic lymphatic leukemia, presented extensive genital herpes infection refractory to treatment with aciclovir and with a partial response to foscarnet, which had to be withdrawn due to systemic adverse effects. The second patient, diagnosed with follicular Hodgkin lymphoma, presented hypertrophic herpes infection refractory to treatment with aciclovir but that responded to intralesional cidofovir and topical imiquimod. As in other immunocompromised patients, herpesvirus infection in hematologic patients can present atypical manifestations, as well as resistance to treatments that are activated by the viral thymidine kinase. A high level of clinical suspicion is therefore needed to make an early diagnosis, together with extensive knowledge of the different treatments available

Brincidofovir treatment of acyclovir-resistant disseminated varicella zoster virus infection in an immunocompromised host.

Brincidofovir (BCV) is a broad-spectrum antiviral agent active in vitro against double-stranded DNA viruses including herpesviruses, adenoviruses, polyomaviruses, and poxviruses. We report successful BCV use in management of disseminated acyclovir- and cidofovir-resistant varicella zoster virus in an immunocompromised hematopoietic stem cell transplant patient with chronic graft-versus-host disease who was intolerant to foscarnet.

Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection.

BACKGROUND: Antiviral-resistant or refractory cytomegalovirus (CMV) infection is challenging, and salvage therapies, foscarnet, and cidofovir, have significant toxicities. Several investigational anti-CMV agents are under development, but more information is needed on outcomes of current treatments to facilitate clinical trial design for new drugs. METHODS: Records of solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients at a single center over a 10-year period were reviewed retrospectively to characterize those who had received foscarnet treatment for ganciclovir-resistant or refractory CMV infection. Data were collected on virologic responses, mortality, and nephrotoxicity. RESULTS: Of 39 patients (22 SOT, 17 HCT), 15 had documented ganciclovir resistance mutations and 11 (28%) of 39 had tissue-invasive CMV. Median duration of foscarnet was 32 days. Virologic failure occurred in 13 (33%) of 39 and relapses of viremia occurred in 31%. Mortality was 12 (31%) of 39 and was higher in HCT than SOT (P = 0.001), although ganciclovir resistance was more common in SOT (P = 0.003). Doses of ganciclovir or valganciclovir were low in 10 (26%) of 39 at some time before switching to foscarnet. Renal dysfunction occurred in 20 (51%) of 39 by end of treatment and in 7 (28%) of 25 after 6 months. CONCLUSIONS: Outcomes of existing treatment for ganciclovir-resistant or refractory CMV are suboptimal, in terms of virologic clearance, renal dysfunction, and mortality. These data should provide background information for future clinical trials of newer antiviral agents.

Successful treatment with foscarnet for ganciclovir-resistant cytomegalovirus infection in a kidney transplant recipient: A case report.

Cytomegalovirus (CMV) infection is the most common infectious complication following solid organ transplantation. Ganciclovir (GCV)-resistant CMV infection may be fatal, and is difficult to treat while avoiding allograft rejection. A 31-year-old woman received a second ABO-incompatible kidney transplant, from her father. Induction therapy consisted of basiliximab and rituximab followed by maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and methylprednisolone. Her CMV serostatus was D(+) /R(-) at second transplant and she received prophylactic low-dose valganciclovir (VGCV). BK polyoma virus nephropathy (BKVN) developed 7 months after transplant concurrent with CMV hepatitis and retinitis. VGCV was increased to a therapeutic dose combined with reduced immunosuppression with minimal methylprednisolone (2 mg/day) and everolimus (0.5 mg/day). However, pp65 antigenaemia continued to increase for 6 weeks. Her CMV was defined as ganciclovir (GCV)-resistant. Foscarnet was therefore administered and her CMV disease resolved within 2 weeks. Kidney allograft dysfunction developed 9 months after transplant, and graft biopsy showed tubulointerstitial injury with crystal deposition suggesting foscarnet nephrotoxicity, with no findings of BKVN or rejection. Kidney function recovered after cessation of foscarnet and the patient had good graft function 18 months after transplant. This case demonstrates the successful use of foscarnet to treat GCV-resistant CMV infection after ABO-incompatible kidney transplant complicated with BKVN, without acute allograft rejection. This case further highlights the need to establish appropriate management for CMV D(+) /R(-) patients to avoid the acquisition of GCV-resistant gene mutations.

Foscarnet, zidovudine and dolutegravir combination efficacy and tolerability for late stage HIV salvage therapy: A case-series experience.

Salvage therapy including foscarnet (PFA), zidovudine (ZDV) and an optimized background ART (OBT) has been shown to be effective in patients with advanced HIV infection, and no therapeutic options. Dolutegravir (DTG) may offer a more active combination. Objective was to describe efficacy and tolerability of PFA-ZDV-DTG containing regimen. In our cohort, we identified patients who: (i) had plasma HIV-1 RNA load (pVL) >50 c/ml (>100 for HIV-2) on combination ART (cART); (ii) had at least 1 PI/r, 1 NRTI, 1 NNRTI (for HIV-1), and at least 1 raltegravir resistance mutations; (iii) were naive to DTG; and (iv) initiated on a PFA-ZDV-DTG containing-regimen with 48 weeks (W48) of follow-up. Out of 5 patients, 2 were infected with HIV-2. At PFA-ZDV-DTG initiation, CD4 cell count was (/mm(3) ) of 64, 40, 10, in HIV-1, and 37, 199, in HIV-2 infected patients; and pVL (log10 c/ml) of 4.8, 5.1, 4.4, in HIV-1, and 3.6, 4.2, in HIV-2 infected patients, respectively. Median OBT genotypic sensitivity score was 1.5 [1-2]. PFA was discontinued in one patient, due to an acute renal failure. At W48, one HIV-1 infected patient had a pVL <50 c/ml and two <200 c/ml; the two HIV-2 infected patients had pVL >100 c/ml. No lack of treatment adherence was observed. In treatment experienced HIV-infected patients, failing cART and without other therapeutic options, a PFA-ZDV-DTG combination therapy could be effective. Renal adverse events should be monitored.

A systematic review of acute kidney injury in pediatric allogeneic hematopoietic stem cell recipients.

The process of allogeneic HSCT in children is associated with frequent AKI and mortality, but the epidemiology is not widely reported. The aim of this review was to summarize the available evidence on incidence, risk factors, timing, and prognosis of AKI in children following HSCT. We systematically reviewed all observational studies reporting incidence and outcomes of AKI in pediatric allogenic HSCT recipients. The minimum criteria for AKI were defined as an increase in sCr ≥ x1.5 or urine output ≤0.5 mL/kg/min over six h. Medline and Embase were searched until March 2014. From 993 electronic records, five were eligible for inclusion (n = 571 patients). The average incidence of AKI within the first 100 days following HSCT was 21.7% (range 11-42%), and the average time of onset was 4-6 wk post-transplant. Risk factors for AKI included cyclosporine toxicity, amphotericin B and foscarnet, SOS, and having a mismatched donor. There were conflicting reports on whether AKI was associated with the development of CKD. AKI is a common and potentially life-threatening complication following HSCT in children. Further quality observational studies are needed to accurately determine the epidemiology and prognosis of AKI in this population.

Intravascular foscarnet crystal precipitation causing multiorgan failure.

We report a case of multiorgan failure resulting from treatment with the antiviral foscarnet in a kidney transplant recipient. Precipitation of foscarnet crystals was confirmed histologically from a biopsy of the transplant using optical and infrared microscopy. In addition to kidney damage resulting from foscarnet crystal precipitation in the tubular lumen and glomerular capillaries, the patient presented with pancreatitis, pancolitis, and myocarditis with shock. Interruption of the treatment led to rapid improvement in her general condition, but did not prevent permanent loss of the kidney transplant. When faced with unexplained multiorgan failure in a patient treated with foscarnet, one should assume this substance to be toxic. A kidney biopsy can confirm this diagnosis.

Foscarnet in the management of cytomegalovirus infections in hematopoietic stem cell transplant patients.

Despite significant advances in the day-to-day management of patients receiving hematopoietic stem cell transplantations, including the introduction of new antiviral drugs, cytomegalovirus (CMV) infection continues to be a major cause of morbidity and mortality. The aim of this article is to undertake a literature-based review of foscarnet in this therapeutic setting and to align current best-published evidence with recent recommendations presented at the European Conference on Infections in Leukaemia. Ganciclovir remains the mainstay of CMV infection/disease antiviral management protocols. However, approximately a third of patients develop severe neutropenia and others become resistant to ganciclovir, and thus, a reasonably large proportion of patients are not able to receive and/or continue with this medication. Foscarnet is a suitable option as both pre-emptive therapy or for the treatment of active disease in these patients. Randomized trials have demonstrated that foscarnet is equally effective when compared with ganciclovir for pre-emptive treatment of CMV infections: the outcome was comparable with ganciclovir in terms of control of antigenemia and survival rates. There is a paucity of information for its use in the prophylaxis of CMV, although preliminary data show that it was effective in some patients at high risk of CMV reactivation. The main adverse events associated with foscarnet are renal impairment, serum electrolyte and hemoglobin disturbances, seizures and local genital irritation/ulceration. Foscarnet is a well-established antiviral option in immunocompromised patients, and it is usually administered as a second-line option to ganciclovir. In patients receiving hematopoietic stem cell transplantation, it has proven efficacy when used pre-emptively to treat CMV reactivation, as an alternative to and also in combination with ganciclovir.

Crystal precipitation and granulomatous inflammation in multiple organs after foscarnet therapy in a lung transplant recipient.

We present the case of a lung transplant recipient with disseminated crystal precipitation, and granulomatous and fibrinous inflammation after therapy with foscarnet (Foscavir; AstraZeneca, Zug, Switzerland) for recurring ganciclovir-resistant cytomegalovirus (CMV) reactivation. This is the first description of systemic crystal precipitation and granulomatous inflammation associated with foscarnet therapy with predominant involvement of the heart, kidneys and lungs.