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Nephrotoxicity due to crystalluria leading to haematuria and acute kidney injury, and lack of efficacy: 6 case reports

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    An event is serious (based on the ICH definition) when the patient outcome is:

    • * death

    • * life-threatening

    • * hospitalisation

    • * disability

    • * congenital anomaly

    • * other medically important event

    “ ”

    A case report of six patients described three women and three men, aged 35−73 years, who developed nephrotoxicity due to crystalluria leading to haematuria or acute kidney injury (AKI) during treatment with foscarnet for cytomegalovirus (CMV) infection, human herpesvirus 6 encephalitis or Herpes simplex virus 1 (HSV1) infection. Additionally, three of these patients exhibited lack of efficacy during treatment with ganciclovir, valganciclovir or letermovir for CMV infection [routes and dosages not stated not stated].

    Patient 1: The 71-year-old woman, who had acute myeloid leukaemia, underwent a nonmyeloablative allogeneic haematopoietic stem cell transplantation. She received conditioning regimen, total body irradiation and graft-versus-host disease (GvHD) prophylaxis. After transplantation, she exhibited multiple complications including a reactivation of cytomegalovirus disease. She was treated with ganciclovir without effect on the viral load of CMV (lack of efficacy). Therefore, based on in vitro documentation of resistance of CMV to ganciclovir, she started receiving foscarnet twice daily. After 14 days from the initiation of foscarnet, foscarnet (phosphonoformate) crystalluria (proven by infrared spectrometry) was observed, along with a nonglomerular haematuria and renal tubular epithelial cells in urine sediment. Progressive elevation of serum creatinine concentration indicated AKI stage 3 on day 25 from the initiation of foscarnet, despite adaptation of foscarnet doses to kidney function (reduced dose). Her foscarnet crystalluria decreased after dose reduction. She was considered to have foscarnet nephrotoxicity due to crystalluria leading to AKI. She died after probable fungal bronchopneumonia and septicaemia while receiving foscarnet.

    Patient 2: The 35-year-old man, who had acute lymphoblastic leukaemia, achieved a second complete remission after unspecified salvage chemotherapy following a first relapse. He underwent a stem cell transplantation. After transplantation, he exhibited multiple complications including a human herpesvirus 6 encephalitis. Therefore, he was treated with ganciclovir, which was replaced after 24 hours by foscarnet twice daily owing to concerns about known associated myelotoxicity with high doses of ganciclovir. After 7 days from the initiation of foscarnet, foscarnet (phosphonoformate) crystalluria (proven by infrared spectrometry) was observed, associated with a nonglomerular haematuria but without renal tubular epithelial cells in urine sediment. He was considered to have foscarnet nephrotoxicity due to crystalluria leading to haematuria. Given the stable kidney function, foscarnet was maintained at same dosage. Later, foscarnet crystalluria decreased. Despite the human herpesvirus 6 encephalitis resolution, he died from acute respiratory failure due to uncontrolled bleeding.

    Patient 3: The 59-year-old woman, who had acute myeloid leukaemia, underwent a successful allogeneic haematopoietic stem cell transplantation after a reduced-intensity conditioning regimen and GvHD prophylaxis. After transplantation, she exhibited multiple complications including a reactivation of CMV disease. She started receiving foscarnet twice daily. After 7 days from the initiation of foscarnet, foscarnet (phosphonoformate) crystalluria (proven by infrared spectrometry) was observed along with renal tubular epithelial cells in urine sediment. No haematuria was noted. After 24 days from the initiation of foscarnet, she developed AKI stage 1. She was considered to have foscarnet nephrotoxicity due to crystalluria leading to AKI. Foscarnet was stopped, which resulted in rapid reversibility of kidney impairment with decrease in foscarnet crystalluria.

    Patient 4: The 63-year-old man, who had alcohol-induced cirrhosis, underwent liver transplantation. He developed CMV infection. Therefore, he was treated with valganciclovir. However, CMV viral load increased further (lack of efficacy). Therefore, he was switched to foscarnet twice daily. After 27 days from the initiation of foscarnet, foscarnet (phosphonoformate) crystalluria (proven by infrared spectrometry) was observed along with glomerular haematuria, leukocyturia and renal tubular epithelial cells in urine sediment. After 47 days from the initiation of foscarnet, he developed AKI stage 1. He was considered to have foscarnet nephrotoxicity due to crystalluria leading to AKI. Meanwhile, CMV viral load decreased but remained present under bitherapy (foscarnet and ganciclovir followed by ganciclovir and letermovir). Elevated creatinine levels persisted despite discontinuation of foscarnet, but foscarnet crystalluria decreased.

    Patient 5: The 73-year-old man, who had myelodysplastic syndrome, underwent haematopoietic stem cell transplantation. He also received GvHD prophylaxis. After transplantation, he exhibited multiple complications including oral herpes (HSV 1) infection. Because of proven in vitro valaciclovir resistance, foscarnet twice daily was started. After 11 days from the initiation of foscarnet, foscarnet (phosphonoformate) crystalluria was observed. Neither red blood cells nor any other cells were seen in the urine sediment. On day 12 of foscarnet initiation, he developed AKI stage 2. He was considered to have foscarnet nephrotoxicity due to crystalluria leading to AKI. Meanwhile, the viral infection was effectively treated. Foscarnet was stopped, which resulted in rapid reversibility of kidney impairment with decrease in foscarnet crystalluria. However, he died 2 months later, from an invasive fungal infection.

    Patient 6: The 70-year-old woman had high-grade myelodysplastic syndrome. After achieving remission with unspecified systemic chemotherapy, she underwent a haploidentical stem cell transplantation. She also received GvHD prophylaxis. Despite anti-CMV prophylaxis with letermovir, her CMV viral load increased from month 3 (lack of efficacy). Therefore, a preemptive treatment with valganciclovir was introduced. Due to a further increase in the CMV viral load despite valganciclovir treatment (lack of efficacy), foscarnet twice daily was subsequently started. On day 9 of foscarnet initiation, foscarnet (phosphonoformate) crystalluria (proven by infrared spectrometry) was observed along with a nonglomerular haematuria and renal tubular epithelial cells in urine sediment. At day 14 from the initiation of foscarnet, she developed AKI stage 1. She was considered to have foscarnet nephrotoxicity due to crystalluria leading to AKI. Foscarnet was stopped, which resulted in rapid reversibility of kidney impairment with decrease in foscarnet crystalluria.

    Reference

    1. Deffert C, et al. Phosphonoformate Crystalluria, A Warning Signal of Foscarnet-Induced Kidney Injury. Kidney International Reports 5: 2102-2108, No. 11, Nov 2020. Available from: URL: http://doi.org/10.1016/j.ekir.2020.08.019

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    Antivirals. Reactions Weekly 1838, 74 (2021). https://doi.org/10.1007/s40278-021-89393-0

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