On July 23, the World Health Organization declared the monkeypox outbreak a public health emergency of international concern [1]. In a case series including 528 individuals with confirmed monkeypox infection, 70 patients were hospitalized, mainly for pain control (proctitis, odynophagia, skin wounds, lymphadenopathy) or treatment of soft-tissue superimposed bacterial infections. Only 2 patients presented with acute kidney injury (AKI) [2]. Presumably, AKI etiology was dehydration and hypovolemia as a consequence of reduced oral intake (painful oral lesions, lethargy) or due to insensible fluid losses (fever and exudate from skin lesions). Accordingly, fluid status assessment and rapid fluid expansion to achieve euvolemia should be prioritized.

The monkeypox virus is a member of the orthopoxvirus genus, and some orthopoxviruses can replicate in a multitude of mammalian cultured cells, including kidney lineages such as pig embryo kidney, baby hamster kidney, human kidney, and rabbit kidney [3]. Thus, human kidney tropism is also possible. To date, no specific host-cell receptors to account for poxviruses’ binding and subsequent entry into cells have been identified. Importantly, even if a broad range of cell lineages could be infected, only a few would ultimately allow completion of the replication cycle [3].

Of the currently reported cases, only a handful of subjects received empirical antiviral treatment. This was mainly with cidofovir [2], a well-known nephrotoxic agent that induces apoptosis in proximal tubular cells, manifesting clinically as Fanconi syndrome and AKI. Almost 40% of the patients exposed to cidofovir developed proteinuria in a randomized clinical trial that included individuals infected with human immunodeficiency virus (HIV) and cytomegalovirus-associated retinitis [4]. A worthwhile remark is that the noxious effects of antivirals without proven efficacy against the monkeypox virus might outweigh theoretical benefits. We assume that only selected patients presenting severe presentations might be deemed potential candidates to receive antivirals because the disease has a predominantly self-limited course. The Centers for Disease Control and Prevention suggests treatment with tecovirimat, an envelope-wrapping protein inhibitor that is FDA-approved [5]. Compassionate use of oral tecovirimat was reported in 14 patients [6]. Intravenous tecovirimat use in patients with kidney function impairment is discouraged due to the likely accumulation and nephrotoxicity of the intravenous ingredient, hydroxypropyl-β-cyclodextrin [5].

The current outbreak has disproportionally affected men who have sex with men (MSM) community. In Brazil, the prevalence of HIV in MSM living in urban centers is 18% [7]. As of August 27, a total of 4,472 laboratory-confirmed monkeypox cases have been reported in Brazil. Our institution has recently hospitalized several MSM patients with monkeypox who were also coinfected with HIV. None developed AKI. The presence of HIV infection is of note since antiretroviral therapy (e.g., tenofovir disoproxil fumarate) can cause nephrotoxicity. In the above-mentioned cohort, 41% of the patients were coinfected with HIV, and, of those, 49% were receiving tenofovir as part of the antiretroviral regimen [2]. In patients with monkeypox who develop AKI, we suggest that tenofovir should be temporarily halted until the resolution of AKI or substituted by another agent without known nephrotoxicity.

For all hospitalized patients with suspected or confirmed monkeypox infection (Fig. 1), we suggest that the initial laboratory workup include a serum creatinine level, urine dipstick test, assessment of urinary albumin-to-creatinine ratio, and urinary protein-to-creatinine ratio. The presence of albuminuria, abnormal proteinuria, urinary albumin-to-protein ratio below 0.5, or normoglycemic glucosuria should prompt specific tests to detect proximal tubule dysfunction. These include urinary uric acid and urinary phosphate because both hypouricemia with hyperuricosuria and hypophosphatemia with hyperphosphaturia are indicative of proximal tubule deterioration. In some circumstances, urinary β2-microglobulin might also be informative (values above 0.30 mg/L are indicative of dysfunction) [8]. Tests to detect proximal tubule dysfunction may also be useful following the initiation of cidofovir, in patients previously receiving tenofovir, or in confirmed cases to assess the possibility of tubular dysfunction associated with direct viral damage.

Proposed management for monkeypox-associated AKI. AKI, acute kidney injury; BUN, blood urea nitrogen; HIV, human immunodeficiency virus; IGFBP7, insulin-like growth factor-binding protein; MSM, men that have sex with men; NGAL, neutrophil gelatinase-associated lipocalin; TIMP-2, tissue inhibitor of metalloproteinase-2.

The assessment of specific urinary biomarkers of tubular stress and injury such as tissue inhibitor of metalloproteinase-2 in conjunction with insulin-like growth factor-binding protein 7 or neutrophil gelatinase-associated lipocalin might enable the early detection of AKI in the absence of increments in serum creatinine or reduction in urine output [9]. Positive biomarker status can prompt the initiation of protective measures such as additional fluid expansion in dehydrated patients, avoidance of cidofovir, or early suspension of tenofovir, aiming to prevent further kidney damage. We suggest the measurement of these biomarkers in the same context applied to the traditional markers of proximal tubule impairment.

Furthermore, hemodialysis centers should delineate a contingency plan for maintenance hemodialysis patients infected with monkeypox. These patients should carry out their sessions in a single-person room, and if transported in common areas of the facility, they should have in place a medical mask, and skin lesions should be covered. Healthcare personnel who enter the patient’s room should wear a gown, gloves, eye protection, and an N95 respirator. Up until the skin lesions are fully healed, the isolation protocol should be kept in place [10].

Monkeypox cases have not been reported in solid organ transplant recipients to date. Therefore, a different disease course, peculiar symptoms, and worse outcomes in kidney transplant patients are only speculative. In retrospective cohorts, immunocompromised patients were more likely to present severe illness [11]. For immunocompromised patients, a replication-deficient live vaccine against Vaccinia virus is available. Nonetheless, its efficacy has not been studied in kidney transplant recipients [12]. Due to limited vaccine supply, only postexposure vaccination in lieu of pre-exposure vaccination is being carried out. Another possible adjuvant treatment is V. virus immunoglobulin, albeit not yet recommended [13]. Organs from deceased or live donors should not be retrieved if these potential donors had a reported monkeypox infection within the past 28 days. Furthermore, an inquiry to ascertain monkeypox exposure or confirmed infection should be added to the pre-donation questionnaire [14].

Herein, we attempted to draw a roadmap for the initial management of monkeypox infection, focusing on the early detection and mitigation of acute kidney insults. We also aim to increase awareness about the associated conditions that might increase the risk of AKI. Finally, we addressed the issues that maintenance dialysis patients and kidney transplant patients will face with the unfolding of the outbreak.

There are no funding sources to declare.

Thiago Reis has received funding for lectures and has been consultant or advisory board member for AstraZeneca, B. Braun, Baxter, bioMérieux, Contatti Medical (CytoSorbents), Eurofarma, Jafron, Lifepharma, and Nova Biomedical. Francisco de Assis Rocha Neves, Emily See, Rogério da Hora Passos, and Bruno Zawadski do not have any potential conflicts of interest; Antônio Fagundes, Jr has received honoraria from Boehringer Ingelheim and Merck Sharp & Dohme; Rinaldo Bellomo has received research grants or has been consultant for Baxter and CSL Behring; Claudio Ronco has received research grants, received funding for lectures, been consultant or advisory board member for Asahi, Astute, B. Braun, Baxter, bioMérieux, Bioporto, CytoSorbents, Estor, Fresenius Medical Care, General Electric (GE), Jafron, Medtronic, and Toray.

Thiago Reis: conceptualization, writing – original draft, and writing – review and editing. Francisco de Assis Rocha Neves, Antônio Fagundes, Jr, Emily See, Rogério da Hora Passos, and Bruno Zawadzki: writing – review and editing. Rinaldo Bellomo: writing – review and editing and supervision. Claudio Ronco: conceptualization, writing – review and editing, and supervision. All the authors were responsible for critical revision of the manuscript and approved the final version before submission.

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