Fatal Long-term Immunosuppressive Therapy With Uncontrolled Repeat Prescription

Abstract

A case of nephrotic syndrome treated with associated cyclophosphamide and corticosteroids came to our attention after over 2 years of self-administered immunosuppressive therapy which remained unchanged and uncontrolled during this period. The self-administered therapy resulted in a severe cell-mediated immunodeficiency (as expressed by a nadir CD4 lymphocyte count of 2 cells/muL). This led to a rapid unfavorable progression of hepatitis B, which was recently acquired and subsequently evolved into a severe cholestatic and fibrosing chronic hepatitis, causing multiple end-organ failure, and ultimately, death. This process was not reversed by lamivudine therapy, hemodialysis, and the use of a Molecular Adsorbent Recirculating System. The role played by repeated drug prescriptions from general practitioners without appropriate clinical and laboratory controls, and that of our patient's depression are discussed. Current literature related to the presented case and the ongoing debate regarding repeated prescriptions are considered in this study.

Kidney failure during HIV disease treated with tenofovir, multiple concurrent diseases and drug therapies

“…chronic hepatitis B, D, and especially C) [90][91][92], but also an increasing prevalence of sexually-transmitted diseases including syphilis [24,[99][100][101] (as in our case), and even hepatitis A [102]. As expected, the extremely different medications prescribed (or self-prescribed, or taken in a not appropriate, even "heterodox" mode by HIV-infected patients themselves) [28,83,[96][97][98]103] have their intrinsic toxicities but they also have potential, varied drug-drug interactions among an almost endless list of drugs potentially used (or useful, or needed, or taken as "recreational" ones) by individuals living with HIV, even more in the years 2010-2011, when the life expectancy of HIV-infected individuals is approaching that of the general population (Table I) [5,8,18,27,36,42,67].…”

“…However, from a strictly clinical and management point of view, the specific identification of the source and the pathological picture are not required to physician in charge of such a medical emergency, given that non-specific supportive (although intensive) monitoring and treatment are always indicated, as a matter of urgency. In the reported patient of ours, the initial discontinuing of tenofovir was appropriate not only because of potential role of this drug in causing a (rare) acute-onset kidney failure (similar to Fanconi's disease in its clinical features), but also because of the drug's prolonged half-life, which is expected during a potentially severe renal insufficiency [10,18,43,62,63,76,79,83]. In addition, it seemed essential to discontinue immediately the anti-hypertensive ACE-inhibitor drug [128], the loop diuretic furosemide, obviously the NSAIDs [10,18,19,43,60,76,93], and maybe metformin too [129,130], which may be associated with severe lactacidemia, regardless of its intrinsic renal safety profile [130].…”

“…Tenofovir is a first-choice nucleoside reverse transcriptase inhibitor for the treatment of HIV infection in the large majority of current therapeutic lines, because of its intrinsic antiviral potency, its safety profile, its convenient once-daily dosage (also as fixed combination with emtricitabine, and even more as a triple fixed association including the first-choice non-nucleoside reverse transcriptase inhibitor efavirenz), and its elevated potency against HBV infection too, which is a frequent comorbidity just relevant for patients living with HIV infection [10,43,76,[80][81][82]. The "intrinsic" tenofovir-associated nephrotoxicity has been extensively and quite well studied [10,18,43,47,62,[74][75][76]79,83,84]. Like other nucleos(t)ide analogues, tenofovir requires intracellular phosphorilation to become pharmacologically active, and at the cell level several different drug carriers may act on the intracellular concentration and disposition of all these drugs [74].…”

“…As expected, the administration of cART is known to reverse the natural history of HIVAN, but the kidney benefits of cART may not be limited to HIVAN only. Unfortunately, we are aware that cART is often underprescribed or incorrectly dosed or taken non only in developing countries, just where HIVAN is more frequent [63,95], but also in industrialized countries [96,97], even more in persons with chronic kidney disorders, with or without a concurrent HIV disease [10,18,19,83,95,98]. As anticipated, the direct effects of HIV infection on the kidney sum up with a varied genetic background and an extremely broad spectrum of immune-mediated factors, physiological conditions like pregnancy [75], and especially underlying comorbidities, immune recovery due to cART itself [10,21,22,63], and especially overwhelming (also non-HIV associated) diseases, the frequent chronic co-infections (i.e.…”

“…The potential causes of a sudden, acute tubular necrosis in our case patient might include an extremely wide spectrum of conditions. After excluding the most common post-renal cause (the obvious bladder outlet obstruction), a pre-renal cause has to be seeked: a cART regimen including tenofovir should be the apparent "major" target for a proportional narrow knowledge of a HIV/AIDS or a clinical infectious disease specialist, also due the well known "intrinsic" kidney toxicity of tenofovir [10,18,37,43,62,76,79,83,85], but… since "Internal Medicine" must be the founding ground of the entire Medicine, we have to consider carefully and promptly all the multiple concomitant conditions and medications, and we have also to look immediately for any possible kind of jatrogenic damage. Actually, a proportionally mild (but critical) volume depletion resulting in a proportional hypotension but without a repeated heart ischemic injury (excluded at first clinical exa- mination and ECG examination, as well as after serum troponin and heart enzymes testing), although relevant heart failure remnants were present and well documented in our case, as shown by an already severe, but stable left ventricle heart damage, and an initial right ventricle impairment, was detected at the last heart ultrasonography.…”