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Abstract

Background

The prevalence of bipolar disorder in HIV-infected patients is higher than the general population. Lithium is the most effective mood stabiliser, while tenofovir disoproxil fumarate (TDF) is frequently used as part of combination antiretroviral therapy (ART). Both TDF and lithium are associated with renal tubular toxicity, which could be additive, or a pharmacokinetic interaction may occur at renal transporters with a decrease in TDF elimination.

Objective

We report on the change in estimated glomerular filtration rate (eGFR) using the modification of diet in renal disease formula in participants who received ART including TDF and were enrolled in a 24 week randomised trial of lithium versus placebo in patients with HIV-associated neurocognitive impairment.

Methods

We included HIV-infected adults with cognitive impairment established on ART for at least 6 months with a suppressed viral load attending public sector ART clinics in Cape Town, South Africa. We excluded participants with an eGFR <60 mL/min and treated with medications predisposing to lithium toxicity. We reviewed participants weekly for the first month for adverse events followed by 4 weekly visits for renal function assessment, adverse event monitoring and adherence. Lithium dose was titrated to achieve the maintenance target plasma concentration of between 0.6 and 1.0 mmol/L. Sham lithium concentrations were generated for participants receiving placebo.

Results

We included 23 participants allocated to the lithium arm and 30 participants allocated to the placebo arm. Baseline characteristics were not statistically different with a mean age of 37.7 and 40.8 years, a median time on ART of 33 and 40 months and an eGFR of 139.3 and 131.0 mL/min in the lithium and placebo arms respectively. There was no statistical significant difference in the reduction in eGFR or increase in potassium between the two arms during the 24 weeks.

Conclusions

We found that 24-week treatment of HIV-infected patients with lithium and TDF did not result in increased nephrotoxicity.

Trial registration The study was registered on the Pan African Clinical Trials Registry (PACTR) with the identifier number PACTR201310000635418. Registered 11 October 2013 before the first participant was enrolled

Keywords: South Africa, Randomised placebo-controlled clinical trial, HIV-associated neurocognitive impairment, HIV, Lithium, Placebo, Antiretroviral therapy, Tenofovir

Background

The prevalence of bipolar disorder in human immunodeficiency virus (HIV)-infected patients is 4-5 times higher than the general population [ 1, 2]. The most effective mood stabiliser is lithium while the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF) is frequently used as part of combination antiretroviral therapy (ART) [ 3]. Both TDF and lithium are associated with renal tubular toxicity, which could be additive [ 4, 5]. Furthermore, a TDF-lithium pharmacokinetic interaction may occur at renal transporters. TDF is eliminated via proximal tubular secretion and renal toxicity is thought to be related to accumulation of intracellular tenofovir in the proximal tubular cell [ 6]. Intracellular TDF inhibits mitochondrial deoxyribonucleic acid (DNA) polymerase gamma with DNA depletion and oxidative respiratory chain dysfunction [ 7]. Mitochondrial dysfunction impairs tubular reabsorption of ions and molecules causing a Fanconi-like syndrome, or may lead to cell apoptosis and acute tubular necrosis [ 7]. TDF is a substrate of a number of transporters at the proximal renal tubule. The organic anion transporter-1 (OATP-1) transports TDF intracellularly while the multi-drug resistance protein 4 (MRP-4) mediates active secretion from the tubular cell [ 8]. In rats lithium impairs OATP-1 function, which may protect against TDF renal toxicity [ 9]. Twenty to eighty seven percent of lithium treated patients develop a reduction in urinary concentrating ability within weeks after starting treatment [ 10]. Lithium-induced nephrogenic diabetes insipidus (NDI) is thought to be caused by downregulation of intracellular calcium signalling with inhibition of glycogen synthase kinase-3-beta (GSK-3-ß), resulting in a number of downstream effects including decreased aquaporin-2 expression [ 11]. Recently it was shown that MRP-1 expression is regulated by GSK-3-β, suggesting that lithium may decrease MRP expression and predispose to TDF renal toxicity [ 12]. The proximal tubule as a common site for TDF and lithium renal toxicity may further contribute to renal toxicity. Lithium-induced renal toxicity may involve any segment of the nephron or kidney although the distal tubule seems to be involved in NDI [ 13]. There is currently no published data on the renal safety of concomitant TDF and lithium.

We previously published the results of a 24 week randomised placebo-controlled trial to study lithium as an adjunctive pharmacotherapy in patients with moderate to severe HIV-associated neurocognitive impairment [ 14]. In this study we report changes in the estimated glomerular filtration rate (eGFR) using the modification of diet in renal disease (MDRD) formula as well as changes in potassium in participants who received ART including TDF who were randomised to lithium or placebo.

Methods

Our methodology has been previously published, but in brief we included HIV-infected adults (≥18 and ≤70 years), established on ART for at least 6 months with a suppressed viral load (HIV RNA <400 copies/mL) with cognitive impairment attending public sector ART clinics in Cape Town, South Africa [ 14]. We dosed lithium carbonate 250 mg tablets (Camcolit ®, manufactured by Norgine) and matching placebo (manufactured by Norgine). We excluded participants who used medications that may predispose to lithium toxicity (diuretics, angiotensin converting enzyme inhibitors or angiotensin receptor blockers and non-steroidal anti-inflammatory medicines), participants with an eGFR of less than 60 mL/min and dehydrated participants with diarrhoea. We reviewed participants weekly for first month followed by 4 weekly visits for adverse events and adherence. After screening and study drug initiation, we repeated renal function (sodium, potassium, urea and creatinine) at weeks 4, 8, 12, 16, 20 and 24. Some participants switched treatment to TDF during the study period, and for this analysis we only included patients who received TDF for the full 24 weeks. Lithium dose was titrated assuming linear pharmacokinetics to achieve the maintenance target plasma concentration of lithium in patients with bipolar mood disorder of between 0.6 and 1.0 mmol/L. Sham lithium concentrations were generated for participants receiving placebo by the study statistician who was unblinded to treatment allocation. After each visit an investigator not directly responsible for participant follow-ups received a log with the participant number, blinded lithium concentration from the study statistician (real or sham), current study drug dose and any adverse events noted by other investigators. Based on the information the investigator recommended lithium and sham dose adjustments for implementation.

Results

We included 53 participants in this analysis with 23 participants allocated to the lithium arm and 30 participants allocated to the placebo arm. Baseline characteristics between the 2 arms were similar and are described in Table 1 . Adherence in both treatment arms were similar and reported previously [ 14]. The proportion of patients with lithium concentrations in the therapeutic range are presented in Fig. 1 . Three participants allocated to the lithium arm developed symptoms of NDI (polyuria) which resolved on dose reduction (p = 0.042 compared to placebo arm). No participant allocated to the placebo arm developed symptoms of NDI. Change in eGFR, creatinine and potassium were similar between the 2 arms (see Figs. 2 , ​,3, 3 , ​,4). 4 ). There was no statistical significant difference between the two arms in the proportion of participants who had a reduction in eGFR (see Table 2 ). There was no statistically significant difference in the eGFR slope between the 2 treatment arms (see Fig. 2 a) (p value = 0.06) when using linear regression.

Table 1

Baseline characteristic

Lithium (n = 23)

Placebo (n = 30)

p value

Gender

Male

n = 1 (4%)

n = 4 (13%)

0.374 e

Female

n = 22 (96%)

n = 26 (87%)

Renal function

Table 2

eGFR MDRD changed

Treatment arm

Week 4 % (n)

Week 8 % (n)

Week 12 % (n)

Week 16 % (n)

Week 20 % (n)

Week 24 % (n)

Increased

Lithium

30.4% (7/23)

39.1% (9/23)

39.1% (9/23)

34.8% (8/23)

39.1% (9/23)

56.5% (13/23)

p = 574 b

Creatinine not measured c

Lithium

0%

0%

0%

4.3% (1/23)

0%

0%

p = 0.197 b

p = 0.574 b

p = 0.687 b

Discussion

We reported the renal safety of lithium co-administered with TDF as part of a 24 week randomised placebo-controlled trial. To the best of our knowledge we described the first safety data of co-administered lithium with TDF. We found that lithium and TDF co-administration did not increase the risk of renal impairment in HIV-infected patients with neurocognitive impairment and preserved renal function over a 24-week period.

NDI is a well-recognised early side effect of lithium administration. Lithium causes dysregulation of the aquaporin-2 water channels in the collecting ducts with impaired pro-urine concentration ability [ 13, 15]. Three patients in the lithium arm developed NDI which resolved with a lithium dose reduction. Lithium-induced nephrotoxicity has been long recognised, but the extent and risk factors required to frame a risk-benefit profile for patients has been much debated [ 16]. A recent population-based study in psychiatric patients with lithium exposure found that monthly eGFR decline was similar in the lithium and reference group after adjusting for co-morbidities, concomitant medication and episodes of lithium toxicity [ 17]. Our findings in a young cohort with no lithium toxicity episodes and limited treatment duration echo these findings.

Our study has several limitations. First, we reported on the safety of lithium dosed with TDF in a randomised placebo-controlled trial that was not powered for this endpoint. Second, we followed patients for 24 weeks and we can only make inferences about the short-term safety of concomitant lithium and TDF administration. Third, we may have missed more subtle markers of tubulopathy as we did not measure urine markers of tubulopathy. Fourth, only approximately half of participants had therapeutic lithium trough concentrations. We collected lithium trough concentrations as soon as participants arrived at the study site and despite best efforts, sample collection time for some participants was beyond 12 h. Last, we excluded patients with renal impairment and concomitant medication which may potentiate lithium toxicity.

We could not rule out nephrotoxicity of long-term concomitant treatment of TDF and lithium and future research should focus on the long-term follow-up of TDF-treated HIV-infected patients with lithium-treated bipolar disorder.

Conclusions

We found that 24-week treatment of HIV-infected patients with lithium and TDF, preserved renal function and no episodes of lithium toxicity did not result in increased nephrotoxicity. To the best of our knowledge we described the first safety data of co-administered lithium with TDF. Our finding supports the renal safety of TDF-based ART in HIV-infected patients with bipolar disorder requiring lithium therapy as a mood stabiliser.

Authors' contributions

ED: study concept and design, analysis and interpretation of data, drafting and revising the manuscript for content, acquisition of data, study supervision and obtaining funding. ML: analysis and interpretation of data, statistical analysis. GM: study concept and design, revising the manuscript for content and obtaining funding. JJ: study concept and design, revising the manuscript for content, study supervision and obtaining funding. ML: statistical analysis. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The study was registered on the Pan African Clinical Trials Registry (PACTR) with the identifier number PACTR201310000635418. Registered 11 October 2013 before the first participant was enrolled.

The study was approved by the human research ethics committees of the University of Cape Town (071/2013) and Stellenbosch University (M13/07/027). All participant signed informed consent prior to participation in the study.

Funding

Norgine Pty (Ltd) unconditionally donated lithium carbonate and identical placebo. Norgine Pty (Ltd) had no input in any aspect of the study.

This study was funded by the European and Developing Countries Clinical Trials Partnership (EDCTP Grant Number SP.2011.41304.065).

Abbreviations

ART

antiretroviral therapy

DNA

deoxyribonucleic acid

eGFR

estimated glomerular filtration rate

GSK-3-β

glycogen synthase kinase-3-beta

HIV

human immunodeficiency virus

MDRD

modification of diet in renal disease

MRP-4

multi-drug resistance protein 4

NDI

nephrogenic diabetes insipidus

OATP-1

organic anion transporter-1

TDF

tenofovir disoproxil fumarate

Contributor Information

Eric H. Decloedt, Email: az.ca.nus@tdeolcedcire.

Maia Lesosky, Email: az.ca.tcu@yksosel.aiam.

Gary Maartens, Email: az.ca.tcu@snetraam.yrag.

John A. Joska, Email: az.ca.tcu@aksoj.nhoj.

References

11. Rej S, Pira S, Marshe V, et al. Molecular mechanisms in lithium-associated renal disease: a systematic review. Int Urol Nephrol. 2016 [[ PubMed] Google Scholar]

Articles from AIDS Research and Therapy are provided here courtesy of BMC

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Renal safety of lithium in HIV-infected patients established on tenofovir disoproxil fumarate containing antiretroviral therapy: analysis from a randomized placebo-controlled trial

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The prevalence of bipolar disorder in HIV-infected patients is higher than the general population. Lithium is the most effective mood stabiliser, while tenofovir disoproxil fumarate (TDF) is frequently used as part of combination antiretroviral therapy ...

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Presentación Diapositivas Biología Cuerpo Humano Vintage Marrón y Blanco

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Sr. Editor: Existe un interés creciente sobre la potencial toxicidad renal de tenofovir, inhibidor de la transcriptasa inversa análogo nucleótido. En los ensayos clínicos realizados con tenofovir no se ha observado mayor toxicidad comparado con placebo, pero tras su comercialización han aparecido casos graves de insuficiencia renal acompañadas de disfunción tubular similares al síndrome de Fanconi, con necrosis del túbulo proximal y que se suelen resolver tras la retirada del fármaco.

El empleo de tenofovir asociado a atazanavir ha sido poco evaluado en la práctica clínica. Los estudios farmacocinéticos realizados entre ambos fármacos indican que atazanavir origina un aumento del área bajo curva (AUC), Cmáx y Cmín de tenofovir, que son mayores en el caso de utilizar atazanavir potenciado con ritonavir. Este aumento en la concentración de tenofovir podría originar un aumento de nefrotoxicidad asociada a este fármaco.

A continuación se presentan dos casos de insuficiencia renal asociados al uso de tenofovir combinado con atazanavir.

Caso 1. Varón de 56 años, con antecedentes de enfermedad pulmonar obstructiva crónica (EPOC) y con volumen de aire espirado en el primer segundo (VEMS) del 57% en tratamiento con salbutamol 100 μg inhalado cada 8 h desde hace 2 años, obesidad con índice de masa corporal (IMC) de 32, dislipidemia en tratamiento dietético desde hace 2 años, hipertensión arterial en tratamiento con enalapril 5 mg/día oral desde hace 2 años e infección por ek VIH estadio B, diagnosticada 12 años antes. Según el resultado del genotipado se inició tratamiento con atazanavir 300 mg/día, con ritonavir 100 mg/día, tenofovir 300 mg/día y lamivudina 300 mg/día vía oral. La cifra de CD4 fue de 610 céls./ml y la carga viral de 2.700 copias/ml. En el momento basal la creatinina era de 0,96 mg/dl y el aclaramiento de creatinina de 85 ml/ min, y sin alteraciones en el urinoanálisis y sedimento urinario. A los 3 meses de iniciar el nuevo tratamiento antirretroviral la creatinina aumentó a 1,8 mg/dl y el aclaramiento disminuyó a 45 ml/min, pH 7,29 UpH, HCO3 18 mmol/l, BSE -6 mmol/l, ácido láctico 0,6 mmol/l (sangre venosa) y proteinuria/24 h de 377 mg/día. A pesar de la retirada de tenofovir, el aclaramiento se mantuvo en 45 ml/min durante 6 meses.

Caso 2. Varón de 48 años, con infección por el VIH estadio A diagnosticada 8 años antes. Hipertensión arterial desde hacía 15 meses en tratamiento con atenolol 100 mg/día oral. Se introdujo atazanavir 300 mg/día con ritonavir 100 mg/día junto a tenofovir 245 mg/día y emtricitabina 200 mg/día vía oral) para simplificar la pauta de inhibidores de proteasa previa (nelfinavir 1.250 mg/12 h, lamivudina 150 mg/12 h y zidovudina 250 mg/12 h vía oral). A nivel basal la creatinina era de 1,10 mg/ml y el aclaramiento de creatinina de 97,5 ml/min, junto a una cifra de CD4 de 520 céls./ml y una carga viral por debajo del límite de detección. A los 2 meses de tratamiento, la creatinina aumentó a 1,56 mg/ml y el aclaramiento disminuyó a 67 ml/min, sin observarse otras alteraciones analíticas de la función renal, que se normalizó tras la retirada de tenofovir en 4 semanas.

En ambos pacientes se excluyeron otras causas de insuficiencia renal aguda, y se realizó un estudio con ecografía renal, ANA, ácido antineutrófilo, complemento, prueba de la reagina plasmática rápida (RPR), antiestreptolisina, serología del virus de la hepatitis C y B (VHC, VHB), cistocinina (CK), calcio, ácido úrico, glucemia y proteinograma que no evidenciaron otra enfermedad subyacente. Además no existían situaciones médicas que condicionaran insuficiencia renal como la depleción de volumen o sepsis, ni se utilizaron fármacos de uso frecuente en la infección por el VIH con capacidad nefrotóxica (pentamidina, anfotericina B, sulfamidas, foscarnet, cidofovir, antiinflamatorios no esteroideos [AINE]). Por lo tanto, el hecho de no existir insuficiencia renal previa y su aparición precoz tras la introducción de tenofovir, relacionan al fármaco en la génesis de la insuficiencia renal.

Los fármacos son una causa frecuente de insuficiencia renal aguda en los pacientes con VIH. En el caso de tenofovir, se han descrito como factores de riesgo asociados al desarrollo de insuficiencia renal: recuento bajo de CD4, bajo peso, sexo femenino y uso de didanosina. El tenofovir se elimina por vía renal a través de la filtración glomerular y secreción tubular proximal. Un aumento de las concentraciones plasmáticas de tenofovir, por interacciones con otros fármacos, provocaría una acumulación de las concentraciones intracelulares en el epitelio tubular proximal hasta producir su necrosis.

En nuestro centro, sólo los dos casos descritos de 48 pacientes que recibieron tratamiento con atazanavir potenciado con ritonavir más tenofovir y otro nucleósido que no fuera didanosina, durante el período de marzo de 2005 hasta septiembre de 2006, presentaron deterioro de la función renal (prevalencia del 4,2%).

Otros factores también pueden facilitar el desarrollo de insuficiencia renal. De esta manera, los pacientes descritos presentaban hipertensión arterial, la cual produce un engrosamiento hialino de la arteriola aferente con la consiguiente disminución de la función glomerular y tubular, sobre el que se añadiría el efecto de tenofovir causando disminución de la función renal. Por otra parte, en el primer caso, no hubo recuperación de la función renal, a pesar de que la insuficiencia renal era de grado II (aumento de 1,6-3 de creatinina respecto al basal según las recomendaciones de la Organización Mundial de la Salud (OMS) para la clasificación de efectos tóxicos agudos). Este paciente era de mayor edad y dislipémico, situaciones que empeoran y aceleran la nefroangioesclerosis asociada a la hipertensión arterial.

La conclusión práctica de los casos comunicados es que antes de la prescripción de tenofovir se debe realizar un examen clínico-analítico que excluya cualquier situación potencial que condicione un deterioro de la función renal, especialmente en casos que reciban de forma concomitante atazanavir.

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Insuficiencia renal aguda asociada al uso de tenofovir combinado con atazanavir en pacientes con infección por el VIH

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Sr. Editor: Existe un interés creciente sobre la potencial toxicidad renal de tenofovir, inhibidor de la transcriptasa inversa

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Deterioro agudo de función renal por tenofovir | Nefrología

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Tenofovir es un inhibidor nucleótido de la transcriptasa inversa, de uso muy extendido como

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Resumen

La hormona antidiurética arginina vasopresina (AVP) es liberada de la hipófisis, y regula la reabsorción de agua en las células principales del túbulo colector renal. La unión de la AVP al receptor tipo 2 de la AVP en la membrana basolateral induce la translocación de los canales acuosos de la acuaporina-2 hacia la membrana apical de las células principales de los túbulos colectores, induciendo la permeabilidad al agua de la membrana. Lo anterior da como resultado la reabsorción de agua en el túbulo colector de la nefrona, bajo la influencia de un gradiente osmótico.

La diabetes insípida nefrogénica es causada por la resistencia parcial o total al efecto de la AVP. La diabetes insípida nefrogénica congénita es una alteración asociada con mutaciones en los genes AVPR2 o AQP2, ocasionando la incapacidad del paciente para concentrar la orina. La diabetes insípida nefrogénica adquirida o secundaria puede ser causada por desbalances electrolíticos (hipercalcemia, hipokalemia), enfermedades renales o extrarrenales y fármacos (toxicidad por litio).

En este artículo se revisan las causas, manifestaciones clínicas, diagnóstico y tratamiento de los pacientes con diabetes insípida nefrogénica. También, con base en la comprensión de los mecanismos íntimos de la alteración, se exploran nuevas estrategias terapéuticas.

Abstract

The anti-diuretic hormone arginine-vasopressin (AVP) is released from the pituitary and regulates water reabsorption in the principal cells of the kidney collecting duct. Binding of AVP to the arginine-vasopressin receptor type-2 in the basolateral membrane leads to translocation of aquaporin-2 water channels to the apical membrane of the principal cells of the collecting duct, inducing water permeability of the membrane. This results in water reabsorption in the collecting duct of the nephron following an osmotic gradient.

Nephrogenic diabetes insipidus is caused by partial or complete renal resistance to the effects of AVP. Congenital nephrogenic diabetes insipidus is a disorder associated with mutations in either the AVPR2 or AQP2 gene, causing the inability of patients to concentrate their urine. Acquired nephrogenic diabetes insipidus can be caused by electrolyte imbalances (e.g., hypercalcemia, hypokalemia), renal/extra-renal diseases and drugs (e.g., lithium toxicity).

This article reviews the causes, clinical manifestations, diagnosis and treatment of patients with nephrogenic diabetes insipidus. Based on more in-depth mechanistic understanding, new therapeutic strategies are current being explored.

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La hormona antidiurética arginina vasopresina (AVP) es liberada de la hipófisis, y regula la reabsorción de agua en las células principales del túbulo colector renal. La unión de la AVP al receptor tipo 2 de la AVP en la membrana basolateral induce la translocación de los canales acuosos de la acuaporina-2 hacia la membrana apical de las células principales de los túbulos colectores, induciendo la permeabilidad al agua de la membrana.