Increased Prevalence and Analysis of Risk Factors for Indinavir Nephrolithiasis

Saltel, Eric; Angel, Jonathan B.; Futter, Norman G.; WALSH, W. G.; O’Rourke, Keith; Mahoney, John E.

doi:10.1016/s0022-5347(05)66911-x

Cited by 51 publications

(20 citation statements)

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“…Indinavir has also been reported to induce urolithiasis in humans; however, none of the mice treated with Indinavir had any signs suggestive of kidney stones (12,23). We also measured plasma liver enzymes as an index of hepatotoxicity.…”

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Inhibition of bilirubin metabolism induces moderate hyperbilirubinemia and attenuates ANG II-dependent hypertension in mice

Vera

Granger²,

Stec³

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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-Population studies indicate that moderate hyperbilirubinemia is associated with reduced incidence of cardiovascular diseases, including hypertension. Despite this correlative evidence, no studies have directly tested the hypothesis that moderate increases in plasma bilirubin levels can attenuate the development of hypertension. This hypothesis was tested by treating mice with Indinavir, a drug that competes with bilirubin for metabolism by UDP-glucuronosyltransferase 1A1 (UGT1A1). Treatment of mice with Indinavir (500 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , gavage) resulted in a twofold increase in plasma unconjugated bilirubin levels. Next, we determined the effect of Indinavir-induced changes in plasma bilirubin on the development of ANG II-dependent hypertension. Moderate hyperbilirubinemia was induced 3 days before the implantation of an osmotic minipump that delivered ANG II at a rate of 1 g ⅐ kg Ϫ1 ⅐ min Ϫ1 . ANG II infusion increased mean arterial pressure (MAP) by 20 mmHg in control mice but by only 6 mmHg in mice treated with Indinavir (n ϭ 6). Similar to Indinavir treatment, direct infusion of bilirubin (37.2 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 iv) resulted in a twofold increase in plasma bilirubin levels and also attenuated the development of ANG II-dependent hypertension. Moderate hyperbilirubinemia resulted in an increase in plasma nitrate/nitrite levels, which averaged 36 Ϯ 2 vs. 50 Ϯ 7 M in ANG II vehicle vs. Indinavir-treated mice (n ϭ 5). Moderate hyperbilirubinemia resulted in attenuation of vascular oxidative stress as determined by dihydroethidium staining of aortic segments. These results indicate that moderate hyperbilirubinemia prevents ANG IIdependent hypertension by a mechanism that may involve decreases in vascular oxidative stress. bilirubin; angiotensin II hypertension; uridine 5Ј-triphosphate-glucuronosyltransferase 1A1, heme oxygenase BILIRUBIN IS ONE of the by-products of heme catabolism by heme oxygenase (HO). Bilirubin is initially produced as biliverdin, which is rapidly converted by biliverdin reductase (BVR). HO and BVR are ubiquitous enzymes that render all mammalian cell types capable of producing bilirubin; however, the majority of circulating bilirubin is derived from the breakdown of hemoglobin by the reticuloendothelial system. The resultant bilirubin circulates bound to albumin to the liver where its entry into hepatocytes is mediated by the organic anion transporting polypeptide 2 (OATP2). Once in the hepatocyte, bilirubin is glucoronidated by UDP-glucuronyltransferase 1A1 (UGT1A1) and subsequently eliminated in the bile ducts through the multidrug resistance protein 2. The conjugated bilirubin is excreted via the common bile duct in the intestines as one of the components of bile salts.Recent population studies have revealed that elevated plasma bilirubin levels are associated with reduced incidence of cardiovascular diseases, including hypertension, coronary artery disease, atherosclerosis, and preeclampsia (5,6,17,19). More recent data from a study of Framingham offspring revealed that individuals ...

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confidence: 99%

Inhibition of bilirubin metabolism induces moderate hyperbilirubinemia and attenuates ANG II-dependent hypertension in mice

Vera

Granger²,

Stec³

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Así, una elevada excreción del fármaco y/o de sus metabolitos, una baja solubilidad del mismo, cambios en el volumen de orina, en el pH, así como la duración del tratamiento, puede jugar un papel fundamental en el incremento de saturación del fármaco en la orina o pueden producir un descenso de los factores locales que inhiben la formación de cálculos. Otros factores de riesgo pueden estar implicados en el desarrollo de cálculos renales, como un fracaso renal, enfermedades hepáticas y/o gastrointestinales, así como historia familiar de litiasis 10,14 .…”

Section: Discussionunclassified

“…Salter y cols. 10 mostraron que el indinavir es un fármaco litogénico que causa cál-culos en un 3% de los enfermos tratados, mientras que Kopp y cols. 3 encontraron que un 8% de los enfermos tratados con este fármaco desarrollaron síntomas urológicos y un 3% padecieron nefrolitiasis.…”

Section: Discussionunclassified

“…La causa de este hecho es debido a que el 20% del indinavir administrado al paciente es aclarado por el riñón 6-9 . Entre los sín-tomas producidos por el indinavir hay que destacar la cristaluria 3,9 y la formación de cálculos renales 2,3,7,[9][10][11] , hechos originados por la poca solubilidad del indinavir en soluciones acuosas. Por eso, el principal factor de riesgo tiene lugar por una ingesta baja en líquidos 6 .…”

Section: Introductionunclassified

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Litiasis renal inducida por indinavir

Villameytide

Fernández-Guerrero

2004

Actas Urológicas Españolas

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RESUMENLITIASIS RENAL INDUCIDA POR INDINAVIR El indinavir es un nuevo, específico y potente fármaco que actúa, como otros agentes anti-retrovirales, inhibiendo la proteasa del virus de la inmunodeficiencia humana (VIH-1) o de la inmunodeficiencia adquirida (SIDA). El indinavir se une al centro activo del enzima, originando un descenso en plasma de ARN VIH-1 y un aumento de los linfocitos T-CD4 "helper" dando origen a un descenso del enzima, necesaria para la maduración y replicación del VIH-1.El presente trabajo estudia la cristaluria de dos de los nueve pacientes que padecían VIH-1 y/o SIDA tratados con indinavir, así como el cálculo formado por uno de los dos pacientes que presentaban cristaluria.El estudio se realizó con microscopio de luz polarizada y por espectrofotometría infrarroja, mostrando que la visualización de la cristaluria con microscopio de luz polarizada es útil para la caracterización de las mismas, así como para el estudio de los cálculos renales es útil el análisis por espectrofotometría infrarroja.PALABRAS CLAVE: Indinavir. VIH-1. SIDA. Cristaluria. Cálculo renal. ABSTRACTINDINAVIR AND RENAL LITHIASIS Indinavir is a new specific and potent drug that inhibits, like other antiretroviral agents, the protease of immune deficiency virus (HIV) or acquired immune deficiency syndrome (AIDS), an enzyme necessary to maduration and replication of the virus. Indinavir has the capacity to bind the active site causing a decrease in plasma of HIV1-RNA and an increase of T-CD 4 helper lymphocytes. The aim of this work is to study in HIV and/or AIDS patients treated with indinavir the crystalluria and the formation of renal calculi due to the clearance of this drug. Two out of nine patients studied in this work presented abundant crystalluria and one of them presented spontaneously passed renal stone.Urinary crystals were studied under polarized-light microscopy and renal stone was analyzed by infrared spectroscopy. L a nefrolitiasis es una complicación frecuente y bien conocida asociada al tratamiento con indinavir y otros anti-retrovirales en la patología del virus de la inmunodeficiencia humana (VIH-1), así como en el síndrome de inmunodeficiencia adquirida (SIDA) 1-5 . La causa de este hecho es debido a que el 20% del indinavir administrado al paciente es aclarado por el riñón 6-9 . Entre los sín-tomas producidos por el indinavir hay que destacar la cristaluria 3,9 y la formación de cálculos renales 2,3,7,[9][10][11] , hechos originados por la poca solubilidad del indinavir en soluciones acuosas. Por eso, el principal factor de riesgo tiene lugar por una ingesta baja en líquidos 6 . El sulfato de

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“…8 The incidence of indinavir-associated nephrolithiasis in adults varies from 4% to 43%. 2,9 Renal complications (including nephrolithiasis) from indinavir are found in 0% to 80% 10 -15 and nephrolithiasis in 0% to 20% 10,[12][13][14][15] of children who have been treated with this drug.…”

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Persistent Sterile Leukocyturia Is Associated With Impaired Renal Function in Human Immunodeficiency Virus Type 1-Infected Children Treated With Indinavir

Rossum¹,

Dieleman

Fraaij³

et al. 2002

Pediatrics

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ABSTRACT. Background. Prolonged administration of indinavir is associated with the occurrence of a variety of renal complications in adults. These well-documented side effects have restricted the use of this potent protease inhibitor in children.Design. A prospective study to monitor indinavir-related nephrotoxicity in a cohort of 30 human immunodeficiency virus type 1-infected children treated with indinavir.Methods. Urinary pH, albumin, creatinine, the presence of erythrocytes, leukocytes, bacteria and crystals, and culture were analyzed every 3 months for 96 weeks. Serum creatinine levels were routinely determined at the same time points. Steady-state pharmacokinetics of indinavir were done at week 4 after the initiation of indinavir.Results. The cumulative incidence of persistent sterile leukocyturia (>75 cells/L in at least 2 consecutive visits) after 96 weeks was 53%. Persistent sterile leukocyturia was frequently associated with a mild increase in the urine albumin/creatinine ratio and by microscopic hematuria. The cumulative incidence of serum creatinine levels >50% above normal was 33% after 96 weeks. Children with persistent sterile leukocyturia more frequently had serum creatinine levels of 50% above normal than those children without persistent sterile leukocyturia. In children younger than 5.6 years, persistent sterile leukocyturia was significantly more frequent than in older children. A higher cumulative incidence of persistent leukocyturia was found in children with an area under the curve >19 mg/L*h or a peak serum level of indinavir >12 mg/L. In 4 children, indinavir was discontinued because of nephrotoxicity. Subsequently, the serum creatinine levels decreased, the urine albumin/creatinine ratios returned to zero, and the leukocyturia disappeared within 3 months.Conclusions. Children treated with indinavir have a high cumulative incidence of persistent sterile leukocyturia. Children with persistent sterile leukocyturia more frequently had an increase in serum creatinine levels of >50% above normal. Younger children have an additional risk for renal complications. The impairment of the renal function in these children occurred in the absence of clinical symptoms of nephrolithiasis. Indinavirassociated nephrotoxicity must be monitored closely, especially in children with risk factors such as persistent sterile leukocyturia, age <5.6 years, an area under the curve of indinavir >19 mg/L*h, and a C max >12 mg/L. Pediatrics 2002;110(2). URL: http://www.pediatrics.org/ cgi/content/full/110/2/e19; human immunodeficiency virus, children, indinavir, nephrotoxicity.ABBREVIATIONS. HIV, human immunodeficiency virus; AUC, area under plasma-concentration curve; IQR, interquartile range. I ndinavir is a potent human immunodeficiency virus (HIV)-protease inhibitor that has been used successfully in adults in combination with nucleoside reverse transcriptase inhibitors to suppress infections by HIV-1. Discontinuation of the antiretroviral therapy rapidly results in virologic rebound, decreased immune function, ...

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Increased Prevalence and Analysis of Risk Factors for Indinavir Nephrolithiasis

Abstract: The clinical prevalence of indinavir nephrolithiasis is much greater than initially reported. Nephrolithiasis during indinavir use does not appear to induce patients to withdraw from the drug.

Cited by 51 publications

References 5 publications

Inhibition of bilirubin metabolism induces moderate hyperbilirubinemia and attenuates ANG II-dependent hypertension in mice

Inhibition of bilirubin metabolism induces moderate hyperbilirubinemia and attenuates ANG II-dependent hypertension in mice

Litiasis renal inducida por indinavir

Persistent Sterile Leukocyturia Is Associated With Impaired Renal Function in Human Immunodeficiency Virus Type 1-Infected Children Treated With Indinavir

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