Litiasis medicamentosa en pacientes Vih+ eb tratamietno con Indinavir / Urinary lithiasis secondary to medication in HIV+patients receiving Indinavir

Objetivo: Los antirretrovirales inhibidores de la proteasa (IP) son fármacos utilizados en el tratamiento de pacientes afectos por el virus de la inmunodeficiencia humana (VIH). Un 20% de la dosis administrada se excreta por el riñón, que en presencia de orina alcalina puede precipitar formando cristales del propio fármaco susceptibles de provocar crisis renoureterales. Métodos: Entre enero del 1998 y junio de 2005 hemos atendido en nuestro centro a 26 pacientes con síntomas de urolitiasis y bajo el tratamiento con antirretrovirales IP. Todos ellos fueron sometidos a exploración física minuciosa, ecografía renoureteral y vesical, urografía intravenosa. Así mismo, se realizó análisis de sangre y anormales y sedimento de orina. Los pacientes fueron tratados ambulatoriamente, salvo aquellos en los que la analgesia con AINEs no fue suficiente para el control del cuadro álgico. Resultados: Todos los pacientes llevaban más de 12 meses de tratamiento con Indinavir. Los 26 pacientes con síntomas de nefrolitiasis representaban un 4% de los sujetos tratados con la dosis recomendada de Crivixan®. La mayoría presentaron dolor en fosa renal casi siempre asociado a microhematuria. De ellos, cinco pacientes requirieron ingreso en nuestra unidad por clínica no controlable de forma ambulatoria. Las pruebas diagnósticas (ecografía y/o UIV) revelaron retraso funcional del riñón (2 casos), ectasia de vía (8 casos) y pequeñas concreciones litiásicas de escasa o nula densidad cálcica (5 casos). El análisis urinario mostró cristaluria sugestiva y un pH alcalino. Todos requirieron tratamiento analgésico e hidratación. En tres casos se redujo la dosis de indinavir, en otro se retiró la medicación y en otro se añadieron 100 mgr de ritonavir. En un caso se intento cateterismo ureteral infructuosamente. La evolución fue satisfactoria en todos ellos. Conclusiones: Es preciso conocer la posibilidad de litiasis medicamentosa en pacientes HIV tratados con IP, si bien, afortunadamente, cada vez se emplean menos. La prevalencia de urolitiasis en los VIH + parece más elevada en función del tiempo de tratamiento con indinavir. Se han observado alteraciones metabólicas en la orina de estos pacientes que contribuyen a una mayor incidencia de litiasis que en la población general (AU)

Objectives: Therapy with protease inhibitors is commonly used in patients infected by human inmunodeficency virus (HIV). 20% of the administered dose is excreted by the kidney, and when alkaline urine is present , indinavir may crystallize forming stones and patients may experience renal colic due to this fact. Methods: Between January 1998 and June 2005, 26 patients receiving antiretroviral treatment with protease inhibitors received care at our hospital because of renal colic or flank pain. All of them underwent physical examination, echography and urography as well as blood and urine analysis. Patients were treated ambulatory excepting those in whom oral analgesics were insufficient to control the pain. Results: All patients had been treated with indinavir for longer than 12 months. They represented 4% of all patients treated with the recommended dose of Crivixan ®. Most of them presented flank pain, associated in most cases to microhaematuria. Five of them required hospitalization because of persistent pain in spite of endovenous analgesia. Imaging tests (echography and urography) showed functional delay of the kidney (2 cases), ureteral stasis (4 cases) and little lithiasic concretions of mild radiologic density (5 cases). Urinalysis revealed suggestive christaluria and alkaline pH. All patients required hidratation and analgesic treatment. In 3 patients indinavir dose was reduced, it was retired in another one, and 100mg of rito-navir were added in another one. Unsuccesfuly ureteral cateterization was tried in one patient. All of them presen-ted symptomatic improvement. Conclusions: We ought to know the capability of indinavir to form urolithiasis in HIV patients treated with protease inhibitors, although its use is decreasing along time. Prevalence of urolithiasis in these patients seems to be higher as length of treatment becomes longer. Metabolic alterations in urine have been proved in these patients, contributing to a higher incidence of lithiasis than in general population (AU)

[Indinavir-associated tubulointerstitial renal disease]. / Néphropathie tubulo-interstitielle associée à l'indinavir.

Indinavir, used for the treatment of HIV disease, forms distinctive crystals in the urine. The crystalluria has been associated principally with several urinary tract abnormalities which may require discontinuation of the drug. We present a case of progressive leucocyturia and renal impairment occurring during indinavir treatment which illustrates vividly the impact of the crystalluria on the tubulointerstitial renal compartment.

Low urine pH is associated with reduced indinavir crystalluria in indinavir-treated HIV-infected individuals.

Indinavir is a potent HIV-1 protease inhibitor included in current antiretroviral therapeutic regimens. It is associated with renal and urological complications ascribed to indinavir crystalluria. We have previously reported that indinavir crystalluria is frequently observed soon after initiation of therapy. In a cohort of 54 asymptomatic indinavir-naive HIV-1-infected individuals during their first year of treatment with indinavir, approximately 25% of urinalyses (U/A) contained indinavir crystals. Because the determinants of the crystalluria are unknown, we examined the relationship between urine specific gravity (SG) and pH, singly and in combination, and indinavir crystalluria in these subjects. A total of 579 U/A were obtained from the study subjects at their scheduled monthly outpatient medical assessments. The frequency of indinavir crystalluria was lower in U/A with lower pH, irrespective of the SG. Conversely, U/A with high pH (> or = 6.0) had a higher frequency of indinavir crystalluria, which was further influenced by the urine SG. As a result, nearly half of the U/A (46.7%) with high pH (> or = 6.0) and intermediate-high SG (> or = 1.015) contained indinavir crystals. In conclusion, the frequency of indinavir crystalluria in asymptomatic HIV-1 infected individuals during their first year of treatment with indinavir was markedly influenced by the urine pH and SG. Our findings suggest that low urine pH may have a protective effect against indinavir crystalluria across the entire range of urine SG.

Effects of escin on indinavir crystallization time in the urine of patients with HIV-I infection: a multicenter, randomized, open-label, controlled, four-period crossover trial.

BACKGROUND: The combination of indinavir, a protease inhibitor, and reverse-transcriptase inhibitors is widely used in the treatment of HIV-1 infection. However, precipitation of indinavir crystals in the renal tubular lumen due to the drug's aqueous insolubility may result in characteristic symptoms of flank pain or classic renal colic. An in vitro study has shown that addition of escin to synthetic urine containing indinavir delayed the crystallization time of indinavir. OBJECTIVE: This study examined the efficacy and tolerability of the addition of escin to highly active antiretroviral therapy containing indinavir to delay the crystallization time of indinavir in urine. METHODS: This was a multicenter, randomized, open-label, controlled, 4-period crossover trial in which each period lasted 4 weeks. HIV-1-infected adults receiving treatment with indinavir plus 2 nucleoside analogue reverse-transcriptase inhibitors in whom plasma viral loads had been undetectable (HIV-1 RNA <200 copies/mL) for at least 6 months were randomly assigned to 1 of 2 groups based on the timing of the initiation of escin. Group I received escin during the second and third treatment periods, and group II received escin during the first and fourth treatment periods. The primary end point was the in vitro crystallization time of indinavir in 24-hour urine specimens, determined at the end of each 4-week period. Tolerability was assessed based on the number of patients with a rebound in plasma viral load and on the numbers of clinically and biologically relevant adverse events (including those requiring discontinuation of treatment). Clinical and laboratory evaluations were performed throughout each 4-week period. RESULTS: Fifty HIV-1-infected patients were enrolled, 47 were randomized to treatment (40 [85.1%] men, 7 [14.9%] women; median [interquartile range] age, 36 [34-45] years), and 30 completed the study. Urine pH and plasma and urine indinavir concentrations were unaffected by the addition of escin to antiretroviral treatment. The mean time to the onset of crystallization was 14.7 minutes with escin (95% Cl, 11.8-17.5) and 9.9 minutes without it (95% Cl, 6.7-13.1). Therefore, the addition of escin increased the mean crystallization time by 5.5 minutes (95% Cl, 1.5-9.5; P = 0.008), representing the overall capacity of study treatment to inhibit indinavir crystallization in the urine. Three of 47 patients had mild gastrointestinal symptoms associated with escin treatment. No episodes of nephrolithiasis were recorded during the study or after the completion of study treatment. CONCLUSION: The results of this prospective clinical trial of the effect of escin on indinavir crystallization time support the possibility that indinavir-associated nephrolithiasis may be prevented by means other than overhydration. Further research is needed in greater numbers of patients over longer follow-up times.

Rapid and simple determination of indinavir in serum, urine, and cerebrospinal fluid using high-performance liquid chromatography.

A method for analysis of indinavir in serum, cerebrospinal fluid, and urine was developed. The method is based on liquid-liquid extraction followed by high performance liquid chromatography with UV detection. The method has a shorter analysis time than previously published methods, and it is sensitive enough to measure levels in all three fluids under routine clinical conditions. The method is linear up to 32 micromol/L, the limit of detection is 0.01 micromol/L, and recovery of the method is 86%. The interassay coefficient of variation at 2.0 micromol/L was 2.8%, and no internal standard is needed. Over 700 clinical samples have been analyzed by this method, and concomitant antiviral drugs do not interfere with the assay. Paroxetin and dipyridamol are the only two compounds encountered to elute with retention times similar to that of indinavir. Examples of chromatograms and a pharmacokinetic curve are given. The method is well suited for routine therapeutic drug monitoring as well as for pharmacokinetic studies for research purposes.

Prospective study of urinalysis abnormalities in HIV-positive individuals treated with indinavir.

Indinavir is a potent protease inhibitor widely used in combination with reverse-transcriptase inhibitors to treat human immunodeficiency virus (HIV) disease. Individuals treated with indinavir are prone to develop urinary complications, including renal colic, renal calculi, lower urinary tract symptoms, and indinavir crystalluria. Although renal stones secondary to indinavir have been described and characterized, little is known about the onset, frequency, and significance of the crystalluria. To document the longitudinal characteristics of indinavir crystalluria and associated urine abnormalities, 54 asymptomatic indinavir-naive HIV-positive individuals had urinalysis testing initially weekly and then monthly during the first year of indinavir treatment. Six hundred eight urinalyses were performed (11 +/- 2 urinalysis/subject), including 579 microscopy examinations performed by a nephrologist (10 +/- 2 examinations/subject). Baseline urinalysis results were essentially normal. After the start of treatment, indinavir crystalluria was frequently observed (67% of subjects). After the first 2 weeks, indinavir crystalluria remained constant at a frequency of approximately 25% of urine sediments examined at each test point. Other urine abnormalities, principally leukocytes (>/=10/high-power field) and casts, were observed in 39% of subjects. These abnormalities were more severe in five subjects, with concomitant increasing serum creatinine levels in three of them. Additional urine findings include the predominance of low pH (/=1.025 in 66% of urinalyses). In conclusion, abnormal urinalysis results were noted frequently during the first year of treatment with indinavir. The main findings were the high proportion of subjects with crystalluria and the relatively high frequency of crystalluria observed consistently throughout. These findings may occasionally be associated with other urine abnormalities, presumably secondary to indinavir crystalluria.

Detection of indinavir crystals in urine: dependence on method of analysis.

OBJECTIVES: To determine the frequency of crystalluria in patients treated with the human immunodeficiency virus protease inhibitor indinavir and to compare methods of detecting crystalluria. METHODS: A total of 308 freshly voided urine specimens from 168 patients treated with indinavir were evaluated by manual microscopy of sediment and microscopy with an automated workstation and by dipstick analysis. RESULTS: Crystals were detected in 22%, 31%, or 32% of specimens using, respectively, an automated workstation, manual microscopy, or both methods. Proteinuria or hemoglobinuria occurred significantly more often in specimens with (28%) than without (18%) crystals. Frequency of crystalluria was unrelated to specific gravity, but it increased at higher pH. Crystals were detected in 21% of specimens with pH less than 6 and 42% of specimens with pH of 6 or higher. CONCLUSIONS: Crystalluria occurs in more than 30% of urine specimens from patients treated with indinavir, but detection rates vary substantially with method of analysis. Manual microscopy detected crystalluria 41% more often than did an automated workstation.

Indinavir crystallization and urolithiasis.

The crystallization of indinavir in synthetic urine at different pH values and indinavir concentrations was kinetically studied. It was found that precipitation time notably decreases at urinary pH values above 6.0. The effects of some products as potential crystallization inhibitors were studied. Some natural saponins such as escin and glycyrrhizic acid provoked a notable increase in the precipitation time of indinavir, this pointing out their possible use to prevent renal tubular solid deposition.

Indinavir crystalluria: identification of patients at increased risk of developing nephrotoxicity.

OBJECTIVE: To determine whether the protease inhibitor indinavir sulfate, which is extremely insoluble at physiologic pH levels and which is known to be associated with nephrolithiasis, is associated with crystalluria at a usual therapeutic dose. METHODS: Freshly voided urine from 27 male human immunodeficiency virus patients being treated with indinavir at a dose of 800 mg, tid, in an outpatient setting and from 20 healthy subjects undergoing routine physical examination was subjected to dipstick urinalysis and microscopic examination of urinary sediments. RESULTS: Three (11%) of 27 patients treated with indinavir developed highly characteristic crystalluria during the course of therapy. No such crystals were observed in the urine of the 20 healthy subjects. CONCLUSION: Indinavir crystalluria was identified in asymptomatic patients treated with usual therapeutic doses of the drug. Screening urines of patients taking indinavir may be useful in identifying patients at risk for developing nephrotoxicity.

Effect of the sample matrix on the determination of indinavir in human urine by HPLC with turbo ion spray tandem mass spectrometric detection.

The HPLC/tandem mass spectrometric (LC/MS/MS) behavior of indinavir, an HIV protease inhibitor, in human urine is presented as an example of a case where endogenous matrix components were found to interfere with the ionization of the target analyte. The MS/MS system used for these experiments was equipped with a turbo ion spray LC interface. Results from two sample preparation procedures (direct dilution of urine vs urine extraction) and two chromatographic systems (low vs. high capacity factor (k')) for the analytes were compared. Additionally, the precision of the analysis that was achieved while using a stable isotope labeled internal standard is contrasted with the results obtained using an analog of indinavir as internal standard. The results obtained indicated that during development and validation of LC/MS/MS based assays the potential effect of co-eluting 'unseen' endogenous species should be evaluated to ensure that sample preparation and chromatography is adequate to overcome the matrix effect problems.

Disposition of indinavir, a potent HIV-1 protease inhibitor, after an oral dose in humans.

Indinavir, N-[2(R)-hydroxy-1(S)-indanyl]-5-[2(S)-tertiary- butylaminocarbonyl-4-(3-pyridylmethyl)piperazino]-4(S)- hydroxy-2(R)-phenylmethylpentanamide (L-735,524,MK-639, ayl-4- Crixivan), is a potent and specific inhibitor of the HIV-1(3 protease for the treatment of AIDS. Disposition of [14C]indinavir was investigated in six healthy subjects after single oral administration of 400 mg. AUC, Cmax, and Tmax values for indinavir were 492 microM x min, 4.7 microM, and 50 min, respectively. The AUC value for the total radioactivity in plasma was 1.9 times higher than that of indinavir, indicating the presence of metabolites. The major excretory route was through feces, and the minor through urine. Mean recovery of radioactivity in the feces was 83.4%. In the urine, mean recoveries of the total radioactivity and unchanged indinavir were 18.7% and 11.0% of the dose, respectively. HPLC radioactivity and LC-MS/MS analyses of urine showed the presence of indinavir and low levels of quaternary pyridine N-glucuronide (M1), 2',3'-trans-dihydroxyindanylpyridine N-oxide (M2), 2',3'-trans-dihydroxyindan (M3) and pyridine N-oxide (M4a) analogs, and despyridylmethyl analogs of M3 (M5) and indinavir (M6). M5 and M6 were the major metabolites in urine. The metabolic profile in plasma was similar to that in urine. Quantitatively, the metabolites in feces accounted for >47% of the dose, which along with the urinary excretion of approximately 19%, suggested that the absorption of the drug was appreciable. In the feces, radioactivity was predominantly due to M3, M5, M6, and the parent compound. Thus, in urine and feces, the prominent metabolic pathways were oxidations and oxidative N-dealkylations. Excretion of the quaternary N-glucuronide metabolite in the urine, which is a minor metabolite in human, was specific to primates.