Imaging characteristics of indinavir calculi

PURPOSE: Indinavir sulfate is an effective protease inhibitor of the human immunodeficiency virus type 1. Use is associated with a significant incidence of crystallization and stone formation in the urinary tract, and these calculi are not visible on plain radiographs. Previously all urinary stones, including uric acid and matrix, were believed to be radiodense on computerized tomography (CT). We conducted a retrospective study to evaluate the radiographic appearance of indinavir calculi. MATERIALS AND METHODS: Retrospective chart review of 36 patients taking indinavir sulfate and presenting with renal colic was performed with attention to presentation, urinalysis, radiographic evaluation and management. Specifically, imaging characteristics on CT were addressed. RESULTS: All patients complained of ipsilateral flank pain and 35 had nausea and/or vomiting. Of 30 patients with dysuria or urgency the majority had hematuria, and most had pyuria and/or proteinuria. No stones were visualized on abdominal radiography. Diagnosis was confirmed on 1 of 13 excretory urograms and 4 of 11 renal ultrasounds. None of 12 CT scans was diagnostic of renal lithiasis. CONCLUSIONS: Indinavir sulfate is a protease inhibitor with poor solubility and significant urinary excretion. Crystallization and stone formation are demonstrated in as many as 20% of patients taking the medication. Most patients present with flank pain, nausea or vomiting and hematuria. Previously CT was thought to identify all urinary calculi with clarity but it cannot reliably confirm the presence of indinavir calculi.     

Urolithiasis associated with indinavir in a patient with spinal cord injury

OBJECTIVE: To report a case of indinavir-induced urolithiasis, and the greater risk of this occurrence in individuals with spinal cord injury (SCI) who require fluid restriction for an intermittent catheterization program (ICP). METHODS: Case report. RESULTS: A 38-year-old man with a T4 ASIA A SCI (according to the American Spinal Injury Association classification scale) and human immunodeficiency virus (HIV) infection was using an ICP and taking indinavir (a protease inhibitor) as part of his antiviral regimen. Cystoscopy was performed to rule out recurrent urethral condylomata. He was found to have a bladder stone measuring 0.5 cm x 0.5 cm x 0.3 cm, which, on analysis, was composed of indinavir (100% exterior, 90% interior). The bladder stone was removed under direct visualization. The plain abdominal radiograph did not reveal any stones. CONCLUSION: Indinavir is a frequently used drug for the treatment of HIV that has the potential to induce urinary lithiasis. This is particularly problematic for individuals with SCI who are on fluid restriction and an ICP. Therefore, cystoscopy and monitoring for indinavir-induced urolithiasis should be undertaken in individuals with SCI who are taking indinavir. Considerations include switching to a different protease inhibitor or choosing an entirely new HIV drug cocktail with less potential for urolithiasis.     

Increased prevalence and analysis of risk factors for indinavir nephrolithiasis

PURPOSE: Indinavir is a protease inhibitor used for treating HIV-1. The drug is lithogenic and was thought to cause a 3% incidence of kidney stones. We evaluated a cohort of patients positive for HIV on indinavir to determine the incidence of indinavir nephrolithiasis and identify risk factors for indinavir stone formation. MATERIALS AND METHODS: Our cohort study of the prevalence of indinavir nephrolithiasis included 155 patients with HIV for 5,732 patient-weeks. The same cohort was then used for a retrospective chart review to assess patient age, weight, duration of drug use, time to stone formation, CD4 count, creatinine, alanine transaminase, and urinary pH and specific gravity as risk factors for stone formation. RESULTS: We estimated the cumulative incidence of indinavir stone formation by the Kaplan-Meier product limit estimator method. At 78 weeks 43.2% of patients had stones (95% confidence interval [CI] 0.292 to 0.543). Increasing age was the only variable that was a statistically significant predictor of indinavair urolithiasis (relative risk 0.955, 95% CI 0.918 to 0.993, p = 0.0159). The mean duration plus or minus standard deviation of indinavir use was statistically the same in each group (42.5 +/- 27. 2 and 40.3 +/- 27.1 weeks in those without and with stones, respectively) despite the observed mean time to stone formation of 23.0 +/- 19.8 weeks. CONCLUSIONS: 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.     

INDINAVIR UROLITHIASIS: AN EMERGING CAUSE OF RENAL COLIC IN PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS

PURPOSE: We evaluate the clinical, diagnostic and radiographic findings in patients on indinavir therapy who presented with renal colic, and propose appropriate treatment options for indinavir urolithiasis. MATERIALS AND METHODS: A total of 16 patients positive for human immunodeficiency virus on indinavir were evaluated for 18 episodes of severe renal colic requiring hospitalization. Laboratory evaluation was performed in all patients followed by an imaging study. Conservative treatment included intravenous hydration, narcotic analgesics and temporary cessation of indinavir. Intervention was elected only in patients with persistent fever or intractable pain. A month after hospital discharge an excretory urogram and metabolic stone evaluation were performed. Mean followup was 9.3 months and 2 patients had recurrent symptoms. RESULTS: All patients presented with nausea or vomiting and hematuria. Imaging studies confirmed obstruction in all patients with 13 radiolucent (indinavir) and 3 radiopaque (calcium oxalate) stones. Patients with radiolucent and radiopaque stones demonstrated significant differences in urinary pH (p = 0.002) and serum creatinine (p = 0.03). Conservative therapy was successful in 11 patients (68.8%) within 48 hours and 4 patients (25%) with radiolucent calculi required endoscopic stenting for persistent fever. Metabolic stone evaluation demonstrated significant hypocitruria (less than 50 mg./24 hours) in all patients with radiolucent calculi. CONCLUSIONS: The urologist should be familiar with this growing cause of renal colic in patients on indinavir therapy. Pure indinavir stones are radiolucent and have a soft, gelatinous endoscopic appearance. Conservative treatment is successful in most patients and if intervention is deemed medically necessary, endoscopic stent placement should be the procedure of choice.     

Urolithiasis associated with protease inhibitors.

OBJECTIVE: We evaluated the radiographic characteristics as well as the clinical management of urolithiasis induced by systemic therapy with indinavir sulfate, a protease inhibitor utilized in the treatment of HIV infection. PATIENTS AND METHODS: Fifteen consecutive HIV-positive male patients (average age 41.3 years) who presented with urolithiasis while being treated with indinavir sulfate (average time 11.1 months) were studied. RESULTS: All patients presented with flank pain, and eight had gross hematuria. All but one patient had microscopic hematuria. The location of the stones was the kidney in three, the proximal ureter in four, and the distal ureter in nine. One patient had both a renal and a proximal ureteral stone. The stones were radiolucent on CT imaging in five patients and could not be seen in five. In the five cases in which a stone was not definitely identified, a diagnosis of urolithiasis was established on the basis of ureteral obstruction and periureteral/renal streaking noted on CT. Treatment included observation with hydration in eight patients, ureteral stent placement in two patients, ureteroscopy in three patients, and extracorporeal shockwave lithotripsy in two patients. Stones were analyzed in five patients and proved to be 100% indinavir in three and a mixture of indinavir, calcium oxalate monohydrate, and calcium oxalate dihydrate in two. CONCLUSIONS: Urolithiasis is a recognized complication of treatment with indinavir sulfate. Pure indinavir stones cannot be seen on CT unless intravenous contrast medium is utilized. Mixed calcium and indinavir stones can occur and may be radiopaque. The majority of HIV-positive patients with symptomatic urolithiasis can be treated conservatively with hydration. Metabolic evaluation of these patients with identification and correction of factors predisposing to stone formation may minimize future recurrences. Administration of this effective medication thus can continue uninterrupted.     

Urological management of indinavir-associated acute renal failure in HIV-positive patients

Introduction Indinavir, a protease inhibitor that is commonly used to treat HIV infection, may cause crystal formation within the renal tubules when urine pH is above 3.5. Crystallization in the urine may lead to intrarenal crystal deposition and acute renal failure (ARF). Aim To establish the beneficial urological management of acute renal failure caused by indinavir treatment of HIV/AIDS patients. Patients––methods Five HIV positive patients (four men, one woman) with a mean age of 32 years (range 28–36 years) were referred to our Department of Urology from an AIDS outpatient Clinic, because of the development of postrenal acute renal failure with continuously elevated creatinine and urea plasma levels after indinavir therapy. Among the initial therapeutic maneuvers, indinavir administration was interrupted for 1 week while bilateral double-J ureteral stents were inserted in all the HIV/AIDS patients, during the first 24–72 h to secure upper-tract drainage. Concurrently urine has been acidified by oral administration of the amino acid l-methionine and oral fluid intake was increased. Results All the patients responded well to the treatment and their renal function was effortlessly restored to normal within a few days. Conclusion HIV-positive patients receiving indinavir therapy might be complicated by acute renal failure, mainly due to intrarenal crystal deposition (tubules) or urolithiasis (postrenal obstruction). This adverse effect may simply manage by the discontinuation of indinavir administration, urine acidification, as well as the possible early insertion of bilateral double-J ureteral stents.     

Frequency of urolithiasis in individuals seropositive for human immunodeficiency virus treated with indinavir is higher than previously assumed

PURPOSE: Indinavir was approved by the Food and Drug Administration in 1996 as a human immunodeficiency type 1 protease inhibitor to treat human immunodeficiency virus infection. Prompted by the high number of patients receiving indinavir who present with renal colic at our institution, we performed a detailed investigation of the true frequency of urolithiasis during indinavir treatment. MATERIALS AND METHODS: We evaluated 105 patients with a mean age of 38.1 years who were treated with indinavir from 1996 to 1997. Before indinavir treatment was initiated all patients underwent renal ultrasonography, urinalysis, and determination of serum sodium, potassium, calcium, uric acid and creatinine. It was recommended that all patients drink 2 l of fluids daily, and all remained under continuous surveillance. RESULTS: Metabolic evaluation and ultrasonography showed no abnormality in any case. A stone episode occurred in 13 men (12.4%) as renal colic during observation. Colic recurred in 1 patient after 2 and 5 months, and in 1 after 2 months. Median duration of indinavir treatment until an acute stone episode was 21.5 weeks (range 6 to 50). A total of 12 stones passed spontaneously. Three patients underwent ureteroscopic calculous removal and 1 was treated with extracorporeal shock wave lithotripsy. CONCLUSIONS: Despite adequate patient information and compliance the rate of nephrolithiasis during indinavir therapy was 12.4%.     

The etiology of urolithiasis in HIV infected patients

PURPOSE: It is commonly thought that urinary lithiasis in HIV infected patients on protease inhibitor therapy is composed primarily of the protease inhibitor itself. Since many HIV infected patients on protease inhibitors presenting to our institution had nonprotease inhibitor stones, we investigated potential underlying metabolic abnormalities that may account for the lithogenesis. MATERIALS AND METHODS: We retrospectively reviewed all HIV infected patients on protease inhibitors with renal colic and evidence of nephrolithiasis who presented to our institution between June 1996 and January 2001. Patients were evaluated for stone composition and metabolic abnormalities of blood and urine when possible. RESULTS: A total of 24 patients were identified, and all were or had been on protease inhibitors (indinavir 14, ritonavir 3, nelfnavir 2, unspecified 5). Of the 14 patients on indinavir only 4 (28.6%) had indinavir containing stones. The remaining stones in this group and in those not on indinavir contained various amounts of calcium oxalate monohydrate and dihydrate, ammonium acid urate and uric acid. Of 10 patients who underwent 24-hour urine collection for metabolic evaluation 8 (80%) had abnormalities, including hypocitraturia in 5, hyperoxaluria in 4, hypomagnesuria in 4, hypercalciuria in 3, increased supersaturation of calcium oxalate in 3 and hyperuricosuria in 2. Abnormalities in the levels of urinary phosphate and sodium were also observed. CONCLUSIONS: HIV infected patients form many types of stones, which probably are attributable to underlying metabolic abnormalities rather than the use of protease inhibitors. A complete metabolic evaluation is warranted in these patients, as a means of guiding treatment to prevent future stone episodes, while avoiding the need to alter antiretroviral regimens.     

Indinavir 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-CD4 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.     

Pyuria in patients treated with indinavir is associated with renal dysfunction

BACKGROUND: Indinavir therapy is associated with a continuum of crystal-related syndromes, including nephrolithiasis, renal colic, flank pain without recognizable stone formation, dysuria and asymptomatic crystalluria. A frank nephropathy has been recognized recently as part of the spectrum. METHODS: A retrospective analysis of 72 HIV-infected individuals receiving indinavir was performed to identify the frequency and risk factors for indinavir-associated nephropathy and urinary complications. Individuals treated with nucleoside analogues alone served as controls. RESULTS: Mean serum creatinine levels rose from 1.03 +/- 0.16 mg/dl to 1.11 +/- 0.22 mg/dl at week 12 and 1.15 +/- 0.27 mg/dl at week 24 (both, p < 0.01). Thirteen individuals developed serum creatinine levels > or =1.4 mg/dl. Increased serum creatinine levels were found more frequently in women (p < 0.01) and were associated with pyuria and microhematuria (p < 0.01). Frank renal colic and/or nephrolithiasis (seven patients) and urinary pH were not associated with serum creatinine levels > or =1.4 mg/dl. The mean duration of indinavir treatment, until sterile pyuria occurred, were 22 weeks and 32 weeks until the first rise of serum creatinine levels to > or =1.4 mg/dl. Ten patients showed both findings, pyuria preceded the first rise in serum creatinine levels to > or = 1.4 mg/dl (18 vs. 27 weeks, p = 0.02). Renal biopsy, done in three patients, revealed tubulointerstitial disease with crystals in collecting ducts. In 21 patients, among them 11 with pyuria, indinavir was replaced for various reasons and pyuria disappeared in nine. In these patients mean serum creatinine levels decreased from 1.43 mg/dl at withdrawal of indinavir to 1.04 mg/dl three months later (p < 0.01). CONCLUSION: Indinavir therapy is associated with a decrease in renal function which is reversible after withdrawal. In addition, indinavir-associated tubulointerstitial disease does no in patients taking indinavir may help to identify patients being at risk for nephrotoxicity.     

Clinical presentation and metabolic features of overt and occult urolithiasis

Although pediatricians are frequently confronted with patients presenting urolithiasis symptoms without obvious stones, the syndrome of occult urolithiasis may be still viewed with some skepticism. We have compared the clinical and metabolic features of 197 children with obvious calculi, 189 with microcalculi (diameter ≤3 mm based on renal sonography), and 114 with symptoms of urolithiasis and normal renal sonography findings. Only microcalculi and normal sonography subjects with a urinary abnormality potentially leading to urolithiasis were included in the study. Age at presentation increased significantly (p = 0.0001) in the groups in the order normal sonography to microcalculi to calculi groups. There was no significant difference among the three groups in terms of family history of urolithiasis, gender distribution, and degree of hypercalciuria, hyperuricosuria, hyperoxaluria, or hypocitraturia. The average frequency of pain attacks of patients with recurrent abdominal pain (RAP) ranged from 3.6 to 4.6 days of pain per month among the three groups, which is four to ninefold lower than that reported for children with functional or organic gastrointestinal RAP. The consistency of many clinical and urinary metabolic characteristics indicates a common underlying disorder in overt and occult urolithiasis. The increase of age at presentation from the normal sonography to microcalculi and calculi groups may reflect progressive crystal accretion leading ultimately to overt stone formation.     

Surgical treatmnt for urolithiasis (in view of medical economics)

Surgical treatment for upper urinary stones has dramatically changed since extracorporeal shock wave lithotripsy (ESWL) was introduced in 1985 in Japan. Since then, the number of ESWL apparatus is increasing year by year, and there were about 800 ESWL apparatus available in Japan in 2001. On the other hand, the number of patients with upper urinary stones are also increasing in Japan, and the age-adjusted annual incidence of first-episode upper urinary tract stones in 1995 was estimated at 68.9 per 100,000 (100.1 in men and 55.4 in women), a steady increase from 54.2 in 1965. Under these circumstances, it would be very important to treat stone patients surgically even from an economical point of view, because the cost of ESWL is very expensive and more than 90% of the patients with urolithiasis are now treated by ESWL. In this paper, the medical economics of urolithiasis in Japan is discussed especially in the surgical treatment.     

Drug-induced urolithiasis

Drugs can cause renal stone formation either by raising excretion rates of naturally occurring stone components or by directly precipitating within the urinary tract. In large series of analysed renal stones, the overall frequency of drug-induced urolithiasis is less than 0.5%. Five clinical presentations of drug-induced crystallization in the kidneys can be recognized: asymptomatic crystalluria, symptomatic crystalluria; stone passage; obstructive uropathy and tubulointerstitial nephritis. In the current literature review, the protease inhibitors used for treatment of patients infected with the human immunodeficiency virus stand out as a new class of drugs that frequently causes crystallization within the urinary tract. The most widely used compound, indinavir, may lead to crystalluria and renal stone formation in up to 50% of patients, and occasionally also causes acute renal failure caused by obstructive uropathy or tubulointerstitial nephritis. On the other hand, ritonavir appears more often to induce (reversible) acute renal failure than stone formation.     

Metaphylaxis of nephrolithiasis

The introduction of extracorporeal shockwave lithotripsy (ESWL), with its noninvasive removal of stones and considerable reduction in the morbidity of stone disease, has revolutionized the therapy of urolithiasis. Unfortunately the propensity for stone recurrence is not altered by removal of stones with ESWL and stone recurrence is still about 50%. Progress in medical treatment has shown how different therapies can prevent the stone recurrence, even though it is often difficult to predict which patient will go on to become a recurrent stone former. With the right evaluation, however, the cause of calculi formation can be treated in 97% of the patients. Primary prevention of urolithiasis includes general prophylaxis in a no-risk population that has never been affected by urinary tract stones, is without familial predisposition, metabolic or genetic alterations, or urinary tract abnormalities or infections and who live in a geographical area that is at risk. Secondary prevention or metaphylaxis of stone disease is aimed at the population at risk, that is patients already affected by the stone disease, with familial predisposition, with urinary tract alterations, with metabolic or genetic alterations (gout, bone or bowel diseases) and urinary infection.     

Hyperoxaluria and urinary tract calculi after jejunoileal bypass

Five patients with jejunoileal shunt for morbid obesity in whom postshunt hyperoxaluria and recurrent urinary tract calculi developed are presented. All the stones were composed of calcium oxalate. The twenty-four hour urinary oxalic acid levels were also elevated in twenty of twenty-six patients who had had jejunoileal shunt for six months or longer. No correlation was present between urolithiasis and the degree of hyperoxaluria.     

Urolithiasis and the protease inhibitor indinavir

OBJECTIVE: To evaluate specific urological abnormalities in patients treated with the protease inhibitor indinavir. METHODS: A series of 155 consecutive human immunodeficiency virus-positive patients were treated with indinavir 800 mg p.o. three times a day. Of these, 14 (9%) treated for 1-321 (average 110) days experienced severe flank pain and were subjected to clinical and laboratory examinations. RESULTS: Abdominal X-ray was consistently negative for stones. Ultrasonography showed upper-tract dilatation in 12 patients. Intravenous urography showed obstruction above a radiolucent obstacle in 7 patients; in 2 cases, there was a marked delay in urine excretion on the obstructed side. The mean urine pH was 6. Urine culture was negative. Serum uric acid, phosphorus, and calcium levels were normal. In 8 patients there was slight renal insufficiency, and 4 patients required ureteral stenting. In all cases, hyperhydration and oral analgesia led to a favorable outcome. In 3 patients, chemical analysis of the stone demonstrated monohydrate indinavir crystals. CONCLUSIONS: In our experience, indinavir therapy is associated with urolithiasis in 9% of the cases. Hydration, analgesia, and acidification of the urine usually lead to a favorable clinical outcome. Prophylactic hydration and acidification of the urine are extremely important.     

Recurrence of upper urinary tract calculi

Treatment of upper urinary tract stones has changed greatly. The recurrence of calculi after the discharge was studied in the 634 patients with urolithiasis admitted to our department during the 9 years up to the end of 1984. The recurrence rate in the 325 cases followed for more than 3 months after the disappearance of the original stones, was 15.6% after 2 years, 27.6% after 5 year and 51.4% after 8 years. In recurrent stone formers, the rate of recurrence thereafter was greater than that of primary stone formers. The growth of calculi was rapid in the renal stone former concomitant with urinary tract infection together with a past history of renal surgery. In relation to the composition of the stone, uric acid calculi tended to recur more often than calculi composed of other substances. In view of recurrence, pyelolithotomy is preferred to renal parenchymal incision.     

Urolithiasis in acromegaly

Hypercalcemia, hypercalciuria, and hyperphosphatemia are common findings in acromegaly, yet there are only a few reports on the occurrence of urinary stones in these patients. We reviewed the files of 64 patients with acromegaly. A total of 8 patients had evidence of renal calculi: 4 patients underwent nephrolithotomy, 3 had stones which were seen on intravenous pyelography, and 1 patient voided a stone. Moreover, 2 other patients suffered from recurrent typical episodes of renal colic. In view of the high incidence of urolithiasis in our series we believe that more attention should be paid to detection of urinary stones in acromegalics to avoid further complications and suffering.     

Urolithiasis in adults with congenital megaureter

The primary presentation of congenital megaureter in adults is rare. Development of urolithiasis may lead to this unusual underlying diagnosis. Urinary tract stones can form either within the dilated ureteral segment or in a part of the upper urinary tract proximal to the abnormal ureteral segment. We report two cases of nephrolithiasis that occurred in adults found to have segmental megaureter. The first case is that of a 58-year-old man who presented with left lower quadrant pain. Computed tomography scan revealed a 2-cm stone in the distal left ureter within an area of isolated segmental distal ureteral dilation. The second case is a 48-year-old man who developed recurrent renal urolithiasis associated with isolated distal megaureter.Although a rare condition in adults, congenital megaureter may present when kidney stones develop as a result of the ureteral abnormality. Typically, stones will develop within the dilated segment of ureter. Atypically, stones may develop away from the site of the underlying abnormality. Congenital megaureter is a diagnosis that urologists and radiologists need to consider in the setting of isolated distal ureteral dilation, as the diagnosis of adult megaureter may require more involved surgical measures to prevent recurrence of adverse symptoms.     

Urolithiasis Associated With Indinavir in A Patient With Spinal Cord Injury

Abstract

Objective: To report a case of indinavir-induced urolithiasis, and the greater risk of this occurrence in individuals with spinal cordinjury (SCI) who require fluid restriction for an intermittent catheterization program (ICP).

Methods: Case report.

Results: A 38-year-old man with a T4 ASIA A SCI (according to the American Spinal lnjury Association classification scale) and human immunodeficiency virus (HIV) infection wasusing an ICP and taking indinavir (a protease inhibitor) as part of his antiviralregimen.Cystoscopy was performed to rule out recurrent urethral condylomata. He was found to haveabladder stone measuring 0.5cm × 0.5 cm × 0.3 cm, which, on analysis, was composed ofindinavir (100% exterior, 90% interior). The bladder stone wasremoved under direct visualization. The plain abdominal radiograph did not reveal any stones.

Conclusion: lndinavir is a frequently used drug for the treatment of HIV that has the potential to induce urinary Iithiasis. This isparticularly problematic for individuals with SCI who are on fluid restriction and an ICP. Therefore, cystoscopy and monitaring forindinavir-induced urolithiasis should be undertaken in individuals with SCI who are takingindinavir. Considerations include switchingto a different protease inhibitor or choosing an entirely new HIV drug cocktail with less potential for urolithiasis.