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IMAGING CHARACTERISTICS OF INDINAVIR CALCULI
Vol. 161, 1085-1087,April 1999 Printed in U.S.A.
IMAGING CHARACTERISTICS OF INDINAVIR CALCULI BRADLEY F. SCHWARTZ, NOAH SCHENKMAN, NOEL A. ARMENAKAS MARSHALL L. STOLLER
AND
From the Department of Urology, University of California, Sun Francisco, California, and Department of Surgery, Section of Urology, Lenox Hill Hospital, New York, New York
ABSTRACT
Purpose: Indinavir sulfate is a n 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 11renal 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. KEY WORDS:kidney calculi, ureteral calculi, diagnostic imaging, protease inhibitors, HIV
Indinavir sulfate is a protease inhibitor used to treat patients with the human immunodeficiency virus type l (HIV1).Development of nephrolithiasis and lower urinary tract symptoms attributed to indinavir crystal formation have been well described, and the incidence ranges from 3 to 2 0 7 ~ . ~Indinavir -~ in its pure form is relatively insoluble in aqueous and insoluble in alkaline or neutral solutions. Solubility exceeds 100 mg./ml. in a pH of less than 3.5 and decreases to 0.03 mg./ml. in a pH of 6.0.s.s To enhance solubility in the gastrointestinal tract indinavir is admixed with hydrogen sulfate, which results in a crystalline powder that is 12 to 20% excreted unchanged in the ~ r i n e .A~combina.~ tion of high urinary excretion and poor solubility in a physiological pH solution, such as urine, may result in crystal formation and subsequent stone development. Urinary calculi are diagnosed using a combination of symptoms, physical examination findings, urinalysis results and radiographic abnormalities. Abdominal radiography is useful in identifying radiodense stones in the kidney and proximal ureters. Visualization of calculi in the middle and distal third of the ureters may be obscured by the bony pelvis or confused with pelvic phleboliths. Pure uric acid stones are radiolucent, and matrix stones are faint and often difficult to visualize. Renal and bladder ultrasonography 1s used with abdominal radiography to identify renal calculi or stones in the intramural ureter using the bladder as an acoustic window. Hydronephrosis may be suggestive of an obstructing ureteral calculus. However, visualization of ureteral calculi is difficult and often not possible. Excretory urography (IVF') is effective in diagnosing urinary calculi but patients with contrast medium allergies or renal insuffiAccepted for publication November 20, 1998.
ciency have a significant risk of contrast medium induced renal dysfunction. The added expense of nonionic agents and increased radiation exposure have encouraged evaluation by other diagnostic methods. Rapid sequence helical computerized tomography (CT) is used to characterize and locate urinary calculi.lO-l*Previously all stone compositions, including uric acid and matrix, were believed to be visualized on CT as radiodense calcifications approaching the density of bone. Recently several of our patients presented with renal colic, hematuria and hydronephrosis on IVP or renal ultrasound. CT confirmed delayed excretion and hydronephrosis consistent with obstructing calculi but no evidence of calcification. We reviewed the charts and imaging studies of our patients suspected of indinavir calculi, and made observations regarding radiological appearance.
MATERIALS A N D METHODS
The University of California at San Francisco has a large population of patients with HIV-1enrolled in drug studies evaluating new antiviral agents. From January 1997 to January 1998,36 patients with symptomatic urolithiasis while taking indinavir sulfate were identified, and the charts and imaging studies were retrospectively reviewed with attention to presentation, urinalysis, radiological evaluation and management. Specifically, imaging characteristics on CT were analyzed.
RESULTS
Of the 36 patients 31 (86%)were men, 4 (11%)were women and 1 (3%)was a transsexual. Mean patient age was 41 years 1085
1086
IMAGING INDINAVIR CALCULI
(range 25 to 65) and the average time taking indinavir before symptoms developed was 5.8 months (range 1 to 30). NO patient had a history of urolithiasis. Duration of symptoms before diagnosis ranged from 1 to 7 days (mean 2.0). Of the patients 35 (97%)presented with acute nausea and vomiting, and all complained of ipsilateral flank pain with costovertebra1 angle tenderness on physical examination (table l),3 (8.3%)had a fever and 30 (83%)complained of lower urinary tract symptoms, such as dysuria, urgency or frequency. Urinalysis was performed at presentation in 25 patients (69%), of whom 22 (88%)had microscopic hematuria, and 18 (72%) each had proteinuria and pyuria. Radiological examination performed initially in 24 of 36 patients (67%)included abdominal radiograph in 12, IW in 13, renal ultrasound in 11and renal CT in 12. Imaging study results were graded as 0-negative or normal, 1-suggestive of a calculus because of calcification, ureteral dilatation, incomplete ureteral visualization or probable renal calcification on ultrasound or CT and 2-clear demonstration of a calculus (table 2). Results were normal on abdominal radiography in 58% of cases, XVP in 4670, ultrasound in 18% and CT in 4276, and suggestive of a calculus in 42, 54, 46 and 58%, respectively. None of the abdominal radiographs was diagnostic while 7.7, 36 and 0% of Ivp,ultrasound and CT, respectively, were confirmatory. Treatment of all patients consisted of pain relief and fluid correction to a euvolemic state. The drug was discontinued in 6 patients (17%)for a n average of 1to 2 weeks. Admission to the hospital for adequate pain relief was required in 2 patients (5.6%),while stent placement was necessary in 3 (8.3%). Of 36 patients 33 (92%) witnessed passing a stone during urination. After short-term followup there were 2 recurrences with uneventful outcomes. DISCUSSION
The search for medical therapies to slow HIV-1 continues as the number of patients contracting the virus increases at a rate of 16,000 per day worldwide. Protease inhibitors have demonstrated great promise in treating such patients, including indinavir sulfate which has poor aqueous solubility and substantial urinary excretion, which are 2 prerequisites for urinary stone formation. Urolithiasis is reported in 4% of patients taking indinavir.13.14 While most reports indicate that these stones are radiolucent on abdominal radiography, characteristics on IW,renal ultrasound and CT have not been discussed to our knowledge. Kopp et al reported on 19 men taking indinavir with urinary tract symptoms, of whom 12 underwent radiographic studies, including IW in 1, renal ultrasound in 2 and CT in 9.7 IVP revealed ipsilateral hydronephrosis and ureteral obstruction despite normal abdominal radiography. Abdominal radiography after intravenous contrast medium for CT showed ureteral dilatation with columning to a radiolucent ureteral calculus. One renal ultrasound was normal and the other demonstrated an ipsilateral renal calculus. CT revealed ipsilateral hydronephrosis in 2 cases, normal findings in 3 and bilateral renal parenchymal defects in 4. These 4 defects proved to be calcifications distributed throughout the renal cortex and/or the medulla, and were perhaps consistent TABLE1. Symptoms and urinalysis of 36 indinavir stone formers
______ Nausedvomiting Flank pain Fever Lower urinary tract symptoms Urinalysis: Red blood count ( 3 or morehigh power field) White blood count Protein
No. (%) 36 (100) 36 (100) 3 (8.3) 30 (83) 25 (69) 22 (88) 18 (72) 18 (72)
TABLE2 . Radiographic fndiws in 24 patients with presumed indinavir calculi Study
No. Suggestive of No. Diagnostic of No. Nondiaenostic Calculus Urinary Calculus
~
Abdominal radiograph
IVP Renal ultrasound CT
7 5 2 5
5 7 5 7
0
1 4 0
-_
with distal renal tubule crystals. Of these 4 crystal defects 3 resolved after drug cessation for 7 to 25 days. Gentle et a1 reported on 7 patients with moderate to high grade obstruction from radiolucent calculi. Abdominal CT demonstrated hydronephrosis without urinary calcifications. John et a1 reported symptomatic hydronephrosis in a 66year-old man with multiple ureteral indinavir calculi diagnosed with ultrasound, IVF' and retrograde urography.4 Rich et a1 identified a 3 mm. obstructing ureteral calculus on N p in a 36-year-old man but whether the stone was radiodense on abdominal radiography was not mentioned.6 Indinavir sulfate in the urinary tract is a brown, mucoid substance not characteristic of most urinary calculi. It has a soft putty-like quality, and can be thought of as a plug which can obstruct, cause renal colic and may eventually calcify. If a stone appears radiodense on abdominal radiography and is clinically consistent with indinavir, it likely contains coexisting calcium constituents. No study to date has confirmed a pure indinavir calculus demonstrating calcifications on abdominal radiography to our knowledge. Urinary pH influences formation and dissolution of several stone types. The solubility of indinavir sulfate is low at physiological pH. When pH decreases below 3.5 the solubility of the drug increases more than 3,000-fold. However, clinically we are unable to achieve this low pH. To increase the solubility of indinavir it is bound to hydrogen sulfate. Urinary pH manipulation has little effect on solubility in the physiological range. Increased hydration and temporary cessation of the protease inhibitor are clinically useful. Our study is significant because no single radiographic modality is demonstrated to be superior in the diagnosis of indinavir calculi. None of the abdominal radiographs was diagnostic and less than 8% of the IVF's confirmed the presence of a calculus. Renal ultrasound was diagnostic or suggestive of a calculus in 82% of cases mainly because of the presence of hydronephrosis. lVP remains a n important diagnostic tool in the evaluation of patients with flank pain and hematuria. However, increasing cost, risk of contrast agent allergy and radiation exposure have encouraged investigation of other diagnostic modalities. CT, once thought to identify all known calculi by their bright appearance, may not prove helpful in the diagnosis of urinary calculi in patients taking indinavir. In our study no calculus was revealed and just over half of the CT scans suggested the presence of a calculus. If a stone is detected on CT in patients taking indinavir, it most likely contains calcium or uric acid in addition to indinavir. Urinalysis is helpful because many patients have hematuria and characteristic crystalluria (fig. l).7 Routine microscopy of urinary sediment reveals indinavir crystals as flat rectangular plates often in a fan or star burst pattern. Patients taking indinavir who present with flank pain and/or lower urinary tract symptoms may undergo diagnostic imaging. Our data suggest that these tests should be interpreted with caution. Inability to visualize a stone does not eliminate diagnosis. We have developed a n algorithm to help evaluate the patient suspected of having an indinavir calculus (fig. 2). Conservative management of greater than 1.5 1. fluid daily and drug cessation should be curative in the majority of cases.
1087
IMAGING INDINAVIR CALCULI
patients taking the drug to crystal and subsequent stone formation. Patients generally present with flank pain, nausea and vomiting, lower urinary tract symptoms (such as urgency and frequency) and hematuria. CT, once thought capable of identifying all known urinary calculi, cannot be used to diagnose indinavir stones. Management consists of pain control, hydration and temporarily stopping the medication.
REFERENCES
FIG. 1. Urinary indinavir crystals on light microscopy
Hfnnaturia Pmtainuria
AbdominaUpelvr
CryStallUda
I
TempwaryaessaWm of lndinavir Pain relief observation
Ureteroscopy Percutaneous nephrostomy
FIG. 2. ClinicL- a -,orithm of HIV-1 and suspected protease inhibitor (indinavir sulfate) calculi. N , intravenous.
CONCLUSIONS
Indinavir sulfate, a protease inhibitor used to treat patients with HIV-l, is poorly soluble a t physiological pH and has significant urinary excretion. These qualities predispose
1. Gentle, D. L., Stoller, M. L., Jarret, T. W., Ward, J. F., Geib, K S. and Wood, A. F.: Protease inhibitor-induced urolithiasis. Urology, 50: 508, 1997. 2. Lerner, L. B., Cendron, M. and b u s , S. N.: Nephrolithiasis from indinavir, a new human immunodeficiency virus drug. J . Urol., 159: 2074, 1998. 3. Martinez, F., Mommeja-Marin, H., Estepa-Maurice, L., Beaufils, H., Bochet, M., Daudon, M., Deray, G. and Katlama, C.: Indinavir crystal deposits associated with tubulointerstitial nephropathy. Nephrol., Dialysis Transplant., 1 3 750, 1998. 4. John, H., Muller, N. J., Opravil, M. and Hauri, D.: Indinavir urinary stones as origin of upper urinary tract obstruction. Urol. Int., 5 9 257, 1997. 5. Gagnon, R. F., Tsoukas, C. M. and Watters, A. K.: Light microscopy of indinavir urinary crystals. Ann. Intern. Med., 128.321, 1998. 6. Rich, J. D., Ramratnam, B., Chiang, M. and Tashima, K. T.: Management of indinavir associated nephrolithiasis. J. Urol., 158 2228, 1997. 7. Kopp, J. B., Miller, K. D., Mican, J . M., Feuerstein, I. M., Vaughan, E., Baker, C., Pannell, L. K. and Fallwn, J.: Crystalluria and urinary tract abnormalities associated with indinavir. Ann. Intern. Med., 127: 119, 1997. 8. Balani, S. K., Arison, B. H., Mathai, L., Kauffman, L. R., Miller, R. R., Steams, R. A,, Chen, I. W. and Lin, J. H.: Metabolites of L-735,524, a potent HIV-1 protease inhibitor, in human urine. Drug Metab. Dispos., 2 3 266, 1995. 9. Lin, J. H., Chen, I. W., Vastag, K. J. and Ostovic, D.: pHdependent oral absorption of L-735,524, a potent HIV protease inhibitor, in rats and dogs. Drug Metab. Dispos., 2 3 730,1995. 10. Vieweg, J., Teh, C., Freed, K., Leder, R. A., Smith, R. H., Nelson, R. H. and Preminger, G. M.: Unenhanced helical computerized tomography for the evaluation of patients with acute flank pain. J . Urol., 160: 679, 1998. 11. Olcott, E. W., Sommer, F. G. and Napel, S.: Accuracy of detection and measurement of renal calculi: in vitro comparison of threedimensional spiral CT, radiography and nephrotomography. Radiology, 204: 19, 1997. 12. Fielding, J . R., Steele, G., Fox, L. A,, Heller, H. and Loughlin, K. R.: Spiral computerized tomography in the evaluation of acute flank pain: a replacement for excretory urography. J. Urol., 157: 2071, 1997. 13. Gulick, R. M., Mellors, J. W., Havlir, D., Eron, J . J., Gonzalez, C., McMahon, D., Richman, D. D., Valentine, F. T., Jonas, L., Meibohm, A,, Emini, E. A. and Chodakewitz, J. A,: Treatment with indinavir, zidovudine and lamiwdine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. New Engl. J. Med., 337:734, 1997. 14. Deutsch, P., Teppler, H. and Squires, K: Antiviral activity of L-735,524, an HIV protease inhibitor, in infected patients. In: Program and Abstracts of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 4-7, Orlando, Florida. Abstract 1-59. 1994.
IMAGING CHARACTERISTICS OF INDINAVIR CALCULI BRADLEY F. SCHWARTZ, NOAH SCHENKMAN, NOEL A. ARMENAKAS MARSHALL L. STOLLER
AND
From the Department of Urology, University of California, Sun Francisco, California, and Department of Surgery, Section of Urology, Lenox Hill Hospital, New York, New York
ABSTRACT
Purpose: Indinavir sulfate is a n 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 11renal 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. KEY WORDS:kidney calculi, ureteral calculi, diagnostic imaging, protease inhibitors, HIV
Indinavir sulfate is a protease inhibitor used to treat patients with the human immunodeficiency virus type l (HIV1).Development of nephrolithiasis and lower urinary tract symptoms attributed to indinavir crystal formation have been well described, and the incidence ranges from 3 to 2 0 7 ~ . ~Indinavir -~ in its pure form is relatively insoluble in aqueous and insoluble in alkaline or neutral solutions. Solubility exceeds 100 mg./ml. in a pH of less than 3.5 and decreases to 0.03 mg./ml. in a pH of 6.0.s.s To enhance solubility in the gastrointestinal tract indinavir is admixed with hydrogen sulfate, which results in a crystalline powder that is 12 to 20% excreted unchanged in the ~ r i n e .A~combina.~ tion of high urinary excretion and poor solubility in a physiological pH solution, such as urine, may result in crystal formation and subsequent stone development. Urinary calculi are diagnosed using a combination of symptoms, physical examination findings, urinalysis results and radiographic abnormalities. Abdominal radiography is useful in identifying radiodense stones in the kidney and proximal ureters. Visualization of calculi in the middle and distal third of the ureters may be obscured by the bony pelvis or confused with pelvic phleboliths. Pure uric acid stones are radiolucent, and matrix stones are faint and often difficult to visualize. Renal and bladder ultrasonography 1s used with abdominal radiography to identify renal calculi or stones in the intramural ureter using the bladder as an acoustic window. Hydronephrosis may be suggestive of an obstructing ureteral calculus. However, visualization of ureteral calculi is difficult and often not possible. Excretory urography (IVF') is effective in diagnosing urinary calculi but patients with contrast medium allergies or renal insuffiAccepted for publication November 20, 1998.
ciency have a significant risk of contrast medium induced renal dysfunction. The added expense of nonionic agents and increased radiation exposure have encouraged evaluation by other diagnostic methods. Rapid sequence helical computerized tomography (CT) is used to characterize and locate urinary calculi.lO-l*Previously all stone compositions, including uric acid and matrix, were believed to be visualized on CT as radiodense calcifications approaching the density of bone. Recently several of our patients presented with renal colic, hematuria and hydronephrosis on IVP or renal ultrasound. CT confirmed delayed excretion and hydronephrosis consistent with obstructing calculi but no evidence of calcification. We reviewed the charts and imaging studies of our patients suspected of indinavir calculi, and made observations regarding radiological appearance.
MATERIALS A N D METHODS
The University of California at San Francisco has a large population of patients with HIV-1enrolled in drug studies evaluating new antiviral agents. From January 1997 to January 1998,36 patients with symptomatic urolithiasis while taking indinavir sulfate were identified, and the charts and imaging studies were retrospectively reviewed with attention to presentation, urinalysis, radiological evaluation and management. Specifically, imaging characteristics on CT were analyzed.
RESULTS
Of the 36 patients 31 (86%)were men, 4 (11%)were women and 1 (3%)was a transsexual. Mean patient age was 41 years 1085
1086
IMAGING INDINAVIR CALCULI
(range 25 to 65) and the average time taking indinavir before symptoms developed was 5.8 months (range 1 to 30). NO patient had a history of urolithiasis. Duration of symptoms before diagnosis ranged from 1 to 7 days (mean 2.0). Of the patients 35 (97%)presented with acute nausea and vomiting, and all complained of ipsilateral flank pain with costovertebra1 angle tenderness on physical examination (table l),3 (8.3%)had a fever and 30 (83%)complained of lower urinary tract symptoms, such as dysuria, urgency or frequency. Urinalysis was performed at presentation in 25 patients (69%), of whom 22 (88%)had microscopic hematuria, and 18 (72%) each had proteinuria and pyuria. Radiological examination performed initially in 24 of 36 patients (67%)included abdominal radiograph in 12, IW in 13, renal ultrasound in 11and renal CT in 12. Imaging study results were graded as 0-negative or normal, 1-suggestive of a calculus because of calcification, ureteral dilatation, incomplete ureteral visualization or probable renal calcification on ultrasound or CT and 2-clear demonstration of a calculus (table 2). Results were normal on abdominal radiography in 58% of cases, XVP in 4670, ultrasound in 18% and CT in 4276, and suggestive of a calculus in 42, 54, 46 and 58%, respectively. None of the abdominal radiographs was diagnostic while 7.7, 36 and 0% of Ivp,ultrasound and CT, respectively, were confirmatory. Treatment of all patients consisted of pain relief and fluid correction to a euvolemic state. The drug was discontinued in 6 patients (17%)for a n average of 1to 2 weeks. Admission to the hospital for adequate pain relief was required in 2 patients (5.6%),while stent placement was necessary in 3 (8.3%). Of 36 patients 33 (92%) witnessed passing a stone during urination. After short-term followup there were 2 recurrences with uneventful outcomes. DISCUSSION
The search for medical therapies to slow HIV-1 continues as the number of patients contracting the virus increases at a rate of 16,000 per day worldwide. Protease inhibitors have demonstrated great promise in treating such patients, including indinavir sulfate which has poor aqueous solubility and substantial urinary excretion, which are 2 prerequisites for urinary stone formation. Urolithiasis is reported in 4% of patients taking indinavir.13.14 While most reports indicate that these stones are radiolucent on abdominal radiography, characteristics on IW,renal ultrasound and CT have not been discussed to our knowledge. Kopp et al reported on 19 men taking indinavir with urinary tract symptoms, of whom 12 underwent radiographic studies, including IW in 1, renal ultrasound in 2 and CT in 9.7 IVP revealed ipsilateral hydronephrosis and ureteral obstruction despite normal abdominal radiography. Abdominal radiography after intravenous contrast medium for CT showed ureteral dilatation with columning to a radiolucent ureteral calculus. One renal ultrasound was normal and the other demonstrated an ipsilateral renal calculus. CT revealed ipsilateral hydronephrosis in 2 cases, normal findings in 3 and bilateral renal parenchymal defects in 4. These 4 defects proved to be calcifications distributed throughout the renal cortex and/or the medulla, and were perhaps consistent TABLE1. Symptoms and urinalysis of 36 indinavir stone formers
______ Nausedvomiting Flank pain Fever Lower urinary tract symptoms Urinalysis: Red blood count ( 3 or morehigh power field) White blood count Protein
No. (%) 36 (100) 36 (100) 3 (8.3) 30 (83) 25 (69) 22 (88) 18 (72) 18 (72)
TABLE2 . Radiographic fndiws in 24 patients with presumed indinavir calculi Study
No. Suggestive of No. Diagnostic of No. Nondiaenostic Calculus Urinary Calculus
~
Abdominal radiograph
IVP Renal ultrasound CT
7 5 2 5
5 7 5 7
0
1 4 0
-_
with distal renal tubule crystals. Of these 4 crystal defects 3 resolved after drug cessation for 7 to 25 days. Gentle et a1 reported on 7 patients with moderate to high grade obstruction from radiolucent calculi. Abdominal CT demonstrated hydronephrosis without urinary calcifications. John et a1 reported symptomatic hydronephrosis in a 66year-old man with multiple ureteral indinavir calculi diagnosed with ultrasound, IVF' and retrograde urography.4 Rich et a1 identified a 3 mm. obstructing ureteral calculus on N p in a 36-year-old man but whether the stone was radiodense on abdominal radiography was not mentioned.6 Indinavir sulfate in the urinary tract is a brown, mucoid substance not characteristic of most urinary calculi. It has a soft putty-like quality, and can be thought of as a plug which can obstruct, cause renal colic and may eventually calcify. If a stone appears radiodense on abdominal radiography and is clinically consistent with indinavir, it likely contains coexisting calcium constituents. No study to date has confirmed a pure indinavir calculus demonstrating calcifications on abdominal radiography to our knowledge. Urinary pH influences formation and dissolution of several stone types. The solubility of indinavir sulfate is low at physiological pH. When pH decreases below 3.5 the solubility of the drug increases more than 3,000-fold. However, clinically we are unable to achieve this low pH. To increase the solubility of indinavir it is bound to hydrogen sulfate. Urinary pH manipulation has little effect on solubility in the physiological range. Increased hydration and temporary cessation of the protease inhibitor are clinically useful. Our study is significant because no single radiographic modality is demonstrated to be superior in the diagnosis of indinavir calculi. None of the abdominal radiographs was diagnostic and less than 8% of the IVF's confirmed the presence of a calculus. Renal ultrasound was diagnostic or suggestive of a calculus in 82% of cases mainly because of the presence of hydronephrosis. lVP remains a n important diagnostic tool in the evaluation of patients with flank pain and hematuria. However, increasing cost, risk of contrast agent allergy and radiation exposure have encouraged investigation of other diagnostic modalities. CT, once thought to identify all known calculi by their bright appearance, may not prove helpful in the diagnosis of urinary calculi in patients taking indinavir. In our study no calculus was revealed and just over half of the CT scans suggested the presence of a calculus. If a stone is detected on CT in patients taking indinavir, it most likely contains calcium or uric acid in addition to indinavir. Urinalysis is helpful because many patients have hematuria and characteristic crystalluria (fig. l).7 Routine microscopy of urinary sediment reveals indinavir crystals as flat rectangular plates often in a fan or star burst pattern. Patients taking indinavir who present with flank pain and/or lower urinary tract symptoms may undergo diagnostic imaging. Our data suggest that these tests should be interpreted with caution. Inability to visualize a stone does not eliminate diagnosis. We have developed a n algorithm to help evaluate the patient suspected of having an indinavir calculus (fig. 2). Conservative management of greater than 1.5 1. fluid daily and drug cessation should be curative in the majority of cases.
1087
IMAGING INDINAVIR CALCULI
patients taking the drug to crystal and subsequent stone formation. Patients generally present with flank pain, nausea and vomiting, lower urinary tract symptoms (such as urgency and frequency) and hematuria. CT, once thought capable of identifying all known urinary calculi, cannot be used to diagnose indinavir stones. Management consists of pain control, hydration and temporarily stopping the medication.
REFERENCES
FIG. 1. Urinary indinavir crystals on light microscopy
Hfnnaturia Pmtainuria
AbdominaUpelvr
CryStallUda
I
TempwaryaessaWm of lndinavir Pain relief observation
Ureteroscopy Percutaneous nephrostomy
FIG. 2. ClinicL- a -,orithm of HIV-1 and suspected protease inhibitor (indinavir sulfate) calculi. N , intravenous.
CONCLUSIONS
Indinavir sulfate, a protease inhibitor used to treat patients with HIV-l, is poorly soluble a t physiological pH and has significant urinary excretion. These qualities predispose
1. Gentle, D. L., Stoller, M. L., Jarret, T. W., Ward, J. F., Geib, K S. and Wood, A. F.: Protease inhibitor-induced urolithiasis. Urology, 50: 508, 1997. 2. Lerner, L. B., Cendron, M. and b u s , S. N.: Nephrolithiasis from indinavir, a new human immunodeficiency virus drug. J . Urol., 159: 2074, 1998. 3. Martinez, F., Mommeja-Marin, H., Estepa-Maurice, L., Beaufils, H., Bochet, M., Daudon, M., Deray, G. and Katlama, C.: Indinavir crystal deposits associated with tubulointerstitial nephropathy. Nephrol., Dialysis Transplant., 1 3 750, 1998. 4. John, H., Muller, N. J., Opravil, M. and Hauri, D.: Indinavir urinary stones as origin of upper urinary tract obstruction. Urol. Int., 5 9 257, 1997. 5. Gagnon, R. F., Tsoukas, C. M. and Watters, A. K.: Light microscopy of indinavir urinary crystals. Ann. Intern. Med., 128.321, 1998. 6. Rich, J. D., Ramratnam, B., Chiang, M. and Tashima, K. T.: Management of indinavir associated nephrolithiasis. J. Urol., 158 2228, 1997. 7. Kopp, J. B., Miller, K. D., Mican, J . M., Feuerstein, I. M., Vaughan, E., Baker, C., Pannell, L. K. and Fallwn, J.: Crystalluria and urinary tract abnormalities associated with indinavir. Ann. Intern. Med., 127: 119, 1997. 8. Balani, S. K., Arison, B. H., Mathai, L., Kauffman, L. R., Miller, R. R., Steams, R. A,, Chen, I. W. and Lin, J. H.: Metabolites of L-735,524, a potent HIV-1 protease inhibitor, in human urine. Drug Metab. Dispos., 2 3 266, 1995. 9. Lin, J. H., Chen, I. W., Vastag, K. J. and Ostovic, D.: pHdependent oral absorption of L-735,524, a potent HIV protease inhibitor, in rats and dogs. Drug Metab. Dispos., 2 3 730,1995. 10. Vieweg, J., Teh, C., Freed, K., Leder, R. A., Smith, R. H., Nelson, R. H. and Preminger, G. M.: Unenhanced helical computerized tomography for the evaluation of patients with acute flank pain. J . Urol., 160: 679, 1998. 11. Olcott, E. W., Sommer, F. G. and Napel, S.: Accuracy of detection and measurement of renal calculi: in vitro comparison of threedimensional spiral CT, radiography and nephrotomography. Radiology, 204: 19, 1997. 12. Fielding, J . R., Steele, G., Fox, L. A,, Heller, H. and Loughlin, K. R.: Spiral computerized tomography in the evaluation of acute flank pain: a replacement for excretory urography. J. Urol., 157: 2071, 1997. 13. Gulick, R. M., Mellors, J. W., Havlir, D., Eron, J . J., Gonzalez, C., McMahon, D., Richman, D. D., Valentine, F. T., Jonas, L., Meibohm, A,, Emini, E. A. and Chodakewitz, J. A,: Treatment with indinavir, zidovudine and lamiwdine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. New Engl. J. Med., 337:734, 1997. 14. Deutsch, P., Teppler, H. and Squires, K: Antiviral activity of L-735,524, an HIV protease inhibitor, in infected patients. In: Program and Abstracts of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 4-7, Orlando, Florida. Abstract 1-59. 1994.