Vol. 113, June Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1975 by The Williams & Wilkins Co.
AN EVALUATION OF THE CURRENT THERAPEUTIC REGIMEN FOR RENAL TUBERCULOSIS MICHAEL WECHSLER
AND
JOHN K. LATTIMER
From the Squier Urological Clinic, Columbia-Presbyterian Medical Center, New York, New York
ABSTRACT
Renal tuberculosis will continue to be a potentially lethal disease and must be considered a diagnostic possibility in all patients with infection in order to discover it in time. Multiple drug regimens have withstood the test of time and it appears that triple drug therapy is more efficacious than 2 drugs since triple drugs permit the skipping of 1 or another of the medications with less danger ofrelapse. Rifampin is a new drug that is well tolerated and efficacious, although expensive. We recommend continuous use of triple drugs for 2 years at least with the continuance of pyridoxine. We advise an excretory urogram, the collection of 3 urine specimens for culture and the passage of ureteral catheters every 6 months during treatment and every 12 months thereafter for 10 years. We do not consider relapse an indication for an operation but for further therapy, using medications to which the patient's organism is proved susceptible by bacteriologic means. Under modern conditions an operation is rarely necessary. Renal tuberculosis is usually a blood-borne disease with focus in the lungs. During the last 10 years we have seen a distinct decrease in the number of cases of renal tuberculosis in our research unit for genitourinary tuberculosis. However, we cannot determine whether this change is owing to a decrease in the actual numbers of cases in the New York area or to the fact that the success of outpatient therapy is now widely recognized and practiced. Nevertheless, during the last 5 years we have used a triple drug regimen consisting of 100 mg. isoniazid 3 times a day, 25 mg. per kg. ethambutol for 2 weeks and then decrease to 15 mg. per kg. (usually 1,200 mg. daily) and 250 mg. cycloserine 2 times a day. Our rationale for 2 years of chemotherapy is based on bacteriologic findings of attenuated viable bacilli in resected specimens after 1 year of therapy and on the better clinical results obtained after 2 years of treatment. Multiple drug regimens have been the mainstay of treatment for renal tuberculosis. Three drug regimens have delayed the emergence of resistant organisms and have been much more effective than single drugs. Prior to the use of the aforementioned regimen we used isoniazid, para-aminosalicylic acid and cycloserine with excellent results in about 100 patients. 1 Although some physicians have stopped using pyridoxine, we have continued to use it (100 mg. daily) and have had none of the potentially serious complications such as peripheral or optic neuritis. Cycloserine has caused no real intolerance if given in 2 divided doses and if stimulants, such Accepted for publication August 9, 1974. Supported in part by the Oscar Villafane Medical Research Gift.
as coffee, are avoided. The low relative effectiveness of cycloserine has encouraged us to look for more effective drugs, while still retaining the advantage of an all-oral drug regimen, with its greater acceptability. During the last 5 years there have been various new agents developed and proved clinically and experimentally of value in the treatment of tuberculosis. However, most treatment data have been accumulated in treating pulmonary tuberculosis. We now have had 5 years of experience with ethambutol, given in combination with isoniazid and cycloserine continuous for 2 years, and have been quite satisfied with this program. Ten patients have now completed 2 years of treatment on this regimen (see table). Before starting therapy we consider it mandatory to obtain visual field and color perception examinations. The patients are instructed that if visual changes of any kind occur they are to stop taking the drug immediately. These changes occurred in 2 patients but were completely reversible in both cases. However, in 1 of these patients we substituted para-aminosalicylic acid for ethambutol, whereas the other patient resumed taking ethambutol. We also have been using as a single daily dosage 300 mg. isoniazid, 500 mg. cycloserine and 15 mg. per kg. ethambutol (usually 1,200 mg. total dose) and have found patient satisfaction and acceptance to be good. The 100 mg. pyridoxine is given at a different time of the day. Because of the slow division time of the tubercle bacilli it is an accepted bacteriologic practice to give all drugs at once in a single daily dose. However, certain patients have had to divide the cycloserine and take 250 mg. 2 times a day
760
THERAPEUTIC REGIMEN FOR RENAL TUBERCULOSIS Pt. Unit No.
X-Ray
Grade
202-12-64 201-54-60 108-34-98
Narrow infundibula Mild ureteral stricture Non-function It. side
1 0 4
196-31-80 190-04-76 123-52-15 186-07-18 187-68-32
Non-function It. side Excluded calix Normal Normal Ureteral stricture
4 2 0 0 0
198-88-07 187-32-41
Non-function upper pole Ureteral straightening and small bladder
4 0
Clinical Presentation Pyuria Orchitis Dysuria and pyuria Pain Pyuria Pyuria Hematuria Hematuria, and pyuria Pain Epididymitis
because of a feeling of light-headedness when they took 500 mg. all at once. Although our current treatment regimen is only 5 years old we have had no relapses as yet. All patients on these drugs have done well clinically. Our criteria for relapse are the reappearance of even 1 positive culture plus pyuria. As of January 1, 197 4 we have added rifampin to our protocol and eliminated cycloserine. In the treatment of pulmonary tuberculosis rifampin given in a single daily dose of 600 mg. before meals has produced conversion of sputum 2 weeks earlier than other pulmonary regimens. 2 When taken with isoniazid it has proved to be effective against pulmonary tuberculosis. Rifampin may occasionally cause a rash, a flu-like syndrome or hyperbilirubinemia with an increase in serum glutamic pyruvic transaminase, according to the literature. The drug may interfere with the hepatic uptake of bilirubin rather than have a direct toxic effect on the liver. 3 We have seen none of these complications but recommend liver chemistry studies and a hemogram every 30 days during treatment. Although the drug is expensive the toxic reactions are mild and less frequent than with most drugs. Since almost all tuberculous renal infections have responded to chemotherapy it is rarely necessary to perform a nephrectomy for tuberculosis. However, there are still certain indications for nephrectomy: 1) intractable pain or pain persisting after more than a year of chemotherapy, 2) hyper-
761
tension unresponsive to medical regimen (and attributable to the tuberculous kidney by tests), 3) fever or 4) hemorrhage. These complications are rare in our series. During the last 10 to 15 years we have performed only 2 nephrectomies and 1 heminephrectomy on tuberculosis patients, whereas prior to 1946 our wards were plentifully supplied with genitourinary tuberculosis cases undergoing an operation. These nephrectomy patients have been treated with various regimens. It is interesting to review these case histories. One patient was a young girl who had known renal tuberculosis. During an evaluation she was found to have papillary fronds growing out of the ureteral orifice. Biopsy showed questionable neoplasia with group II to III urinary Papanicolaou from the left kidney. She underwent a nephroureterectomy and was found to have squamous metaplasia of the ureter. Another patient was a 52-year-old physician referred from Guatemala who had been treated but had persistent pain requiring codeine. He had a nephrectomy and is doing well 4 years later. The third patient was a young man from Greece who had a palpable flank mass with severe pain. He had a duplicated system and a non-functioning upper pole. A heminephrectomy was performed and he did quite well. Thus, in rare instances, indications for an operation may still occur. However, having the operation does not relieve the patient or his doctor of following the operation with 2 years of triple drug chemotherapy. Any patient with renal tuberculosis must always be assumed to have other active foci of tuberculosis, which must be treated with chemotherapy. REFERENCES 1. Lattimer, J. K., Wechsler, H., Ehrlich, R. M. and
Fukushima, K.: Current treatment for renal tuberculosis. J. Urol., 102: 2, 1969. 2. Newman, R., Doster, B. E., Murray, F. J. and Woolpert, S. F.: Rifampin in initial treatment of pulmonary tuberculosis. Amer. Rev. Resp. Dis., 109: 216, 1974. 3. Raleigh, J. W.: Rifampin in treatment of advanced pulmonary tuberculosis. Report of a VA cooperative pilot study. Amer. Rev. Resp. Dis., 105: 397, 1972.
THE JOURNAL OF UROLOGY
Copyright© 1975 by The Williams & Wilkins Co.
AN EVALUATION OF THE CURRENT THERAPEUTIC REGIMEN FOR RENAL TUBERCULOSIS MICHAEL WECHSLER
AND
JOHN K. LATTIMER
From the Squier Urological Clinic, Columbia-Presbyterian Medical Center, New York, New York
ABSTRACT
Renal tuberculosis will continue to be a potentially lethal disease and must be considered a diagnostic possibility in all patients with infection in order to discover it in time. Multiple drug regimens have withstood the test of time and it appears that triple drug therapy is more efficacious than 2 drugs since triple drugs permit the skipping of 1 or another of the medications with less danger ofrelapse. Rifampin is a new drug that is well tolerated and efficacious, although expensive. We recommend continuous use of triple drugs for 2 years at least with the continuance of pyridoxine. We advise an excretory urogram, the collection of 3 urine specimens for culture and the passage of ureteral catheters every 6 months during treatment and every 12 months thereafter for 10 years. We do not consider relapse an indication for an operation but for further therapy, using medications to which the patient's organism is proved susceptible by bacteriologic means. Under modern conditions an operation is rarely necessary. Renal tuberculosis is usually a blood-borne disease with focus in the lungs. During the last 10 years we have seen a distinct decrease in the number of cases of renal tuberculosis in our research unit for genitourinary tuberculosis. However, we cannot determine whether this change is owing to a decrease in the actual numbers of cases in the New York area or to the fact that the success of outpatient therapy is now widely recognized and practiced. Nevertheless, during the last 5 years we have used a triple drug regimen consisting of 100 mg. isoniazid 3 times a day, 25 mg. per kg. ethambutol for 2 weeks and then decrease to 15 mg. per kg. (usually 1,200 mg. daily) and 250 mg. cycloserine 2 times a day. Our rationale for 2 years of chemotherapy is based on bacteriologic findings of attenuated viable bacilli in resected specimens after 1 year of therapy and on the better clinical results obtained after 2 years of treatment. Multiple drug regimens have been the mainstay of treatment for renal tuberculosis. Three drug regimens have delayed the emergence of resistant organisms and have been much more effective than single drugs. Prior to the use of the aforementioned regimen we used isoniazid, para-aminosalicylic acid and cycloserine with excellent results in about 100 patients. 1 Although some physicians have stopped using pyridoxine, we have continued to use it (100 mg. daily) and have had none of the potentially serious complications such as peripheral or optic neuritis. Cycloserine has caused no real intolerance if given in 2 divided doses and if stimulants, such Accepted for publication August 9, 1974. Supported in part by the Oscar Villafane Medical Research Gift.
as coffee, are avoided. The low relative effectiveness of cycloserine has encouraged us to look for more effective drugs, while still retaining the advantage of an all-oral drug regimen, with its greater acceptability. During the last 5 years there have been various new agents developed and proved clinically and experimentally of value in the treatment of tuberculosis. However, most treatment data have been accumulated in treating pulmonary tuberculosis. We now have had 5 years of experience with ethambutol, given in combination with isoniazid and cycloserine continuous for 2 years, and have been quite satisfied with this program. Ten patients have now completed 2 years of treatment on this regimen (see table). Before starting therapy we consider it mandatory to obtain visual field and color perception examinations. The patients are instructed that if visual changes of any kind occur they are to stop taking the drug immediately. These changes occurred in 2 patients but were completely reversible in both cases. However, in 1 of these patients we substituted para-aminosalicylic acid for ethambutol, whereas the other patient resumed taking ethambutol. We also have been using as a single daily dosage 300 mg. isoniazid, 500 mg. cycloserine and 15 mg. per kg. ethambutol (usually 1,200 mg. total dose) and have found patient satisfaction and acceptance to be good. The 100 mg. pyridoxine is given at a different time of the day. Because of the slow division time of the tubercle bacilli it is an accepted bacteriologic practice to give all drugs at once in a single daily dose. However, certain patients have had to divide the cycloserine and take 250 mg. 2 times a day
760
THERAPEUTIC REGIMEN FOR RENAL TUBERCULOSIS Pt. Unit No.
X-Ray
Grade
202-12-64 201-54-60 108-34-98
Narrow infundibula Mild ureteral stricture Non-function It. side
1 0 4
196-31-80 190-04-76 123-52-15 186-07-18 187-68-32
Non-function It. side Excluded calix Normal Normal Ureteral stricture
4 2 0 0 0
198-88-07 187-32-41
Non-function upper pole Ureteral straightening and small bladder
4 0
Clinical Presentation Pyuria Orchitis Dysuria and pyuria Pain Pyuria Pyuria Hematuria Hematuria, and pyuria Pain Epididymitis
because of a feeling of light-headedness when they took 500 mg. all at once. Although our current treatment regimen is only 5 years old we have had no relapses as yet. All patients on these drugs have done well clinically. Our criteria for relapse are the reappearance of even 1 positive culture plus pyuria. As of January 1, 197 4 we have added rifampin to our protocol and eliminated cycloserine. In the treatment of pulmonary tuberculosis rifampin given in a single daily dose of 600 mg. before meals has produced conversion of sputum 2 weeks earlier than other pulmonary regimens. 2 When taken with isoniazid it has proved to be effective against pulmonary tuberculosis. Rifampin may occasionally cause a rash, a flu-like syndrome or hyperbilirubinemia with an increase in serum glutamic pyruvic transaminase, according to the literature. The drug may interfere with the hepatic uptake of bilirubin rather than have a direct toxic effect on the liver. 3 We have seen none of these complications but recommend liver chemistry studies and a hemogram every 30 days during treatment. Although the drug is expensive the toxic reactions are mild and less frequent than with most drugs. Since almost all tuberculous renal infections have responded to chemotherapy it is rarely necessary to perform a nephrectomy for tuberculosis. However, there are still certain indications for nephrectomy: 1) intractable pain or pain persisting after more than a year of chemotherapy, 2) hyper-
761
tension unresponsive to medical regimen (and attributable to the tuberculous kidney by tests), 3) fever or 4) hemorrhage. These complications are rare in our series. During the last 10 to 15 years we have performed only 2 nephrectomies and 1 heminephrectomy on tuberculosis patients, whereas prior to 1946 our wards were plentifully supplied with genitourinary tuberculosis cases undergoing an operation. These nephrectomy patients have been treated with various regimens. It is interesting to review these case histories. One patient was a young girl who had known renal tuberculosis. During an evaluation she was found to have papillary fronds growing out of the ureteral orifice. Biopsy showed questionable neoplasia with group II to III urinary Papanicolaou from the left kidney. She underwent a nephroureterectomy and was found to have squamous metaplasia of the ureter. Another patient was a 52-year-old physician referred from Guatemala who had been treated but had persistent pain requiring codeine. He had a nephrectomy and is doing well 4 years later. The third patient was a young man from Greece who had a palpable flank mass with severe pain. He had a duplicated system and a non-functioning upper pole. A heminephrectomy was performed and he did quite well. Thus, in rare instances, indications for an operation may still occur. However, having the operation does not relieve the patient or his doctor of following the operation with 2 years of triple drug chemotherapy. Any patient with renal tuberculosis must always be assumed to have other active foci of tuberculosis, which must be treated with chemotherapy. REFERENCES 1. Lattimer, J. K., Wechsler, H., Ehrlich, R. M. and
Fukushima, K.: Current treatment for renal tuberculosis. J. Urol., 102: 2, 1969. 2. Newman, R., Doster, B. E., Murray, F. J. and Woolpert, S. F.: Rifampin in initial treatment of pulmonary tuberculosis. Amer. Rev. Resp. Dis., 109: 216, 1974. 3. Raleigh, J. W.: Rifampin in treatment of advanced pulmonary tuberculosis. Report of a VA cooperative pilot study. Amer. Rev. Resp. Dis., 105: 397, 1972.
