Hematuria in Renal Transplant Recipients STEVEN R. PREVITE, M.D., GARY T. MURATA, M.D., CARL A. OLSSON, M.D., GUNTHER W. SCHMITT, M.D., DONALD C. NABSETH, M.D., SANG 1. CHO, M.D.
From the Transplant Service, Boston Veterans Administration Hospital, Tufts University Medical School and Boston University Medical School Boston, Massachusetts
This study is a retrospective analysis of microscopic and gross hematuria in 127 male renal transplant recipients. The incidence of hematuria was 12%. The causes of hematuria were similar to those in the general population with inflammatory conditions predominating. Urologic malignancy was not found. Hematuria heralded rejection episodes in three instances. Complete evaluation of hematuria revealed pathology of the urinary tract in every instance.
L ARCOM AND CARTER in 194814 reported their findings in 3000 consecutive single voided specimens from young men applying for insurance. In 60 instances, or only two per cent, the sediments contained 2-3 red blood cells (RBC) per high power field (HPF) and in only 23 or 0.7%, were 4-5 RBC per HPF observed. The rarity of microscopic hematuria in a nor-
mal population suggests its importance, and subsequent work has revealed an incidence of urologic lesions of varying significance in 56% of patients with asymptomatic microhematuria.8 In a series of 1000 patients with gross hematuria, urologic cancer was found in 22%.15 The transplant population is obviously unique from urologic and immunologic standpoints. The increased incidence of neoplasia in this group is well known.19 though only 11 urologic malignancies have thus far been reported.25 The purpose of this study is to ascertain whether significant hematuria (greater than 4-5 RBC per HPF) is more common in this population, and whether hematuria is more commonly symptomatic of malignancy in this group. Materials and Methods The charts of all patients who underwent transplantation at the Boston Veterans Administration Hospital from 1969 to 1976 were reviewed. This included 137 transplants in 127 patients of which 58 presently have functioning grafts. All patients were males. Age at the time of transplantation ranged from 24 to 62 with a me-
dian age of 46 and an average age of 43. Only two patients were over 60 years of age. Patients were followed until transplant nephrectomy or death. Patients with nonfunctioning in situ grafts were included as at risk for development of hematuria. Donor nephrectomies and transplantations were performed using standard techniques. One hundred eight patients received cadaver transplants while 29 received living-related transplants. In recipients of cadaver kidneys, the method of preservation used in most instances was continuous pulsatile perfusion as described by Belzer and Kountz1 using cryoprecipitated human AB plasma. Immunosuppression regimens included steroid in tapering dosages and azathioprine, 2-3 mg/kg daily. Antilymphocyte globulin was used until August 1975. Radiation of the graft with 150 rads every other day for three doses was used until December 1975. Rejection episodes were normally treated with I.V. methylprednisolone sodium succinate, 1 g daily for three doses. Definition of graft failure was return to hemodialysis. Transplant nephrectomies were performed if the rejected kidneys were found to be the source of morbidity such as persistent fever, hypertension, infection, graft tenderness or bleeding. All transplant recipients have been studied with routine urinalysis in every clinic visit. This clinic visit was made once a week in the immediate post transplant period, after which the frequency of clinic visits was determined by the clinical condition. The definition of microscopic hematuria for this study was greater than 4-5 RBC per HPF on more than one urine sediment 30 days or more after transplantation. Patients with hematuria in the perioperative period (less than 30 days) were not included in our statistical analysis as this hematuria usually represented a complication of surgery. There were two such patients with gross hematuria three and eight days post-
Address correspondence to: Sang I. Cho, M.D., Department of Surgery, Boston, V.A. Hospital, 150 South Huntington Avenue, Boston, Massachusetts 02130. Submitted for publication: July 16, 1977. 0003-4932-78-0200-0219-0060 © J. B. Lippincott Company
219
Ann. Surg.
PREVITE AND OTHERS
220
TABLE 1. Age and Final Diagnoses of Patients with Gross and Microscopic Hematuria
Patient
Age
T.M. B.P.
41 51
Cadaver Cadaver
Gross Gross
L.K. S. W. A.M. A.H. K.A. S.M. L.T. A.L. B.C. E.O. C.C.
29 50 53 56 44 26 48 50 43 56 50
Cadaver Cadaver Cadaver Cadaver Cadaver Cadaver Cadaver Cadaver Living-Related Living-Related Living-Related
Micro Gross Gross Gross Gross Gross Gross Micro Micro Micro Gross
Contusion Recurrent Disease UTI Prostatitis Rejection Prostatitis Cystitis Cystica Acute Rejection Contusion Cystitis Cystica Contusion UTI Calcium Oxalate
J.M. M.P. R.W.
23 32 39
Cadaver Living-Related Cadaver
Gross Gross Gross
Acute Rejection Meatitis Meatitis
Type of Hematuria
Donor
Diagnosis
Calculus
operatively with renal artery thrombosis and transplant rupture (acute rejection) respectively. Evaluation of patients included routine bacteriologic and acid fast bacterial culture, urine cytology and excretory urography (IVP) in all patients, and renal scan, arteriography, retrograde ureteropyelography, bladder biopsy and/or kidney biopsy when indicated. Cystoscopy was performed in all cases but three. In these three cases, the diagnosis was evident after history, physical examination, laboratory data, and IVP were obtained (blunt trauma, urinary tract infection, calcium oxalate calculus spontaneously passed while in the hospital). Hematuria cleared with appropriate therapy in these three cases, and has not recurred.
9
February 1978
turia occurred in 16 patients, an incidence of 12%. Table 1 lists patient age, type of hematuria and final diagnosis. Relative to the site of bleeding, there was an even distribution between upper and lower urinary tracts (Table 2). Inflammatory conditions were diagnosed in eight patients (50% of total). Included were urinary tract infection (UTI) (2), cystitis cystica (2), meatitis (2), and prostatitis (2) (Table 3). The two patients with UTI presented with irritative lower urinary tract symptomatology, microscopic hematuria, pyuria, and bacteriuria with culture yielding greater than 100,000 colony count of E. coli in both instances. Antibody coating studies were not done. Both patients responded promptly to appropriate antibiotics and the likely site of infection was the lower urinary tract. The diagnosis of cystitis cystica was made on the basis of cystoscopic appearance confirmed by bladder biopsy. Both patients with meatitis had meatal stenosis: one was congenital while the other was secondary to partial penectomy carried out previously for squamous cell carcinoma (biopsy proved no recurrence). Three patients had hematuria resulting from trauma. Two patients who sustained blunt trauma to the graft presented with gross hematuria, while one patient had microscopic hematuria (Table 3). Evaluation of hematuria yielded no other diagnosis and hematuria subsided with conservative treatment. Renal biopsy was not obtained. Three patients with acute rejection episodes presented with gross hematuria (Table 3). Complete evaluation of hematuria and clinical impression strongly suggested rejection episodes. All three patients responded to the conventional treatment for rejection and hematuria resolved. Renal biopsy was done in one patient, revealing acute and chronic rejection. Recurrent disease (membranoproliferative glomerulonephritis) was diagnosed in one patient on the basis of kidney biopsy after complete evaluation for gross
Results
There
were
137 transplanted kidneys in 127 patients
at risk for hematuria for variable periods of time. HemaTABLE 2. Site of Origin of Hematuria
Upper urinary tract Kidney Ureter
Lower urinary tract Bladder Prostatic urethra Meatus
Number
%
8
50
7 1
8 4 2 2
50
TABLE 3. Etiology of Heinaturia
A. Inflammatory Conditions UTI Cystitis Cystica Meatitis Prostatitis B. Trauma C. Acute Rejection D. Recurrent Disease (Glomerulonephritis) E. Calculus (Calcium Oxalate)
Number
%
(8)
50
(2) (2) (2) (2) (3)
(3) (1)
19 19 6
(1) (16)
6 100%
Vol. 187.9 No. 2
HEMATURIA IN TRANSPLANT RECIPIENTS
hematuria and decreasing renal function had not yielded a definite diagnosis. One patient presented with gross hematuria and spontaneously passed a calcium oxalate calculus. Evaluation revealed no further calculous disease and normal renal function.
Discussion The etiology and site of origin of hematuria in the transplant recipient is similar to that of the general population. The 12% incidence of hematuria in these patients, however, is obviously much higher than that in the general population. This may reflect the basic anatomic alterations (pelvic location of kidney, ureteroneocystostomy, etc.) and/or immunosuppression of this group, predisposing these patients to trauma, calculous disease or urinary tract infection. This finding of inflammatory conditions in 50% of the patients with hematuria is similar to that of other large series of patients with microscopic8 and gross hematuria.15 The occurrence of trauma as a cause of hematuria in 19% of the patients is more frequent than occurs in the general population.15 The position of the transplanted kidney, lying anteriorly in the pelvis, is more vulnerable to trauma than the kidney's orthotopic site. 13 One patient in our group who passed a calcium oxalate calculus presented with total, gross, painless hematuria. Transplant ureteral obstruction can present without pain because of the division of nerve fibers. Stone formation in transplant patients has been briefly mentioned in other reports, and include four patients with infective stones and one with nephrocalcinosis secondary to primary oxalosis.16'22'23 Hyperparathyroidism is a well-known problem in the transplant population,4'20 and the possibility of calcium containing stone disease must be considered even in the absence of pain. Further evaluation of our patient revealed moderate elevations of serum calcium and parathormone levels. Early acute rejection episodes presented as gross hematuria in three of our patients or 19% of all patients with hematuria. All three patients responded to conventional therapy for rejection although one patient has since gone on to chronic rejection. The reversal of acute rejection presenting as gross hematuria has been reported. 17 Earlier transplant workers have commented on the presence of lympocytes, renal tubular cells, and red blood cell casts in the urine sediment of patients with impending rejection.11 Microscopic hematuria alone, however, may herald a rejection episode. Glomerulonephritis in the transplanted kidney, either as recurrent disease18'26 or as a new secondary disease,9 may be associated with hematuria. One patient in our
221
group presented with gross hematuria due to recurrent glomerulonephritis and subsequently returned to hemodialysis. This is the usual course when recurrent glomerulonephritis develops.18'26 On the basis of a known increased risk of malignancy in immunosuppressed patients, the question is raised whether 'hematuria in the transplant population is symptomatic of urologic malignancy more commonly than in the general population. Our analysis revealed no cases of genito-urinary malignancy. However, our series is small, with only 16 of 127 patients demonstrating hematuria. Our patients are generally younger than the normal age group in which cancer of the bladder becomes the most common cause of hematuria.10 Only two of our total group were older than 60 years of age. However, cancer of the bladder in transplant recipients has been found in the younger age group. The seven reported cases' have occurred in patients from 24 to 52 years of age with an average age of 40 years.2'6'12 The duration of immunosuppression in these patients ranged from 12 to 72 months. Of interest is that adenocarcinoma of the bladder accounted for 25% of all reported bladder cancers in transplant patients,12 while the incidence of adenocarcinoma in the general population is in the order of two per cent of all bladder cancers.7 There is histologic evidence that'cystitis cystica is associated with some adenocarcinomas of the bladder.21'24 Two patients in our group presented with microscopic hematuria and were found to have biopsy proven cystitis cystica. Follow-up cytologic examination of one of these patients has been suspicious though repeat random biopsies have revealed nonspecific cystitis. Both patients will be closely followed with IVP, urine cytology, cystoscopy and bladder biopsy. The question arises of the advisability of arteriography and/or renal biopsy in cases of otherwise unexplained hematuria. After routine evaluation of 237 nontransplant patients with hematuria, 25 were classified as unexplained and underwent further studies including renal arteriography and renal biopsy.3 Arteriography yielded a diagnosis in only one patient (arteriovenous fistula). A diagnosis was suggested in ten patients by renal biopsy (focal glomerulonephritis in seven) but in none was any therapy required. The transplant population is similar in that arteriography adds little in the evaluation of hematuria except to complete the evaluation when a mass lesion or an arteriovenous fistula is suspected (graft pain, bruit, hypertension, history of needle biopsy).5 Renal biopsy may be indicated to guide treatment in the transplant recipient with hematuria and deteriorating renal function, as it may differentiate rejection from recurrent or new glomerulonephritis. However, routine renal
PREVITE AND OTHERS
222
biopsy may add little to the diagnostic evaluation of the transplant recipient with isolated hematuria. Despite the absence of urologic malignancy in our series, we advocate complete roentgenologic, cystoscopic, and cytologic examination of all transplant recipients with hematuria. In every instance, the evaluation of hematuria revealed a significant lesion in the urinary tract. As this young population ages and is exposed for longer periods of time to urinary carcinogens and immunosuppressive medications, urothelial cancer may be more frequently diagnosed.
References 1. Belzer, F. 0. and Kountz, S. L.: Preservation and Transplantation of Human Cadaver Kidneys: A 2 Year Experience. Ann. Surg., 172:394, 1970. 2. Biggs, A. W.: Carcinoma of the Bladder in a Renal Transplant Patient. J. Urol., 109:417, 1973. 3. Burkholder, G. V., Dotin, L. N., Thomason, W. B., et al.: Unexplained Hematuria. JAMA, 210:1720, 1969. 4. Chatterjee, S. N., Massry, S. G., Friedler, R. M., et al.: High Incidence of Persistent Secondary Hyperparathyroidism After Renal Transplantation. Surg. Gynecol. Obstet., 143:440, 1976. 5. Diaz-Buxo, J. A., Kapen, D. F. and Donadio, J. V.: Renal Allograft Ateriovenous Fistula Following Percutaneous Biopsy. J. Urol., 122:557, 1974. 6. Duncon, R. E., Keys, R. H., Bennett, D. W., et al.: Squamous Cell Carcinoma of the Ureterovesical Junction After Renal Transplantation. J. Urol., 114:628, 1973. 7. Friedel, G. H., Bell, J. R., Burney, S. W., et al.: Histopathology and Classification of Urinary Bladder Carcinoma. Urologic Clin. North Am., 3:53, 1976. 8. Greene, L. F., O'Shaughnessy, E. J. and Hendricks, E. D.: Study of 500 Patients with Asymptomatic Microhematuria. JAMA, 161:610, 1956. 9. Hamberger, J., Crosnier, J. and Dormant, J.: Observation in Patients with a Well-tolerated Homotransplanted Kidney: Possibility of New Secondary Disease. Ann. N.Y. Acad. Sci., 120:558, 1964.
Ann.
Surg. * February 1978
10. Higgins, C. C.: The Clinical Significance of Hematuria. JAMA, 166:203, 1958. 11. Hume, D. M., Magee, J. H., Kauffman, J. H., et al.: Renal Homotransplantation in Man in Modified Recipients. Ann. Surg., 158:608, 1%3. 12. Ito, T. Y. and Martin, D. C.: Tumors of the Bladder in Renal Transplant Patients: Report of a Case of Adenocarcinoma and Review of Known Cases. J. Urol., 117:52, 1977. 13. Krane, R. J., Cho, S. I. and Olsson, C. A.: Renal Transplant Ureteral Obstruction Simulating Retroperitoneal Fibrosis. JAMA, 225:607, 1973. 14. Larcom, R. C. and Carter, G. H.: Erythrocytes in Urinary Sediment: Identification and Normal Limits with a Note on the Nature of Granular Casts. J. Lab. Clin. Med., 33:875, 1948. 15. Lee, L. W. and Davis, E.: Gross Urinary Hemorrhage: A Symptom Not a Disease. JAMA, 153:782, 1953. 16. MacKinnon, K. J., Oliver, J. A., Morehouse, D. D., et al.: Cadaver Renal Transplantation: Emphasis on Urological Aspects. J. Urol., 99:486, 1968. 17. MacKinnon, L. B., Anderson, E. E. and Schulman, C. C.: Renal Allograft Rejection Presenting with Gross Hematuria: Case Report. Acta Urol. Belg., 40:825, 1972. 18. Merrill, J. P.: Glomerulonephritis in Renal Transplants. Transplant Proc., 1:994, 1969. 19. Penn, I. and Starzl, T. E.: Malignant Tumors Arising de novo in Immunosuppressed Organ Transplant Recipients. Transplantation, 14:407, 1972. 20. Pletka, P. G., Strom, T. B., Hampers, C. L., et al.: Hyperparathyroidism in Human Kidney Transplant Recipients. Nephron, 17:371, 1976. 21. Salm, R.: Neoplasia of the Bladder and Cystitis Cystica. Br. J. Urol., 39:67, 1967. 22. Starzl, T. E., Groth, C. G., Putnam, C. W., et al.: Urological Complication in 216 Human Recipients of Renal Transplants. Ann. Surg., 172:1, 1970. 23. Straffon, R. A., Kiser, W. S., Stewart, B. H., et al.: Four Years' Clinical Experience with 138 Kidney Transplants. J. Urol. 99:479, 1968. 24. Tannenbaum, M.: Cystitis Cystica: Proliferative Epithelial Lesion in Urinary Bladder. Urology, 7:202, 1976. 25. The 12th Report of the Human Transplant Registry Prepared by the Advisory Committee to the Transplant Registry. JAMA, 233:787, 1975. 26. West, C. D.: Membranoproliferative Hypocomplementemic Glomerulonephritis. Nephron, 11:134, 1973.
From the Transplant Service, Boston Veterans Administration Hospital, Tufts University Medical School and Boston University Medical School Boston, Massachusetts
This study is a retrospective analysis of microscopic and gross hematuria in 127 male renal transplant recipients. The incidence of hematuria was 12%. The causes of hematuria were similar to those in the general population with inflammatory conditions predominating. Urologic malignancy was not found. Hematuria heralded rejection episodes in three instances. Complete evaluation of hematuria revealed pathology of the urinary tract in every instance.
L ARCOM AND CARTER in 194814 reported their findings in 3000 consecutive single voided specimens from young men applying for insurance. In 60 instances, or only two per cent, the sediments contained 2-3 red blood cells (RBC) per high power field (HPF) and in only 23 or 0.7%, were 4-5 RBC per HPF observed. The rarity of microscopic hematuria in a nor-
mal population suggests its importance, and subsequent work has revealed an incidence of urologic lesions of varying significance in 56% of patients with asymptomatic microhematuria.8 In a series of 1000 patients with gross hematuria, urologic cancer was found in 22%.15 The transplant population is obviously unique from urologic and immunologic standpoints. The increased incidence of neoplasia in this group is well known.19 though only 11 urologic malignancies have thus far been reported.25 The purpose of this study is to ascertain whether significant hematuria (greater than 4-5 RBC per HPF) is more common in this population, and whether hematuria is more commonly symptomatic of malignancy in this group. Materials and Methods The charts of all patients who underwent transplantation at the Boston Veterans Administration Hospital from 1969 to 1976 were reviewed. This included 137 transplants in 127 patients of which 58 presently have functioning grafts. All patients were males. Age at the time of transplantation ranged from 24 to 62 with a me-
dian age of 46 and an average age of 43. Only two patients were over 60 years of age. Patients were followed until transplant nephrectomy or death. Patients with nonfunctioning in situ grafts were included as at risk for development of hematuria. Donor nephrectomies and transplantations were performed using standard techniques. One hundred eight patients received cadaver transplants while 29 received living-related transplants. In recipients of cadaver kidneys, the method of preservation used in most instances was continuous pulsatile perfusion as described by Belzer and Kountz1 using cryoprecipitated human AB plasma. Immunosuppression regimens included steroid in tapering dosages and azathioprine, 2-3 mg/kg daily. Antilymphocyte globulin was used until August 1975. Radiation of the graft with 150 rads every other day for three doses was used until December 1975. Rejection episodes were normally treated with I.V. methylprednisolone sodium succinate, 1 g daily for three doses. Definition of graft failure was return to hemodialysis. Transplant nephrectomies were performed if the rejected kidneys were found to be the source of morbidity such as persistent fever, hypertension, infection, graft tenderness or bleeding. All transplant recipients have been studied with routine urinalysis in every clinic visit. This clinic visit was made once a week in the immediate post transplant period, after which the frequency of clinic visits was determined by the clinical condition. The definition of microscopic hematuria for this study was greater than 4-5 RBC per HPF on more than one urine sediment 30 days or more after transplantation. Patients with hematuria in the perioperative period (less than 30 days) were not included in our statistical analysis as this hematuria usually represented a complication of surgery. There were two such patients with gross hematuria three and eight days post-
Address correspondence to: Sang I. Cho, M.D., Department of Surgery, Boston, V.A. Hospital, 150 South Huntington Avenue, Boston, Massachusetts 02130. Submitted for publication: July 16, 1977. 0003-4932-78-0200-0219-0060 © J. B. Lippincott Company
219
Ann. Surg.
PREVITE AND OTHERS
220
TABLE 1. Age and Final Diagnoses of Patients with Gross and Microscopic Hematuria
Patient
Age
T.M. B.P.
41 51
Cadaver Cadaver
Gross Gross
L.K. S. W. A.M. A.H. K.A. S.M. L.T. A.L. B.C. E.O. C.C.
29 50 53 56 44 26 48 50 43 56 50
Cadaver Cadaver Cadaver Cadaver Cadaver Cadaver Cadaver Cadaver Living-Related Living-Related Living-Related
Micro Gross Gross Gross Gross Gross Gross Micro Micro Micro Gross
Contusion Recurrent Disease UTI Prostatitis Rejection Prostatitis Cystitis Cystica Acute Rejection Contusion Cystitis Cystica Contusion UTI Calcium Oxalate
J.M. M.P. R.W.
23 32 39
Cadaver Living-Related Cadaver
Gross Gross Gross
Acute Rejection Meatitis Meatitis
Type of Hematuria
Donor
Diagnosis
Calculus
operatively with renal artery thrombosis and transplant rupture (acute rejection) respectively. Evaluation of patients included routine bacteriologic and acid fast bacterial culture, urine cytology and excretory urography (IVP) in all patients, and renal scan, arteriography, retrograde ureteropyelography, bladder biopsy and/or kidney biopsy when indicated. Cystoscopy was performed in all cases but three. In these three cases, the diagnosis was evident after history, physical examination, laboratory data, and IVP were obtained (blunt trauma, urinary tract infection, calcium oxalate calculus spontaneously passed while in the hospital). Hematuria cleared with appropriate therapy in these three cases, and has not recurred.
9
February 1978
turia occurred in 16 patients, an incidence of 12%. Table 1 lists patient age, type of hematuria and final diagnosis. Relative to the site of bleeding, there was an even distribution between upper and lower urinary tracts (Table 2). Inflammatory conditions were diagnosed in eight patients (50% of total). Included were urinary tract infection (UTI) (2), cystitis cystica (2), meatitis (2), and prostatitis (2) (Table 3). The two patients with UTI presented with irritative lower urinary tract symptomatology, microscopic hematuria, pyuria, and bacteriuria with culture yielding greater than 100,000 colony count of E. coli in both instances. Antibody coating studies were not done. Both patients responded promptly to appropriate antibiotics and the likely site of infection was the lower urinary tract. The diagnosis of cystitis cystica was made on the basis of cystoscopic appearance confirmed by bladder biopsy. Both patients with meatitis had meatal stenosis: one was congenital while the other was secondary to partial penectomy carried out previously for squamous cell carcinoma (biopsy proved no recurrence). Three patients had hematuria resulting from trauma. Two patients who sustained blunt trauma to the graft presented with gross hematuria, while one patient had microscopic hematuria (Table 3). Evaluation of hematuria yielded no other diagnosis and hematuria subsided with conservative treatment. Renal biopsy was not obtained. Three patients with acute rejection episodes presented with gross hematuria (Table 3). Complete evaluation of hematuria and clinical impression strongly suggested rejection episodes. All three patients responded to the conventional treatment for rejection and hematuria resolved. Renal biopsy was done in one patient, revealing acute and chronic rejection. Recurrent disease (membranoproliferative glomerulonephritis) was diagnosed in one patient on the basis of kidney biopsy after complete evaluation for gross
Results
There
were
137 transplanted kidneys in 127 patients
at risk for hematuria for variable periods of time. HemaTABLE 2. Site of Origin of Hematuria
Upper urinary tract Kidney Ureter
Lower urinary tract Bladder Prostatic urethra Meatus
Number
%
8
50
7 1
8 4 2 2
50
TABLE 3. Etiology of Heinaturia
A. Inflammatory Conditions UTI Cystitis Cystica Meatitis Prostatitis B. Trauma C. Acute Rejection D. Recurrent Disease (Glomerulonephritis) E. Calculus (Calcium Oxalate)
Number
%
(8)
50
(2) (2) (2) (2) (3)
(3) (1)
19 19 6
(1) (16)
6 100%
Vol. 187.9 No. 2
HEMATURIA IN TRANSPLANT RECIPIENTS
hematuria and decreasing renal function had not yielded a definite diagnosis. One patient presented with gross hematuria and spontaneously passed a calcium oxalate calculus. Evaluation revealed no further calculous disease and normal renal function.
Discussion The etiology and site of origin of hematuria in the transplant recipient is similar to that of the general population. The 12% incidence of hematuria in these patients, however, is obviously much higher than that in the general population. This may reflect the basic anatomic alterations (pelvic location of kidney, ureteroneocystostomy, etc.) and/or immunosuppression of this group, predisposing these patients to trauma, calculous disease or urinary tract infection. This finding of inflammatory conditions in 50% of the patients with hematuria is similar to that of other large series of patients with microscopic8 and gross hematuria.15 The occurrence of trauma as a cause of hematuria in 19% of the patients is more frequent than occurs in the general population.15 The position of the transplanted kidney, lying anteriorly in the pelvis, is more vulnerable to trauma than the kidney's orthotopic site. 13 One patient in our group who passed a calcium oxalate calculus presented with total, gross, painless hematuria. Transplant ureteral obstruction can present without pain because of the division of nerve fibers. Stone formation in transplant patients has been briefly mentioned in other reports, and include four patients with infective stones and one with nephrocalcinosis secondary to primary oxalosis.16'22'23 Hyperparathyroidism is a well-known problem in the transplant population,4'20 and the possibility of calcium containing stone disease must be considered even in the absence of pain. Further evaluation of our patient revealed moderate elevations of serum calcium and parathormone levels. Early acute rejection episodes presented as gross hematuria in three of our patients or 19% of all patients with hematuria. All three patients responded to conventional therapy for rejection although one patient has since gone on to chronic rejection. The reversal of acute rejection presenting as gross hematuria has been reported. 17 Earlier transplant workers have commented on the presence of lympocytes, renal tubular cells, and red blood cell casts in the urine sediment of patients with impending rejection.11 Microscopic hematuria alone, however, may herald a rejection episode. Glomerulonephritis in the transplanted kidney, either as recurrent disease18'26 or as a new secondary disease,9 may be associated with hematuria. One patient in our
221
group presented with gross hematuria due to recurrent glomerulonephritis and subsequently returned to hemodialysis. This is the usual course when recurrent glomerulonephritis develops.18'26 On the basis of a known increased risk of malignancy in immunosuppressed patients, the question is raised whether 'hematuria in the transplant population is symptomatic of urologic malignancy more commonly than in the general population. Our analysis revealed no cases of genito-urinary malignancy. However, our series is small, with only 16 of 127 patients demonstrating hematuria. Our patients are generally younger than the normal age group in which cancer of the bladder becomes the most common cause of hematuria.10 Only two of our total group were older than 60 years of age. However, cancer of the bladder in transplant recipients has been found in the younger age group. The seven reported cases' have occurred in patients from 24 to 52 years of age with an average age of 40 years.2'6'12 The duration of immunosuppression in these patients ranged from 12 to 72 months. Of interest is that adenocarcinoma of the bladder accounted for 25% of all reported bladder cancers in transplant patients,12 while the incidence of adenocarcinoma in the general population is in the order of two per cent of all bladder cancers.7 There is histologic evidence that'cystitis cystica is associated with some adenocarcinomas of the bladder.21'24 Two patients in our group presented with microscopic hematuria and were found to have biopsy proven cystitis cystica. Follow-up cytologic examination of one of these patients has been suspicious though repeat random biopsies have revealed nonspecific cystitis. Both patients will be closely followed with IVP, urine cytology, cystoscopy and bladder biopsy. The question arises of the advisability of arteriography and/or renal biopsy in cases of otherwise unexplained hematuria. After routine evaluation of 237 nontransplant patients with hematuria, 25 were classified as unexplained and underwent further studies including renal arteriography and renal biopsy.3 Arteriography yielded a diagnosis in only one patient (arteriovenous fistula). A diagnosis was suggested in ten patients by renal biopsy (focal glomerulonephritis in seven) but in none was any therapy required. The transplant population is similar in that arteriography adds little in the evaluation of hematuria except to complete the evaluation when a mass lesion or an arteriovenous fistula is suspected (graft pain, bruit, hypertension, history of needle biopsy).5 Renal biopsy may be indicated to guide treatment in the transplant recipient with hematuria and deteriorating renal function, as it may differentiate rejection from recurrent or new glomerulonephritis. However, routine renal
PREVITE AND OTHERS
222
biopsy may add little to the diagnostic evaluation of the transplant recipient with isolated hematuria. Despite the absence of urologic malignancy in our series, we advocate complete roentgenologic, cystoscopic, and cytologic examination of all transplant recipients with hematuria. In every instance, the evaluation of hematuria revealed a significant lesion in the urinary tract. As this young population ages and is exposed for longer periods of time to urinary carcinogens and immunosuppressive medications, urothelial cancer may be more frequently diagnosed.
References 1. Belzer, F. 0. and Kountz, S. L.: Preservation and Transplantation of Human Cadaver Kidneys: A 2 Year Experience. Ann. Surg., 172:394, 1970. 2. Biggs, A. W.: Carcinoma of the Bladder in a Renal Transplant Patient. J. Urol., 109:417, 1973. 3. Burkholder, G. V., Dotin, L. N., Thomason, W. B., et al.: Unexplained Hematuria. JAMA, 210:1720, 1969. 4. Chatterjee, S. N., Massry, S. G., Friedler, R. M., et al.: High Incidence of Persistent Secondary Hyperparathyroidism After Renal Transplantation. Surg. Gynecol. Obstet., 143:440, 1976. 5. Diaz-Buxo, J. A., Kapen, D. F. and Donadio, J. V.: Renal Allograft Ateriovenous Fistula Following Percutaneous Biopsy. J. Urol., 122:557, 1974. 6. Duncon, R. E., Keys, R. H., Bennett, D. W., et al.: Squamous Cell Carcinoma of the Ureterovesical Junction After Renal Transplantation. J. Urol., 114:628, 1973. 7. Friedel, G. H., Bell, J. R., Burney, S. W., et al.: Histopathology and Classification of Urinary Bladder Carcinoma. Urologic Clin. North Am., 3:53, 1976. 8. Greene, L. F., O'Shaughnessy, E. J. and Hendricks, E. D.: Study of 500 Patients with Asymptomatic Microhematuria. JAMA, 161:610, 1956. 9. Hamberger, J., Crosnier, J. and Dormant, J.: Observation in Patients with a Well-tolerated Homotransplanted Kidney: Possibility of New Secondary Disease. Ann. N.Y. Acad. Sci., 120:558, 1964.
Ann.
Surg. * February 1978
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