POLYCYTHEMIA ROGER
NELLANS,
PETER
OTIS, M.D.
DONALD
FOLLOWING
RENAL TRANSPLANTATION
M.D.
C. MARTIN, M.D.
From the Department of Surgery, University of California, Irvine, California
ABSTRACT -Among 60 renal allograft recipients, 3 patients were found to be polycythemic with hematocrits greater than 55 and were studied extensively with various hematologic and radiographic procedures. None of the patients showed evidence of erythropoietin-secreting malignancies, renal cysts, hydronephrosis, or hypoxemia. All had elevated erythropoietin levels, and 1 showed evidence of platelet trapping in his transplanted kidney, suggesting that the chronic polycythemia may be related to transvlant rejection.
Polycythemia (erythrocytosis) following renal transplantation has been mentioned in the literature by several investigators.‘-’ Its exact significance is open for debate, but it has been postulated that it may be due to transplant rejection.3,8 Herein we report the development of polycythemia (hematocrit greater than 55) in 3 of 60 renal transplant recipients. Multiple attempts were made to determine whether rejection was the cause of the polycythemia. Material and Methods The 3 transplant recipients received kidneys between May, 1970, and December, 1972, using identical surgical techniques by the same surgeons. All were followed closely postoperatively with serial hemoglobins, hematocrits, white blood counts, platelet counts, blood urea nitrogens, creatinines, and creatinine clearances. On development of polycythemia each patient was seen in consultation by the hematology service. This work-up included bone marrow aspiration and interpretation, total blood and red blood cell volume using 51Cr-labeled red blood cells, plasma volume using lz51-labeled albumin, arterial blood gases, kaolin-activated partial thromboplastin time,g Quick prothrombin time,lO factor V and factor VIII assays, 11,12leukocyte alkaline phosphatase scores, and vitamin B12 binding capacity.
Malignancies known to cause polycythemia were excluded with liver scans, liver function tests, intravenous pyelograms of the patient’s own as well as his transplanted kidneys, mediastinal tomograms, chest roentgenograms, and careful obstetric-gynecologic examination by staff gynecologists. Platelet and fibrinogen sequestration studies were performed using 5gCr-labeled isologous human platelets and ‘251-labeled autologous human fibrinogen.‘3i3 Platelet and fibrinogen sequestration in the renal parenchyma was determined by recording scintillations per minute with the Nuclear-Chicago gamma counter over the transplanted kidney, contralateral iliac fossa, and precordial area serially for seven days. More than 120 per cent (transplant/precordium) activity was considered significant for both fibrinogen and platelets.’ In addition urine specimens were analyzed for fibrin degradation products. l4 Serum erythropoietin was measured by Peter Dukes, M.D., at Childrens Hospital of Los Angeles and University of Southern California, using the 5gFe uptake technique in polycythemic mice. All serum samples, taken prior to phlebotomy, were collected at 8 A.M., frozen immediately, and stored at minus 20°C. until tested. Serum erythropoietin content of these patients was expressed as the erythrocyte 5gFe uptake produced by the serum when injected into mice with hypoxia-induced polycythemia.
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76mlAnin
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MONTHS
FIGURE 1.
Case 1. Hematologic data, serum creatinine levels, and drug treatment.
Case Reports Case 1
A sixty-three-year-old Caucasian male with a past history of recurrent calculi underwent a left heminephrectomy in 1949 for a persistent fistula following removal of a staghorn calculus. In 1956 chronic renal failure gradually developed. A kidney biopsy in 1970 revealed nephrosclerosis, pyelonephritis, and chronic glomerulonephritis, In June, 1970, a home dialysis program was started. From 1970 to 1971 he had multiple admissions for uremia, the last of which was complicated by severe gastrointestinal bleeding, requiring fifteen units of blood to maintain his hematocrit between 20 and 22. On October 9, 1972, the patient received a cadaveric renal transplant to his left iliac fossa which functioned promptly. In January, 1974, it was noted for the first time that his hematocrit was 59 at which time he was phlebotomized (Fig. 1). Red blood cell mass was 56 ml. per kilogram (normal, 28 to 30 ml. per kilogram) and the plasma volume 34 ml. per kilogram (normal, 34 to 60 ml. per kilogram). The serum erythropoietin level prior to phlebotomy was 1.6 per cent (control, 0.6 per cent). Arterial blood gases, liver function studies, liver and brain scans, chest roentgenograms, mediastinal tomo-
grams, coagulation studies, vitamin B12 binding capacity, and leukocyte alkaline phosphatase scores were all normal. An intravenous pyelogram revealed a small atrophic kidney on the right and a heminephritic-atrophic kidney on the left. Fibrin degradation products could not be detected in the urine. 1251fibrinogen uptake studies did not show any tendency to sequester fibrinogen in the transplanted kidney (Fig. 2A); however, platelet sequestration studies showed remarkable platelet trapping within the first twenty-four hours after injection (Fig. 2B). His renal function has remained stable on azathioprine 100 mg. per day and prednisone 25 mg. per day. Case 2
A twenty-eight-year-old white woman with a six-year history of chronic pyelonephritis was maintained on home dialysis for three years prior to receiving a cadaveric renal graft. Her hematocrits while on hemodialysis averaged 25. The graft functioned poorly for the first twenty-five days, during which time she was maintained on hemodialysis. A needle biopsy of the graft twenty days after tranplantation revealed a moderate interstitial chronic infiltrate found predominately around arterioles, consistent with a chronic
180
1 250
FIGURE 2. Case I, A; Case 2, 0; Case 3, 0. (A) ‘25Zfibrinogen uptake studies in our 3 patients. (B) 5gCr platelet sequestration studies in same patients. Transplantlprecordium ratios were expressed as percentage; values greater than 120 per cent were considered signi$cant.
2oc
150
100
50
234567 DAYS rejection reaction. Twenty-seven days following transplantation her renal function improved sufficiently to obviate the need for dialysis. For the first month following transplantation the patient maintained her preoperative hematocrit; however, over the next year her hematocrit rose progressively, reaching a high of 62 in December, 1973 (Fig. 3). At this time a serum erythropoietin level of 1.3 per cent (control, 0.6 per cent) was obtained. The red blood cell mass was 56 ml. per kilogram (normal, 28 to 30 ml. per kilogram), and the plasma volume was 36 ml. per kilogram (normal, 34 to 60 ml. per kilogram). Liver and brain scans, liver function studies, arterial blood gases, coagulation studies, vitamin B12 binding capacity, and leukocyte alkaline phosphatase scores were normal. Intravenous pyelogram revealed nonvisualization of her right kidney and a small atrophic left kidney without evidence of a lesion. The transplanted kidney appeared normal. A pelvic examination, chest x-ray film, and mediastinal tomography failed to demonstrate any evidence of tumor. Bone marrow studies revealed mild erythroid hyperplasia. 1251 fibrinogen uptake study was inconclusive, the platelet sequestration study revealed no platelet trapping (Fig. 2A and B),
and fibrin degradation products were not present in the urine. Renal function remained stable on azathioprine 100 mg. per day and prednisone 20 mg. per day. Case 3 A thirty-two-year-old white male with chronic renal failure secondary to chronic glomerulonephritis was begun on hemodialysis in June, 1970. He received a cadaveric renal transplant on July 27, 1970, and was given a total of 450 rads in divided doses to the graft in the immediate postoperative period for possible rejection. Hemodialysis was maintained for two weeks postoperatively until renal function sufficiently improved. Hospitalization was again indicated in October, 1970, for threatened rejection. Treatment with methylprednisolone sodium succinate (Solu-Medrol), 1 G m. daily, was successful in reversing the rejection. Following transplantation, the patient’s hematocrit steadily increased for six months reaching a level of 55 in January, 1971 (Fig. 4). An open renal biopsy in August, 1971, revealed mild interstitial fibrosis and focal pyelonephritis. For two and one-half years his hematocrit remained
65-
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14
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3.
Case 2. Hematologic
0
4
8
12
data serum creatinine
16
20
24
28
32
levels, and
36
40
drug treatment.
44
48
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MONTHS
FIGURE
UROLOGY
4.
/ AUGUST1975
Case 3. Hematologic
/ VOLUMEVI,
data serum creatinine
NUMBER2
levels, and drug treatment.
161
unchanged; however, in March, 1973, his creatinine rose to 2 mg. per 100 ml. resulting in more vigorous immunosuppressive therapy. In September, 1973, despite no apparent deterioration in his renal function, his hematocrit rose to 62. A serum erythropoietin level performed soon after was 5.4 per cent (control 0.6 per cent). The red blood cell volume was 45 ml. per kilogram (normal 28 to 30 ml. per kilogram) and the plasma volume was 36 ml. per kilogram (normal 34 to 60 ml. per kilogram). Liver and brain scans, liver function studies, chest roentgenograms, mediastinal tomograms, arterial blood gases, coagulation studies, vitamin B12 binding capacity, and leukocyte alkaline phosphatase scores were within normal limits. Intravenous pyelogram revealed bilateral atrophic kidneys with the transplanted kidney appearing normal. Bone marrow studies revealed mild erythroid hyperplasia. No fibrin degradation products were present in the urine. lz51 fibrinogen uptake studies were inconclusive and 51Cr platelet sequestration studies showed no evidence of platelet trapping (Fig. 2A and B). Interestingly, superficial thrombophlebitis and later multiple pulmonary emboli developed. He was managed successfully with phlebotomy and anticoagulation. Currently, the patient’s renal function has remained stable, and he is being maintained on azathioprine 100 mg. per day and prednisone 25 mg. per day. Comment Erythropoietin is a hormone active in the regulation of red blood cell production. Secondary polycythemia may be due to a compensatory or inappropriate elaboration of erythropoietin. The latter may merely be a pathologic exaggeration of erythropoietin secretion by the tissues which normally produce it, or an inappropriate production and secretion by tissues not normally involved in its production. It is generally thought that the major source of erythropoietin or its precursor is the kidney. Extrarenal production has been documented, probably arising from the liver, but appears to be inadequate to maintain normal erythropoiesis. l2 The finding of elevated levels of serum erythropoietin in all of our patients indicated that the polycythemia was secondary and probably resulted from the transplanted kidney. It has been previously documented that renal artery clamping stimulates erythropoietin release in dogs.13 No clinical evidence of renal artery stenosis, such as bruit or delayed appearance of
162
contrast on intravenous pyelogram, was present in our cases, and the risk of arteriography did not appear warranted. Nies, Cohn, and Schrier’ noted that perhaps small vessel damage secondary to rejection led to renal ischemia and resultant erythropoietin release. Swales and Evans4 postulated that only a low-grade rejection process would produce polycythemia. Supporting this concept, Murphy et al. l5 have demonstrated that renal anoxia parallels erythropoietin release up to a point and that more severe degrees of anoxia (that is, renal cortical anaerobic glycolysis above 40 per cent) are not associated with significant erythropoietin release. It should be noted that even if certain hypoxic requirements for erythropoietin release were exceeded leading to erythropoietin production, polycythemia would not occur if the bone marrow was incapable of responding to the erythropoietin stimulus. The damaging effects of immunosuppressive therapy and/or uremia on bone marrow may account for the relative rarity of polycythemia in renal allograft recipients. To investigate this further, the sera of all patients who have had successful transplants are presently being assayed for erythropoietin activity. In these 3 patients multiple studies were performed to detect chronic low-grade rejection. All tests of renal function remained unchanged. In addition no fibrinogen trapping in the transplanted kidneys could clearly be shown, and no fibrin degradation products were present in the urine, suggesting that fibrinogen was not being deposited in the microvasculature of the transplanted kidney. However, in 1 patient (Case 1) platelet trapping, which is an index of vascular damage, did occur within the first twenty-four hours (Fig. 2A and B). All of our patients had an elevated red blood cell mass with normal plasma volumes, indicating “true” polycythemia. Swales and Evans4 reported 4 of 6 patients having contracted plasma volumes and therefore a “relative” polycythemia. “True” polycythemia can be either primary (polycythemia Vera) or secondary. Polycythemia vera appeared unlikely because of normal white blood counts, platelet counts, leukocyte alkaline phosphatase scores, vitamin B12 binding capacities, and, most important, elevated serum erythropoietin values. An attempt was then made to rule out all secondary causes of polycythemia. It is well known that patients on chronic immunosuppressive therapy have a higher incidence of malignancy than the general population. Studies were performed to exclude renal, cerebellar,
UROLOGY
/ AUGUST 1975 / VOLUME
VI, NUMBER
2
adrenal, uterine, ovarian, and liver malignancy. In addition, renal cysts, hydronephrosis, and causes of tissue hypoxia were excluded. It is interesting to speculate that excessive erythropoietin secretion might in fact be arising from the patient’s own kidneys. Varkarakis et al. 6 report on 1 case which showed reversal of polycythemia following bilateral nephrectomy of the patient’s own glomerulonephritic kidneys. One can only speculate whether bilateral nephrectomy would be of benefit in our cases. Perhaps selective renal vein erythropoietin levels would have been of value; however, since previously reported cases indicate that this process is self-limiting and not necessarily of bad prognostic significance, more invasive measures were not indicated in these cases. Most investigators report polycythemia occurring three to four months following transplantation, with the exception of 1 case reported by Swales and Evans4 in which polycythemia developed fifteen months following transplantation. Most of the cases reported maintain their polycythemic state from six to fourteen months then spontaneously return to normal ranges. Our cases demonstrated the first onset of polycythemia seven to thirteen months following transplantation and have all persisted to the present time. The duration of polycythemia in these cases was ten, sixteen, and forty-eight months (Figs. 1, 3 and 4). Wu et all6 reported the development of polycythemia in 2 patients after each received a graft from the same cadaver donor. They postulated that it was likely that the kidneys from the donor contributed to the development of true polycythemia. This was not the case, however, in our series since polycythemia failed to develop in 2 other recipients of kidneys from the same cadavers. Some investigators report a high incidence of thromboembolic complications and note that the major morbidity is due to this rather than rejection In 1 patient in our series (Case 3) thrombophlebitis developed in a lower extremity nearly four years following the onset ofpolycythemia at a time when his hematocrit was 60. Subsequently pulmonary emboli developed, which were documented by lung scan. He was treated successfu 11y with phlebotomy and anticoagulation. We believe that to lessen the morbidity which results from these complications, hematocrits should be maintained below 55 and prompt an-
UROLOGY /
AUGUST 1975 /
VOLUME VI, NUMBER 2
ticoagulation boembolism
therapy occur.
begun
if signs of throm-
Irvine, California 92664 (DR.
ACKNOWLEDGMENT. Mortimer Joyce Hostetler, R.N., cooperated vided technical assistance.
Morton,
NELLANS)
M. D., and
with this study and pro-
References
1. NIES, B. A., COHN, R., and SCHRIER, S. L.: Erythemiaafter renal transplantation, N. Engl. J. Med. 273: 785 (1965). 2.
3.
4. 5.
6.
7.
8.
9.
DENNY, W. F., FLANNIGAN,W. J., and ZUKOSHI,C. F. : Serial erythropoietin studies in patients undergoing renal homotransplantation, J. Lab. Clin. Med. 67: 386 (1966). ABBRECHT, P. H., and GREENE, J. A., JR.: Serum erythropoietin after renal homotransplantation, Ann. Intern. Med. 65: 908 (1966). SWALES, J. D., and EVANS, D. B.: Erythemiain renal transplantation, Br. Med. J. 2: 80 (1969). JEPSON, J. H., et al. : Characteristics of erythropoiesis following human renal homotransplantation, Transplant. Proc. 3: 353 (1971). VARKARAKIS,M. J., et al.: Polycythemia following renal transplantation unrelated to the allograft, J. Surg. Oncol. 3: 157 (1971). YEBOAH, E. D., CHISHOLM,G. D., SHORT, M. D., and PETRIE, A. : The detection and prediction of acute rejection episodes in human renal transplants using radioactive fibrinogen, Br. J. Urol. 45: 273 (1973). ABBRECHT, P. H., TURCOTTE, J. G., and VAXDER, A. J.: Plasma erythropoietin and renin activity after canine renal allotransplantation, J. Lab. Clin. Med. 71: 766 (1968). PROCTOR, R. R., and RAPAPORT,S. I.: The partial thromboplastin time with kaolin. A simple screening test for first stage plasma clotting factor deficiencies, Am. J. Clin. Pathol.
10.
11.
12.
13. 14.
15.
36: 212 (1961).
QUICK,A. J., STANLEY-BROWN,M., ~~~BANCROFT, F. W.: A study of the coagulation defect in hemophilia and in jaundice, Am. J. Med. Sci. 190: 501 (1935). STORMORKEN,H.: The preparation of proaccelerin deficient (parahemophilia) plasma for the assay of proacceleria, Stand. J. Clin. Lab. Invest, 9: 273 (1957). POOL, J. G., and ROBINSON,J. : Assay of plasma antihemophilia globulin (AHG), Br. J, Hematol. 5: 17 (1959). MORTON, M.: Personal communication, 1974. MERSKEY, C., KLEINER, G. G., and JOHNSON, A. J. : Quantitative estimation of split products of fibrinogen in human serum, relation to diagnosis and treatment, Blood 28: 1 (1966). MURPHY, G. P., et al.: Correlation of renal metabolism with erythropoietin release in hypertensive dogs with renal artery stenosis, Invest. Urol. 4: 372 (1967).
16.
WU, K. K., et d. : Erythrocytosis after renal transplantation, Arch. Intern. Med. 32: 898 (1973).
163
NELLANS,
PETER
OTIS, M.D.
DONALD
FOLLOWING
RENAL TRANSPLANTATION
M.D.
C. MARTIN, M.D.
From the Department of Surgery, University of California, Irvine, California
ABSTRACT -Among 60 renal allograft recipients, 3 patients were found to be polycythemic with hematocrits greater than 55 and were studied extensively with various hematologic and radiographic procedures. None of the patients showed evidence of erythropoietin-secreting malignancies, renal cysts, hydronephrosis, or hypoxemia. All had elevated erythropoietin levels, and 1 showed evidence of platelet trapping in his transplanted kidney, suggesting that the chronic polycythemia may be related to transvlant rejection.
Polycythemia (erythrocytosis) following renal transplantation has been mentioned in the literature by several investigators.‘-’ Its exact significance is open for debate, but it has been postulated that it may be due to transplant rejection.3,8 Herein we report the development of polycythemia (hematocrit greater than 55) in 3 of 60 renal transplant recipients. Multiple attempts were made to determine whether rejection was the cause of the polycythemia. Material and Methods The 3 transplant recipients received kidneys between May, 1970, and December, 1972, using identical surgical techniques by the same surgeons. All were followed closely postoperatively with serial hemoglobins, hematocrits, white blood counts, platelet counts, blood urea nitrogens, creatinines, and creatinine clearances. On development of polycythemia each patient was seen in consultation by the hematology service. This work-up included bone marrow aspiration and interpretation, total blood and red blood cell volume using 51Cr-labeled red blood cells, plasma volume using lz51-labeled albumin, arterial blood gases, kaolin-activated partial thromboplastin time,g Quick prothrombin time,lO factor V and factor VIII assays, 11,12leukocyte alkaline phosphatase scores, and vitamin B12 binding capacity.
Malignancies known to cause polycythemia were excluded with liver scans, liver function tests, intravenous pyelograms of the patient’s own as well as his transplanted kidneys, mediastinal tomograms, chest roentgenograms, and careful obstetric-gynecologic examination by staff gynecologists. Platelet and fibrinogen sequestration studies were performed using 5gCr-labeled isologous human platelets and ‘251-labeled autologous human fibrinogen.‘3i3 Platelet and fibrinogen sequestration in the renal parenchyma was determined by recording scintillations per minute with the Nuclear-Chicago gamma counter over the transplanted kidney, contralateral iliac fossa, and precordial area serially for seven days. More than 120 per cent (transplant/precordium) activity was considered significant for both fibrinogen and platelets.’ In addition urine specimens were analyzed for fibrin degradation products. l4 Serum erythropoietin was measured by Peter Dukes, M.D., at Childrens Hospital of Los Angeles and University of Southern California, using the 5gFe uptake technique in polycythemic mice. All serum samples, taken prior to phlebotomy, were collected at 8 A.M., frozen immediately, and stored at minus 20°C. until tested. Serum erythropoietin content of these patients was expressed as the erythrocyte 5gFe uptake produced by the serum when injected into mice with hypoxia-induced polycythemia.
65z a r.b 0 Ti E
5545
I”
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0
2
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6
8
IO
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72ml/min
81ml/min
76mlAnin
14
16
18
20
22
24
MONTHS
FIGURE 1.
Case 1. Hematologic data, serum creatinine levels, and drug treatment.
Case Reports Case 1
A sixty-three-year-old Caucasian male with a past history of recurrent calculi underwent a left heminephrectomy in 1949 for a persistent fistula following removal of a staghorn calculus. In 1956 chronic renal failure gradually developed. A kidney biopsy in 1970 revealed nephrosclerosis, pyelonephritis, and chronic glomerulonephritis, In June, 1970, a home dialysis program was started. From 1970 to 1971 he had multiple admissions for uremia, the last of which was complicated by severe gastrointestinal bleeding, requiring fifteen units of blood to maintain his hematocrit between 20 and 22. On October 9, 1972, the patient received a cadaveric renal transplant to his left iliac fossa which functioned promptly. In January, 1974, it was noted for the first time that his hematocrit was 59 at which time he was phlebotomized (Fig. 1). Red blood cell mass was 56 ml. per kilogram (normal, 28 to 30 ml. per kilogram) and the plasma volume 34 ml. per kilogram (normal, 34 to 60 ml. per kilogram). The serum erythropoietin level prior to phlebotomy was 1.6 per cent (control, 0.6 per cent). Arterial blood gases, liver function studies, liver and brain scans, chest roentgenograms, mediastinal tomo-
grams, coagulation studies, vitamin B12 binding capacity, and leukocyte alkaline phosphatase scores were all normal. An intravenous pyelogram revealed a small atrophic kidney on the right and a heminephritic-atrophic kidney on the left. Fibrin degradation products could not be detected in the urine. 1251fibrinogen uptake studies did not show any tendency to sequester fibrinogen in the transplanted kidney (Fig. 2A); however, platelet sequestration studies showed remarkable platelet trapping within the first twenty-four hours after injection (Fig. 2B). His renal function has remained stable on azathioprine 100 mg. per day and prednisone 25 mg. per day. Case 2
A twenty-eight-year-old white woman with a six-year history of chronic pyelonephritis was maintained on home dialysis for three years prior to receiving a cadaveric renal graft. Her hematocrits while on hemodialysis averaged 25. The graft functioned poorly for the first twenty-five days, during which time she was maintained on hemodialysis. A needle biopsy of the graft twenty days after tranplantation revealed a moderate interstitial chronic infiltrate found predominately around arterioles, consistent with a chronic
180
1 250
FIGURE 2. Case I, A; Case 2, 0; Case 3, 0. (A) ‘25Zfibrinogen uptake studies in our 3 patients. (B) 5gCr platelet sequestration studies in same patients. Transplantlprecordium ratios were expressed as percentage; values greater than 120 per cent were considered signi$cant.
2oc
150
100
50
234567 DAYS rejection reaction. Twenty-seven days following transplantation her renal function improved sufficiently to obviate the need for dialysis. For the first month following transplantation the patient maintained her preoperative hematocrit; however, over the next year her hematocrit rose progressively, reaching a high of 62 in December, 1973 (Fig. 3). At this time a serum erythropoietin level of 1.3 per cent (control, 0.6 per cent) was obtained. The red blood cell mass was 56 ml. per kilogram (normal, 28 to 30 ml. per kilogram), and the plasma volume was 36 ml. per kilogram (normal, 34 to 60 ml. per kilogram). Liver and brain scans, liver function studies, arterial blood gases, coagulation studies, vitamin B12 binding capacity, and leukocyte alkaline phosphatase scores were normal. Intravenous pyelogram revealed nonvisualization of her right kidney and a small atrophic left kidney without evidence of a lesion. The transplanted kidney appeared normal. A pelvic examination, chest x-ray film, and mediastinal tomography failed to demonstrate any evidence of tumor. Bone marrow studies revealed mild erythroid hyperplasia. 1251 fibrinogen uptake study was inconclusive, the platelet sequestration study revealed no platelet trapping (Fig. 2A and B),
and fibrin degradation products were not present in the urine. Renal function remained stable on azathioprine 100 mg. per day and prednisone 20 mg. per day. Case 3 A thirty-two-year-old white male with chronic renal failure secondary to chronic glomerulonephritis was begun on hemodialysis in June, 1970. He received a cadaveric renal transplant on July 27, 1970, and was given a total of 450 rads in divided doses to the graft in the immediate postoperative period for possible rejection. Hemodialysis was maintained for two weeks postoperatively until renal function sufficiently improved. Hospitalization was again indicated in October, 1970, for threatened rejection. Treatment with methylprednisolone sodium succinate (Solu-Medrol), 1 G m. daily, was successful in reversing the rejection. Following transplantation, the patient’s hematocrit steadily increased for six months reaching a level of 55 in January, 1971 (Fig. 4). An open renal biopsy in August, 1971, revealed mild interstitial fibrosis and focal pyelonephritis. For two and one-half years his hematocrit remained
65-
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IO
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14
16
18
20
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FIGURE
3.
Case 2. Hematologic
0
4
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12
data serum creatinine
16
20
24
28
32
levels, and
36
40
drug treatment.
44
48
52
MONTHS
FIGURE
UROLOGY
4.
/ AUGUST1975
Case 3. Hematologic
/ VOLUMEVI,
data serum creatinine
NUMBER2
levels, and drug treatment.
161
unchanged; however, in March, 1973, his creatinine rose to 2 mg. per 100 ml. resulting in more vigorous immunosuppressive therapy. In September, 1973, despite no apparent deterioration in his renal function, his hematocrit rose to 62. A serum erythropoietin level performed soon after was 5.4 per cent (control 0.6 per cent). The red blood cell volume was 45 ml. per kilogram (normal 28 to 30 ml. per kilogram) and the plasma volume was 36 ml. per kilogram (normal 34 to 60 ml. per kilogram). Liver and brain scans, liver function studies, chest roentgenograms, mediastinal tomograms, arterial blood gases, coagulation studies, vitamin B12 binding capacity, and leukocyte alkaline phosphatase scores were within normal limits. Intravenous pyelogram revealed bilateral atrophic kidneys with the transplanted kidney appearing normal. Bone marrow studies revealed mild erythroid hyperplasia. No fibrin degradation products were present in the urine. lz51 fibrinogen uptake studies were inconclusive and 51Cr platelet sequestration studies showed no evidence of platelet trapping (Fig. 2A and B). Interestingly, superficial thrombophlebitis and later multiple pulmonary emboli developed. He was managed successfully with phlebotomy and anticoagulation. Currently, the patient’s renal function has remained stable, and he is being maintained on azathioprine 100 mg. per day and prednisone 25 mg. per day. Comment Erythropoietin is a hormone active in the regulation of red blood cell production. Secondary polycythemia may be due to a compensatory or inappropriate elaboration of erythropoietin. The latter may merely be a pathologic exaggeration of erythropoietin secretion by the tissues which normally produce it, or an inappropriate production and secretion by tissues not normally involved in its production. It is generally thought that the major source of erythropoietin or its precursor is the kidney. Extrarenal production has been documented, probably arising from the liver, but appears to be inadequate to maintain normal erythropoiesis. l2 The finding of elevated levels of serum erythropoietin in all of our patients indicated that the polycythemia was secondary and probably resulted from the transplanted kidney. It has been previously documented that renal artery clamping stimulates erythropoietin release in dogs.13 No clinical evidence of renal artery stenosis, such as bruit or delayed appearance of
162
contrast on intravenous pyelogram, was present in our cases, and the risk of arteriography did not appear warranted. Nies, Cohn, and Schrier’ noted that perhaps small vessel damage secondary to rejection led to renal ischemia and resultant erythropoietin release. Swales and Evans4 postulated that only a low-grade rejection process would produce polycythemia. Supporting this concept, Murphy et al. l5 have demonstrated that renal anoxia parallels erythropoietin release up to a point and that more severe degrees of anoxia (that is, renal cortical anaerobic glycolysis above 40 per cent) are not associated with significant erythropoietin release. It should be noted that even if certain hypoxic requirements for erythropoietin release were exceeded leading to erythropoietin production, polycythemia would not occur if the bone marrow was incapable of responding to the erythropoietin stimulus. The damaging effects of immunosuppressive therapy and/or uremia on bone marrow may account for the relative rarity of polycythemia in renal allograft recipients. To investigate this further, the sera of all patients who have had successful transplants are presently being assayed for erythropoietin activity. In these 3 patients multiple studies were performed to detect chronic low-grade rejection. All tests of renal function remained unchanged. In addition no fibrinogen trapping in the transplanted kidneys could clearly be shown, and no fibrin degradation products were present in the urine, suggesting that fibrinogen was not being deposited in the microvasculature of the transplanted kidney. However, in 1 patient (Case 1) platelet trapping, which is an index of vascular damage, did occur within the first twenty-four hours (Fig. 2A and B). All of our patients had an elevated red blood cell mass with normal plasma volumes, indicating “true” polycythemia. Swales and Evans4 reported 4 of 6 patients having contracted plasma volumes and therefore a “relative” polycythemia. “True” polycythemia can be either primary (polycythemia Vera) or secondary. Polycythemia vera appeared unlikely because of normal white blood counts, platelet counts, leukocyte alkaline phosphatase scores, vitamin B12 binding capacities, and, most important, elevated serum erythropoietin values. An attempt was then made to rule out all secondary causes of polycythemia. It is well known that patients on chronic immunosuppressive therapy have a higher incidence of malignancy than the general population. Studies were performed to exclude renal, cerebellar,
UROLOGY
/ AUGUST 1975 / VOLUME
VI, NUMBER
2
adrenal, uterine, ovarian, and liver malignancy. In addition, renal cysts, hydronephrosis, and causes of tissue hypoxia were excluded. It is interesting to speculate that excessive erythropoietin secretion might in fact be arising from the patient’s own kidneys. Varkarakis et al. 6 report on 1 case which showed reversal of polycythemia following bilateral nephrectomy of the patient’s own glomerulonephritic kidneys. One can only speculate whether bilateral nephrectomy would be of benefit in our cases. Perhaps selective renal vein erythropoietin levels would have been of value; however, since previously reported cases indicate that this process is self-limiting and not necessarily of bad prognostic significance, more invasive measures were not indicated in these cases. Most investigators report polycythemia occurring three to four months following transplantation, with the exception of 1 case reported by Swales and Evans4 in which polycythemia developed fifteen months following transplantation. Most of the cases reported maintain their polycythemic state from six to fourteen months then spontaneously return to normal ranges. Our cases demonstrated the first onset of polycythemia seven to thirteen months following transplantation and have all persisted to the present time. The duration of polycythemia in these cases was ten, sixteen, and forty-eight months (Figs. 1, 3 and 4). Wu et all6 reported the development of polycythemia in 2 patients after each received a graft from the same cadaver donor. They postulated that it was likely that the kidneys from the donor contributed to the development of true polycythemia. This was not the case, however, in our series since polycythemia failed to develop in 2 other recipients of kidneys from the same cadavers. Some investigators report a high incidence of thromboembolic complications and note that the major morbidity is due to this rather than rejection In 1 patient in our series (Case 3) thrombophlebitis developed in a lower extremity nearly four years following the onset ofpolycythemia at a time when his hematocrit was 60. Subsequently pulmonary emboli developed, which were documented by lung scan. He was treated successfu 11y with phlebotomy and anticoagulation. We believe that to lessen the morbidity which results from these complications, hematocrits should be maintained below 55 and prompt an-
UROLOGY /
AUGUST 1975 /
VOLUME VI, NUMBER 2
ticoagulation boembolism
therapy occur.
begun
if signs of throm-
Irvine, California 92664 (DR.
ACKNOWLEDGMENT. Mortimer Joyce Hostetler, R.N., cooperated vided technical assistance.
Morton,
NELLANS)
M. D., and
with this study and pro-
References
1. NIES, B. A., COHN, R., and SCHRIER, S. L.: Erythemiaafter renal transplantation, N. Engl. J. Med. 273: 785 (1965). 2.
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DENNY, W. F., FLANNIGAN,W. J., and ZUKOSHI,C. F. : Serial erythropoietin studies in patients undergoing renal homotransplantation, J. Lab. Clin. Med. 67: 386 (1966). ABBRECHT, P. H., and GREENE, J. A., JR.: Serum erythropoietin after renal homotransplantation, Ann. Intern. Med. 65: 908 (1966). SWALES, J. D., and EVANS, D. B.: Erythemiain renal transplantation, Br. Med. J. 2: 80 (1969). JEPSON, J. H., et al. : Characteristics of erythropoiesis following human renal homotransplantation, Transplant. Proc. 3: 353 (1971). VARKARAKIS,M. J., et al.: Polycythemia following renal transplantation unrelated to the allograft, J. Surg. Oncol. 3: 157 (1971). YEBOAH, E. D., CHISHOLM,G. D., SHORT, M. D., and PETRIE, A. : The detection and prediction of acute rejection episodes in human renal transplants using radioactive fibrinogen, Br. J. Urol. 45: 273 (1973). ABBRECHT, P. H., TURCOTTE, J. G., and VAXDER, A. J.: Plasma erythropoietin and renin activity after canine renal allotransplantation, J. Lab. Clin. Med. 71: 766 (1968). PROCTOR, R. R., and RAPAPORT,S. I.: The partial thromboplastin time with kaolin. A simple screening test for first stage plasma clotting factor deficiencies, Am. J. Clin. Pathol.
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QUICK,A. J., STANLEY-BROWN,M., ~~~BANCROFT, F. W.: A study of the coagulation defect in hemophilia and in jaundice, Am. J. Med. Sci. 190: 501 (1935). STORMORKEN,H.: The preparation of proaccelerin deficient (parahemophilia) plasma for the assay of proacceleria, Stand. J. Clin. Lab. Invest, 9: 273 (1957). POOL, J. G., and ROBINSON,J. : Assay of plasma antihemophilia globulin (AHG), Br. J, Hematol. 5: 17 (1959). MORTON, M.: Personal communication, 1974. MERSKEY, C., KLEINER, G. G., and JOHNSON, A. J. : Quantitative estimation of split products of fibrinogen in human serum, relation to diagnosis and treatment, Blood 28: 1 (1966). MURPHY, G. P., et al.: Correlation of renal metabolism with erythropoietin release in hypertensive dogs with renal artery stenosis, Invest. Urol. 4: 372 (1967).
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