Renal Transplantation for Progressive Systemic Sclerosis with Renal Failure Case Repot-tand Review of Previous Experience George E. Merino, MD, MS, Minneapolis, Minnesota David E. R. Sutherland, MD, PhD, Minneapolis, Minnesota Carl M. Kjellstrand, MD, Minneapolis, Minnesota Richard L. Simmons, MD, Minneapolis, Minnesota John S. Najarian, MD, Minneapolis, Minnesota
Rapidly progressive renal failure is the most lethal and unpredictable manifestation of scleroderma (primary systemic sclerosis [PSS]) [I]. PSS patients whose kidneys are also involved apparently have a poorer prognosis than patients whose kidneys are unaffected [2-41. Therefore, replacing the PSS-damaged kidney by transplantation when the lesions in other organs are not life threatening appears justified. Since the pathophysiology of the renal syndrome is obscure, the fate of the transplanted kidney can only be surmised. Nephrectomy and transplantation in PSS patients raise intriguing possibilities, such as whether or not PSS will recur in the grafted kidneys and if immunosuppressive drugs will interfere with the natural course of the disease. According to a representative of the American College of Surgeons, National Institute of Health, Renal Transplant Registry (telephone interview, August 1976), six patients have received kidney transplants for PSS-induced renal failure. Information on three of them is available in the literature [5-71. Details on two other patients were forwarded to us through personal communications [12,13]. This is a report of our experience with one other PSS patient whose cadaveric kidney transplant rapidly deteriorated over a three month period.
From the Departments of Surgery and Medicine, University of Minnesota Health Sciences Center, Minneapolis, Minnesota. Reprint requests should be addressed to George E. Merino, MD, Box 41 Mayo Memorial Building, University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455.
Volume 133, June 1977
Case Report Clinical History
A forty-one year old woman was transferred on July 3, of Minnesota Hospitals for acute onset of hypertension and azotemia. Two weeks before, she had been hospitalized elsewhere for Raynaud’s syndrome, hemoptysis, chest pain, and peripheral edema. A diagnosis of pleuropericarditis with moderate heart failure was made. She was severely hypertensive and was receiving 100 mg of furosemide (Lasix@) per’ day. The patient had been treated with little effect with prednisone (40 mg/day) and phenilbutazone (400 mg/day) for seronegative arthritis involving the wrists, elbows, knees, and ankles. Results of the latex fixation test, LE cell preparation, and sedimentation rate test had all been within normal limits. When we first examined the patient, she was lethargic and severely hypertensive (blood pressure, 210/130 mm Hg). She had arteriolar narrowing of fundi, cyanotic atrophy of the fingertips, and thickening of hand skin and hand joints. Bilateral basilar rales were audible, and presacral and pretibial edema were also present. Hemoglobin level was 12.2 gm/lOO ml, white blood cell count 15,200, blood urea nitrogen level (BUN) 115 mg/lOO ml, creatinine clearance 6.5 mg/lOO ml, potassium (K+) 7.6 mEq/lOO ml, and platelet count 112,000/mm3. There was 2+ proteinuria. A renal arteriogram demonstrated normal renal arteries with poor visualization of the intrarenal branches and absent visualization of the arcades and interlobular arteries (no nephrographic effect). Both kidneys were 11 cm in diameter. The patient was treated with hemodialysis, methyldopa (Aldomete), and hydralazine. The result of a skin biopsy confirmed the diagnosis of PSS. One week after admission a combined bilateral nephrectomy and splenectomy procedure was performed as 1975 to the University
745
Merino et al
Figure 1. Progressive systemic sclerosis is apparent in this skin biopsy specimen from our paiienf. Atrophy of fhe epidermis and collagen hypertrophy of the dermis are visible. (Hematoxylin and eosin stain; original magnff/cation X 60; reduced 10 per cent. )
a preparation for kidney transplantation. The patient’s blood pressure dramatically returned to normal values. In October, three months after admission, she received a kidney’transplant from a 2-HL-A antigen-matched cadaver donor. The graft functioned immediately. The postoperative course was complicated by a urinary leak at the ureterocystic junction that required ureteral reimplantation. Renal function normalized progressively during the next three weeks and the patient returned home in November. At that time her serum creatinine level was stable at 1.3 mg/lOO ml, BUN was 45 mg/lOO ml, and urinalysis results were within normal limits. She was receiving 30 mg of prednisone and 75 mg of azathioprine (Imuran@) daily. One month later the patient was rehospitalized because of a rapid increase in her serum creatinine level to 2.4 mg/lOO ml. BUN was 94 mg/lOO ml, blood pressure 175/110 mm Hg, and there was 2+ proteinuria. The patient received a standard antirejection regimen [8] plus three separate radiation treatments of 250 r every other day for six days. Creatinine levels continued to rise steadily and blood pressure remained greater than 110mm Hg diastolic. Nine days later the antirejection regimen was repeated plus injection of antilymphocyte globulins (ALG), 40 mg/kg body weight, for four days. She required platelet transfusion when her platelet count decreased to 24,000/mm3; her
746
Figure 2. Interstitial fibrosis and concentric intimal hyperptasia of the interlobular arteries are seen in the patient’s own kidneys. ( Trichrome stain; origina/ magnification X 750; reduced 10 per cent. )
white blood count reached a low value of 2,400 cel!s/ mm3. In December, three months after transplantation, transplant nephrectomy was performed. The patient’s status improved. She is now on chronic hemodialysis. Pathology
An initial histologic examination of the &in reyealed atrophy of the epidermis and appendages, homogenization and hypertrophy of the collagen bundles of the dermis, and fibrinoid changes of the small arteriolar vessels with chronic perivascular inflammation. (Figure 1.) The patient’s kidneys had a grossly granular appearance with an atrophic renal cortex. Microscopically, the most nbticeable changes were in the interlobular arteries and afferent arterioles where concentric intimal hyaerplasia had caused significant narrowing of the lumina of the vessels. There was extensive interstitial fibrosis and tubular atrophy. (Figure 2.) Antihuman IgM was densely present in the afferent arteriolar endothelium and the glomerular basement membrane. The stain for IgG and IgA was scarcely positive and there were traces of CAand Cd along the vascular endothelium. Grossly, the transplanted kidney was pale and edematous with petechial hemorrhages. There was prominent intimal thickening of the interlobular arteries and afferent arteriolae consisting of concentric, mucoid, edematous,
The AmericanJournal
of Surgery
Progressive Systemic Sclerosis
Figure 3. lhe mucoid intimal proliferation an of interlobular artery in the grafted kidney three months after transplantation. Trichrome ( stain; original magnification X 375; reduced per 10 cent. )
Figure 4. Fibrinoid necrosis and glomerular mesangiai proliferation are also apparent in this biopsy specimen of the transplanted kidney. Trichrome ( stain; original magnification X 375; reduced per 70 cent. )
intimal thickening. (Figure 3.) The arcuate and larger arteries were entirely normal. Interstitial fibrosis and collagen condensation were abundant and mononuclear infiltrates were either scarce or absent. Glomerular changes included globulation of the tufts with glomerular extension of the arteriolar fibrinoid necrosis and increased thickness of the mesangium and capillary loops. (Figure 4.) Immunofluorescence studies revealed antihuman IgM, fibrin stain involving interlobular arteries, and glomerular capillaries. C:j and Cd were also present.
a clinical
Comments Kidneys are a frequent site of involvement in PSS, although conflicting incidences have been reported. In the largest series of patients with scleroderma, Tuffanelli and Winkelmann [4] identified only nineteen (2.6 per cent) of 727 patients as having serious renal disease. In 1969 D’Angelo et al [9] analyzed the autopsy results of patients with PSS, comparing their findings with the autopsy reports of fifty-eight other patients who died of other diseases. The characteristic renal lesion of PSS was observed in 58 per cent of the patients with PSS but in only 8.9 per cent of the controls. Cannon et al [6) calculated
Volume 133, June 1977
incidence of renal disease of 45 per cent of 210 patients with PSS who were reviewed retrospectively. Of the forty patients who were subjected to postmortem examination, 90 per cent had histologic evidence of renal abnormalities. Despite the relatively high frequency of renal failure as the cause of death in PSS patients, dialysis and transplantation have seldom been used. Because of the abnormal clotting and frequent occlusion of arterial-venous shunts, fistulas, or grafts, chronic hemodialysis is more difficult in these patients [5,10]. The progressive nature of PSS and the associated multiple organ involvement have often discouraged treatment by renal transplantation. The first account of renal transplantation in a patient with PSS [5] reported excellent function of the cadaver donor allograft at the last evaluation eighteen months after transplantation. (Table I, patient 1.) The transplant was done in June 1970 on a forty year old seaman with polyarthalgias and Raynaud’s phenomenon for fifteen years before the onset of rapidly progressive renal failure and severe hypertension. Skin biopsy and biopsy of the patient’s own kidney were unquestionably diagnostic of diffuse
747
Merino et al
TABLE I
Summary of Data for PSS Patients Who
Received
a Kidney
Transplant
Time from PSS Onset Patient No.
Sex/Age (yr)
1
M/40
2
F/23
3 yr
240/l
3
F/40
5 yr
185/105
4
M/31
2 yr
190/l
5
F/24
10 mo
2301130
Mother
6
F/41
4 mo
210/130
Cadaver
*Highest
Transpktation
measurement
Hypertension* (mm Hg) 200/120
15yr
50
Source of Graft
Function Graft
Cadaver
Excellent at 18 mo Very poor at 3 yr Excellent at 14 mo Excellent at 14 mo Removed at2mo Removed at3mo
Mother Mother
10
Sister
Histology Graft
of Reported
No biopsy
Richardson
Chronic rejection No biopsy
Cannon
No biopsy
Anderson
Recurrent scleroderma Recurrent scleroderma
Woodhall
Hayes
Merino
by [5]
et al [6] [12] [13] et al [7] et al
reported.
PSS. In the eighteen months after successful renal transplantation and immunosuppression including prednisone, the systemic manifestations of PSS were largely improved. In 1974 Cannon et al [6] reported continued function of a kidney transplant from a living related donor at the time of their report, seven months after transplantation. (Table I, patient 2.) This patient, a twenty-three year old woman who underwent transplantation in July 1973 had Raynaud’s phenomenon and had had a positive skin biopsy for PSS since two years before transplantation. She was severely hypertensive until bilateral nephrectomy. The histopathology of her kidneys was undoubtedly that of PSS. After transplantation and immunosuppression with azathioprine and prednisone, her Raynaud’s syndrome and sclerodactyly remained stable. From personal communication [II] we understand that the patient’s graft functioned well for two years but during the third year deteriorated rapidly. In June 1975 her creatinine clearance was 5 ml/min, and the result of the kidney biopsy was consistent with chronic rejection, with no specific changes indicating that PSS had recurred [II 1. Another patient underwent transplantation in Ju!y 1973 in Sidney, Australia [12]. This forty year old woman (Table I, patient 3) had had PSS since 1970 when she first manifested Raynaud’s phenomenon, hypertension, esophageal dismotility, positive antinuclear factor, and progressive renal failure. Because of the impossibility of obtaining vascular accesses to her limbs, the patient had been on peritoneal dialysis for one month prior to transplantation. She received a 2 HL-A antigen-matched kidney from her mother and was treated with azathioprine and prednisone. The graft function is excellent three years later, with
748
of
a serum creatinine level of 1.3 mg/lOO ml. The patient is normotensive. Her own kidneys have been left in place. No histopathologic evidence of PSS was obtained. In another instance, (Table I, patient 4) a thirtyone year old man with biopsy-proved PSS, renal failure, Raynaud’s phenomenon, and hypertension since late 1973, received an antigen-matched kidney from a sister in August 1974. His renal function is excellent fourteen months after transplantation with apparent improvement of the systemic lesions. The graft had not been biopsied at the time of communication [13]. In a recent report, Woodhall et al [7] described the case of a twenty-four year old woman with biopsyproved PSS, severe hypertension, and renal failure who received a living related donor kidney graft in September 1974 immediately after a bilateral nephrectomy procedure. (Table I, patient 5.) The initial graft function was excellent on an immunosuppressive regimen of cyclophosphamide, azathioprine, and prednisone. One month later accelerated loss of allograft function occurred. Methylprednisolone and radiation treatment were unsuccessful and the graft was removed two months after transplantation. Histopathology and immunofluorescence study of the graft were characteristic of an acute PSS kidney, and antinuclear antibodies, characteristic of PSS, could be demonstrated from eluates of the graft as well as from the patient’s own kidneys. The latter case and our own case (Table I, patient 6) have in-common the rapid progressive deterioration of the transplanted kidney together with the total unresponsiveness to antirejection treatment and the swift recurrence of intrarenal vascular disease typical of PSS.
The American Journal of Surgery
Progressive Systemic Sclerosis
The mucoid intimal proliferation of the interlobular and afferent arterioles, the periadventitial fibrosis and mesangial hypercellularity, the scarcity of lymphoid infiltrate, the immunohistochemical findings identical to those in the patient’s own kidneys would also indicate acute recurrence of PSS in the transplanted kidney. However, malignant nephrosclerosis, acute rejection, and acute scleroderma share histologic and histochemical findings and perhaps immunologic mechanisms to the point that, at least in our case, some doubt is still justified. The possible interference of PSS with the rejection mechanism and the interference of the immunosuppressive regimen on the progression of the systemic disease remain open to speculation. The progression of PSS appears somewhat more rapid and aggressive in patients 5 and 6 (Table I) than in the first four patients with successful transplantations. This suggests that a malignant or acute pattern of PSS leading to renal failure is related to rapid recurrence of renal PSS lesions. Further evidence is of course needed. However, since it is likely that renal transplantation as a treatment for PSS with renal failure will receive larger acceptance in the future, a word of caut,ion concerning patient selection and prognosis is indicated. Summary Renal transplantation for terminal renal failure as a result of scleroderma (progressive systemic sclerosis [PSS]) seems justified if other organs have not been severely damaged by the disease. The recurrence of PSS in the graft, not observed in early reports,’ appears to have caused the rapid failure of a cadaveric graft in a forty year old woman with acute PSS. A similar case of rapid PSS recurrence in the transplant
Volume 133, June 1977
has been recently reported by others [ 71. A more aggressive pattern of PSS seems to differentiate these two patients in whom recurrence was observed from four previous patients with long-term graft function. The possibility of rapid renal transplant loss should be considered in the selection and prognosis of acute PSS patients. References 1. Jensen EH, Lund J: Acute nephropathy as cause of death in scleroderma. A ten-year review from Denmark. Dan MedBu// 18: 79,1971. 2. Medsger TA Jr, Masi AT, Rodnan GP, et al: Survival with systemic sclerosis (scleroderma). A life-table analysis of clinical and demographic factors in 309 patients. Ann lntem Med 75: 369, 1971. 3. Moore HC, Sheehan HL: The kidney of scleroderma. Lancet 1: 68, 1952. 4. Tuffanelli DL, Winkelmann RK: Systemic scleroderma. A clinical study of 727 cases. Arch Dermatol84: 359, 1961, 5. Richardson JA: Hemodialysis and kidney transplantation for renal failure from scleroderma. Arthritis Rheum 16: 265, 1973. 6. Cannon PJ, Hassar M, Case DB, et al: The relationship of hypertension and renal failure in scleroderma (progressive systemic sclerosis) to structural and functional abnormalities of the renal cortical circulation. Medicine 53: 1, 1974. 7. Woodhall PB, McCoy RC, Gunnells JC, Seigler HF: Apparent recurrence of progressive systemic sclerosis in a renal allograft. JAMA 236: 1032, 1976. 8. Foker JE, Najarian JS: Technique, Complications and Results, p 123. Transplantation, Vol2 (Najarian JS, Simmons RL, ed). Philadelphia, Lea & Febiger, 1972. 9. D’Angelo WA, Fries JF, Masi AT, et al: Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med 46: 428, 1969. 10. Dichosos CC: The kidney in progressive systemic sclerosis, p 57. The Kidney in Systemic Disease (Suki WN, Eknoyan G, ed). New York, John Wiley, 1976. 11. Jacob G: Personal communication. Columbia Presbyterian Medical Center, New York, August 1976. 12. Hayes JM: Personal communication. St. Vincent’s Hospital, Darlingurst, Sidney, Australia, October 1976. 13. Anderson RC: Personal communication. Hennepin General Hospital, Minneapolis, Minnesota, August 1976.
749
Rapidly progressive renal failure is the most lethal and unpredictable manifestation of scleroderma (primary systemic sclerosis [PSS]) [I]. PSS patients whose kidneys are also involved apparently have a poorer prognosis than patients whose kidneys are unaffected [2-41. Therefore, replacing the PSS-damaged kidney by transplantation when the lesions in other organs are not life threatening appears justified. Since the pathophysiology of the renal syndrome is obscure, the fate of the transplanted kidney can only be surmised. Nephrectomy and transplantation in PSS patients raise intriguing possibilities, such as whether or not PSS will recur in the grafted kidneys and if immunosuppressive drugs will interfere with the natural course of the disease. According to a representative of the American College of Surgeons, National Institute of Health, Renal Transplant Registry (telephone interview, August 1976), six patients have received kidney transplants for PSS-induced renal failure. Information on three of them is available in the literature [5-71. Details on two other patients were forwarded to us through personal communications [12,13]. This is a report of our experience with one other PSS patient whose cadaveric kidney transplant rapidly deteriorated over a three month period.
From the Departments of Surgery and Medicine, University of Minnesota Health Sciences Center, Minneapolis, Minnesota. Reprint requests should be addressed to George E. Merino, MD, Box 41 Mayo Memorial Building, University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455.
Volume 133, June 1977
Case Report Clinical History
A forty-one year old woman was transferred on July 3, of Minnesota Hospitals for acute onset of hypertension and azotemia. Two weeks before, she had been hospitalized elsewhere for Raynaud’s syndrome, hemoptysis, chest pain, and peripheral edema. A diagnosis of pleuropericarditis with moderate heart failure was made. She was severely hypertensive and was receiving 100 mg of furosemide (Lasix@) per’ day. The patient had been treated with little effect with prednisone (40 mg/day) and phenilbutazone (400 mg/day) for seronegative arthritis involving the wrists, elbows, knees, and ankles. Results of the latex fixation test, LE cell preparation, and sedimentation rate test had all been within normal limits. When we first examined the patient, she was lethargic and severely hypertensive (blood pressure, 210/130 mm Hg). She had arteriolar narrowing of fundi, cyanotic atrophy of the fingertips, and thickening of hand skin and hand joints. Bilateral basilar rales were audible, and presacral and pretibial edema were also present. Hemoglobin level was 12.2 gm/lOO ml, white blood cell count 15,200, blood urea nitrogen level (BUN) 115 mg/lOO ml, creatinine clearance 6.5 mg/lOO ml, potassium (K+) 7.6 mEq/lOO ml, and platelet count 112,000/mm3. There was 2+ proteinuria. A renal arteriogram demonstrated normal renal arteries with poor visualization of the intrarenal branches and absent visualization of the arcades and interlobular arteries (no nephrographic effect). Both kidneys were 11 cm in diameter. The patient was treated with hemodialysis, methyldopa (Aldomete), and hydralazine. The result of a skin biopsy confirmed the diagnosis of PSS. One week after admission a combined bilateral nephrectomy and splenectomy procedure was performed as 1975 to the University
745
Merino et al
Figure 1. Progressive systemic sclerosis is apparent in this skin biopsy specimen from our paiienf. Atrophy of fhe epidermis and collagen hypertrophy of the dermis are visible. (Hematoxylin and eosin stain; original magnff/cation X 60; reduced 10 per cent. )
a preparation for kidney transplantation. The patient’s blood pressure dramatically returned to normal values. In October, three months after admission, she received a kidney’transplant from a 2-HL-A antigen-matched cadaver donor. The graft functioned immediately. The postoperative course was complicated by a urinary leak at the ureterocystic junction that required ureteral reimplantation. Renal function normalized progressively during the next three weeks and the patient returned home in November. At that time her serum creatinine level was stable at 1.3 mg/lOO ml, BUN was 45 mg/lOO ml, and urinalysis results were within normal limits. She was receiving 30 mg of prednisone and 75 mg of azathioprine (Imuran@) daily. One month later the patient was rehospitalized because of a rapid increase in her serum creatinine level to 2.4 mg/lOO ml. BUN was 94 mg/lOO ml, blood pressure 175/110 mm Hg, and there was 2+ proteinuria. The patient received a standard antirejection regimen [8] plus three separate radiation treatments of 250 r every other day for six days. Creatinine levels continued to rise steadily and blood pressure remained greater than 110mm Hg diastolic. Nine days later the antirejection regimen was repeated plus injection of antilymphocyte globulins (ALG), 40 mg/kg body weight, for four days. She required platelet transfusion when her platelet count decreased to 24,000/mm3; her
746
Figure 2. Interstitial fibrosis and concentric intimal hyperptasia of the interlobular arteries are seen in the patient’s own kidneys. ( Trichrome stain; origina/ magnification X 750; reduced 10 per cent. )
white blood count reached a low value of 2,400 cel!s/ mm3. In December, three months after transplantation, transplant nephrectomy was performed. The patient’s status improved. She is now on chronic hemodialysis. Pathology
An initial histologic examination of the &in reyealed atrophy of the epidermis and appendages, homogenization and hypertrophy of the collagen bundles of the dermis, and fibrinoid changes of the small arteriolar vessels with chronic perivascular inflammation. (Figure 1.) The patient’s kidneys had a grossly granular appearance with an atrophic renal cortex. Microscopically, the most nbticeable changes were in the interlobular arteries and afferent arterioles where concentric intimal hyaerplasia had caused significant narrowing of the lumina of the vessels. There was extensive interstitial fibrosis and tubular atrophy. (Figure 2.) Antihuman IgM was densely present in the afferent arteriolar endothelium and the glomerular basement membrane. The stain for IgG and IgA was scarcely positive and there were traces of CAand Cd along the vascular endothelium. Grossly, the transplanted kidney was pale and edematous with petechial hemorrhages. There was prominent intimal thickening of the interlobular arteries and afferent arteriolae consisting of concentric, mucoid, edematous,
The AmericanJournal
of Surgery
Progressive Systemic Sclerosis
Figure 3. lhe mucoid intimal proliferation an of interlobular artery in the grafted kidney three months after transplantation. Trichrome ( stain; original magnification X 375; reduced per 10 cent. )
Figure 4. Fibrinoid necrosis and glomerular mesangiai proliferation are also apparent in this biopsy specimen of the transplanted kidney. Trichrome ( stain; original magnification X 375; reduced per 70 cent. )
intimal thickening. (Figure 3.) The arcuate and larger arteries were entirely normal. Interstitial fibrosis and collagen condensation were abundant and mononuclear infiltrates were either scarce or absent. Glomerular changes included globulation of the tufts with glomerular extension of the arteriolar fibrinoid necrosis and increased thickness of the mesangium and capillary loops. (Figure 4.) Immunofluorescence studies revealed antihuman IgM, fibrin stain involving interlobular arteries, and glomerular capillaries. C:j and Cd were also present.
a clinical
Comments Kidneys are a frequent site of involvement in PSS, although conflicting incidences have been reported. In the largest series of patients with scleroderma, Tuffanelli and Winkelmann [4] identified only nineteen (2.6 per cent) of 727 patients as having serious renal disease. In 1969 D’Angelo et al [9] analyzed the autopsy results of patients with PSS, comparing their findings with the autopsy reports of fifty-eight other patients who died of other diseases. The characteristic renal lesion of PSS was observed in 58 per cent of the patients with PSS but in only 8.9 per cent of the controls. Cannon et al [6) calculated
Volume 133, June 1977
incidence of renal disease of 45 per cent of 210 patients with PSS who were reviewed retrospectively. Of the forty patients who were subjected to postmortem examination, 90 per cent had histologic evidence of renal abnormalities. Despite the relatively high frequency of renal failure as the cause of death in PSS patients, dialysis and transplantation have seldom been used. Because of the abnormal clotting and frequent occlusion of arterial-venous shunts, fistulas, or grafts, chronic hemodialysis is more difficult in these patients [5,10]. The progressive nature of PSS and the associated multiple organ involvement have often discouraged treatment by renal transplantation. The first account of renal transplantation in a patient with PSS [5] reported excellent function of the cadaver donor allograft at the last evaluation eighteen months after transplantation. (Table I, patient 1.) The transplant was done in June 1970 on a forty year old seaman with polyarthalgias and Raynaud’s phenomenon for fifteen years before the onset of rapidly progressive renal failure and severe hypertension. Skin biopsy and biopsy of the patient’s own kidney were unquestionably diagnostic of diffuse
747
Merino et al
TABLE I
Summary of Data for PSS Patients Who
Received
a Kidney
Transplant
Time from PSS Onset Patient No.
Sex/Age (yr)
1
M/40
2
F/23
3 yr
240/l
3
F/40
5 yr
185/105
4
M/31
2 yr
190/l
5
F/24
10 mo
2301130
Mother
6
F/41
4 mo
210/130
Cadaver
*Highest
Transpktation
measurement
Hypertension* (mm Hg) 200/120
15yr
50
Source of Graft
Function Graft
Cadaver
Excellent at 18 mo Very poor at 3 yr Excellent at 14 mo Excellent at 14 mo Removed at2mo Removed at3mo
Mother Mother
10
Sister
Histology Graft
of Reported
No biopsy
Richardson
Chronic rejection No biopsy
Cannon
No biopsy
Anderson
Recurrent scleroderma Recurrent scleroderma
Woodhall
Hayes
Merino
by [5]
et al [6] [12] [13] et al [7] et al
reported.
PSS. In the eighteen months after successful renal transplantation and immunosuppression including prednisone, the systemic manifestations of PSS were largely improved. In 1974 Cannon et al [6] reported continued function of a kidney transplant from a living related donor at the time of their report, seven months after transplantation. (Table I, patient 2.) This patient, a twenty-three year old woman who underwent transplantation in July 1973 had Raynaud’s phenomenon and had had a positive skin biopsy for PSS since two years before transplantation. She was severely hypertensive until bilateral nephrectomy. The histopathology of her kidneys was undoubtedly that of PSS. After transplantation and immunosuppression with azathioprine and prednisone, her Raynaud’s syndrome and sclerodactyly remained stable. From personal communication [II] we understand that the patient’s graft functioned well for two years but during the third year deteriorated rapidly. In June 1975 her creatinine clearance was 5 ml/min, and the result of the kidney biopsy was consistent with chronic rejection, with no specific changes indicating that PSS had recurred [II 1. Another patient underwent transplantation in Ju!y 1973 in Sidney, Australia [12]. This forty year old woman (Table I, patient 3) had had PSS since 1970 when she first manifested Raynaud’s phenomenon, hypertension, esophageal dismotility, positive antinuclear factor, and progressive renal failure. Because of the impossibility of obtaining vascular accesses to her limbs, the patient had been on peritoneal dialysis for one month prior to transplantation. She received a 2 HL-A antigen-matched kidney from her mother and was treated with azathioprine and prednisone. The graft function is excellent three years later, with
748
of
a serum creatinine level of 1.3 mg/lOO ml. The patient is normotensive. Her own kidneys have been left in place. No histopathologic evidence of PSS was obtained. In another instance, (Table I, patient 4) a thirtyone year old man with biopsy-proved PSS, renal failure, Raynaud’s phenomenon, and hypertension since late 1973, received an antigen-matched kidney from a sister in August 1974. His renal function is excellent fourteen months after transplantation with apparent improvement of the systemic lesions. The graft had not been biopsied at the time of communication [13]. In a recent report, Woodhall et al [7] described the case of a twenty-four year old woman with biopsyproved PSS, severe hypertension, and renal failure who received a living related donor kidney graft in September 1974 immediately after a bilateral nephrectomy procedure. (Table I, patient 5.) The initial graft function was excellent on an immunosuppressive regimen of cyclophosphamide, azathioprine, and prednisone. One month later accelerated loss of allograft function occurred. Methylprednisolone and radiation treatment were unsuccessful and the graft was removed two months after transplantation. Histopathology and immunofluorescence study of the graft were characteristic of an acute PSS kidney, and antinuclear antibodies, characteristic of PSS, could be demonstrated from eluates of the graft as well as from the patient’s own kidneys. The latter case and our own case (Table I, patient 6) have in-common the rapid progressive deterioration of the transplanted kidney together with the total unresponsiveness to antirejection treatment and the swift recurrence of intrarenal vascular disease typical of PSS.
The American Journal of Surgery
Progressive Systemic Sclerosis
The mucoid intimal proliferation of the interlobular and afferent arterioles, the periadventitial fibrosis and mesangial hypercellularity, the scarcity of lymphoid infiltrate, the immunohistochemical findings identical to those in the patient’s own kidneys would also indicate acute recurrence of PSS in the transplanted kidney. However, malignant nephrosclerosis, acute rejection, and acute scleroderma share histologic and histochemical findings and perhaps immunologic mechanisms to the point that, at least in our case, some doubt is still justified. The possible interference of PSS with the rejection mechanism and the interference of the immunosuppressive regimen on the progression of the systemic disease remain open to speculation. The progression of PSS appears somewhat more rapid and aggressive in patients 5 and 6 (Table I) than in the first four patients with successful transplantations. This suggests that a malignant or acute pattern of PSS leading to renal failure is related to rapid recurrence of renal PSS lesions. Further evidence is of course needed. However, since it is likely that renal transplantation as a treatment for PSS with renal failure will receive larger acceptance in the future, a word of caut,ion concerning patient selection and prognosis is indicated. Summary Renal transplantation for terminal renal failure as a result of scleroderma (progressive systemic sclerosis [PSS]) seems justified if other organs have not been severely damaged by the disease. The recurrence of PSS in the graft, not observed in early reports,’ appears to have caused the rapid failure of a cadaveric graft in a forty year old woman with acute PSS. A similar case of rapid PSS recurrence in the transplant
Volume 133, June 1977
has been recently reported by others [ 71. A more aggressive pattern of PSS seems to differentiate these two patients in whom recurrence was observed from four previous patients with long-term graft function. The possibility of rapid renal transplant loss should be considered in the selection and prognosis of acute PSS patients. References 1. Jensen EH, Lund J: Acute nephropathy as cause of death in scleroderma. A ten-year review from Denmark. Dan MedBu// 18: 79,1971. 2. Medsger TA Jr, Masi AT, Rodnan GP, et al: Survival with systemic sclerosis (scleroderma). A life-table analysis of clinical and demographic factors in 309 patients. Ann lntem Med 75: 369, 1971. 3. Moore HC, Sheehan HL: The kidney of scleroderma. Lancet 1: 68, 1952. 4. Tuffanelli DL, Winkelmann RK: Systemic scleroderma. A clinical study of 727 cases. Arch Dermatol84: 359, 1961, 5. Richardson JA: Hemodialysis and kidney transplantation for renal failure from scleroderma. Arthritis Rheum 16: 265, 1973. 6. Cannon PJ, Hassar M, Case DB, et al: The relationship of hypertension and renal failure in scleroderma (progressive systemic sclerosis) to structural and functional abnormalities of the renal cortical circulation. Medicine 53: 1, 1974. 7. Woodhall PB, McCoy RC, Gunnells JC, Seigler HF: Apparent recurrence of progressive systemic sclerosis in a renal allograft. JAMA 236: 1032, 1976. 8. Foker JE, Najarian JS: Technique, Complications and Results, p 123. Transplantation, Vol2 (Najarian JS, Simmons RL, ed). Philadelphia, Lea & Febiger, 1972. 9. D’Angelo WA, Fries JF, Masi AT, et al: Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med 46: 428, 1969. 10. Dichosos CC: The kidney in progressive systemic sclerosis, p 57. The Kidney in Systemic Disease (Suki WN, Eknoyan G, ed). New York, John Wiley, 1976. 11. Jacob G: Personal communication. Columbia Presbyterian Medical Center, New York, August 1976. 12. Hayes JM: Personal communication. St. Vincent’s Hospital, Darlingurst, Sidney, Australia, October 1976. 13. Anderson RC: Personal communication. Hennepin General Hospital, Minneapolis, Minnesota, August 1976.
749
