Renal Transplantation for Diabetic Glomerulosclerosis

Renal Transplantation for Diabetic Glomerulosclerosis JOHN S. NAJARIAN, M.D., CARL M. KJELLSTRAND, M.D., RICHARD L. SIMMONS, M.D., THEODORE J. BUSELMEIER, M.D., BARRY VON HARTITZSCH, M.D., FREDERICK C. GOETZ, M.D.

Tremia causes a significant number of deaths in patients with juvenile onset diabetes who are between the ages of 30 and 40 years old.8 Most dialysis and transplantation programs, however, exclude the insulin dependent diabetic from their program. The many potential inherent complications of these patients-poor wound healing, steroid intolerance, and poor resistance to infection-place them in a substantially higher risk category than patients who do not have diabetes. In addition, their rehabilitation potential is usually small because of progressive retinopathy, neuropathy, enteropathy, and cardiovascular disease. The predicted difficulties are all illustrated by the poor results described by several groups that used chronic hemodialysis for the treatment of diabetic renal failure. Blagg et al.1 have reported that eight of 12 patients started on hemodialysis had died within 1 year and no patient survived 2 years of dialysis. Four of the ten diabetic patients dialyzed by Drukker et al.3 died within a year, and Leonard et al.6 reported that 42 insulin dependent diabetic patients on hemodialysis (39 months average) had an overall mortality of 48%. Myocardial infarction was the most frequent cause of death, and progressive retinopathy markedly interfered with rehabilitation. Patients with diabetes have been routinely accepted for transplantation at the University of Minnesota since 1966. Between May, 1969 and December, 1972, two-

From the Departments of Surgery and Medicine, University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455.

thirds of all the patients with diabetes that were reported to the NIH/ACS Transplant Registry, were transplanted by us. Our first series of 10 diabetic patients received both pancreatic-duodenal and kidney transplants.7 The pancreatic-duodenal transplants were discontinued in May, 1969. Since then another 45 kidneys were transplanted to 40 insulin dependent diabetic patients for end-stage renal failure, and their results follow.

Materials and Methods No formal criteria for acceptance or rejection as a candidate for a kidney graft was applied, but six prospective patients were denied admittance to our program. Two were denied because of advanced age and four because of overwhelming complications of diabetes (neuropathy, blindness, peripheral vascular disease, heart failure.) Previous myocardial infarction, blindness or severe neuropathy were not individually regarded as contraindications, however, combinations of these complications usually excluded the patient as a transplant candidate. The mean age for the 40 transplanted diabetic patients (16 women, 24 men) at the time of transplantation was Supported by the National Institutes of Health Grants #MO 33.3 years (range 21-48). The mean duration of diabetes RROO400 and by a grant (RR-400) from the General Clinical was 19.8 years (range 11-34). The mean serum creatiResearch Centers Program of the Division of Research Resources, nine level at the time of the first dialysis (or transplanNational Institutes of Health. tation in one case) was 14.2 mg./100 ml. (range 5.8Reprint requests: Dr. John S. Najarian, Professor and Chairman, Department of Surgery, University of Minnesota Health 23.6), mean predialysis blood urea nitrogen was 110 Sciences Center, Box #195 Mayo Memorial Building, Minneapolis, mg./100 ml. (range 40-303). All had severe hypertension and all but one were receiving large doses of antiMinnesota 55455. Presented at the Annual Meeting of the American Surgical hypertensive drugs (Table 1). Association, Los Angeles, California, April 25-27, 1973. All of the prospective candidates, except two, were 477

NAJARIAN, KJELLSTRAND, SIMMONS, BUSELMEIER,

478 TABLE 1.

Characteristics of 40 Transplanted Patients with Diabetes Mellitus

Age (Years) Diabetes duration (Years) Follow-up months Creatinine when accepted BUN when accepted All insulin-dependent All except one severely hypertensive

Mean 33.3 19.8 20. 14.2 110.

Range 21-48 11-34 4-48

5.8-23.6 40-303

dialyzed, and underwent bilateral nephrectomy and splenectomy before receiving a transplant at a later date. One of the two exceptions did not receive dialysis before bilateral nephrectomy and splenectomy. The other patient received his transplant and splenectomy as one procedure; the patient's diseased kidneys were not excised. All patients underwent a series of routine treatments and diagnostic tests.4 EKG, chest roentgenograms, visual acuity testing according to the Snellen Method, and voiding cystourethrograms were performed in all patients. Antilymphocyte globulin (10-20 mg./Kg.) was given all patients for 10-14 days. Imuran therapy was started at 5 mg./Kg. and rapidly tapered to 3 mg./Kg. or less, if leukopenia and thrombocytopenia ensued. Recipients of related donor kidneys received starting doses of prednisone at 1 mg./Kg. 1 day; recipients of cadaver kidneys were started on 2 mg./Kg./day. The dosages were tapered to Y -1/3 mg./Kg. Rejection episodes were diagnosed by rising serum creatinine and abnormal renograms; they were treated with local irradiation, 1 Gm. methyl prednisolone IV for 3 days and an increase in oral Prednisone doses. The patients were hospitalized for 2-3 weeks after transplantation. They were then followed on an outpatient basis every other day for the first month and then at increasing intervals. No patient has been lost during

follow-up. Biopsy specimens of the donor kidneys taken at the time of transplant and then at 1, 2 and 3-year intervals, were evaluated by an independent pathology group, with the aid of light, immunofluorescence and electron microscopy. We have compared these kidneys transplanted in diabetic patients with other groups of renal recipients at the University of Minnesota. The first control group included 40 nondiabetic patients matched for age, sex and source of donor (cadaver or related). In the diabetic patients, who were transplanted, some instances have also been compared to all nondiabetic patients transplanted by us during the same period. Results Survival: Table 2 shows that 31 of the 40 diabetic patients (78%) are alive 4 months to 4 years after

HARTITZSCH AND GOETZ Ann. Surg. * October 1973

TABLE 2. Survival of Transplant Recipients with Diabetes Mellitus Patients 40 16 24 8 32 9 26 5

Total Women Men Cadaver Recipients Related Recipients 40 Years * two on dialysis

(%) (78) (88) (71) (88) (75) (67) (84) (60)

Alive 31* 14 17 7 24 6 22 3

transplantation. Eighty-eight % (seven of eight) of the cadaver kidney recipients are alive, while only 75% (24 of 32) of the diabetic patients who received kidneys from related donors are alive. Figure 1 shows the cumulative survival curve for the 40 diabetic patients. Four years post-transplantation 80% of the recipients of cadaver kidneys are alive, while only 45% of the patients who received kidneys from relatives are alive. Figure 2 shows the cumulative survival curve for all nondiabetic patients transplanted by us from 1968 to 1972. There is no difference between the groups in the survival of cadaver kidney recipients. The significant data are that 909% of the nondiabetic patients who received a related kidney are alive at 5 years, while only 45% of the diabetic recipients of related donor kidneys are alive at 4 years. No correlation could be made between survival rate and (a) duration of diabetes, (b) age of onset of diabetes, (c) visual acuity for the best and worst eye, (d) EKG abnormalities, or (e) increasing age (Table 2). Of five patients 100 Mo_ mem

.0--- @ Cadaver Donor m

m

M

(7/18 ah've)

0-

..' 0

50

Re/a/ed Donor (24/32 alive)

c

a1) .i_

0

2

3

4

5

Years Post Transplant FIG. 1. Cumulated survival of diabetic recipients after renal transplantation (1969-1972). For related donor recipients, the total survival was 75% but the cumulated 3Y2 year survival was only 4071. Many late deaths occurred in this group. The total survival of diabetic recipients receiving cadaver donor kidneys was 88%. The cumulated 3-year survival was 80%. Dialysis may act as a selection of "biologically fit" diabetic recipients waiting for long period of time for a cadaver kidney, only the "best" survive to be transplanted with a cadaver kidney.

DIABETIC GLOMERULOSCEROSIS

Vol. 178 * No. 4

100

Re/aoed Donor ,*-*oft _(74/82 GIIVe!

479

TABLE 3. Causes of Death in 40 Kidney Transplant Recipients with Diabetes Mellitus

Cadaver Donor (46/56 G/Ve} *

Myocardial infarct Infection Urological Complications Suicide One patient also had myocardial infarct

3 3* 2 1

50

(-)

2

3

4

5

Years Pbst Transplant FIG. 2. Cumulated survival of nondiabetic recipients age 15 to 45 years that were transplanted by us between 1968 and 1972. The results following cadaver transplant is approximately the same as for diabetic patients. The result following related transplants are markedly superior in the nondiabetic recipients (compare to Fig. 1).

the age of 40, two are dead, and are thus not different from the patients below 40. However, of the three surviving patients over age 40, one has had two serious

over

myocardial infarcts and one was hospitalized for 4 months after transplantation because of bladder complications. Sex of the patient was well correlated with survival; 16 women, only two (12%) are dead, but for 24 men, seven (29%) are dead. Thus, diabetic men have twice the death rate of women in our series. This is no different in nondiabetic patients. Causes of Death: Table 3 shows that nine patients with diabetes have died since receiving kidney grafts. Three deaths were caused primarily by fatal infections. Two patients had "pure" infectious deaths; overwhelming Herpes Simplex in one and pseudomonas septicemia in another. The third patient was dying of pneumonia when she developed a myocardial infarct and arrest. Myocardial infarcts were the primary cause of three other deaths. Urological problems caused the deaths of two other recipients. In one of these patients a paralyzed neurogenic bladder secondary to diabetes contributed to death that was caused by a combination of repeated rejection episodes and urinary tract infections. The second patient lost his second transplanted kidney because of a cystotomy rupture which led to repeated infections and marasmus on dialysis and ultimately death. One patient with ongoing severe chronic rejection committed suicide. Kidney Function: Of the 45 transplants to 40 recipients 16 have ultimately failed. Table 4 depicts the absolute loss of these kidneys according to donor source

and first and second transplants. Figure 3, shows the cumulative loss rate of these kidneys, calculated according to the method of Merrell and Schulman.9 Table 5 summarizes the causes of the 16 kidney losses. Eight kidneys were lost because the recipient died of causes other than graft rejection, although one patient did have evidence of severe chronic rejection, and another had a neurogenic bladder. Three kidneys were lost because of ureteral necrosis and one kidney was lost because of a bladder rupture. One of these latter patients died following the loss of his kidney. Arterial thrombosis caused the loss of one graft and three losses were due to chronic rejection. Of the ten primary related grafts that were lost (Table 4) six were due to death of the patients, two were caused by rejection, and ureteral necrosis and arterial thrombosis each caused one death. The three primary cadaver kidneys were lost due to the death of one patient, ureteral necrosis in another, and rejection of the graft itself in the third patient. One related kidney, which was a second graft, was lost due to the death of the patient. Two second cadaver kidney grafts were lost, one because of bladder leak and one because of ureteral necrosis.

The renal function and blood pressure in the surviving patients is summarized in Table 6. The mean creatinine level in the 23 diabetic patients who presently have functioning related kidneys is 1.3 mg./,100 ml. (range 0.6-2.5). Only one patient has creatinine equal to or higher than 2.0 mg./100 ml. The corresponding figure for the control kidneys matched for age and sex and source of kidney is 1.2 mg./100 ml. (range 0.8-2.0). Also, in this group one patient has a creatinine level of 2.0 mg./100 ml. Of the six patients who presently have functioning, cadaver grafts and diabetes the mean creatinine is 1.1 mg./100 ml. (range 0.8-1.4). The figures in the conTABLE 4. Effect of Donor Source on Kidney Functional Survival in Patients with Diabetes Mellitus

First Transplant Donor Source Functioning Related 23/32 Cadaver 5/8 Second Transplant Related 1/2 1/3 Cadaver

NAJARIAN, KJELLSTRAND, SIMMONS, BUSELMEIER,

480

HARTITZSCH AND GOETZ Ann. Surg. October 1973 -

TABLE 6. Functional Results* in 29 Patients with Functioning Kidneys

1004IU

Matched Nondiabetic Control

0

0-

Diabetic Patients

U)

a) -o

50

__ *=

uml

-mm

CadaGver Kidneys //

funcfion1ngq)

Re/aoed Kidneys (23/34 functfonlingI

C

c 0

-)

c

o0

2 3 4 5 Years Post Transplant FIG. 3. Functional survival of kidneys transplanted into diabetic recipients (1969-1972). The early loss rate of cadaver kidneys is higher than the related kidney loss. The ultimate results are approximately the same, because of more late deaths among the diabetic recipients who received a related kidney (compare Fig. 1).

trol group are exactly the same. The diabetic patients with related kidneys underwent 12 rejection episodes, versus eight in the control group. No patient had more than two rejection episodes. In the cadaver donor group six diabetic recipients experienced five rejection episodes versus two in the control group. No patient experienced more than two rejection episodes. There was no difference in blood pressure between the diabetic patient group and the matched controls. The mean blood pressure in the diabetic group was 123/74 mm. Hg (range 100-160/ 60-100). The corresponding values in the matched nondiabetic control group were 121/80 mm. Hg (range 96150/60-100). The same amounts of antihypertensive drugs were given in the two groups.

Complications Table 7 summarizes the complications following transplantation that appeared in the patients with diabetes mellitus. Myocardial Problems: No less than six of the 40 patients with diabetes have experienced myocardial infarcts after transplantation. A myocardial infarct was the direct cause of death in three cases, and it contributed to death in one patient who died of pneumonia. In addition, two patients, both over 40 years of age, have had severe but TABLE 5. Causes of Loss of Kidney in 40 Recipients with Diabetes Mellitus

Death of patient Rejection Urological complication Arterial thrombosis

8 3 4 1

Creatinine mg./100ml. 1.3(0.6-2.5) Rejection 0.59(0-2) Blood pressure 123/74 (100-160/60-100) * Results expressed as mean followed

1.2(0.8-2.0) 0.34 (0-1) 121/80 (96-150/60-1OO) by range in parenthesis

nonfatal myocardial infarcts. The EKGs of all patients were reviewed to determine if any of these infarcts could have been foreseen. The charts were also reviewed for history of angina. Thirteen patients had normal EKGs but three had experienced infarcts after transplantation. In 12 instances the EKG was interpreted as showing left ventricular hypertrophy; two of these patients experienced myocardial infarct. In 12 other instances there were nonspecific S-T changes on the EKG; one of these patients died of myocardial infarct. Two EKGs did show evidence of previous myocardial infarct, but none of these patients had any postoperative coronary problems. Although five patients gave a history of chest pain upon exertion, none had any further problems after transplantation. Apparently, the EKG and history of angina are not reliable indicators of myocardial problems after transplantation. Urological Complications: Urological complications increased after transplantation and resulted in loss of four kidneys. Three losses were due to ureteral necrosis and one was caused by a bladder leak. Ureteral necrosis occurred in three of 45 diabetic transplants, but only in four of 251 nondiabetic transplants. A bladder leak was noted in four of 45 diabetic transplants, a complication which occurred in only two of 251 nondiabetic transplant recipients. In addition, one graft in a diabetic patient developed a neurogenic bladder. This patient had a voiding cystourethrogram showing some residual urine, but so did ten other diabetic patients who did not TABLE 7.

Complications in Diabetic Transplant Patients After Transplant

No Clinical Transplant Problem Present before

Complication Residual urine Bladder leak Ureteral necrosis Myocardial infarcts Severe peripheral neuropathy Severe peripheral vascular disease Severe ketoacidosis Severe hypoglycemia

10

9

0 0 2

2

7

7

1 11 16

Same Worse New 0 1 4 3 6 0

1 11

16

6 0 0

Vol. 178 * No. 4

DIABETIC GLOMERULOSCEROSIS

develop

a similar problem. The very high incidence of urinary complication 17% (eight of 46) is in marked contrast to the 2.4% (six of 251) that occurred in the nondiabetic transplant patients. Particularly, ureteral necrosis

the most detrimental as this complication always led to loss of the kidney. Contrarily, three of four bladder leaks healed after conservative management and repeated surgical interventions which required prolonged hospitalization. Visual Acuity: The visual acuity of our diabetic recipients that we have followed for more than 4 months has been previously described.5 Only one-half of the patients had eyesight better than 20/100 when grafted, and little change occurred after transplantation.5 Stabilization of vision after transplantation may be due to photocoagulation which many of the patients received. However, most of the loss of eyesight occurred in the year immediately before transplantation. We feel this may be due to the added insult of hypertensive retinopathy and uremia in combination with the diabetic retinopathy. It would probably be best to transplant the diabetic patient before his uremia is too severe, to determine if eyesight at that stage of regression can be preserved. Neuropathy: Electromyography revealed peripheral neuropathy in all our patients with diabetes. Following transplantation, no clear change had occurred on these electrophysiological examination results, although, clinically all patients have improved considerably. Seven patients had severe weakness and atrophy in the legs before transplantation, and, three were bedridden posttransplantation. One of these was parapalegic before transplantation. No patient remained bedridden after transplantation and the parapalegic patient improved to walking with a cane; the other patients could walk without any support. None of the patients who did not have evidence of severe neuropathy or marked weakness pretransplantation, have deteriorated after grafting. Eight patients had evidence of autonomic neuropathy with severe gastroenteropathy before transplantation. These patients had large dilated stomachs, vomiting, regurgitation, diarrhea, and constipation. These symptoms improved in all and only one patient remained symptomatic. This patient died of uremia following chronic rejection, and repeated infections, eight months after transplantation. Peripheral Vascular Disease: Many patients had diffuse calcification of their vessels but only one patient developed peripheral (finger tip) necrosis before transplantation.2 Post-transplant two other patients developed finger tip necrosis. All these patients had arteriovenous side-to-side fistulae. A vascular steal syndrome may account for the necrosis because no complications have occurred in the patients who had either the distal artery tied after fistulae formation, or in a patient who had a

was

481 shunt. Three patients developed necrosis of some toes that required limited toe amputation. Two patients lost both their hypogastric and external iliac arteries because of thrombosis in the artery after transplantation. One of these patients developed gangrene of several toes and the other patient has severe intermittent claudication. Diabetic Management: There have been no episodes of ketoacidosis post-transplantation. A few minor episodes of hypoglycemia have occurred but none have required hospitalization nor glucagon. Generally, the patient's insulin requirements decreased with progressive renal failure. The mean insulin dose immediately before nephrectomy was 38 units/day decreasing to 32 units/ day after bilateral nephrectomy. The requirement then rose dramatically following transplant, to 52 units/day at one month, and 77 units/day 1 year post-transplant. Absence of Recurrent Disease: There has been no evidence of recurrent diabetic nephropathy in the transplanted kidneys. Ten 1-year biopsies, six 2-year biopsies and two 3-year biopsies have been interpreted by an independent pathology group as only showing mild rejection. There was no evidence of diabetic nephropathy. Secondary complications of diabetes contributing to renal failure, hypertension, or urinary tract infections have not been a problem different from that in the nondiabetic

patients., Rehabilitation: (Table 8) Three men with diabetes, and a new kidney, have fathered children. One diabetic woman became pregnant 2 years after transplantation and was delivered through a cesarean section. Both mother and child are well. There are no congenital abnormalities of any of the children. Of the present 29 patients with functioning kidneys, 20 are totally rehabilitated in that they are independent, either managing homes and/or have returned to their original employment. Seven are partially rehabilitated and require some support, and two are not rehabilitated at all. Two patients are on dialysis after graft failure. Discussion

The results of renal transplantation for the treatment of diabetic nephropathy are markedly better than those reported for chronic hemodialysis'.5'6'7'10 although these results may have improved of late.1"'0 Until these results of dialysis have been better documented, however, transplantation is the treatment of choice for the diabetic patients with renal failure. TABLE 8. Rehabilitation of 29 Diabetic Patients with Functioning Grafts Total rehabilitated

Partially rehabilitated No rehabilitation

20

7 2

(69%) (24%) ( 7%)

NAJARIAN, KJELLSTRAND, SIMMONS, BUSELMEIER, HARTITZSCH AND GOETZ Ann. Surg. * October 1973 482 Nevertheless, the diabetic patient with renal failure is enteropathy have improved to the asymptomatic state truly a high risk patient. The death rate following following transplantation. These encouraging findings transplantation to diabetic patients is twice that of the suggest that many of the symptoms of advanced diadeath rate in nondiabetic patients. The high incidence betes may be due to uremic overlay on a basically asymof late cardiac deaths is particularly discouraging. tomatic diabetic process. So far there is no evidence of Diabetic patients are more complicated in other ways continuing severe hypertension, recurrent infection or as well. During dialysis they reveal an increased ten- deterioration of vision after transplantation. dency toward fluid retention, and hypotensive episodes Our present plan is to transplant the diabetic patient during ultrafiltration are common.5 Shunts are difficult to before severe uremia to investigate if better preservation construct and maintain since arteriosclerosis is more of eyesight will occur. We now try to transplant the diasevere. Complications of fingertip necrosis have occurred betic patient when the creatinine is only 6 to 8 mg./100 after fistula formation, presumably because of a vascular ml. instead of the previous transplant level of 14 mg./100 steal syndrome.2 During transplantation the iliac arteries ml. This strategy may well reduce the pretransplant are difficult to use and frequently require endarterectomy mortality as well. to obtain an adequate hypogastric or common iliac artery The original concern was that recurrence of Kimmelfor anastomosis. Careful attention to hemostasis is im- stiel-WVilson disease would lead to early renal deterioraportant, because postoperative hematomia formation tion but his consequence has not been born out by markedly increases the risk of infection. transplant biopsies taken up to 3 years after transplantaAfter transplantation the two major complications are tion. However, the diabetic person lives with the disease myocardial infarction and urinary tract leaks. We have for a mean of 20 years before end-stage renal failure tried to determine if it is possible to predict which pa- becomes life threatening. Therefore, even if the diabetic tients will have postoperative coronary occlusions by re- renal disease ultimately recurs, it may be as long as 20 viewing their EKG and previous history of angina. Un- years before the new kidney is affected. fortunately, we have not found any pretransplantation It is interesting to note that women do twice as well indicators that can reliably foretell success or failure. Re- as men following transplantation. This may be due to views of EKGs or histories of chest pain have not been the more advanced atherosclerotic disease in men, which able to foretell later myocardial catastrophe. We have would accentuate the progressive vascular disease of found no indicators of later peripheral vascular prob- the diabetic. lems, either. Several logistical and ethical questions remain to be There may be several reasons for the high incidence answered. If late deaths continue to occur, even when a of urologic complications in these patients. Marked os- related kidney has been used, the question of transplanmotic diuresis due to steroid induced glycosuria in the tation from a living donor has to be reconsidered. On early post-transplant period may lead to distension of the other hand, if it is felt that using a living related the diabetic patient's bladder. If the Foley catheters are donor is not ethically justified, is it logistically sensible removed in the third postoperative day, as is usually to let the diabetic patient compete with a nondiabetic the case in our nondiabetic patients, the bladder may (and therefore a better risk) patient for cadaver kidneys, become overdistended and contribute to rupture. Con- always in short supply? It will require a few more years sequently, this complication should be obviated by leav- until the therapeutic value of renal transplantation in ing the Foley catheter in several days longer until better patients with diabetic glomerulosclerosis is definitely healing has occurred, and the diuresis is not as excessive. answered. Ureter leaks occurred in three of 46 transplants. In two Summary instances the entire length of the ureter was necrotic within 2 to 8 weeks following transplant. It is possible 1. Forty patients with end-stage diabetic renal disease that the normal transplant ureter fails to obtain its total received 45 renal transplants at the University of Minneblood supply from the kidney and must rely on collateral sota. Thirty-one patients are alive and 29 have good blood supply from the adjacent pelvic tissues. In the renal function. diabetic patients small vessel disease may prevent rapid 2. There is no evidence of recurrent diabetic renal collateral circulation from developing, thereby predispos- disease up to 4 years post-transplant. ing to ureter necrosis and leakage. 3. Eyesight stabilizes following renal transplantation Even though the above complications can cause and diabetic-uremic neuropathy, gastroenteropathy, and discouraging results the transplanted patient with dia- bladder dysfunction tend to improve. betes mellitus can be rehabilitated. Diabetes is readily 4. Though insulin requirements are increased after controlled despite the use of steroids; primary wound transplantation, the management of the diabetes itself infections are rare and diabetic neuropathy and gastro- is not a problem.

Vol. 178 * No. 4

DIABETIC GLOMERULOSCEROSIS

5. Urological problems and myocardial infarcts increase in diabetic recipients, when compared to nondiabetic transplant recipients. 6. Diabetics are better candidates for renal transplantation than for hemodialysis. Diabetics should not be categorically excluded from the benefits of renal transplantation.

5.

6.

References 1. Blagg, C. R., Eschbach, J. W., Sawyer, T. K. and Casaretto, A. A.: Dialysis for Endstage Diabetic Nephropathy. Proc. Clin. Dialysis and Transplant Forum, 1:133, 1971. 2. Buselmeier, T. J., Najarian, J. S., Simmons, R. L., Rattazzi, L. C., Von Hartitzsch, B., Callender, C. O., Goetz, F. C. and Kjellstrand, C. M.: A-V Fistulas and the Diabetic: Ischemia and Gangrene May Result in Amputation. Proc. Am. Soc. Artif. Internal Organs, 2:10, 1973. 3. Drukker, W., Haagsma-Schouten, W. A. G., Alberts, C. H. R. and Baarda, B.: Report of Regular Dialysis Treatment in Europe. Proc. Europ. Dialysis and Transplant Assoc., 7:3, 1970. 4. Kjellstrand, C. M., Simmons, R. L., Buselmeier, T. J. and Najarian, J. S.: Kidney. I. Recipient Selection, Medical

DISCUSSION

DR. JOHN R. BENFIELD (Los Angeles): If we recall the past 15 years of lung transplantation research during which time the focus has advanced from re-implantation to allografting, the ultimate test for graft has always been how well they have sustained life in the face of impaired function on the contralateral side. Dr. Veith has beautifully shown us how his group has tested the ability of lung grafts to sustain life in humans and in dogs with contralateral emphysema. I would like to ask Dr. Veith whether or not dogs with unilateral papain emphysema will tolerate contralateral pneumonectomy and whether he can define for us what is meant by mild, moderate and severe papain emphysema. I think it is important to have this information in order to understand the contribution of the transplant to the sustaining of life. A little over 3 years ago, Dr. Charles Wildevuur of the University of Grongingen in The Netherlands and I were privileged to obtain the cooperation of 20 lung transplant surgeons throughout the world to allow us to pull together what had been learned from their 23 clinical trials. Dr. Veith is to be congratulated upon the progress he has made in the intervening time. However, the fact remains that the clinical results of 32 trials by 22 surgeons to date have lagged far behind kidney grafting as so nicely shown us by Dr. Najarian. One cannot help but wonder whether it is indeed possible to accomplish successful lung transplantation in humans with acceptable regularity. Dr. Michael Peter working in our laboratory has compared rejection rate and causes for failure in lung grafts as compared to kidney allografts. This has yielded evidence that the rejection rates of these two organs are essentially the same and from this we can infer that it is possible to obtain similar results with lung transplantation as with kidney grafting. However, failing lung transplants were more rapidly lethal than failing renal allografts for a variety of reasons, including the lung's inherent fragility and its non-specific response to injury. Therefore, through the application of immunoassay technics, we

View publication stats

7.

8. 9. 10.

483

Management, and Dialysis. In Najarian, J. S. and Simmons, R. L. (eds.): Transplantation, Philadelphia: Lea and Febiger, 1972, p. 418. Kjellstrand, C. M., Simmons, R. L., Goetz, F. C., Kline, M.B., Buselmeier, T. J. and Najarian, J. S.: Mortality and Morbidity in Diabetic Patients Accepted for Renal Transplantation. Proc. Europ. Dialysis and Transplant Assoc., 9:345, 1972. Leonard, A., Raiji, L., Comty, C. M., Wathen, R., Rattazzi, T. and Shapiro, F. L.: Experience with Endocarditis in a Large Kidney Disease Program. Proc. Amer. Soc. Artif. Internal Organs, 2:36, 1973. Lillehei, R. C., Simmons, R. L., Najarian, J. S., Weil, R., Uchida, H., Ruiz, J. O., Kjellstrand, C. M. and Coetz, F. C.: Pancreatico-duodenal Allotransplantation: Experimental and Clinical Experience. Ann. Surg., 172:405, 1970. Marble, A., White, P., Bradley, R. F. and Krall, L. P.: Joslin's Diabetes Mellitus. Philadelphia, Lea and Febiger, 1971. Merrell, M., Shulman, L. E.: Determination of Prognosis in Chronic Disease, Illustrated by Systemic Lupus Erythematosus. J. Chron. Dis., 1:12, 1955. Simmons, R. L., Uranga, V. M., LaPlante, E. S., Buselmeier, T. J., Kjellstrand, C. M. and Najarian, J. S.: Pulmonary Complications in Transplant Recipients. Arch. Surg., 105: 260, 1972.

have directed our efforts at learning to prevent the secondary lethal pulmonary injury or sequelae of rejection. On my only slide I thought it would be interesting to look at what has happened in the past 3 years in our laboratory. If we look at the duration of survival and graft function in three experimental groups, we see that the mean survival has increased 14.7 days in mongrel recipients in 1970 to over 65 days in a current group of inbred beagles in which the mean duration of graft function is 49 days. I present these data only to show that the results in lung transplantation laboratory are now better than the results in canine renal allografting when kidney transplantation etnerged into the clinical arena in the early 1960's. In summary, I have tried to make two points. First, we now understand lung allograft rejection better than in the past and there is reason to believe that we can therefore combat it more effectively than previously. Secondly, our graft function and recipient survival data in the laboratory are now quite respectable, considering the difficulties of canine preparations. These two points have recently become clear and they are ainong the reasons that I now feel that we can now achieve successful human lung transplantation and Dr. Veith has showed us some of his efforts in that direction this morning. We feel somewhat different from Dr. Veith with regard to the selection of patients, and our efforts at the present time are going to be geared toward patients with restrictive lung disease, thereafter planning to proceed to patients with emphysema. I congratulate Dr. Veith on his fine presentation, and I would like to urge that laboratory clinical efforts in lung transplantation continue until success is achieved. DR. RICHARD E. WILSON (Boston): I congratulate Dr. Najarian's group on their really pioneering efforts because they have convinced many of us who do transplants that it is in fact justified to perform renal allografts in diabetic recipients. We have a much smaller series but certainly confirm his findings. I wish to make a couple of comments. First, an important philosophic one. I think that blindness in the patient should not be a contraindication to performing a graft. In fact, rehabilitation may be much easier in a blind patient who