the third kidney transplant

The Third Kidney Transplant

James A. Schulak, MD, Iowa City, Iowa

Dal 0. Nghlem, MD, Iowa City, Iowa Louis Ercolanl, MD, Iowa City, Iowa

Robert J. Carry, MD, Iowa City, Iowa

As reported by the Standards Committee of the American Society of Transplant Surgeons [I], approximately 30 to 40 percent of patients who receive a cadaver kidney transplant will lose the graft within 1 year because of irreversible rejection. It has been our experience that the majority of these patients will enthusiastically seek retransplantation rather than be committed to life-long dialysis. Although data from both single [2,3] and multicenter [4] studies have suggested that second transplants are a rea- sonable therapeutic option, especially when the first graft is not immediately rejected, very little has been reported regarding the outcome of third renal allo- grafts. At the University of Iowa, approximately 20 percent of our potential recipient pool have previously rejected two kidneys and desire a third. To better counsel these patients regarding this option, as well as to formulate a general policy regarding third transplants, we have reviewed our experience with tertiary kidney grafts. The findings of this study are presented herein.

Material and Methods

Fourteen third kidney transplantations were performed between January 1969 and December 1982. Twelve kidneys were from cadaver donors whereas 2 were from HLA- identical, mised lymphocyte culture nonreactive siblings. There were 11 male and 3 female recipients with an age range at the time of the third transplant operation of 14 to 51 years. End-stage renal failure was due to glomerulone- phritis in five of the patients, hypertensive nephropathy in two, pyelonephritis in two, lupus erythematosus in one, medullary cystic disease in one, polycystic kidney disease in one, nephrotic syndrome in one, and diabetic glomeru- losclerosis in one. One patient died with hepatitis and pneumonia 3 months after transplantation, and another patient died from pneumonia 6 months after transplan- Fran ttw Trsm#WMb San4ce, unhmaity oi kwa Ho@tals and Clinics, Iowa Cl& Iowa.

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tation. Three other patients died from nontransplant- related causes long after returning to maintenance hemodialysis. Other major complications were a perforated sigmoid colon, graft rupture and wound infection, ruptured external iliac artery after transplant nephrectomy, and staphylococcal infection of the hip.

Various factors were analymd to determine their possible effects on the survival of these third renal aliogmk These included graft source for all three transplants; length of survival of the first two grafts, degree of human leukocyte antigen-A (HLA-A), -B and -DR antigen compatibility between donor and recipient, and level of presensitization to a random panel. The effect of blood transfusiins on third graft survival was not considered since all of the recipients had been previously transfused.

Immunosuppression consisted of the traditional agents, azathioprine and prednisone, according to a protocol de- scribed previously [S]. Rejection episodes were treated with methylprednisolone pulses (15 mg/kg) for 3 to 5 days. In addition, several of the later patients were treated with antithymocyte globulin (Atgame, Upjohn Laboratories, Kalameaoo, MI) either prophylactically or for steroid re- sistant rejection.

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The donor source and graft survival of each kidney are listed in Table I. Six of the third grafts survived for between 6 months and a year, but only three of these are currently functioning with graft survival of 6,3, and 1 years. The patient whose graft has survived for 1 year will probably also enjoy long-term graft survival as he has not yet experienced any major rejection episodes. Progressive chronic rejection developed in the other three patients. Two of the three returned to maintenance hemodialysis at 8 and 18 months, whereas the last patient died from pneumonia 6 months postoperatively. Seven of the remaining eight patients (Patients 8 through 14, Table I) lost their grafts because of early, acute, irreversible rejection with survival times of 7,9,9,17, 21,29, and 50 days postoperatively. The eighth patient in this latter group died from immunosup-

Volume 147, Wuuary 1984 269

Schulak et al

TABLE I Effects of Grafl Source and Burvivd on the Outcome of Third Kldney Traneplantation

Patient First Craft Second Graft’

Source Survival Source Survival Source Third Craft

Survival

1

3 4 5 6 7 6 9

10 11 12 13

LRD LRD CAD CAD CAD CAD CAD LRD CAD CAD CAD LRD CAD

5 yr 3.5 yr 7d 3mo 6mo 2.5 yr 2.5 mo 10 13d 6d lld 12d 42 d

CAD CAD CAD LRD CAD CAD CAD CAD CAD CAD CAD CAD CAD

1.5 yr 6d Od 3 yr 3.5 yr Od 31 d 35d 27d 62d 1 yr Od Od

CAD CAD

CAD CAD CAD LRD CAD CAD CAD CAD CAD LRD

6 yr (functioning) 3 yr (functioning) 1.6 yrt 1 yr (functioning) 6mo 6mo 3 mot 50d 21 d 19d 17d 9d 9d

14 CAD 5d CAD 7d CAD 7d

l Survival times of 0 and 35 days in patients 6 and 6, respectively, were due to technical losses. in Patients 3 and 12, the kidneys never functioned, but rejection was ultimately diagnosed on the transplant nephrectomy specimens.

t Chronic rejection developed in this patient in less than 1 year, and the serum creatinine level was 7.6 mg/di at 1 year. LRD = living related donor; CAD = cadaver donor.

pression-induced pneumonia 3 months postoperatively with a subnormally functioning, chronically rejecting kidney.

Of the six patients (Patients 1 through 6, Table I) with third graft survival of at least 6 months, five enjoyed more than 1 year survival of either their first or second kidney. Moreover, all three patients with currently functioning third transplants experienced more than 3 year survival of their first or second living related donor kidney. In contrast, of the eight patients (Patients 7 through 14, Table I) in whom severe, irreversible rejection developed in the first 6 months after their third transplant operation, six experienced a similar outcome with both of their first two grafts as well. Both of the remaining patients (Patients 8 and 11, Table I) suffered prompt acute rejection of their first grafts, however, second graft loss was due to technical factors in one of the patients and chronic rejection starting at 6 months in the other. All in all, in no patient who experienced unsuccessful first and second transplantations as defined by graft survival of less than 1 year was long- term function of the third kidney observed.

The degree of HLA-A and -B antigen compatibility did not appear to affect the outcome of these tertiary cadaver transplantations (Table II). Greater than two-antigen compatibility was present for the third cadaver kidneys in five of these patients; two with early, irreversible rejection and three with survival of longer than 6 months. Complete HLA-A and -B identity was present for two of our patients with currently functioning third transplants whereas the other was a complete mismatch. HLA-DR typing data were available for both the donor and recipients in five of these patients. Only one patient received a DR compatible kidney, and he lost his graft because of acute rejection 21 days postoperatively. Three

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patients received transplants with single DR antigen mismatched grafts. One of these latter kidneys was still functioning 1 year postoperatively, whereas the others were rejected at 17 days and 8 months. In addition, one patient received a two DR antigen mismatched kidney which also was rejected early at 29 days. In both recipients of HLA-identical living related donor third grafts transplantation was unsuccessful despite their presumably being D-locus compatible as defined by mixed lymphocyte culture nonreactivity. Again, both of these patients experienced early immunologic loss of their previous two kidneys as well. The level of presensitization for these patients is also listed in Table II. No apparent cor- relation exists between third graft survival and level of preformed antibody as one of our three successful patients was highly sensitized to the random panel (55 percent), whereas the other two were not (0 and 7 percent).

Comments

Retransplantation with cadaver donor kidneys has been demonstrated to be a successful therapeutic option for patients who experience late chronic rather than early acute rejection of their first graft. Both Freier et al [2] and Opelz et al [4] have reported significantly better survival of secondary grafts when first grafts survive longer than 3 months. Similarly, Gifford et al [6] have suggested that the critical length of primary graft survival is 1 year after which second transplantations had increased survival potential. Regarding tertiary transplantation, Opelz and Terasaki [7] in a multicenter study, have reported that 1 year graft survival for third kidneys was only 18 percent when the preceding transplant was rejected within 1 to 3 months. This compared unfa- vorably to the 50 percent 1 year tertiary graft survival

The Ameflcan Journal of Surpery

The lWd Kidney Transplant

HLA-AfltiQMB Levelof Third MismatcM Ptesen5i- &aft

P&lent A&B DR tkation' Survivai+~

: 4 NDS x z

55% 0 6yr 3 yr 3 99% 1.0yr

4 0 1 7% lyr 5 2 1 0 8mo 6 2 ND 0 6mo 5 0 ND 53% 3mo

1 ND 68% 50d 9 2 2 90% 10 f 0 3% Ei 11 1 55% 17d 12 : ND 0 Qd 13 ND 0 Qd 14 0 ND 33% 7d

ND=notdone. l PercentprefcwmedaMxxJytoarandatnpanel. +Patients7and13receivedlIvingrelataddona graftsfromHLA-identical, mixedlymphocytecutture nomeactive siblings. ~Fht&nta1,2,end4havefunctkwtinggfafts.

when second kidney5 functioned for more than 1 year. In agreement with the aforementioned study, the data obtained from this series of patient5 also suggest that a prediction of the outcome of a third graft can be made baaed on the survival of the first two transplanted kidneys. Eight of our patient5 experienced early, irreversible rejection of their third transplants. None of these patient5 experienced successful primary or secondary transplantation with survival of either previous graft for more than 1 year. These data suggest perhaps that as long as the use of standard immunosuppression with azothioprine and prednisone is contemplated, patient5 who have lost their first two grafts to early rejection should not be offered a third because rejection appears to be an almost certain outcome.

The six remaining patient5 experienced third graft survival of more than 6 months. All of these patient5 enjoyed prolonged survival of more than one year for one of their first two grafts. Moreover, all three patients with currently functioning third kidneys had survival of more than 3 years for one of their previous kidneys. However, relying on the outcome of the second graft alone as a prognosticator of third graft success would have resulted in one of our successful recipient5 not receiving a third transplant since she had rejection of her second kidney 8 days postoperatively. Thus, these data suggest that extended survival of more than 1 year for at least one of the antecedent graft5 should be a prerequisite for per- forming tertiary transplantation with standard immunosuppression.

Our group has previously demonstrated a marked graft survival advantage in primary cadaver kidney transplantation for recipient5 of either double DR antigen matched or DR antigen compatible kidneys

when compared with those who received either a single or double DR antigen mismatched graft 151. In addition, Opelz and Terasaki [S] have also reported significantly improved graft survival in recipient5 of second kidney5 when HLA-DR incompatibility was avoided. Their report, however, did not include data for tertiary tran5plantation. Unfortunately, we were not able to evaluate the effect of DR antigen matching on third transplants due to the small size of our series and to the fact that in only five of our patient5 was DR typing data available for both the donor and recipient. Of interest, however, is the fact that the one patient in this series with a DR antigen compatible third graft lost this kidney in less than 1 month with acute rejection.

The outcome of third kidney transplantation in our group of patients with unsuccessful first and second transplantation5 suggests that these patient5 may be immunologically unique. Despite previous blood transfusions in all, use of antithymocyte globulin in some and optimal HLA-D (mixed lymphocyte culture nonreactivity) and -DR matching in three, all of these patient5 lost their third grafts in- cluding both recipient5 of HLA-identical sibling donor grafts. Thus, it appears that living related donor transplantation may also be contraindicated in this subgroup of potential retransplantation candidates. On the other hand, Ferguson et al [9] have reported preliminary clinical evidence that cyclosporine may be very efficacious in preventing irreversible rejection in the setting of retransplantation. If this latter observation is confii as widespread experience with cyclcmporine is gained, there may still be hope for successful third transplantation in this group of patients.

In conclusion, should patients receive transplants

271

a third time? Based on review of this small series, the best answer appears to be a qualified yes. These data suggest that candidates for tertiary transplantation may be identified as those who have had at least one relatively successful previous transplantation with graft survival of more than 2 years as seen in three of our patients. On the other hand, those who have lost both their fiit and second kidneys to rejection in less than 1 year clearly should not receive a third kidney as long as traditional methods of immunosuppression are employed. Hopefully, with advances in phar- macologic immunosuppression, such as cyclosporine, in immunogenetics, such as the discovery of the DR antigen locus; and in experimental immunology with the perfection and clinical adaptation of specific immunosuppression, the problem of tertiary transplantation will be resolved by the elimination of its need.

Summary

To determine the feasibility of third kidney transplantation, the experience at the University of Iowa was evaluated. The success of 14 such transplantations was dependent on the outcome of both of the previous graft operations. Three successful third transplantations with graft survival of 6 years, 3 years, and 1 year have occurred in recipients with more than 1 year survival of a previous kidney. Conversely, graft loss due to rejection developed in all patients who experienced graft survival of less than

1 year for both antecedent grafts. Moreover, HLA-A and -B matching and level of presensitization were not predictive of success in this series. These data suggest that third kidney transplantation using conventional immunosuppression may not be ap- propriate in the subgroup of patients who have clearly lost their first two grafts to early rejection.

References

1. Standards Committee of the American Society of Transplant Surgeons. Current results and expectations of renal trans- pfantation. JAMA 1981:248:1330-l.

2. Freier DTE, Haines RF, Losenzweig J, Niedemuber J, Konnak J, Turcotte JG. Sequential renal transplants:, some surgical and immunological implications on management of the first homograft. Surgery 197679282-7.

3. Ascher NL, Arenhotz DH, Simmons RL, Najarian JS. 100 second renal altografts from a single transpiantation institution. Transplantation 1979;27:30-4.

4. Cpelz G, Mickey MR, Terasaki PI. Prolonged survival of second human kidney transpiants. Science 1972;178:617.

5. (joekenNE,ThormwonJS,CaryRI.A2_yeartrUofpospective HA-DR matching. Effects on renal atlograft suvfval and rate of transplantation. Transplantation 1981;32:522-7.

6. Gifford RRM, Sutherland DER, Fryd DS, Simmons RL, Najarian JS. Duration of first renal allograft survival as indlcator of second allograft outcome. Surgery 1980;8&611-8.

7. Dpelr 0, Terasaki Pi. Absenoe of knmunizatlon effect In human kidney retransplantatlon. N Engl J Med 1978;299:399-74.

8. Opel2 G, Terasaki PI. tnternational study of histocompatibility in renal transptantatlon. Transplantatton 1982;33:87-95.

9. Ferguson RM, Rynasiewicz JJ, SuWrtand DER, Simmons RL, Najarian JS. Cyclosporin A in renal transptantation: a pro- spective randomized trial. Surgery 1982;92:175-82.

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the third kidney transplant

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