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EXPANDING THE LIVING RELATED DONOR POOL IN RENAL TRANSPLANTATION: USE OF MARGINAL DONORS
0022-5347/00/1631-0033/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 163, 33–36, January 2000 Printed in U.S.A.
EXPANDING THE LIVING RELATED DONOR POOL IN RENAL TRANSPLANTATION: USE OF MARGINAL DONORS ANANT KUMAR, ANIL MANDHANI, BALBIR SINGH VERMA, ANEESH SRIVASTAVA, AMIT GUPTA, RAJ KUMAR SHARMA AND MAHENDRA BHANDARI From the Department of Urology and Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
ABSTRACT
Purpose: In a living related transplantation program it is not always possible to find an ideal donor. Sometimes the only available donor in the family has some benign disease or suboptimal renal anatomy or physiology, or is too old to be accepted and defined as a marginal donor. However, with proper screening the donor pool can be increased by accepting these marginal donors and treating the benign diseases which is beneficial to the donor. We evaluate the outcome of grafts from marginal donors. Materials and Methods: From July 1988 to August 1997, 581 live related transplantations were performed. Of the donors 52 were older than 60 years and 34 had associated benign renal or nonrenal anomaly or disease. These donors were accepted after thorough questioning and consultation with family members. The recipients of graft from elderly donors were evaluated for the number of rejections, serum creatinine at last followup and graft survival. Results: Of the recipients 52 received grafts from elderly donors with a mean age of 62.6 6 3.7 years. Mean followup was 34.14 6 0.7 months. The 2 and 5-year actuarial graft survival was 96% and 74%, respectively. Creatinine was normal (less than 1.5) in 37% of recipients and 1.5 to 2.5 mg.% in 46%. The rejection rate in postoperative month 1 was 29%. All donors underwent simultaneous surgery to treat the benign disease, and all did well after surgery. Conclusions: By accepting these marginal donors a 14.6% increase in the living related donor pool was achieved without compromising recipient or donor safety. Otherwise these recipients would have been forced to undergo unrelated transplantation or be maintained on dialysis, which is particularly difficult in a developing country. Donors with associated disease benefited from cure. KEY WORDS: kidney, transplantation, living donors, kidney transplantation
table). Marginal donors were defined as those who were not ideal in terms of age, glomerular filtration rate, or renal anomaly or benign disease. All recipients had triple immunosuppression with cyclosporine, azathioprine and prednisolone. Donors with associated renal and nonrenal anomaly or disease were accepted after thorough questioning and consultation with family members. All donors were informed of the inconveniences and short-term risks of diagnostic procedures, the pain and discomfort of nephrectomy, and the
Living related transplantation has better graft and patient survival, as it is an elective procedure, and free of complications of procurement and preservation. The only limiting factor is the availability of a donor. Often the only available donor does not satisfy the ideal criteria and has some form of benign renal or nonrenal anomaly or disease. These donors are considered marginal. In India about 80,000 patients annually are added to the pool of those with end stage renal disease and only 2.4% will receive a transplant. This low transplantation rate is due to an almost nonexistent cadaver program. Although brain death is defined and the government has legalized cadaveric donation, a cadaveric program is not popular due to social and ethical reasons, poor infrastructure and financial constraints. Dialysis is expensive and not available to all patients and, thus there is a compulsion to accept marginal donors to meet partially the need of renal replacement without jeopardizing donor health and transplantation outcome. We report our results of marginal donor use and its safety in a living related donor program.
Marginal donors No. Pts. Elderly donors Renal anomaly and disease: Low glomerular filtration rate Renal artery stenosis Renal calculus Ureteral stone Renal cyst Ectopic kidney Angiomyolipoma Nonrenal diseases: Hypertension Cholelithiasis Ovarian cyst Breast fibroadenoma BPH Multinodular goiter Difficult intubation Pulmonary tuberculosis
PATIENTS AND METHOD
The records of 581 living related transplantations performed from July 1988 to June 1998 were reviewed retrospectively. Of the donors 52 were older than 60 years and 34 had associated renal or nonrenal anomaly or disease (see Accepted for publication August 13, 1999. 33
52 6 2 3 1 2 1 1 2 5 4 1 1 1 1 3
34
MARGINAL DONORS FOR RENAL TRANSPLANTATION
potential social, economic and psychological risks. Donation was voluntary. Of the donors 6 had a low glomerular filtration rate with a cumulative rate of less than 45 ml. per minute. Grafts with renal cysts were evaluated to rule out malignancy, including frozen section biopsy before kidney removal. Cysts were unroofed, the resultant cavity was filled with oxidized regenerated cellulose and the cavity margins were sutured. Of the donors 3 with a small calculus in the kidney and 1 with a nonobstructive lower ureteral stone were accepted for transplantation. The small pelvic stone in 1 donor was removed after graft harvesting via a small pyelotomy incision. The lower ureteral stone was delivered from the cut end of the ureter after removal of the graft. The other 2 patients underwent postoperative lithotripsy in the prone position. The 2 normotensive candidates with unilateral renal artery stenosis and normal renal function were accepted as donors. The renal artery was cut beyond the stenosis, leaving the diseased segment behind, and the normal distal part was anastomosed end-to-end with the internal iliac artery. All 3 donors had a normal renal artery in the opposite kidney. A candidate with a left ectopic kidney with 4 arteries and 3 veins was also accepted as a donor. The upper polar artery was anastomosed end-to-end with the internal iliac artery, the middle 2 arteries were fashioned into a common stump which was anastomosed end-to-side with the external iliac artery and the lower polar artery was anastomosed with the inferior epigastric artery of the recipient. The 2 smaller vein were tied and the larger vein was anastomosed end-to-side with the external iliac vein of the recipient. The 2 hypertensive donors on an antihypertensive medication were also accepted for transplantation. The right kidney was chosen when simultaneous cholecystectomy was indicated for gallstones. Symptomatic large ovarian cysts were treated with the patient under the same anesthesia after ruling out malignancy by cytology and frozen section before donor nephrectomy. Followup of all donors consisted of clinical evaluation, blood pressure measurement and laboratory tests, including hemogram, blood sugar, blood urea nitrogen, serum creatinine and urinalysis, especially for protein, at postoperative months 1, 3 and 6, and yearly thereafter. Donors with stone and benign diseases were evaluated for recurrence. The number of rejection episodes, serum creatinine at last followup and graft survival in recipients of grafts from elderly donors were recorded. Graft survival was calculated using a KaplanMeier curve. Complications and morbidity were also analyzed to assess the safety of using such donors. RESULTS
Of the donors 52 had a mean age of 62.6 6 3.7 years, with a male-to-female ratio of 1.2:1. Total followup ranged from 13 to 72 months (mean 34.15 6 0.7). Actuarial 2 and 5-year graft survival was 96% and 74%, respectively, and was comparable to graft survival in recipients of kidneys from young donors (fig. 1). Of the recipients 37% have maintained serum creatinine within the normal range of less than 1.5 mg.% (fig. 2). Of the recipients 18 (29%) had acute rejection episodes during first 3 months. Only 3 recipients had 2 episodes of acute rejection during followup. Of the donors 6 with a mean age of 57 6 3 years had a mean global glomerular filtration rate of 43.5 6 1.8 and a mean single kidney rate of 22.3 6 2 ml. per minute. Average increase in the glomerular filtration rate was 14 6 1.5 ml. per minute (mean 20.16 6 7) in recipients with followup ranging from 7 to 30 months. Serum creatinine was normal in 5 recipients and maintained at 2 mg.% in 1 who received a kidney from an 81-year-old donor. The 2 kidneys with 5 3 3 and 4 3 3 cm. solitary cysts have functioned well at 1-year followup with a mean increase in
FIG. 1. Cumulative graft survival in recipients of graft from elderly donors.
FIG. 2. Serum (s.) creatinine at last followup in recipients of graft from elderly donors.
glomerular filtration rate of 14 ml. per minute. Followup ultrasound has shown no evidence of cyst recurrence in these recipients. Both kidneys from 2 donors 50 and 67 years old with renal artery stenosis functioned well in recipients at followup of 7 and 28 months. There was no increase in antihypertensive drug requirement in recipients. Donors are also being followed and to date have required no increase in antihypertensive drug dosage. In the donor with an ectopic kidney the graft kidney perfused well and produced urine immediately. The recipient was doing well 6 months after transplantation. In 1 donor a 2 3 2 cm. angiomyolipoma was diagnosed on frozen section. After enucleating the lesion the graft was safely transplanted. The recipient died of viral encephalitis 3 months later. Of the recipients 2 underwent lithotripsy in the prone position 6 weeks after transplantation. The stones were 2 3 6 and 3 3 5 mm., which required 2,200 and 3,600 shock waves, respectively, for complete clearance. Another patient had an 8 mm. caliceal stone which migrated to the pelvis during donor nephrectomy and was removed via ex vivo pyelolithotomy. The lower ureteral stone could easily be removed from the cut end of the distal remaining ureter after removal of the graft. No recurrence has been noted at followup of 16 months to 6.5 years and grafts are functioning well with normal serum creatinine. The 2 recipients of kidneys from hypertensive donors on 1 drug functioned well after 4 and 22 months of followup. The glomerular filtration rate increased from 22 to 69 ml. per minute, creatinine was normal and there was no increase in antihypertensive drug dosage in recipient or donor. An asymptomatic patient with documented tubercular mild pleural effusion and 2 with active pulmonary tuberculosis were treated with isoniazid, rifampicin, pyrazinamide and ethambutol for 8 weeks before removing the kidney. These donors had a normal excretory urogram. The 3 consecutive samples of morning urine for acid-fast bacilli were negative. All 3 recipients have received isoniazid prophylaxis for 1 year and none has any evidence of tuberculosis after a mean followup of 14 6 5 months. A 47-year-old donor had a difficult airway with a Mallampatri score of IV, and so tracheostomy was performed for giving anesthesia.1 The donor did well and there was no morbidity except for a scar in the neck. Of 5 donors with symptomatic gallstones 3 underwent simultaneous cholecystectomy. A donor with an asymptomatic common bile duct stone underwent exploration via a midline
MARGINAL DONORS FOR RENAL TRANSPLANTATION
incision with T tube drainage afterwards. There was no added morbidity. A 55-year-old donor with symptomatic benign prostatic hyperplasia (BPH), American Urological Association symptom score 22 and peak flow 12 ml. per minute was initially treated with terazosin, and transurethral resection of the prostate was performed 3 months later. Of 4 large symptomatic mucinous ovarian cysts 2, 9 3 5 3 6 and 6 3 5 3 4 cm. were operated on simultaneously after ruling out malignancy. Ovariotomy was performed after safe removal of the graft kidney, which required 40 additional minutes with the patient under the same anesthesia. Donors with breast fibroadenoma and multinodular goiter are doing well after nephrectomy. Average followup was 32 months (range 1 to 7 years). All donors complained of occasional aches and pain over the scar in the first few months. The majority have a bulge in the flank (pseudohernia) at the operated site. To date no donor has shown worsening of preoperative blood pressure, blood urea nitrogen or serum creatinine, or had proteinuria. Donors with low glomerular filtration rate had no increase in serum creatinine at followup. In fact all donors have shown a 15% to 20% increase in glomerular filtration rate of the remaining kidney, which is not surprising as we always left the better functioning kidney in the donor and removed the relatively poorly functioning kidney. Donors with stone disease had no evidence of recurrence at 1 to 6.5 years of followup. There was no change in hypertensive status, requirement for antihypertensive drugs or development of proteinuria in the hypertensive donor at followup of only up to 22 months. Of the donors 1 died in a roadside traffic accident, 1 committed suicide 6 months postoperatively when the recipient lost the graft after acute rejection and the 81-year-old donor died of pulmonary infection 3 years after donation. DISCUSSION
Advances in surgical techniques and anesthesia have made living donor nephrectomy a routine surgical procedure. Mortality and morbidity of live donor nephrectomy are 0.03% and 0.23%, respectively.2, 3 In our 581 donors no mortality or morbidity has required intensive care. Elderly donors are usually not accepted in a living related program due to age related changes in glomeruli, vulnerability to acute tubular necrosis and immunological changes, all of which might lead to a poor outcome. However, many series including ours have shown acceptable results.4 –7 Kostakis et al reported no statistically significant difference of graft survival between donors younger and older than 60 years.8 Graft survival has been comparable from donors younger and older than 55 years.9 Our study demonstrated a 5-year graft survival of 76%. It has been observed that recipients of kidneys from elderly donors maintain creatinine at a higher level.10, 11 In 1 study serum creatinine of recipients at 1 year stabilized between 2 and 2.4 mg.%, and was higher in recipients taking cyclosporine. The authors found that cumulative patient and graft survival at 1 and 5 years was independent of donor age.11 Thus, the general health of the donor and functional renal reserve, and not chronological age should determine the upper age limit of an ideal donor. In our study creatinine was normal in 36% of recipients and maintained between 1.6 and 2.6 mg.% in 34%. It is not unusual to accept kidneys with small cysts. Donors with an anatomical abnormality are accepted at 15% of United Network of Organ Sharing approved transplant centers.12 In 2 of our donors large solitary cysts were unroofed after confirming their benign nature, and both grafts are functioning well. Incidence of asymptomatic fibromuscular disease was 3.8% in potential donor evaluation.13 The pres-
35
ence of mild atherosclerosis and fibromuscular disease does not preclude kidney donation.14, 15 Of the centers recognized by the United Network of Organ Sharing 15% accept donors with unilateral fibrodysplasia.12 Linder et al reported 3 cases of medial fibroplasia in donors, including 1 living donor.16 Of the 3 recipients 1 had re-stenosis of the renal artery within 4.5 months of transplantation with secondary hypertension which required angioplasty. The remaining 2 recipients were well at 3-year followup. Thus, cadaveric kidneys with moderate lesions could be considered for transplantation since progression of the disease is slow.16 Of 19 recipients who received a graft from a cadaveric donor (mean age 50.8 years) with fibromuscular dysplasia 5 had hypertension in 4.4 years, including 3 with bilateral disease.11 Therefore, donors without hypertension and unilateral involvement are acceptable for renal transplantation.17 Our 2 donors with unilateral renal artery stenosis without any evidence of hypertension and atherosclerosis are doing well after kidneys were removed by resecting the artery distal to the stenosis. After proper screening of living donors those with unilateral disease can be considered for donation with regular followup of serum creatinine, glomerular filtration rate and blood pressure monitoring. An ectopic kidney can be accepted for donation in the absence of a suitable donor. However, the possibility of an abnormal anatomy and multiple vessels should be considered. In living donor related graft lithiasis one must consider the risk of stone recurrence in the donor and the technical difficulty of approaching the stone if it causes ureteral obstruction in the graft. The incidence of donor graft lithiasis in a cadaveric transplant program was 0.46% and 0.4% in 2 series, which is close to the incidence of 0.33% in the general population.18, 19 The presence of a calculus does not affect the outcome of the graft kidney.20 The probability of stone recurrence in a person after an episode of stone disease is 60% in 10 years, and only 20% require surgical intervention. The maximum possible intervention rate would be approximately 10%. The likelihood of recurrence further decreases in an asymptomatic patient with a less than 1 cm. single stone, which is often metabolically inactive.21 In our study neither the donors nor the recipients had stone disease recurrence at up to 6.5 years of followup. The prone position is best suited for shock wave lithotripsy.20 –24 Donors with nonobstructive ureteral stones and good renal function can also be considered for transplantation. Pyelolithotomy might impair the vascularity of the distal ureter of the graft kidney but a vertical small incision is safe as demonstrated in our case. Accepting hypertensive donors in living related transplant programs has been controversial. In cadaveric transplantation comparatively low actuarial graft survival was reported at 1 year in a hypertensive donor group.25 Primary nonfunction of the graft kidneys was higher by 13.6% in the hypertensive group.25 Fear of preexisting hypertensive nephropathy of donor origin favors graft biopsy and kidneys from cadaveric donors. If there are significant pathological changes, the kidney should be discarded.26 However, no sufficient data are available to correlate hypertensive changes with graft function in living related transplantation. Social and economic constraints to sustain hemodialysis, and a lack of ideal donors have forced us to accept living elderly donors with hypertension on a single drug with successful results. However, long-term followup with more cases is needed. Donors with symptomatic gallstones were treated with simultaneous cholecystectomy through the same incision used for right donor nephrectomy. This procedure entailed no added risk to the donor and required 35 additional minutes after retrieval of the graft. Choosing the right kidney gives the advantage of removing the gallbladder through the same incision with the patient in the same position and under the same anesthesia.
36
MARGINAL DONORS FOR RENAL TRANSPLANTATION
As elderly donors are being frequently considered, it is not unusual to find a donor with BPH symptoms. Our donor with symptomatic BPH was treated with terazosin initially and transurethral prostatic resection was performed later. Simultaneous transurethral prostatic resection may incur added risk, and so our procedure was postponed for a later date when effective medical therapy was available. Other associated diseases of donors can also be managed safely before or during a procedure with the same anesthesia as in our study. There is an added benefit to the donor to undergo additional surgery simultaneously. In the developing world pulmonary tuberculosis is common. These donors should be adequately treated for 8 weeks with 4 drugs before donor nephrectomy. Recipients should receive isoniazid prophylaxis for at least 1 year. However, one should rule out renal involvement of tuberculosis before accepting such donors and, thus, pulmonary tuberculosis should be a relative contraindication and each case should be considered separately. None of our donors had worsening of preoperative blood pressure or renal function, or evidence of proteinuria. All donors with a low glomerular filtration rate had 15 to 20% improvement in the rate of the remaining kidney. It is noteworthy that we always removed the relatively worse kidney for transplantation. Thus, these donations are safe, provided the donors are carefully evaluated and counseled. Surgeons wishing to perform such donation surgery should be required to read the landmark article by Kasiske et al.27
7. 8. 9. 10. 11. 12. 13. 14. 15.
16. 17.
CONCLUSIONS
The 14.6% of our patients who received a kidney from a marginal donor did well, and it is obvious that such kidneys should be accepted for transplantation after thorough donor evaluation. If we had rejected these marginal donors, recipients would have been forced to undergo unrelated transplant elsewhere or live on maintenance dialysis, which is not an economically viable option in our country. Healthy donors should not be rejected based on chronological age, and the presence of renal and nonrenal diseases or anomalies, which can be treated or corrected simultaneously without compromising graft function and donor health. REFERENCES
1. Mallampati, S. R., Gatt, S. P., Gugino, L. D. et al: A clinical sign to predict difficult tracheal intubation: a prospective study. Can Anaesth Soc J, 32: 429, 1985. 2. Najarian, J. S., Chavers, B. M., McHugh, L. E. et al: 20 years or more of follow-up of living kidney donors. Lancet, 340: 807, 1992. 3. Johnson, E. M., Remucal, M. J., Gillingham, K. J. et al: Complications and risks of living donor nephrectomy. Transplantation, 64: 1124, 1997. 4. Langle, F., Sautner, T., Grunberger, T. et al: Impact of donor age in graft function on living-related kidney transplant. Transpl Proc, 24: 2725, 1992. 5. Koyama, H. and Cecka, J. M.: Rejection episodes. In: Clinical Transplants. Edited by P. Terasaki and J. M. Cecka. Los Angeles: UCLA Tissue Typing Laboratory, 1993. 6. Isoniemi, H., von Willebrand, E., Krogerus, L. et al: The effect of
18. 19. 20. 21. 22. 23.
24. 25. 26. 27.
donor age on kidney graft function and on histopathological findings. Transpl Proc, 24: 328, 1992. Kumar, A., Kumar, R. V., Srinadh, E. S. et al: Should elderly donors be accepted in a live related renal transplant program? Clin Transpl, 8: 523, 1994. Kostakis, A. J., Kyriakidis, S., Garbis, S. et al: The fate of renal transplant from elderly living related donors. Transpl Proc, 22: 1432, 1990. Kim, Y. S., Kim, S. I., Suh, J. S. et al: Use of elderly living related donors in renal transplantation. Transpl Proc, 22: 1325, 1992. Hayashi, T., Koga, S., Higashi, Y. et al: Living-related renal transplantation from elderly donor (older than 66 years of age). Transpl Proc, 27: 984, 1995. Sumrani, N., Delaney, V., Ding, Z. K. et al: Renal transplant from elderly living donors. Transplantation, 51: 305, 1991. Bia, M. J., Ramos, E. L., Danovitch, G. M. et al: Evaluation of living renal donors. The current practice of U.S. transplant centers. Transplantation, 69: 322, 1995. Cragg, A. H., Smith, T. P., Thompson, B. H. et al: Incidental fibromuscular dysplasia in potential renal donors: long-term clinical followup. Radiology, 172: 145, 189. Spring, D. B., Salvatierra, O., Jr., Palubinskas, A. J. et al: Results and significance of angiography in potential kidney donors. Radiology, 133: 45, 1979. Frick, M. P. and Goldberg, M. E.: Uro- and angiographic findings in a “normal” population: screening of 151 symptom-free potential transplant donors for renal disease. AJR Am J Roentgenol, 134: 503, 1980. Linder, R., Billing, H., Tibell, A. et al: Transplant of kidneys with fibromuscular dysplasia. Transpl Proc, 22: 398, 1990. Serrano, D. P., Flechner, S. M., Modlin, C. S. et al: The use of kidneys from living donors with renal vascular disease: expanding the donor pool. J Urol, 157: 1587, 1997. Van Gansbeke, D., Zalcman, M., Matos, C. et al: Lithiasic complications of renal transplantation: the donor graft lithiasis concept. Urol Radiol, 7: 157, 1985. Lerut, J., Lerut, T., Gruwez, J. A. et al: Case profile: donor graft lithiasis. Unusual complication of renal transplantation. Urology, 14: 627, 1979. Wheatley, M., Ohl, D. A., Sonda, L. P., III et al: Treatment of renal transplant stones by extracorporeal shock wave lithotripsy in the prone position. Urology, 37: 57, 1991. William, R. E.: Longterm survey of 538 patients with upper urinary tract stones. Br J Urol, 35: 416, 1963. Wills, M. I. and Fenely, R. C.: Extracorporeal shock wave lithotripsy in renal transplant patient. Br J Urol, 70: 690, 1992. Bhadauria, R. P., Ahlawat, R., Kumar, R. V. et al: Donor-gifted allograft lithiasis: extracorporeal shock wave lithotripsy with over table module using the Lithostar Plus. Urol Int, 55: 51, 1995. Greif, F., Dreznick, Z. and Jacob, E. T.: Calculus in 16-year-old cadaveric kidney transplant. A unique case and literature review. Nephron, 55: 423, 1990. Ratner, L. E., Joseph, V., Zibari, G. et al: Transplantation of kidneys from hypertensive cadaveric donor. Transpl Proc, 27: 989, 1995. Alexander, J. W.: Expanded donor criteria: background and suggestions for kidney donation. Richmond: United Network for Organ Sharing Ad Hoc Donation Committee, 1992. Kasiske, B. L., Ravenscraft, R., Ramos, E. L. et al: The evaluation of living renal transplant donors: clinical practice guidelines. Ad Hoc Clinical Practice Guidelines Subcommittee of the Patient Care and Education Committee of the American Society of Transplant Physicians. J Am Soc Nephrol, 7: 2288, 1996.
Vol. 163, 33–36, January 2000 Printed in U.S.A.
EXPANDING THE LIVING RELATED DONOR POOL IN RENAL TRANSPLANTATION: USE OF MARGINAL DONORS ANANT KUMAR, ANIL MANDHANI, BALBIR SINGH VERMA, ANEESH SRIVASTAVA, AMIT GUPTA, RAJ KUMAR SHARMA AND MAHENDRA BHANDARI From the Department of Urology and Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
ABSTRACT
Purpose: In a living related transplantation program it is not always possible to find an ideal donor. Sometimes the only available donor in the family has some benign disease or suboptimal renal anatomy or physiology, or is too old to be accepted and defined as a marginal donor. However, with proper screening the donor pool can be increased by accepting these marginal donors and treating the benign diseases which is beneficial to the donor. We evaluate the outcome of grafts from marginal donors. Materials and Methods: From July 1988 to August 1997, 581 live related transplantations were performed. Of the donors 52 were older than 60 years and 34 had associated benign renal or nonrenal anomaly or disease. These donors were accepted after thorough questioning and consultation with family members. The recipients of graft from elderly donors were evaluated for the number of rejections, serum creatinine at last followup and graft survival. Results: Of the recipients 52 received grafts from elderly donors with a mean age of 62.6 6 3.7 years. Mean followup was 34.14 6 0.7 months. The 2 and 5-year actuarial graft survival was 96% and 74%, respectively. Creatinine was normal (less than 1.5) in 37% of recipients and 1.5 to 2.5 mg.% in 46%. The rejection rate in postoperative month 1 was 29%. All donors underwent simultaneous surgery to treat the benign disease, and all did well after surgery. Conclusions: By accepting these marginal donors a 14.6% increase in the living related donor pool was achieved without compromising recipient or donor safety. Otherwise these recipients would have been forced to undergo unrelated transplantation or be maintained on dialysis, which is particularly difficult in a developing country. Donors with associated disease benefited from cure. KEY WORDS: kidney, transplantation, living donors, kidney transplantation
table). Marginal donors were defined as those who were not ideal in terms of age, glomerular filtration rate, or renal anomaly or benign disease. All recipients had triple immunosuppression with cyclosporine, azathioprine and prednisolone. Donors with associated renal and nonrenal anomaly or disease were accepted after thorough questioning and consultation with family members. All donors were informed of the inconveniences and short-term risks of diagnostic procedures, the pain and discomfort of nephrectomy, and the
Living related transplantation has better graft and patient survival, as it is an elective procedure, and free of complications of procurement and preservation. The only limiting factor is the availability of a donor. Often the only available donor does not satisfy the ideal criteria and has some form of benign renal or nonrenal anomaly or disease. These donors are considered marginal. In India about 80,000 patients annually are added to the pool of those with end stage renal disease and only 2.4% will receive a transplant. This low transplantation rate is due to an almost nonexistent cadaver program. Although brain death is defined and the government has legalized cadaveric donation, a cadaveric program is not popular due to social and ethical reasons, poor infrastructure and financial constraints. Dialysis is expensive and not available to all patients and, thus there is a compulsion to accept marginal donors to meet partially the need of renal replacement without jeopardizing donor health and transplantation outcome. We report our results of marginal donor use and its safety in a living related donor program.
Marginal donors No. Pts. Elderly donors Renal anomaly and disease: Low glomerular filtration rate Renal artery stenosis Renal calculus Ureteral stone Renal cyst Ectopic kidney Angiomyolipoma Nonrenal diseases: Hypertension Cholelithiasis Ovarian cyst Breast fibroadenoma BPH Multinodular goiter Difficult intubation Pulmonary tuberculosis
PATIENTS AND METHOD
The records of 581 living related transplantations performed from July 1988 to June 1998 were reviewed retrospectively. Of the donors 52 were older than 60 years and 34 had associated renal or nonrenal anomaly or disease (see Accepted for publication August 13, 1999. 33
52 6 2 3 1 2 1 1 2 5 4 1 1 1 1 3
34
MARGINAL DONORS FOR RENAL TRANSPLANTATION
potential social, economic and psychological risks. Donation was voluntary. Of the donors 6 had a low glomerular filtration rate with a cumulative rate of less than 45 ml. per minute. Grafts with renal cysts were evaluated to rule out malignancy, including frozen section biopsy before kidney removal. Cysts were unroofed, the resultant cavity was filled with oxidized regenerated cellulose and the cavity margins were sutured. Of the donors 3 with a small calculus in the kidney and 1 with a nonobstructive lower ureteral stone were accepted for transplantation. The small pelvic stone in 1 donor was removed after graft harvesting via a small pyelotomy incision. The lower ureteral stone was delivered from the cut end of the ureter after removal of the graft. The other 2 patients underwent postoperative lithotripsy in the prone position. The 2 normotensive candidates with unilateral renal artery stenosis and normal renal function were accepted as donors. The renal artery was cut beyond the stenosis, leaving the diseased segment behind, and the normal distal part was anastomosed end-to-end with the internal iliac artery. All 3 donors had a normal renal artery in the opposite kidney. A candidate with a left ectopic kidney with 4 arteries and 3 veins was also accepted as a donor. The upper polar artery was anastomosed end-to-end with the internal iliac artery, the middle 2 arteries were fashioned into a common stump which was anastomosed end-to-side with the external iliac artery and the lower polar artery was anastomosed with the inferior epigastric artery of the recipient. The 2 smaller vein were tied and the larger vein was anastomosed end-to-side with the external iliac vein of the recipient. The 2 hypertensive donors on an antihypertensive medication were also accepted for transplantation. The right kidney was chosen when simultaneous cholecystectomy was indicated for gallstones. Symptomatic large ovarian cysts were treated with the patient under the same anesthesia after ruling out malignancy by cytology and frozen section before donor nephrectomy. Followup of all donors consisted of clinical evaluation, blood pressure measurement and laboratory tests, including hemogram, blood sugar, blood urea nitrogen, serum creatinine and urinalysis, especially for protein, at postoperative months 1, 3 and 6, and yearly thereafter. Donors with stone and benign diseases were evaluated for recurrence. The number of rejection episodes, serum creatinine at last followup and graft survival in recipients of grafts from elderly donors were recorded. Graft survival was calculated using a KaplanMeier curve. Complications and morbidity were also analyzed to assess the safety of using such donors. RESULTS
Of the donors 52 had a mean age of 62.6 6 3.7 years, with a male-to-female ratio of 1.2:1. Total followup ranged from 13 to 72 months (mean 34.15 6 0.7). Actuarial 2 and 5-year graft survival was 96% and 74%, respectively, and was comparable to graft survival in recipients of kidneys from young donors (fig. 1). Of the recipients 37% have maintained serum creatinine within the normal range of less than 1.5 mg.% (fig. 2). Of the recipients 18 (29%) had acute rejection episodes during first 3 months. Only 3 recipients had 2 episodes of acute rejection during followup. Of the donors 6 with a mean age of 57 6 3 years had a mean global glomerular filtration rate of 43.5 6 1.8 and a mean single kidney rate of 22.3 6 2 ml. per minute. Average increase in the glomerular filtration rate was 14 6 1.5 ml. per minute (mean 20.16 6 7) in recipients with followup ranging from 7 to 30 months. Serum creatinine was normal in 5 recipients and maintained at 2 mg.% in 1 who received a kidney from an 81-year-old donor. The 2 kidneys with 5 3 3 and 4 3 3 cm. solitary cysts have functioned well at 1-year followup with a mean increase in
FIG. 1. Cumulative graft survival in recipients of graft from elderly donors.
FIG. 2. Serum (s.) creatinine at last followup in recipients of graft from elderly donors.
glomerular filtration rate of 14 ml. per minute. Followup ultrasound has shown no evidence of cyst recurrence in these recipients. Both kidneys from 2 donors 50 and 67 years old with renal artery stenosis functioned well in recipients at followup of 7 and 28 months. There was no increase in antihypertensive drug requirement in recipients. Donors are also being followed and to date have required no increase in antihypertensive drug dosage. In the donor with an ectopic kidney the graft kidney perfused well and produced urine immediately. The recipient was doing well 6 months after transplantation. In 1 donor a 2 3 2 cm. angiomyolipoma was diagnosed on frozen section. After enucleating the lesion the graft was safely transplanted. The recipient died of viral encephalitis 3 months later. Of the recipients 2 underwent lithotripsy in the prone position 6 weeks after transplantation. The stones were 2 3 6 and 3 3 5 mm., which required 2,200 and 3,600 shock waves, respectively, for complete clearance. Another patient had an 8 mm. caliceal stone which migrated to the pelvis during donor nephrectomy and was removed via ex vivo pyelolithotomy. The lower ureteral stone could easily be removed from the cut end of the distal remaining ureter after removal of the graft. No recurrence has been noted at followup of 16 months to 6.5 years and grafts are functioning well with normal serum creatinine. The 2 recipients of kidneys from hypertensive donors on 1 drug functioned well after 4 and 22 months of followup. The glomerular filtration rate increased from 22 to 69 ml. per minute, creatinine was normal and there was no increase in antihypertensive drug dosage in recipient or donor. An asymptomatic patient with documented tubercular mild pleural effusion and 2 with active pulmonary tuberculosis were treated with isoniazid, rifampicin, pyrazinamide and ethambutol for 8 weeks before removing the kidney. These donors had a normal excretory urogram. The 3 consecutive samples of morning urine for acid-fast bacilli were negative. All 3 recipients have received isoniazid prophylaxis for 1 year and none has any evidence of tuberculosis after a mean followup of 14 6 5 months. A 47-year-old donor had a difficult airway with a Mallampatri score of IV, and so tracheostomy was performed for giving anesthesia.1 The donor did well and there was no morbidity except for a scar in the neck. Of 5 donors with symptomatic gallstones 3 underwent simultaneous cholecystectomy. A donor with an asymptomatic common bile duct stone underwent exploration via a midline
MARGINAL DONORS FOR RENAL TRANSPLANTATION
incision with T tube drainage afterwards. There was no added morbidity. A 55-year-old donor with symptomatic benign prostatic hyperplasia (BPH), American Urological Association symptom score 22 and peak flow 12 ml. per minute was initially treated with terazosin, and transurethral resection of the prostate was performed 3 months later. Of 4 large symptomatic mucinous ovarian cysts 2, 9 3 5 3 6 and 6 3 5 3 4 cm. were operated on simultaneously after ruling out malignancy. Ovariotomy was performed after safe removal of the graft kidney, which required 40 additional minutes with the patient under the same anesthesia. Donors with breast fibroadenoma and multinodular goiter are doing well after nephrectomy. Average followup was 32 months (range 1 to 7 years). All donors complained of occasional aches and pain over the scar in the first few months. The majority have a bulge in the flank (pseudohernia) at the operated site. To date no donor has shown worsening of preoperative blood pressure, blood urea nitrogen or serum creatinine, or had proteinuria. Donors with low glomerular filtration rate had no increase in serum creatinine at followup. In fact all donors have shown a 15% to 20% increase in glomerular filtration rate of the remaining kidney, which is not surprising as we always left the better functioning kidney in the donor and removed the relatively poorly functioning kidney. Donors with stone disease had no evidence of recurrence at 1 to 6.5 years of followup. There was no change in hypertensive status, requirement for antihypertensive drugs or development of proteinuria in the hypertensive donor at followup of only up to 22 months. Of the donors 1 died in a roadside traffic accident, 1 committed suicide 6 months postoperatively when the recipient lost the graft after acute rejection and the 81-year-old donor died of pulmonary infection 3 years after donation. DISCUSSION
Advances in surgical techniques and anesthesia have made living donor nephrectomy a routine surgical procedure. Mortality and morbidity of live donor nephrectomy are 0.03% and 0.23%, respectively.2, 3 In our 581 donors no mortality or morbidity has required intensive care. Elderly donors are usually not accepted in a living related program due to age related changes in glomeruli, vulnerability to acute tubular necrosis and immunological changes, all of which might lead to a poor outcome. However, many series including ours have shown acceptable results.4 –7 Kostakis et al reported no statistically significant difference of graft survival between donors younger and older than 60 years.8 Graft survival has been comparable from donors younger and older than 55 years.9 Our study demonstrated a 5-year graft survival of 76%. It has been observed that recipients of kidneys from elderly donors maintain creatinine at a higher level.10, 11 In 1 study serum creatinine of recipients at 1 year stabilized between 2 and 2.4 mg.%, and was higher in recipients taking cyclosporine. The authors found that cumulative patient and graft survival at 1 and 5 years was independent of donor age.11 Thus, the general health of the donor and functional renal reserve, and not chronological age should determine the upper age limit of an ideal donor. In our study creatinine was normal in 36% of recipients and maintained between 1.6 and 2.6 mg.% in 34%. It is not unusual to accept kidneys with small cysts. Donors with an anatomical abnormality are accepted at 15% of United Network of Organ Sharing approved transplant centers.12 In 2 of our donors large solitary cysts were unroofed after confirming their benign nature, and both grafts are functioning well. Incidence of asymptomatic fibromuscular disease was 3.8% in potential donor evaluation.13 The pres-
35
ence of mild atherosclerosis and fibromuscular disease does not preclude kidney donation.14, 15 Of the centers recognized by the United Network of Organ Sharing 15% accept donors with unilateral fibrodysplasia.12 Linder et al reported 3 cases of medial fibroplasia in donors, including 1 living donor.16 Of the 3 recipients 1 had re-stenosis of the renal artery within 4.5 months of transplantation with secondary hypertension which required angioplasty. The remaining 2 recipients were well at 3-year followup. Thus, cadaveric kidneys with moderate lesions could be considered for transplantation since progression of the disease is slow.16 Of 19 recipients who received a graft from a cadaveric donor (mean age 50.8 years) with fibromuscular dysplasia 5 had hypertension in 4.4 years, including 3 with bilateral disease.11 Therefore, donors without hypertension and unilateral involvement are acceptable for renal transplantation.17 Our 2 donors with unilateral renal artery stenosis without any evidence of hypertension and atherosclerosis are doing well after kidneys were removed by resecting the artery distal to the stenosis. After proper screening of living donors those with unilateral disease can be considered for donation with regular followup of serum creatinine, glomerular filtration rate and blood pressure monitoring. An ectopic kidney can be accepted for donation in the absence of a suitable donor. However, the possibility of an abnormal anatomy and multiple vessels should be considered. In living donor related graft lithiasis one must consider the risk of stone recurrence in the donor and the technical difficulty of approaching the stone if it causes ureteral obstruction in the graft. The incidence of donor graft lithiasis in a cadaveric transplant program was 0.46% and 0.4% in 2 series, which is close to the incidence of 0.33% in the general population.18, 19 The presence of a calculus does not affect the outcome of the graft kidney.20 The probability of stone recurrence in a person after an episode of stone disease is 60% in 10 years, and only 20% require surgical intervention. The maximum possible intervention rate would be approximately 10%. The likelihood of recurrence further decreases in an asymptomatic patient with a less than 1 cm. single stone, which is often metabolically inactive.21 In our study neither the donors nor the recipients had stone disease recurrence at up to 6.5 years of followup. The prone position is best suited for shock wave lithotripsy.20 –24 Donors with nonobstructive ureteral stones and good renal function can also be considered for transplantation. Pyelolithotomy might impair the vascularity of the distal ureter of the graft kidney but a vertical small incision is safe as demonstrated in our case. Accepting hypertensive donors in living related transplant programs has been controversial. In cadaveric transplantation comparatively low actuarial graft survival was reported at 1 year in a hypertensive donor group.25 Primary nonfunction of the graft kidneys was higher by 13.6% in the hypertensive group.25 Fear of preexisting hypertensive nephropathy of donor origin favors graft biopsy and kidneys from cadaveric donors. If there are significant pathological changes, the kidney should be discarded.26 However, no sufficient data are available to correlate hypertensive changes with graft function in living related transplantation. Social and economic constraints to sustain hemodialysis, and a lack of ideal donors have forced us to accept living elderly donors with hypertension on a single drug with successful results. However, long-term followup with more cases is needed. Donors with symptomatic gallstones were treated with simultaneous cholecystectomy through the same incision used for right donor nephrectomy. This procedure entailed no added risk to the donor and required 35 additional minutes after retrieval of the graft. Choosing the right kidney gives the advantage of removing the gallbladder through the same incision with the patient in the same position and under the same anesthesia.
36
MARGINAL DONORS FOR RENAL TRANSPLANTATION
As elderly donors are being frequently considered, it is not unusual to find a donor with BPH symptoms. Our donor with symptomatic BPH was treated with terazosin initially and transurethral prostatic resection was performed later. Simultaneous transurethral prostatic resection may incur added risk, and so our procedure was postponed for a later date when effective medical therapy was available. Other associated diseases of donors can also be managed safely before or during a procedure with the same anesthesia as in our study. There is an added benefit to the donor to undergo additional surgery simultaneously. In the developing world pulmonary tuberculosis is common. These donors should be adequately treated for 8 weeks with 4 drugs before donor nephrectomy. Recipients should receive isoniazid prophylaxis for at least 1 year. However, one should rule out renal involvement of tuberculosis before accepting such donors and, thus, pulmonary tuberculosis should be a relative contraindication and each case should be considered separately. None of our donors had worsening of preoperative blood pressure or renal function, or evidence of proteinuria. All donors with a low glomerular filtration rate had 15 to 20% improvement in the rate of the remaining kidney. It is noteworthy that we always removed the relatively worse kidney for transplantation. Thus, these donations are safe, provided the donors are carefully evaluated and counseled. Surgeons wishing to perform such donation surgery should be required to read the landmark article by Kasiske et al.27
7. 8. 9. 10. 11. 12. 13. 14. 15.
16. 17.
CONCLUSIONS
The 14.6% of our patients who received a kidney from a marginal donor did well, and it is obvious that such kidneys should be accepted for transplantation after thorough donor evaluation. If we had rejected these marginal donors, recipients would have been forced to undergo unrelated transplant elsewhere or live on maintenance dialysis, which is not an economically viable option in our country. Healthy donors should not be rejected based on chronological age, and the presence of renal and nonrenal diseases or anomalies, which can be treated or corrected simultaneously without compromising graft function and donor health. REFERENCES
1. Mallampati, S. R., Gatt, S. P., Gugino, L. D. et al: A clinical sign to predict difficult tracheal intubation: a prospective study. Can Anaesth Soc J, 32: 429, 1985. 2. Najarian, J. S., Chavers, B. M., McHugh, L. E. et al: 20 years or more of follow-up of living kidney donors. Lancet, 340: 807, 1992. 3. Johnson, E. M., Remucal, M. J., Gillingham, K. J. et al: Complications and risks of living donor nephrectomy. Transplantation, 64: 1124, 1997. 4. Langle, F., Sautner, T., Grunberger, T. et al: Impact of donor age in graft function on living-related kidney transplant. Transpl Proc, 24: 2725, 1992. 5. Koyama, H. and Cecka, J. M.: Rejection episodes. In: Clinical Transplants. Edited by P. Terasaki and J. M. Cecka. Los Angeles: UCLA Tissue Typing Laboratory, 1993. 6. Isoniemi, H., von Willebrand, E., Krogerus, L. et al: The effect of
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donor age on kidney graft function and on histopathological findings. Transpl Proc, 24: 328, 1992. Kumar, A., Kumar, R. V., Srinadh, E. S. et al: Should elderly donors be accepted in a live related renal transplant program? Clin Transpl, 8: 523, 1994. Kostakis, A. J., Kyriakidis, S., Garbis, S. et al: The fate of renal transplant from elderly living related donors. Transpl Proc, 22: 1432, 1990. Kim, Y. S., Kim, S. I., Suh, J. S. et al: Use of elderly living related donors in renal transplantation. Transpl Proc, 22: 1325, 1992. Hayashi, T., Koga, S., Higashi, Y. et al: Living-related renal transplantation from elderly donor (older than 66 years of age). Transpl Proc, 27: 984, 1995. Sumrani, N., Delaney, V., Ding, Z. K. et al: Renal transplant from elderly living donors. Transplantation, 51: 305, 1991. Bia, M. J., Ramos, E. L., Danovitch, G. M. et al: Evaluation of living renal donors. The current practice of U.S. transplant centers. Transplantation, 69: 322, 1995. Cragg, A. H., Smith, T. P., Thompson, B. H. et al: Incidental fibromuscular dysplasia in potential renal donors: long-term clinical followup. Radiology, 172: 145, 189. Spring, D. B., Salvatierra, O., Jr., Palubinskas, A. J. et al: Results and significance of angiography in potential kidney donors. Radiology, 133: 45, 1979. Frick, M. P. and Goldberg, M. E.: Uro- and angiographic findings in a “normal” population: screening of 151 symptom-free potential transplant donors for renal disease. AJR Am J Roentgenol, 134: 503, 1980. Linder, R., Billing, H., Tibell, A. et al: Transplant of kidneys with fibromuscular dysplasia. Transpl Proc, 22: 398, 1990. Serrano, D. P., Flechner, S. M., Modlin, C. S. et al: The use of kidneys from living donors with renal vascular disease: expanding the donor pool. J Urol, 157: 1587, 1997. Van Gansbeke, D., Zalcman, M., Matos, C. et al: Lithiasic complications of renal transplantation: the donor graft lithiasis concept. Urol Radiol, 7: 157, 1985. Lerut, J., Lerut, T., Gruwez, J. A. et al: Case profile: donor graft lithiasis. Unusual complication of renal transplantation. Urology, 14: 627, 1979. Wheatley, M., Ohl, D. A., Sonda, L. P., III et al: Treatment of renal transplant stones by extracorporeal shock wave lithotripsy in the prone position. Urology, 37: 57, 1991. William, R. E.: Longterm survey of 538 patients with upper urinary tract stones. Br J Urol, 35: 416, 1963. Wills, M. I. and Fenely, R. C.: Extracorporeal shock wave lithotripsy in renal transplant patient. Br J Urol, 70: 690, 1992. Bhadauria, R. P., Ahlawat, R., Kumar, R. V. et al: Donor-gifted allograft lithiasis: extracorporeal shock wave lithotripsy with over table module using the Lithostar Plus. Urol Int, 55: 51, 1995. Greif, F., Dreznick, Z. and Jacob, E. T.: Calculus in 16-year-old cadaveric kidney transplant. A unique case and literature review. Nephron, 55: 423, 1990. Ratner, L. E., Joseph, V., Zibari, G. et al: Transplantation of kidneys from hypertensive cadaveric donor. Transpl Proc, 27: 989, 1995. Alexander, J. W.: Expanded donor criteria: background and suggestions for kidney donation. Richmond: United Network for Organ Sharing Ad Hoc Donation Committee, 1992. Kasiske, B. L., Ravenscraft, R., Ramos, E. L. et al: The evaluation of living renal transplant donors: clinical practice guidelines. Ad Hoc Clinical Practice Guidelines Subcommittee of the Patient Care and Education Committee of the American Society of Transplant Physicians. J Am Soc Nephrol, 7: 2288, 1996.