Pediatric Annals

Organ Transplantation in Children

Frank M Guttman, MD, FRCS (C)

Abstract

INTRODUCTION

The possibility of transplantation of organs, limbs, or other vital structures has always been in the imagination of man. It was not until the revolutionary studies of John Hunter that progress was achieved. Hunter demonstrated that transplantation was feasible and preservation, by cold, was a natural phenomenon. However, the full realization of organ transplantation began in the 20th century. In the early 1950s, the first kidney transplants were carried out in twins.1 In the past 30 years, we have learned that kidney transplants are not experiments and are highly successful in children who otherwise would not live and would be severely stunted.2'3

There still remain two very serious problems in transplantation. First, rejection of foreign tissue is a major concern, necessitating medication of the recipient with toxic drugs. There are some new developments in this area, namely the extensive use of Cyclosporin A CyA).4'5 Cyclosporin A is an extract of the fungii of Cylindrocarpon lucidum and Trichoderma polysporum, whose immunodepressive properties were first described in 1976 by Borei et al.1 Cyclosporin A suppresses cellular and hormonal immunity without bone marrow depression or other prohibitive organ toxicity. The results have been very encouraging as will be outlined in each organ section. The exact action of CyA is not clear. It does not cause T-cell depletion nor does it decrease in vitro immune reactivity. CyA seems to provide a reversible circulating inhibitory factor that blocks the ability of an intact immune apparatus from responding to stimulation by donor antigen.6

Transplantation antigens are clustered mainly on one chromosome, which in man is the 6th (the major histocompatibility complex -MHC). HLA (human leukocyte antigens) can be detected by serological typing. Typing of these HLA, A and B antigens permits the choice of more compatible donors than unselected individuals. Thus siblings are good donors in that some will have identical H LA antigens. With unrelated donors, typing has less relevance to graft survival. Matching at another sublocus, called D locus, has evolved over the past few years and this DR (D related) antigen may be of more value in predicting outcome in cadaver grafts.718

Miller's group has recently demonstrated the importance of pre-t ran spiani transfusions, splenectomy, cadaver haplotype matching, suppressor cell assays and T-cell monitoring to continue to increase good results for each factor.9

The second problem facing transplanters is organ procurement.10 Closely related to this problem is prolonged organ preservation. There are over 100,000 fatal accidents in the United States each year and about 15,000 kidney transplants required but only a fraction of this number are carried out due in large part to the problems of procurement. Once an organ is obtained, there is an emergency situation to find the appropriate recipient. Despite the shortage of organs, some are wasted since present methods of storage do not safely extend beyond 72 hours. Beizer established the usefulness of machine-preserved kidneys which is widely used. Collins, and then Sacks, have simplified the preservation procedures by the use of cold flush with intracellular type solutions, followed by storage on ice.

A significant advance will occur if organ freezing can become a reality.10 In 1949, Smith, Polge and associates, discovered that antifreeze (glycerol) would protect rooster spermatozoa frozen for several days down to -8O0C. Since then glycerol and dimethylsulfoxide have been used as cry o protect i ve agents during freezing of RBC, WBC, bone marrow, skin, cornea, ova, embryos, parathyroid pieces, and pancreatic islets. Partial and sporadic success has been obtained with spleen, bowel and kidney."'12 Should we be able to store organs in the future in liquid nitrogen (-196°C) for months and years, transplantation…

INTRODUCTION

The possibility of transplantation of organs, limbs, or other vital structures has always been in the imagination of man. It was not until the revolutionary studies of John Hunter that progress was achieved. Hunter demonstrated that transplantation was feasible and preservation, by cold, was a natural phenomenon. However, the full realization of organ transplantation began in the 20th century. In the early 1950s, the first kidney transplants were carried out in twins.1 In the past 30 years, we have learned that kidney transplants are not experiments and are highly successful in children who otherwise would not live and would be severely stunted.2'3

There still remain two very serious problems in transplantation. First, rejection of foreign tissue is a major concern, necessitating medication of the recipient with toxic drugs. There are some new developments in this area, namely the extensive use of Cyclosporin A CyA).4'5 Cyclosporin A is an extract of the fungii of Cylindrocarpon lucidum and Trichoderma polysporum, whose immunodepressive properties were first described in 1976 by Borei et al.1 Cyclosporin A suppresses cellular and hormonal immunity without bone marrow depression or other prohibitive organ toxicity. The results have been very encouraging as will be outlined in each organ section. The exact action of CyA is not clear. It does not cause T-cell depletion nor does it decrease in vitro immune reactivity. CyA seems to provide a reversible circulating inhibitory factor that blocks the ability of an intact immune apparatus from responding to stimulation by donor antigen.6

Transplantation antigens are clustered mainly on one chromosome, which in man is the 6th (the major histocompatibility complex -MHC). HLA (human leukocyte antigens) can be detected by serological typing. Typing of these HLA, A and B antigens permits the choice of more compatible donors than unselected individuals. Thus siblings are good donors in that some will have identical H LA antigens. With unrelated donors, typing has less relevance to graft survival. Matching at another sublocus, called D locus, has evolved over the past few years and this DR (D related) antigen may be of more value in predicting outcome in cadaver grafts.718

Miller's group has recently demonstrated the importance of pre-t ran spiani transfusions, splenectomy, cadaver haplotype matching, suppressor cell assays and T-cell monitoring to continue to increase good results for each factor.9

The second problem facing transplanters is organ procurement.10 Closely related to this problem is prolonged organ preservation. There are over 100,000 fatal accidents in the United States each year and about 15,000 kidney transplants required but only a fraction of this number are carried out due in large part to the problems of procurement. Once an organ is obtained, there is an emergency situation to find the appropriate recipient. Despite the shortage of organs, some are wasted since present methods of storage do not safely extend beyond 72 hours. Beizer established the usefulness of machine-preserved kidneys which is widely used. Collins, and then Sacks, have simplified the preservation procedures by the use of cold flush with intracellular type solutions, followed by storage on ice.

A significant advance will occur if organ freezing can become a reality.10 In 1949, Smith, Polge and associates, discovered that antifreeze (glycerol) would protect rooster spermatozoa frozen for several days down to -8O0C. Since then glycerol and dimethylsulfoxide have been used as cry o protect i ve agents during freezing of RBC, WBC, bone marrow, skin, cornea, ova, embryos, parathyroid pieces, and pancreatic islets. Partial and sporadic success has been obtained with spleen, bowel and kidney."'12 Should we be able to store organs in the future in liquid nitrogen (-196°C) for months and years, transplantation will become an elective, well-matched procedure much as blood transfusion is today.

KIDNEY

While there was some initial resistance to the idea of transplantation of kidneys in children, the results have overcome this reticence. There is no doubt that with living related donors (LRD), a common source of kidneys in children, the results have improved enormously. Salvietera's group has reported a 1 00% graft survival over two years and 95% for four years in LRD (HLA identical).3 In cadaver kidney transplantation, using CyA, Calne reports 86% survival.4

In children, the indications for transplantation are mainly glomerulonephritis, infection, and malformation - the hypoplastic-dysplastic kidney. ' 3'14 We have learned since that kidney transplantation should not be done for steroid resistant nephrotic syndrome or for oxalosis where recurrence in the donor kidney will take place. Many other types of kidney failure may be treated by transplantation: congenital nephrotic syndrome, membran opro li ferative glomerulitis (MpG), hereditary interstitial nephritis, Alports syndrome, lupus nephritis, anaphylactoid purpura, hemolytic uremie syndrome, neurogenie bladder, bladderneck obstruction, and medullary cystic disease. When there is recent activity of the nephritis, Goodpasture .-yndrome, IgA nephropathy, systemic lupus, or MpG nephritis, transplants should be delayed.15 Cystinosis is particularly frequent in Quebec.16 At St.

Justine Hospital, 11 of these patients have been transplanted. This represents about 18% of the transplants in children in Quebec.15 Although cysteine crystals are found in the transplanted kidney, this does not affect their function.15'16

A child may be transplanted at any age but the technical difficulties are increased for infants weighing less than 10 kg. There must be a careful evaluation of the progression of the illness. The creatinine level alone is not the sole indicator of when to put the child on the dialysistransplant program. These two modalities are not exclusive but complementary. Especially in children, transplantation should be entertained early and some patients have been transplanted almost directly without long-term dialysis.

DONORS

Cadaver donors should be used in children when parents are unavailable.17 The results with LRD are certainly superior. It is rare that a compatible parent will not agree to the donation. There is a psychological gain that has been demonstrated in several studies on this subject. Siblings have also been donors as have children to parents. Careful selection and discussion of risk are essential. Psychosocial evaluation and counselling for the family should be available and encouraged.18

Bilateral nephrectomy is reserved for patients with infection or hypertension who do not respond to dialysis.

Elements in the evaluation are the growth and development of the child. Chronic ambulatory peritoneal dialysis (CAPD) has become an attractive alternative to hemodialysis under some conditions because of the dramatic reduction in sepsis by the use of a closed system with infrequent connector changes. " CAPD is especially indicated when vascular access is difficult in the small child, or in acute renal failure. The contraindication to CAPD is severe intraperitoneal hemorrhage as a result of thrombocytopenia associated with the hemolytic-uremic syndrome. Other indications for CAPD are small children (< 20 kg) who have rejected one or more renal allografts, or who have high levels of lymphocytotoxic antibodies.

LIVER

At present, there is no choice other than cadaver donation in liver transplantation. The long-term results of Calne's and Starzl's series have been disappointing. Well over 300 liver transplants have been carried out; the longest survival is over ten years and the one-year survival is about 50%. ] The operation is a difficult one, with many complications. The indications for children should be confined to biliary atresia and several enzyme deficiency diseases. The results of liver transplantation in metastatic cancer have been poor. Calne feels that liver transplantation is of value in primary cancer of the liver.1

There has been a spectacular advance by the combination of Cyclosporin A with small dose steroids.20 In adults, survival was nearly doubled by the use of CyA. In eight pediatrie patients undergoing hepatic transplantation, seven are well from 5'/6 to 16 months following treatment with CyA.20 These are very encouraging results and point to the necessity of organizing organ procurement in a rational manner.

Other avenues of development for the future are artificial extracorporeal liver support systems of charcoal hemo-perfusion21 which have been used in animals and man for recovery of consciousness in hepatic coma and intrasplenic hepatocyte infusion.22

These methods may become more attractive if donor liver procurement remains a grave problem.

HEART

There is not yet a reliable artificial means to increase the survival rate for patients awaiting heart transplantations (as in dialysis).23 However, progress in artificial hearts has been made.24 Mechanical hearts have been placed into calves and goats. In the Kolff group's recent report, with new improvements, nine calves have survived five months or longer on the totally artificial pneumatic heart, the longest surviving 268 days.24 There still are problems for long-term survival with mineralization of the diaphragm and vegetative endocarditis. Kolff s group has also implanted a mechanical heart for two to three months, and then transplanted this animal with the normal heart of its chimeric twin.26

The technique of orthotopic cardiac transplantation was developed by Lower and S hum way in animals. Barnard in Cape Town, and Shumway in Palo Alto have continued heart transplantation in many although the widespread enthusiasm of ten years ago has diminished. At Stanford, the series is now over 200 and in South Africa, 30. Barnard reports that of these, 15 are alive four months to five and one half years after transplantation. Eight or nine whose transplants were performed during the last 18 months remain alive. Shumway's results are 65% for one-year survival and 50% for five-year survival.23

The indications for heart transplantation are presently ischemie heart disease with severe myocardial involvement which cannot be improved by orthodox surgery, and cardiomyopathy which does not respond to conservative measures. The outlook for progress in this domain is good, especially with the advent of newer programs of immunosuppression. It is entirely conceivable that heart, or heart-lung transplantation (which is technically easier) may prove of service in the future to infants and children who presently cannot be helped by medicine or surgery."

BOWEL

While total parenteral nutrition (TPN) has alleviated the acute problem of short or almost nil bowel syndrome which we see in the neonate, the outlook of 60 to 70 years of home-TPN is horrendous. It is generally accepted that at least 1 5 cm to 20 cm of the bowel and the ileocecal valve are required for life and that without the valve at least 40 cm of small bowel are required.11

Lillehei first suggested and tried small bowel transplantation in animals and men.27 Although this has been attempted about nine times from 1967to 1976, there were no successes and transplantation of bowel ceased. However, recent experimental work on small bowel transplantation with Cyclosporin A in dogs has been very encouraging.28 The initial problems were related on the one hand to rejection and on the other, to graft vs. host disease (GVHD). Langer et al have reported that CyA when given intramuscularly (IM) initially and then orally will prolong graft survival in dogs to 103.8 ± 39.4 days. The longest survivor died after 432 days. This was significantly longer than that of control dogs (12.5 ± 4.6 days), or orally CyA-treated dogs (30.4 ± 7.6 days). All control dogs, seven orally treated, and only two of the IM/oral group died of acute rejection. This is in contrast to standard immunosuppressive therapy where survival has been prolonged only 5 to IO days beyond controls. Low-dose irradiation of the graft, ex vivo, has also resulted in prolonged survival as well as a marked reduction in GVHD. Therefore there is now perhaps some glimmer of hope that massive intestinal loss, incompatible with life, will have some solution.

PANCREAS

The treatment of diabetes me Hi t us is a major medical problem leading to several severe complications.29'30 The availability of transplantation as a mode of treatment has been limited to those diabetics who have had, in addition, end stage renal disease and kidney transplantation. Allotransplantation of pancreas in these circumstances does not add to the immunosuppressive regimen. Najarian's group has been the leader in this field but the pancreas, either as an organ graft or digested into islets, has been found to be fairly tmmunogenic with early rejection. In animal experimentation, the secondary effects of diabetes on the retina and the kidney have been reversed after pancreatic transplantation. Serious complications of vascularized grafts have been due to the leakage of activated exocrine fluid. Segmental pancreatic allografting with blockage of the duct by neoprene injection has been described as has the process of allowing the peritoneum to handle an open duct, where the pancreatic juice is not activated. The results of these trials have been fair.

Autotransplantation of enzyme digested islets has been carried out in patients with severe unremitting pancreatitis where there is no duct ectasia."'32 In animals, these islets injected into the portal vein (rats) or into the spleen (dogs) have been shown to nest, to grow, and to produce insulin, glucagon, somatostatin and pancreatic peptide. These islets can reverse diabetes and its secondary effects. Lacey et al have described islet transplantation across major histocompatability barriers with the use of one injection of anti-lymphocyte serum.33 Thus, xenotransplantation of adequate numbers of islets from higher primates may be feasible for all diabetics if the side effects of immunosuppression are minimal. Cyclosporin A has also been used successfully to allow xenotransplantation of islets.

BONE MARROW

In the 1950s, it was demonstrated that shielding the spleen, or the infusion of genetically identical marrow from another mouse, would protect an animal against lethal irradiation. In dogs, total body irradiation (TBI) well above the usual lethal exposure is required so that the bone marrow transplant will be accepted. Dog bone marrow stem cells can be stored for months and years in liquid nitrogen, protected by dimethylsulfoxide. Stem cells in the buffy coat of peripheral blood can repopulate irradiated marrow. Matching for HLA, prior blood transfusions, and treatment for GVHD by methotrexate were shown to be factors in success.

The validity of these experimental observations has been well established and expanded into widespread clinical adaptation. Bone marrow transplantation is now the treatment of choice for young patients with severe aplastic anemia, and infants with some forms of congenital severe combined immunodeficiency.34 There is some evidence that allogenic marrow transplantation may be a viable therapeutic option for patients with acute non-Iymphocytic leukemia in first remission and acute lymphocytic leukemia in second remission.34 The hazards of bone marrow transplants such as viral disease and graft vs. host disease may be affected by Interferon, Cyclosporin A and Acyclovir (Burroughs & Wellcome Company). These agents may extend the use of the procedure to many other malignant disorders where total body irradiation and bone marrow rescue is promising. Autologous marrow for hematologie rescue has been used in Stage III and Stage IV varied childhood malignancies where the marrow is commonly involved with malignancy.36 Encouraging results have been obtained in abdominal lymphoma, rhabdomyosarcoma, and retinoblastoma; disappointing results with neuroblastoma.

Bone marrow transplantation has been used syngeneically, in acute leukemia, chronic myelogenous leukemia and non-Hodgkin lymphoma.

NEURAL TRANSPLANTATION

Regeneration of neuronal connections and disturbed pathways in the brain and spinal cord has always been thought to be impossible in man. In somesubmammalian vertebrates, regeneration is possible.37 In recent years there is a growing body of evidence showing that many types of central neurones in mammals can regenerate, and that the adult mammalian brain under certain circumstances may rebuild circuits and form new functional connections in response to a lesion.

In rats, where intracephalic neural grafting has been tested, embryonic CNS tissue can be made to survive transplantation to the brains of adult recipients and the transplants have formed extensive reciprocal connections with the host brain. In the future, advances may be made permitting treatment of congenital degenerative disorders, as well as acquired injuries to the peripheral and central nervous systems.

PULMONARY TRANSPLANTS

While not successful in man to date, with new methods of safe immunosuppression, lung transplants may again be resumed.38 The scarcity of clean donor lungs free of infection will probably always be an obstacle to extensive pulmonary transplantation. Recent reports of the utility of extracorporeal membrane oxygenator (ECMO) suggests that this may be a way to save a transplant during the initial crucial period. With these developments, it is possible that lung transplant may be feasible for severe bronchopulmonary dysplasia.

REFERENCES

1. Calne RY: Transplant surgery: Current status. BrJSurg I980; 67:765-77!.

2. Fine RN, Malekzadeh MH, Pennisi AJ. et al: Long-term results of renal transplantation in children. Pediatrics October 4, I977.

3. Salvatierra OJr, Feduska NJ, Cochrum KC, et al: The impact of 1 ,000 renal transplants at one center. Ann Surg 1977; 186:424-435.

4. Calne RY, White DJG, Evans DB, et al: Cyclosporin A in cadaveric organ transplantation. Br Med J 1981; 282:934-936.

5. Starzl TE, Weil R ??, Iwatsuki S, et al: The use of Cyclosporm A and P red n is one in cadaver kidney transplantation. Surg Gvnecol Obsiet 1980; 151:17-26.

6. Ferguson RM, Fidelus-Gort R, Rynasiewicz JJ, et al: The immunosuppressive action of Cyclosporin A (CyA) in man. Presented at the American Society of Transplant Surgeons, Chicago, June 1982.

7. Guttmann RD: Medical Progress, Renal Transplantation, Part One. N Eng! J Med 1979; 301:975-981.

8. Guttmann RD: Medical Progress, Renal Transplantation, Part Two. ,V Engl J Med 1 979; 30I:1038:I048.

9. Severyn W, K y ria k ides C. Fuller L, et al: Kidney transplantation by use of splene« o my and transfusions, cadaver haploiype matching, suppressor cell assays, and T-cell monitoring. Surgery 1981; 90:364-375.

10. Lehr HB: Progress in long-term organ freezing. Transpl Proc 1 97 1; 3: 1 565.

11. Gunman FM: Intestine, in Karow AM, Pegg DE(eds): Organ Preservation for Transplantation, ed 2. New York, Marcel Dekker Ine, 1982, pp 639-653.

12. Guttman FM, Lizin J, Robitaille P. et al: Survival of canine kidneys after treatment with dimethylsulfoxide, free/ing at -5O0C and thawing by microwave illumination. Cryohiology 1977; 14:559.

13- Hodson EM, Najarían JS, Kjellslrand CM, et al: Renal transplantation in children ages 1 to 5 years. Pediatrics 1978; 61:458-464.

14. Blanchard H. Robitaille P. Guttman FM, et al: Renal Transplantation in Children: Two Years Experience al Sie. Justine Hospital. Toronto, The Royal College of Physicians and Surgeons of Canada. 1977.

15. Robitaille P. Mongeau J-G, Yaz beck S, et al: La greffe renale en pediatrie; Experience accumulée a l'Hôpital Sic-Justine depuis 1974. 1982. unpublished data.

16. Malekzadeh MH, Neustein HB, Schneider JA. et al: Cadaver renal transplantation in children with cystinosis. Am J Med 1977; 63:525-533.

17. Glass NR. S lì liman RM, Butt KM, et al: Results of renal transplantation using pediatrie cadaver donors. Surgery 1979; 85:504-508.

18. Korsh BM. Negrctc VF, Gardner JE, et al: Kidney transplantation in children; Psychosocial follow-up study on child and family. J Pediatrics 1973; 83:399-408.

19. Fine RN: Medical progress: Peritoneal dialysis update. / Pediair 1982; 100:1-7.

20. Starzl TE, Iwatsuki S, Klimmalm G, et al: Liver transplantation, 1980. with particular reference to Cy clos porin- A. Transplant Proc 1981a; 13:281-285.

21. ChangTMS: Hemoperfmion in 1981. Conirib Nephroi 1982; 29:11-22.

22. Mito M, Ebata H, K usano M, et al: Morphology and function of isolated he pa t ocy t es transplanted into rat spleen. Transplantation 1979; 28:499-505.

23. Barnard CN, Barnard MS, Cooper KKC, et al: The present status of heterotopic cardiac transplantation. J Thorac Cardiovasc Surg 1981; 81:433-439.

24. Hastings WL, Aaron JL, Deneris J, et al: A retrospective study of nine calves surviving five months on the pneumatic total artificial heart. Trans Am Soc Ariif Intern Organs 1981; 27:71-75.

25. Atsumi K, FuJ i masa K. Imachi H, et al: Three goats survived for 288 days, 243 days and 232 days with hybrid total artificial heart (HTAH), Trans Am Soc Ariiflniern Organs 1981; 27:77-81.

26. Olsen DB, Devries WC, Oyer PE, el al: Artificial heart implantation, later cardiac transplantât ion in the calf. Trans Am Soc Artif Intern Organs 1981; 27:132-136.

27. Lillehei RC, Goldberg S, Goot B, et al: The present status of intestinal transplantation. Am J Surg 1963; 105:58.

28. Reznick RK, Craddock GN, Langer B, et al: Structure and function of small bowel allografts in the dog: Immunosuppression with Cyclosporin A. Can J Surg 1982:25:51-55.

29. Najarían JS, Sutherland DER, Matas AJ, et al: Human islet autotransplantation following pancreatectomy. Transplant Proc 1979; 1 1:336-340.

30. Sutherland DER: International human pancreas and islet transplant registry. Transplant Proc 1980; 12:229-236.

31. Najarían JS, Sutherland DER, Baumgartner D. et al: Total or near total pancreatectomy and islet au tot ran spiantai ion for treatment of chronic pancreatitis. Ann Surg 1980; 192:526-542.

32. Guttman FM, Goldman HY, Wolfson P: Autotransplantation of cultured isolated islets after pancreatectomy. Presented at American Pediatrie Surgical Association, Phoenix, May, 1982.

33. Lacy PE, DavieJM, Finke EH: Prolongation ofisletxenograftsurvival(rat to mouse). Diabetes 1981; 30:285-291.

34. Thomas ED: The role of marrow transplantation in the eradication of malignant disease. Cancer 1982; 49:1963-1969.

35. Santos GW. Kaizer H, O'Reilly RJ. et al: Bone marrow transplantation in malignancy. Presented at American Society for Clinical Oncology, Washington, 1982.

36. Ekert H, Ellis WM, Waters KD, et al: Autologous bone marrow rescue in the treatment of advanced tumors of childhood. Cancer 1982; 49:603-609.

37. Bjorklund A. Stenevi U: Reconstruction of brain circuitries by neural transplants. Trends in Neurosciences December, 1979, pp 301-306.

38. Norin AJ, E meso n EE, Kamholz SL, et al: Treatment of canine lung allografts with Cyclosporin A as the sole initial immunosuppressive agent: Short and long term effects and cessation of therapy. Presented at the American Society of Transplant Surgeons Chicago, June, 1982.

10.3928/0090-4481-19821101-10

Sign up to receive

Journal E-contents