Pediatric Annals

Renal Transplantation in Children

Ora Yadin, MD; Paul C Grimm, MD; Robert B Ettenger, MD

Abstract

Although children with end-stage renal disease (ESRD) have a choice of several types of dialysis, successful kidney transplantation remains the optimal therapy. A successful transplant allows for improved physical, social, and psychological rehabilitation, permitting a quality of life that is usually not attainable with dialysis.

Improvements in histocompatibility matching, immunosuppressive management, peri- and postoperative care, and diagnosis and treatment of rejection have all contributed to improved patient survival and graft outcome in renal transplantation. Nevertheless, kidney transplantation in children presents a series of special challenges and considerations. Children differ from adults in that they are constantly growing and developing. As a result, there are technical, metabolic, immunologie, and psychological factors that make children unique. These factors must be dealt with if renal transplantation is to be as successful in children as it is in adults.

This article reviews the current status of pediatric renal transplantation, emphasizing immunosuppressive regimens, possible complications, and the impact of the new transplant technologies on graft outcome.

INCIDENCE AND ETIOLOGY OF ESRD

According to the US Renal Data System report, 11 patients per million population aged 0 to 19 years began ESRD therapy in 1988.1 The majority of children presenting with ESRD are between the ages of 11 and 15 years. In infants under the age of 1, the incidence approaches 0.2 per million.

A report from the European Dialysis Transplant Association (EDTA) pediatrie registry from 1985 listed the primary renal diseases in 1946 children with ESRD between 1980 and 1983 as glomerulonephritis (24-3%), pyelonephritis and interstitial nephritis (24%), hereditary diseases (15.1%), multisystem diseases (10.5%), renal hypoplasia (7.5%), vascular diseases (2.8%), other disease (9%), and diagnosis unknown (6.8%).2 Establishing the cause of ESRD in children whenever possible is important because certain structural abnormalities may require surgical correction (eg, remnant posterior urethral valves), and some metabolic or glomerular diseases have a high incidence of posttransplant recurrence (eg, focal segmentai glomeruloscierosis) that might require special treatment plans.

Between October 1, 1987 and December 31, 1989, 1856 children under the age of 18 were awaiting a cadaveric kidney transplantation in the United States, representing 4-5% of the national waiting list for all ages. Of 1334 transplants performed during that period, 675 (5.9%) were performed in children under the age of 18.3

RENAL GRAFT OUTCOME IN PEDlATRIC RECIPIENTS

Data from the EDTA on 879 cadaver renal transplants performed between 1983 and 1986 in children aged 1 to 15 years4 and from the North American Pediatrie Renal Transplant Cooperative Study (NAPRTCS) report in 199O5 indicate an 87% to 90% 1- to 3-year graft survival for live related donor (LRD) recipients and a 65% to 77% 1- to 3-year graft survival for cadaveric renal grafts. However, few studies report long-term (10 to 15 years) graft outcomes. In firstcadaver donor kidney transplantation, 10-year graft survival rates ranged from 40% to 47%. The cumulative patient survival rate at 15 years was 57%, and the graft survival rate was 19%. No cadaver-donor retransplants were reported to have survived more than 15 years.6-8

FACTORS AFFECTING PEDIATRIC RENAL TRANSPLANT OUTCOME

Donor Age

Sufficient evidence exists today to support the fact that kidneys from very young donors have an inferior outcome particularly when given to pediatrie recipients. Kidneys from donors younger than \.}fi years of age often fail because of a high incidence of primary nonfunction and graft thrombosis. Results are controversial when considering donors between 2 and 6 years of age. The young transplanted kidney has been shown to grow with time. Nevertheless, a large body of evidence supports the conclusion that kidneys from donors 2 to 6 years of age have graft survival rates 20% to…

Although children with end-stage renal disease (ESRD) have a choice of several types of dialysis, successful kidney transplantation remains the optimal therapy. A successful transplant allows for improved physical, social, and psychological rehabilitation, permitting a quality of life that is usually not attainable with dialysis.

Improvements in histocompatibility matching, immunosuppressive management, peri- and postoperative care, and diagnosis and treatment of rejection have all contributed to improved patient survival and graft outcome in renal transplantation. Nevertheless, kidney transplantation in children presents a series of special challenges and considerations. Children differ from adults in that they are constantly growing and developing. As a result, there are technical, metabolic, immunologie, and psychological factors that make children unique. These factors must be dealt with if renal transplantation is to be as successful in children as it is in adults.

This article reviews the current status of pediatric renal transplantation, emphasizing immunosuppressive regimens, possible complications, and the impact of the new transplant technologies on graft outcome.

INCIDENCE AND ETIOLOGY OF ESRD

According to the US Renal Data System report, 11 patients per million population aged 0 to 19 years began ESRD therapy in 1988.1 The majority of children presenting with ESRD are between the ages of 11 and 15 years. In infants under the age of 1, the incidence approaches 0.2 per million.

A report from the European Dialysis Transplant Association (EDTA) pediatrie registry from 1985 listed the primary renal diseases in 1946 children with ESRD between 1980 and 1983 as glomerulonephritis (24-3%), pyelonephritis and interstitial nephritis (24%), hereditary diseases (15.1%), multisystem diseases (10.5%), renal hypoplasia (7.5%), vascular diseases (2.8%), other disease (9%), and diagnosis unknown (6.8%).2 Establishing the cause of ESRD in children whenever possible is important because certain structural abnormalities may require surgical correction (eg, remnant posterior urethral valves), and some metabolic or glomerular diseases have a high incidence of posttransplant recurrence (eg, focal segmentai glomeruloscierosis) that might require special treatment plans.

Between October 1, 1987 and December 31, 1989, 1856 children under the age of 18 were awaiting a cadaveric kidney transplantation in the United States, representing 4-5% of the national waiting list for all ages. Of 1334 transplants performed during that period, 675 (5.9%) were performed in children under the age of 18.3

RENAL GRAFT OUTCOME IN PEDlATRIC RECIPIENTS

Data from the EDTA on 879 cadaver renal transplants performed between 1983 and 1986 in children aged 1 to 15 years4 and from the North American Pediatrie Renal Transplant Cooperative Study (NAPRTCS) report in 199O5 indicate an 87% to 90% 1- to 3-year graft survival for live related donor (LRD) recipients and a 65% to 77% 1- to 3-year graft survival for cadaveric renal grafts. However, few studies report long-term (10 to 15 years) graft outcomes. In firstcadaver donor kidney transplantation, 10-year graft survival rates ranged from 40% to 47%. The cumulative patient survival rate at 15 years was 57%, and the graft survival rate was 19%. No cadaver-donor retransplants were reported to have survived more than 15 years.6-8

FACTORS AFFECTING PEDIATRIC RENAL TRANSPLANT OUTCOME

Donor Age

Sufficient evidence exists today to support the fact that kidneys from very young donors have an inferior outcome particularly when given to pediatrie recipients. Kidneys from donors younger than \.}fi years of age often fail because of a high incidence of primary nonfunction and graft thrombosis. Results are controversial when considering donors between 2 and 6 years of age. The young transplanted kidney has been shown to grow with time. Nevertheless, a large body of evidence supports the conclusion that kidneys from donors 2 to 6 years of age have graft survival rates 20% to 40% lower than those from adolescents or adults.9 Recently, it has also been shown that kidneys from donors over 50 years of age are also suboptimal as organs for pediatrie recipients.10 Thus, the optimal ages for cadaveric renal donors appears to be between the ages of 6 and 50 years.

Recipient Age

Recipients younger than 6 years of age have a lower graft survival rate than older individuals.11 Primary graft nonfunction and vascular thrombosis occur more frequently in this age group. According to the NAPRTCS data, the 1-year cadaver-graft survival for infants under 2 years of age is only 50%, compared to 70% for older age groups.5 When adult LRD grafts are used, results are better, although in the NAPRTCS study, 1-year graft survival of LRD grafts into recipients under 2 years of age was 73% compared with 86% to 94% in older age groups.

Graft survival in children aged 2 to 6 years has improved dramatically over the past few years as a result of a better understanding of immunosuppression in children and improvement in transplant surgical techniques. Recent reports show excellent graft survival in infants and young children; at the University of California Los Angeles (UCLA), the 1-year graft survival in children under 6 years of age is 93%.

Human Leukocyte Antigen (HLA) Matching

The importance of HLA matching in living-related transplantation is undeniable. Renal transplants from HLA identical sibling donors have the highest rates of success with 1-year graft survival in excess of 90% in most centers. Allografts from haploidentical siblings or parental donors generally have survival rates that exceed those of cadaver-donor transplants.

In cadaveric renal transplantation, the relative importance of HLA matching has been repeatedly questioned, particularly since the cyclosporine A (CyA) era began in the mid-1980s. Initially, single-center reports showed no difference between well- and poorlymatched grafts in CyA-treated patients. However, more recent reports coming from larger databases, such as the Collaborative Transplant Study (CTS) with more than 10 000 first-cadaver grafts, showed statistically and clinically significant matching effects.12 The value of optimal HLA matching appears to be even more important when long-term graft outcome is considered. Optimally matched HLA-B and HLA-DR cadaverdonor grafts have a calculated half-life (ie, the number of years to the time when half the grafts are lost) of approximately 12 years, compared to a half-life of only about 5 to 7 years for less well-matched grafts.

Despite these data, the value of sharing cadaverdonor transplants on the basis of HLA matching continues to be controversial. This is because sharing is often associated with prolonged storage time, and the resultant graft dysfunction, although transient, predisposes to decreased graft survival. A recently reported series of perfectly matched cadaveric kidneys shared among 56 distant centers showed a 1-year survival rate of 90% for these organs compared with a 79%, 1-year graft survival rate observed in a control group where the kidneys were not as well matched, but were not transported over long distances.13 A national policy of sharing perfectly HLA-matched kidneys is currently in effect and on the basis of this data would seem to be warranted. National longdistance sharing based on lesser degrees of matching is still often problematic because of the deleterious effects of storage time.

Presensitization

The presence in a recipient's serum of antibodies against HLA antigens of the kidney donor can result in hyperacute rejection, an. immediate explosive and. irreversible form of rejection. To avoid this, a crossmatch using recipient serum and donor lymphocytes is performed before every transplant to detect anti-HLA antibody. Such presensitization with anti-HLA antibodies can be acquired by exposure to antigenic stimuli such as blood transfusions or a previously failed transplant or pregnancy. Highly sensitized patients must wait an inordinately long period of time for a crossmatchnegative transplant and remain at risk to develop many dialysis-associated complications.

Primary Renal Disease

Recurrence of primary renal disease in the renal transplant patient accounts for about 5% of graft loss in children. The two main categories of renal disease that can potentially involve the graft are inherited metabolic diseases and primary glomerulonephritis. In addition, one must be concerned with transplantation following the hemolytic uremie syndrome (HUS) and in the presence of prior malignancy.

Inherited Metabolic Diseases. Inherited metabolic diseases that can involve the graft include diabetes mellitus, hyperoxaturia, cystinosis, and sickle cell anemia.

Primary hyperoxaluria type I. This is an autosomal recessive disease characterized by increased oxalate excretion and resultant nephrocalcinosis, calcium oxalate stone formation, and ultimately ESRD. Until recently, patients with hyperoxaluria type I were regarded as untransplantable because recurrent oxalate deposition in the graft led to almost invariable graft failure. Recent reports have suggested that successful transplantation in children with hyperoxalosis may be possible and stressed the importance of minimizing oxalate deposition in the graft with vigorous pretransplant dialysis to lower oxalate blood levels. Immediate postoperative diuresis, management with pyridoxine, neutral phosphate, magnesium, and noncalciuric diuretic therapy, as well as avoiding infection and graft dysfunction due to acute tubular necrosis or rejection are crucial. Nevertheless, longterm follow-up has revealed that even with this regimen, the incidence of recurrence is quite high.14 Recently, preliminary but optimistic reports suggest that combined liver and kidney transplantation may allow for an improved outcome because the liver serves as the source for the deficient enzyme thereby sparing the transplanted kidney from the toxic effects of oxalate deposition.

Cystinosis. In cystinosis, although cystine crystals have been described in the graft interstitium, recurrence of Fanconi's syndrome after transplantation has not been described, and the cystine seems to interfere little with the kidney function. In fact, transplantation has been recommended as preferred therapy for children with cystinosis although other extrarenai manifestations (eg, photophobia and hypothyroidism) continue to progress after transplantation.

Sickle cell anemia. Renai failure from sickle cell anemia is not uncommon, although the mechanism of renal deterioration is not well established. In 1987, Miner et al reported the first case of recurrence of sickle cell nephropathy after transplantation.15 An additional report of recurrence has since appeared,16 describing recurrence of sickle cell nephropathy leading to graft failure in four of eight patients. The overall results in this latter series were a 25%, 1-year graft survival rate.

Glomerulonephriris. Virtually all types of glomerulonephritis have been reported to recur after transplantation.

Focoi gtomeridosclerosis (FGS). Focal glomerulosclerosis is the most common glomerular disease causing ESRD in children. The reported frequency of recurrence in children varies between 5% and 50%, with an average of about 30%. Approximately half of those who develop recurrence lose the graft. Factors associated with an increased risk of recurrence include: a short history of the nephrotic syndrome in the native kidneys prior to development of ESRD (<3 years), age greater than 6 years at the onset of the original disease, presence of mesangial proliferation in the native kidney biopsy, and recurrence in a previous transplant. Recurrent FGS develops in 80% of subsequent transplants. While proteinuria may be massive and may occur within hours of transplantation, it can also have a more insidious, delayed onset. There is no definitive treatment for recurrent FGS. Early use of plasmapheresis and high-dose CyA has been associated with complete or partial remission in eight of nine patients with recurrent FGS at UCLA1 but controlled studies are necessary.

Membranoproliferative glomerulonephritis (MPGN). Histological evidence of recurrence occurs in both type I and II MPGN. In children, the recurrence rate of type I MPGN ranges from 30% to 70% with graft loss occurring in 30%. In type II MPGN, recurrence is the rule rather than the exception, at least as defined by ultrastructural findings, but graft failure due to recurrent disease occurs in only 10%.

IgA nepkropathy. IgA nephropathy has been described to recur in 30 of 64 (47%) patients from various groups. Recurrence rarely leads to graft loss, and most patients only have minor clinical manifestations such as microscopic hematuria and mild intermittent proteinuria. Rarely, however rapidly progressive graft failure may result from recurrence.

Henoch-Schonkin purpura nephropathy. A variant of IgA nephropathy, Henoch-Schönlein purpura nephropathy also has been reported to recur. These recipients show little clinical manifestation of recurrence, although occasionally recurrence may be severe and lead to active purpuric skin lesions, nephrotic syndrome, and rapid graft failure. The recommendation has been made that transplantation should be avoided until 6 to 12 months from the last episode of purpura.

Systemic lupus erythematosiis (SLE). Recurrence of SLE is quite rare. When SLE does occur, it is usually of minor clinical importance and is amenable to increases in immunosuppressive therapy.

Alpori's syndrome (hereditary nephritis). This syndrome is characterized by the absence of a specific glomerular basement membrane antigen.17 Strictly speaking, recurrence of Alport's syndrome does not occur. However, a minority of patients will generate an antibody to the glomerular basement membrane antigen of the transplanted kidney. The clinical picture is then one of rapidly progressive glomerulonephritis and graft failure. Plasma exchange and substitution of cytoxan for imuran is occasionally effective in blunting the process, but graft failure is the usual outcome.

Acquired Renal Diseases. Hemolytic uremie syndrome (HUS) is the most common cause of primary renal failure in children. It has been suggested that HUS may recur in more than 50% of cases although this is not a universal experience. Hemolytic uremie syndrome has different subtypes, and it is likely that these subtypes vary in their propensity to recur.

Malignancies. Wilms' tumor is the malignancy that most often leads to ESRD in children. A kidney transplantation should be postponed for at least I year following resection and treatment in order to detect persistence of the malignancy and avoid overwhelming sepsis following transplantation.

PREPARING THE CHILD FOR RENAL TRANSPLANTATION

To optimize the outcome of renal transplantation in children with chronic renal failure, preexisting potential medical and surgical problems need to be defined and definitely addressed.

Histocompatibility Testing

Human leukocyte antigen-A, HLA-B, HLA-C, and HLA-DR typing are performed. In addition, periodic testing for anti-HLA antibodies is performed, especially if the potential recipient has received a blood transfusion or rejected a prior renal transplant. To detect deleterious antibodies, the serum of the recipient is tested against the lymphocytes of the prospective donor immediately prior to transplantation. The transplant is not performed if this crossmatch technique reveals the presence of anti-HLA antibody.

Chest X-Ray, Electrocardiogram, and Echocardiogram

Hypertension and chronic fluid overload during dialysis may predispose the child to left ventricular hypertrophy. In long-standing situations, severe hypertensive cardiomyopathy may supervene with a global cardiac dyskinesia. Even at this relatively late stage, renal transplantation may be beneficial to cardiac function.

Infections

Infections should be diagnosed and treated prior to transplantation in order to avoid overwhelming sepsis with the immunosuppressive treatment instituted following transplantation. The urinary tract, as well as the peritoneal catheter tunnel and peritoneal fluid if the patient is on peritoneal dialysis, are the most frequent sites of pretransplant infections.

Antibodies to Human Immunodeficiency Virus (HIV), Hepatitis B and C, Cytomegalovirus (CMV), and Epstein-Barr Virus (EBV)

Patients must be tested for antibodies to HIV, hepatitis B and C, CMV, and EBV at appropriate intervals, keeping in mind the following:

* HIV. Active HIV is an absolute contraindication to transplantation.

* Hepatitis. Patients with chronic hepatitis may be at risk for chronic liver disease with immunosuppression.

* CMV. It has been well documented that CMV infection may be carried as a latent infection in the transplanted kidney and transmitted to the seronegative recipient. Moreover the incidence of CMV infection increases with age. Thus, young children are often seronegative and may need specific drug prophylactic strategies when receiving grafts from seropositive donors.

* EBV. It is important to establish die EBV antibody status of the potential recipient because of the increasing incidence of EBV-associated lymphoproliferative syndrome (LPS) in the posttransplant period. There is some suggestion that a primary EBV infection, combined with vigorous treatment with antilymphocyte preparations, may predispose to a particularly aggressive form of LPS.

Urological Diseases

Vesiculo-Ureteral Reflux. The presence of significant reflux is often associated with recurrent infection. If these infections cannot be controlled with antibiotic prophylaxis, native kidney nephrectomy may be required as a last resort.

Structurally Abnormal Urinary Tract. Children with abnormal tracts can be transplanted with success rates equivalent to those seen in children with other renal diseases, although there is a higher incidence of posttransplant urinary tract infection and urinary leaks. Remnant posterior urethral valves or urethral strictures should be identified and repaired if possible. If a child has a neurogenic bladder, it is possible to use setf-catheterization safely after transplantation.

Hypertension

Hypertension must be controlled with adequate dialysis, antihypertensive agents, or, as an absolute last resort, with bilateral nephrectomy.

Renal Osteodystrophy

While transplantation may improve osteodystrophy in general, pretransplant treatment is important to avoid such complications as severe posttransplant hypercalcémie in secondary hyperparathyroidism.

Previously Rejected Grafts

Previously rejected grafts should be left in situ if asymptomatic. This may theoretically lower antiHLA antibody levels.

Factors Affecting Metabolism of Immunosuppressive Agents

Table

TABLE 1Drugs That Change the Metabolism or Action of Immunosuppresstve Agents Used In Transplantation

TABLE 1

Drugs That Change the Metabolism or Action of Immunosuppresstve Agents Used In Transplantation

Convulsive disorders should be controlled with drugs that do not interfere with the metabolism of immunosuppressive agents planned for posttransplantation use. Anticonvulsant drugs such as phénobarbital and phenytoin activate the hepatic p450 microsomal enzyme system. This will accelerate the metabolism of CyA and corticosteroids, making appropriate therapeutic levels difficult to achieve. Carbamazepine also activates the p450 system, but its effect is not as strong. It is therefore clinically preferable to the other anticonvulsant drugs. Other drugs also may interfere with the metabolism of the immunosuppressive medications (Table 1). Hepatic function also should be evaluated; abnormalities may affect metabolism of immunosuppressive agents.

IMMUNOSUPPRESSION

The immunosuppressive agents used in pediatrie renal transplantation include cyclosporine, corticosteroids, azathioprine, and antilymphocytic preparations.

Corticosteroids

Using the combination of azathioprine and corticosteroids, the 1-year cadaveric graft survival rate in children was 50% to 65%. With this drug combination, average doses of prednisone in one study ranged between .29 mg/kg and .38 mg/kg at 1 year.18 Most of the side effects during that earlier era were a result of the corticosteroids and included obesity, cushingoid features, hyperlipidemia, aseptic necrosis of bone, cataract formation, acne, hypertension, and growth retardation. Since the advent of CyA, some centers have attempted to wean their patients from corticosteroids, while others continue corticosteroids on an alternate-day basis. At UCLA, daily low-dose corticosteroids are used indefinitely, having been influenced by the observation that alternate-day steroid use may be accompanied by decreased compliance and impaired allograft function.

Corticosteroids appear to augment CyA-mediated immunosuppression. In at least one study where pediatrie graft recipients were slowly weaned from prednisone, acute rejection rates of 56% were reported; half of the rejection episodes led to permanent allograft impairment or return to dialysis.19 Other studies suggest that corticosteroids can be successfully withdrawn, but even in these studies, only 30% to 50% can be successfully maintained off prednisone.

Azathioprine

Azathioprine in combination with prednisone was the mainstay of maintenance immunosuppression in renal transplantation for more than 20 years. It is now considered an adjunct to prednisone and CyA in a "triple therapy" regimen, allowing for lower doses of the other two agents. The main side effects of azathioprine are neutropenia and hepatic enzyme elevations. Some centers have electively converted recipients from CyA to azathioprine to prevent CyA toxicity or because of the financial burden of CyA therapy.

Cyclosporine A

Cyclosporine A has become the mainstay of maintenance immunosuppression because of its efficiency in preventing rejection.20 In general, children have not shared in the benefits of CyA in cadaveric graft outcome improvement to the same extent that adults have. On average, children metabolize CyA more rapidly than do adults. Moreover, the metabolism of CyA tends to be even more rapid in young children. Compounding this problem, oral CyA absorption tends to be reduced in the small child. As a result, target CyA levels are often difficult to achieve with conventional adult dosing. To achieve therapeutic drug levels, mean CyA doses per kilogram of body weight are significantly higher in young children than in adolescents.

There is yer another problem with CyAk early use in pediatrie renal transplantation. CyA has significant nephrotoxic activity, especially during early allograft dysfunction. Long reanastomosis times are common in pediatrie renal transplantation and adversely affect graft survival rates in recipients receiving CyA. It is therefore probable that the early institution of CyA in the presence of allograft dysfunction may result in suboptimal glomerular filtration rate (GFR).

This is particularly worrisome in some children because optimal growth is critically dependent on optimal allograft function.21 For this reason, we use an immunosuppressive regimen tailored specifically for children. With this protocol, CyA is not introduced until good allograft function is established. This is accomplished by the use of an antilymphocyte preparation to provide baseline immunosuppression until CyA can be started, a so-called sequential regimen. This regimen has been quite effective in improving cadaveric transplant outcome. In 60 recipients of first cadaveric allografts at UCLA, the use of CyA with sequential immunosuppression was associated with improved cadaver-donor allograft outcome at 1, 2, and 3 years after transplantation of 91%, 86% and 83%, respectively. Similarly, in recipients of cadaverdonor retransplants, the results were also significantly better in 25 patients who received CyA in a sequential therapy iashion than in those who received a combination of azathioprine/prednisone or CyA/ prednisone from the outset of transplantation.

The most significant CyA-associated side effect is nephrotoxicity associated with renal vasoconstriction. Hypertension is seen in more than 80% of CyA-treated renal allograft recipients. It appears to be in large measure due to increased renal sodium reabsorption. Calcium channel blockers are the preferred treatment for the hypertension associated with CyA because they may relax some of the CyAinduced afferent arteriolar vasoconstriction.

Hepatotoxicity is most often manifested by a mild cholestatic picture. Phosphate and magnesium wasting often occur early posttransplant and may become clinically significant, requiring supplementation. Seizures have been noted as a sign of CyA-associated neurotoxicity, and this may be aggravated by hypomagnesemia. Cosmetic side effects include hypertrichosis, coarsening of the facial features, and gingival hypertrophy. This latter side effect may be aggravated by the use of calcium channel blockers.

Antilymphocyte Preparations

These include antibodies of both polyclonal (ATG and ALG) and monoclonal (OKT3) types. These agents can be successfully used for both prophylaxis against rejection and the treatment of rejection episodes. The perioperative prophylactic use of antilymphocyte preparations significantly delays the onset of first acute rejection episodes. These agents have been successfully used to reverse acute rejection episodes and frequently reverse even steroid-resistant rejection episodes.

Noncardiogenic pulmonary edema is the most serious "first-dose" side effect of OKT3. Other firstdose effects include fever, chills, bronchospasm, diarrhea, headache, and vomiting. Later side effects of OKT3 include susceptibility to infection, especially viral, which increases with prolonged or recurrent use.

IMPAIRED GRAFT FUNCTION

While the most common cause of renal allograft dysfunction is rejection, there are a number of other conditions that also can result in decreased urine output and/or a rise in serum creatinine and blood urea nitrogen at different periods after transplantation. The differential diagnosis includes CyA nephrotoxicity, prerenal azotemia secondary to dehydration, urinary obstruction, infection, and renal artery stenosis. It is important to note that the characteristic signs of acute rejection seen in the azathioprine era (fever, graft swelling, pain, and oliguria) are most often absent with CyA immunosuppression. In small children with large allografts, the most sensitive indication of rejection is hypertension. It is also important to remember that in small children, a small rise in the serum creatinine can reflect significant diminution in the GFR.

A number of diagnostic procedures are available to help establish the cause of renal allograft dysfunction (Table 2). Imaging the graft by ultrasound, doppler ultrasonography, and tadionuclide scanning will give information about renal blood flow, allograft function, obstruction to urine flow, and urinary extravasation. A fine needle aspiration biopsy is safe, easy, and useful early in the posttransplant period; fine needle aspiration biopsy allows cytologie examination of both renal parenchymal cells and cells infiltrating the allograft. Diagnoses of rejection, acute tubular necrosis, and CyA nephrotoxicity can be made with a high degree of accuracy. It is also possible to diagnose CMV infection by identifying CMV antigens or their DNA sequences in the tubular cells obtained by fine needle aspiration biopsy.

The diagnostic "gold standard" remains the percutaneous allograft core biopsy. It is an easily performed procedure, even in very small children, and when indicated, it should not be deferred. By histological examination, CyA toxicity and acute rejection can be differentiated, and the presence of chronic rejection can be documented. Moreover, if acute rejection is present, the pathological type of rejection can be established. Generally; the core biopsy is by far the best and surest way to select the therapy for allograft dysfunction once structural abnormalities (eg, urinary obstruction and renal artery stenosis) are eliminated.

Table

TABLE 2Diagnosis of Acute Rejection In Children

TABLE 2

Diagnosis of Acute Rejection In Children

First-line treatment of acute allograft rejection in children has been the administration of intravenous pulses of methylprednisolone 5 mg/kg to 10 mg/kg daily for 3 days, without altering the basal maintenance immunosuppression. Altemativel>; an oral prednisone "pulsing" routine can be employed in which large doses (2.5 mg/kg to 5 mg/kg) are used for 3 days, followed by a 3- to 4-day tapering to baseline maintenance immunosuppression. These regimens are effective in reversing 70% to 80% of rejection episodes. However, in 20% to 30% of patients, renal function fails to return to baseline or continues to worsen after completion of high-dose steroid therapy. In these situations, antilym' phocyte preparations might be required for reversal of the "steroid resistant" rejection episode. OKT3 is effective in treating steroid-resistant rejection, with a reversal rate in excess of 90%.

COMPLICATIONS IN RENAL TRANSPLANTATION

Infections

Infections in the immunosuppressed child remain the major cause of morbidity and mortality among transplant patients. Bacterial infections of the lungs and urinary tract remain common particularly in the first few months after transplantation. Urinary tract infections can progress to urosepsis in children, especially in the first few weeks post-transplantation or after an anti-rejection treatment course. Opportunistic infections in general, including such unusual bacterial infections as Serratia marcescens and Listeria monocytogenes are usually not manifest until 1 to 2 months after transplant.

Infections with viruses from the herpesvirus group (CMV, herpesvirus hominis, varicella zoster, and EBV) are the most troublesome. They are particularly of concern in children because children often have not acquired immunity to these agents prior to transplantation, and primary infections with these viruses are usually the most severe. In the allograft recipient, CMV infection may be due either to transmission of a new CMV strain by the allograft or blood transfusions or to reactivation of the recipient's own latent strain of CMV. Cytomegalovims disease can be mild or quite devastating in children, with a clinical picture that can include prolonged fever, leukopenia, thrombocytopenia, hemolytic anemia, interstitial pneumonitts, hepatic dysfunction, gastrointestinal ulcération, and allograft insufficiency. Cytomegalovims infection also has been linked to an increased risk of graft loss from rejection. A decrease in the pharmacologie immunosuppression often leads to fester resolution of CMV infection. The use of prophylactic intravenous immunoglobulin (IVIg) - either standard IVIg or CMV hyperimmune IVIg - is effective in reducing the severity of CMV disease in renal and bone marrow transplant recipients.22 Similarly, oral acyclovir used prophy tactical Iy at high doses (800 mg/M2 four times a day) is associated with a reduction in morbidity from CMV infection.

Varicella infections are common and occur with a wide variety of manifestations. These range from mild disease to rapidly progressive severe involvement with encephalitis, pneumonitis, hepatic failure, pancreatitis, disseminated intravascular coagulation, and death. When a child with a transplant is exposed to varicella, he or she should receive zoster-immune globulin (VZIG) within 72 hours of exposure. Zoster-immune globulin is effective in modulating disease in 75% of cases. A transplant recipient who develops chickenpox should begin receiving parenteral acyclovir with' out delay. In addition, azathioprine should be withheld until 2 days after the last new crop of vesicles has appeared. Ine most commonly seen manifestation of varicella zoster infection in older pediatrie transplant recipients is herpes zoster, which occurs in up to 10% of renal transplant recipients. Patients presenting with dermatome-distributed lesions should also receive parenteral acyclovir until the vesicles are all crusted over and no new lesions appear.

Epstein-Barr virus infection occurs in approximately 75% of seronegative patients. Even in immunosuppressed children, most EBV infections are clinically silent. A small proportion may develop an EBV-associated, B-cell LPS, which may be related to vigorous immunosuppression in addition to EBV infections. Children and adolescents are more likely to develop an aggressive form of EBV infection related to LPS that is not truly neoplastic. Most recommendations include acyclovir or gancyclovir and discontinuation of immunosuppression, although these may be of only limited value. In contrast, the adult form of LPS is truly neoplastic. Herpes simplex virus may manifest as typical labial ulcérations or may be widespread. Oral (and intravenous, when necessary) acyclovir therapy shortens clinical disease and duration of viral shedding. Papiilomaviruses cause the warts that are common in pediatrie transplant recipients. They have been implicated in the development of squamous cell carcinoma in this group of patients.

Fungal and protozoan infections, once common in the renal transplant setting, are dramatically less common today. This is in part because current practice is to limit maintenance and antirejection immunosuppression. It is more important to avoid prolonged overimmunosuppression rather than risk serious morbidity and death from overwhelming infections. Nevertheless, serious infections still occur caused by both fungi and Pneumocystis connu. Many centers use trimethoprim-sulfamethoxasole prophylactically for the first few months after transplantation against P carina, pneumonia. This also decreases the incidence and severity of urinary tract infections.

Fungal infection generally presents as pneumonia, although many other sites of infection are possible. Cryptococcal meningitis is a particularly worrisome complication. When treating fungal infections in the renal transplant recipient, it is noteworthy that amphotericin B and CyA are synergistic in their nephrotoxic potential. The new antifungal agent fluconazole moderately interferes with CyA metabolism but appears to have no synergistic nephrotoxicity and appears to be a good therapeutic alternative to amphotericin B.

Hypertension

Hypertension occurs in more than 75% of children after transplantation. In the immediate posttransplant period, hypertension is usually related to hypervolemia, particularly in the child with decreased urine output. It is also a frequent finding in acute rejection, resolving with reversal of the rejection episode. The etiologies of persistent posttransplant hypertension include chronic rejection (60%), renal artery stenosis (20%), effects of the in-situ native kidneys (5%), recurrence of primary renal disease (5%), and unknown (10%). Added to this is the fact that both CyA and corttcosteroids contribute significantly to posttransplant hypertension, due, at least in part, to sodium retention.

Calcium channel blocking agents are our agents of choice in treating hypertension in this setting because they improve renal blood flow in CyA-treated patients and are natriuretic. One drawback of these agents is that, together with CyA, they (particularly nifedipine) can be associated with significant gingival hyperplasia. Some of the calcium channel blockers (eg, verapamil and diltiazem) significantly elevate CyA blood levels. In patients prone to medical noncompliance, the use of these agents may complicate management in that noncompliance with the antihypertensive regimen can result in a precipitous fall in the cyclosporine level and rejection.

Growth Retardation

Short stature is one of the most common and serious consequences of renal insufficiency occurring in childhood. The earlier in life that ESRD develops, the greater the growth retardation. Catch-up growth is rare despite intensive conservative treatment. Children accepted for transplantation are usually 2 to 5 standard deviation scores (SDSs) below the median for height for normal controls. Although growth after a kidney transplantation is often superior to growth during dialysis, a normal growth pattern is not always attained. Factors affecting growth after transplantation include age at transplant, corticosteroid use, and allograft function. Analysis of the NAPRTCS data shows that recipients under 5 years of age grew significantly better than any other age group after transplantation.23 These studies suggest that expedited transplantation may be justified in the young child in an attempt to normalize stature.

The exact mechanism by which corticosteroids impair growth is unknown. They may act to suppress growth and delay puberty by blunting both growth hormone and gonadotropin secretion, by increasing normally present somatomedin inhibitors, or by directly impairing cartilage growth. The degree of growth impairment is directly related to the steroid dose. In patients receiving more than 5 mg of prednisone daily, growth hormone levels are lower than normal.

Some centers have attempted to withdraw corticosteroid therapy in posttransplantation children who are receiving CyA. In one study of 15 patients who had discontinued prednisone for more than 6 months, 13 showed accelerated growth. Unfortunately, in those in whom corticosteroid withdrawal cannot be successfully maintained, allograft rejection often occurs with a resultant decrease in GFR. This may impact growth negatively because most growth improvement is observed when the GFR is at least 90 mL/minute/1.73M2.

Some centers have attempted to optimize growth using alternate-day steroids. At UCLA, we have maintained patients on low-dose daily prednisone and found that the best growth occurred in those patients managed on a prednisone dosage of =£.24 mg/kg/day. We have shown a significantly improved growth velocity in both prepubertal and pubertal children with renal transplants treated with recombinant human growth hormone for 6 to 36 months.24 Renal function was well preserved during the treatment period, and the incidence of rejection episodes was similar during the treatment period to the equivalent period prior to recombinant human growth hormone treatment. However, the effect of recombinant human growth hormone treatment on GFR is not yet known. Thus, the use of recombinant human growth hormone, while encouraging, must still be approached with caution.

Delayed Sexual Maturation

Delayed puberty is a common consequence of chronic renal failure. Half of the girls and one third of the boys reach sexual maturity later than 95% of the normal population. There was no significant difference between the GFR in the children with and without delayed puberty. It is likely that long-term steroid treatment interferes with the onset and progression of puberty and the pubertal growth spurt.

In girls who are pubertal before transplantation and become amenorrheic during the course of chronic renal failure, menses usually return within 6 months to 1 year after transplantation. Adolescent patients should be given appropriate contraceptive information. While oral contraceptive agents are effective, they are not without their adverse effects including hypertension, abnormal coagulability, and an increase in CyA levels. New agents with very low hormone dosages appear to be the most appropriate oral agents.

Adolescent transplant recipients have successfully borne children. The only consistently reported neonatal abnormality has been an increased incidence of prematurity, but approximately half of newborns are small for dates. Deterioration of renal function during pregnancy occurs in about 12% of patients, more frequently in those with preexisting impaired graft function. This renal impairment may reverse after parturition in some, but not all, patients. Adolescent boys can successfully father children, and again, no consistent pattern of abnormalities has been reported in their offspring.

Noncompliance

Psychosocial and emotional problems in children and adolescents undergoing ESRD therapy frequently manifest themselves as noncompliance with the posttransplantation therapeutic regimen. Failure to consistently take the prescribed immunosuppressive medications remains a major cause of rejection and subsequent graft failure. Acute allograft rejection occurring beyond the first months after transplantation is very often due to medication noncompliance. In our pediatrie cadaveric allograft recipients who were on triple therapy with CyA, prednisone, and azathioprine for at least 6 months, approximately 50% were found to have had at least one episode of significant noncompliance. Of these, 13% lost their graft as a direct consequence of noncompliance and 18% suffered a significant reduction in renal function. Noncompliance is a particular problem among adolescents - 64% of patients between the ages of 12 and 20 years admitted to at least one episode of significant noncompliance. The adolescent's strong desire not to stand out as "different" among his or her peers conflicts with the continued reminder of chronic disease that medication taking engenders. This is particularly true when medications alter physical appearance. Ambivalence between desire for parental protection and autonomy, combined with the "magical" belief in his or her invulnerability sets the stage for the adolescent's experimentation with noncompliance.

Prognostic signs of noncompliance include noncompliance with the pretransplant dialysis regimen, a disorganized family structure, iemale sex, and a history of previous graft loss due to noncompliance. Personality problems related to low self-esteem and poor social adjustment are found with higher frequency in noncompliant patients. Noncompliance in children must be suspected when diminution in cushingoid features, sudden unexplained weight loss, or unexplained reduction in the patient's renal function or CyA levels are noticed. Acute rejection should be suspected, diagnosed, and treated promptly if present. Psychological support is of utmost importance if long-term graft function is to be salvaged.

REHABILITATION

Within 1 year after transplantation, more than 90% of children attend school, and only 8% are not involved in any vocational or educational programs. In a survey of 30 long-term survivors (>10 years) of pediatrie renal transplantation, 86% considered their health to be good to excellent, 43% had married, and 77% were either working, attending school, or raising children full-time.25 The most common medical complications included warts (30%), skin cancer (13%), mild cataracts (40%), hypertension (27%), atherosclerotic vascular disease (10%), and various musculoskeletal complaints (70%). Only 16% of these patients manifested the psychiatric complaints of depression or mood swings.

CONCLUSION

Current dialysis techniques, particularly those using peritoneal dialysis, have dramatically improved the care of children with ESRD. Yet, the remaining morbidities of dialysis and the incomplete rehabilitation of dialyzed children make this a suboptimal treatment modality. A well-functioning renal transplant still provides the best possible outcome for a child with ESRD at this time. These children, their families, and health-care teams face a complex lifelong challenge. Transplantation does not "cure" kidney disease, but substitutes one unphysiologic condition for another. Even with today's transplantation technology, concerns remain about growth, the long-term effects of the immunosuppressive medications, and the psychological adjustments that must be made in response to the uncertainties inherent in the transplantation process. In the posttransplant state, there is the ever-present worry about rejection, as well as the medications' known and as yet unknown side effects. A better understanding of transplantation immunology and allograft rejection may in the near future allow the development of specific immunologicai unresponsiveness, thus permitting long-term allograft success without nonspecific and burdensome pharmacological immunosuppression.

REFERENCES

1. United States Renal Data System. USRDS 1990 Annual Daw Report. Bethesda, Md: The National Institutes of Health, National Insature of Diabetes ani Digestive and Kidney Disease; 1990.

2. Demography of dialysis and transplantation in children in Europe, 1985. Repon from the European Dialysis and Transplant Association Registry. Nepfrroi Dial Transplant. 1989;:235-243.

3. Yuge J, Cecka JM. Pediatrie recipienti and donors. In: Terasaki PI, ed. Clinical Transpiaus 1990. Lc* Angeles, Califi UCLA Tissue Typing Laboratory; 1990:425-436.

4. Broyer M. Kidney transplantation in children: data from the EDTA registry Transplant Proc. 1989;Z1:1958-1988.

5. NAPRTCS. The 1989 report of the North American Pediatrie Renal Transplant Cooperative Study. Pediatric Nephrolagy. 1990;4:542-553.

6. Broyer M, Gagnadoux MF, Guest G, et al. Kidney transplantation in children: results of 383 grafts performed at Enfants Malades Hospital from 1973 to 1984. Adv Nephrol. 1987;16:307-334.

7. Najarian JS, So SK, Simmons RL, et al. The outcome of 304 primary renal transplants in childten (1968-1985). Ann Surg. 1986; 204: 246-258.

8. Potter D, Fesuka N, Melier J, et al. Twenty years of renal transplantation in children. Pediatrics. I986;77:465-470.

9. Merkel FK, Ing TS, Ahmadian Y, et al. Transplantation in and of the young. J Urol. 1974;11:679-686.

10. Harmon WE, Stablein D, Alexander SR, Tejani A. Graft thrombosis in pediatrie renal transplant recipients. A report of the North American Cooperativi; Study Transplantation. 1991;51:406-412.

11. Arbus GS, Geary DF, McLorie GA, et al. Pediatrie renal transplant: a Canadian perspective. Kidney Int. 1986;30:S31-S34.

12. Opelz G, Collaborative Transplant Study. Effect of HLA matching in 10000 cyctosporine-treated cadaver kidney transplants. Transplant Proc. 1987;19:641-646.

13. Terasaki PI, Takemoto S, Mickey MR. A report on 123 six-antigen matched cadaver kidney transplants. Clinical Transplantation. 1989;3:301-305.

14. Katz A, Kim Y, Scheintnan J, et al. Long-term outcome of kidney transplantation in children with oxalosis. Transplant Prac. 1989;21:2033-2035.

15. Miner DJ, Jorkasky DK, Perloff LJ, et al. Recurrent sickle cell nephropathy in a transplant kidney. Am J Kidney Dis. 1987;10:306-313.

16. Barber WH, Deierhoi MH, Julian BA, et al. Renal transplantation in sickle cell disease. Clinical Transplantation. 1987;1:169-175.

17. McCoy RC, Johnson HK, Stone WJ et al. Absence of nephritogenic GBM antigen(s) in some patients with hereditary nephritis. Kidney Int. 1982;121:642-652.

18. Ettenger RB, Rosenthal JT, Marik JL, et al. Improved cadaveric renal transplant outcome in children. Pediatric Nephrology. 1991;5:137-142.

19. Reisman L, Lieberman KV, Burrows L, et al. Follow-up of cyclosporine-rreated pediatrie renal allograft recipients after cessation of prednisone. Transplantation. 1990;49:76-80.

20. Emmel EA, Verweij CL, Durand DB, et al. Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science. 1989;246:1617-1620.

21. Ettenger RB, Blifeld C, Prince H, et al. The pediatric nephrologists' dilemma: growth after transplantation and its interaction with age as a possible immunologic variable. J Pediatr. 1987;111:1022-1025.

22. Khawand N, Light JA, Brems W, et al. Does intravenous immunoglobulin prevent primary cytomegalovirus disease in kidney transplant recipients? Transplant Proc. 1989;21:2072-2074.

23. Tejani A, Stablein D, Alexander SR. Growth in North American children one year after renal transplantation. A report of the North American Pediatric Renal Transplant Cooperative Study. Kidney Int. 1990;37:614. Abstract.

24. Fine RH, Yadin G, Nelson PA, et al. Recombinant human growth hormone treatment of children following renal transplantation. Pediatric Nephrology. 1991;5:147151.

25. Lee HM, Mendez-Picon G, Posner ME The status of rehabilitation, morbidity, and mortality of long-term survivais of pediatrie kidney transplants. Transplant Proc. 1989;21:1989-1991.

TABLE 1

Drugs That Change the Metabolism or Action of Immunosuppresstve Agents Used In Transplantation

TABLE 2

Diagnosis of Acute Rejection In Children

10.3928/0090-4481-19911201-05

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