Pediatric renal transplantation and its challenges

TRANSPLANTATION REVIEWS VOLll,NO2

APRIL 1997

Pediatric Renal Transplantation Challenges

and Its

OscarSaluatieva, Jr, Diana Tannty, Robert Mak, EdwardA&y, Kevin Lemley, Fiona Mackie, Sam So, GregoryB. Hammer, Elliot J. Krane, and Susan B. Con&

R

enal transplantation clearly provides the optimum therapy for children with end-stage renal disease (ESRD). Although the first successful renal transplant was performed in 1954, the lirst reported results of transplantation in children did not occur until 1966.’ It was evident from these early experiences that pediatric renal transplantation posed major challenges that can now best be managed by an experienced and integrated pediatric medical, surgical, and anesthesia team to ensure that the most successful outcomes are achieved. There are a number of technical, metabolic, immunologic, and psychological factors that make children and adolescents uniquely different from adults.2 With the exception of infants and small children, pediatric renal transplantation has lagged only slightly behind the advances and outcomes achieved with transplantation in adults. The story with infants and small children has been considerably different. Before 1980, infants and small children with ESRD were generally not considered candidates for renal transplantation, and only selected patients were considered for dialysis. In the 198Os, infants and small children were being treated in greater numbers, but peritoneal dialysis, and not renal transplantation, was considered the primaty therapy of choice for these patients.3 Subsequently, the report of good results with renal transplantation in infants and small children has shown that trans-

Fmrn the Departmen oJSurgety, the Lkpatintenl of Pediabiu, and the Lkpartmenl oJAne.rthesiin, Stanjrd Uniti& Medical Cenkr, Palo Allo, CA. Aa%s rep& requesl.s lo Oscar Salvatiewa, Jr, MD, Slarfwd Vniwrsi& Medical Center, 703 Wekh Rd, Suite HZ, Palo ANo, CA 94304. Cojyrighl 0 I997ty M/.B. Saunders Company 0955-470x’97/1102-000I$5.00/0 Transplantation

Revitws,

plantation can also be successfully carried out in the small child and can result in excellent outcomes.4 Today in 1997, pediatric renal transplantation is more successful than ever at a number of specialized centers, with results equivalent to those achieved for adults. This article will discuss some of the salient considerations important in achieving optimum success with renal transplantation in children. Besides a review of some of the pertinent literature, it will also rely on the personal surgical experience of one of our authors (OS) with over 500 pediatric transplants, particularly in regards to some of the technical aspects as well as the approach to the management of congenital urologic abnormalities.

Incidence and Etiologies of ESRD The incidence of EXD in the United States varies by age group with an incidence rate of 10 per million population for ages 0 to 19 years, compared with 96 for ages 20 to 44 years, 426 for ages 45 to 64 years, 953 for ages 65 to 74 years, and 838 for ages 75 and over (IO per million pediatric v 2,313 per million adult).5 Thus, ESRD is much more common in adults than children. The causes of FSRD in adults are also strikingly different than in children.5*GThe latest United States Renal Data System (USRDS) Annual Data Report shows that the leading causes of ESRD in the United States (with the vast majority being adult cases) are diabetes (37.2%), hypertension (30.3%), glomerulonephritis (12.3%), cystic kidney diseases (3.0%), interstitial nephritis (3.0%), collagen vascular diseases (2.2%), and obstructive nephropathy (2.0%): In contrast, the causes of ESRD in the strictly pediatric age group are much different (Table I). In children, congenital

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Table 2. Percent of Graft Survival NAPRTCS

Table 1. Causes of ESRD in Pediatric Transplant Recipients Lk7gnmis

%

AplastiJhypoplastic/dysplastic kidneys Congenital obstructive uropathy Focal segmental glomerulosclerosis Reflux nephropathy Systemic immunological disease Chronic glomerulonephritis Congenital nephrotic syndrome Prune belly syndrome Polycystic kidney disease Hemolytic uremic syndrome Medullary cystic disease/juvenile nephronophthisis Cystinosis Familial nephritis Pyelonephritis/interstitial nephritis Renal infarct (cortical necrosis) Idiopathic crescentic glomerulonephritis Membranoproliferative glomerulonephritis type II Oxalosis Wilm’s tumor Other Unknown

17.0 16.8 11.5 5.7 4.7 4.3 3.1 3.1 2.8 2.8 2.6 2.7 2.2 2.2 2.1 1.7 1.0 0.8 0.5 6.6 3.7

Data from Kohaut et al!

structural abnormalities of the urinary tract and other congenital problemspredominate. Therefore, proper surgical managementof these abnormalities and the strategic integration of this management with the renal transplant is of critical importance. Also of significanceis that focal segmentalglomerulosclerosis(FSGS) accounts for 11.5% of pediatric ESRD compared with only 1.6% of adult ESRD.5,6 Thus, managementof recurrent diseasefrom FSGS is also of critical importance in ultimate pediatric graft outcomes.

Kidney Graft Survival The best analysisof graft survival in pediatric recipients is published by the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), which was organized in 1987. Their latest report includes an analysisof 3,445 renal transplants performed betweenJanuary 1, 1987 and February 18, 1994.6A total of 46% of the transplants performed were from living donors (40% parents and 6% other living donors), whereas 54% were from cadaveric donors. Kidney graft survival as reported by NAPRTCS isshownin Table 2. By contrast, the latest USRDS l-year graft survival rates for all United States living donor and cadaver grafts are 92% and 84%,respectively.5

I Year (TO)

2 Years (%)

5 Years (740)

90 78

86 72

74 58

Living donor Cadaver donor Data rrom Kohaut et al.”

Recipients of less than 2 years of age and black recipients have significantly reduced graft survival rates. These recipients have graft survival rates at 3 years that are equivalent to the graft survival rates of all pediatric recipients at 5 years. For recipients less than 2 years old, graft survival at 3 years was75%for living donor transplants and 5 1%for cadaveric transplants, whereasblack recipients have a S-year graft survival of 72% for living donor grafts and 57% for cadaveric grafts.G Causes of Graft Loss The causesof 852graft failures are shownin Table 3. Three principal observationscan be made from an analysisof this data: I. A total of 19%of all graft losseswere causedby technical causesof which primary vascular thrombosiswas the predominant event (13%). Vascular thrombosis tends to occur earlier, rather than later, and hasbeen reported to account for 22.5% of all graft failures that occurred during the first 60 days after transplantation.7 In contrast, priTable 3. Causes of852 Graft Failures Came

Technical Vascular thrombosis Primary nonfunction Miscellaneous technical Renal artery stenosis Immunological Hyperacute rejection, <24 h Accelerated acute rejection, 2-7 days Acute rejection Chronic rejection Immunosuppression related Infection, discontinued medication Cyclosporine toxicity Patient discontinued medication Malignancy Kidney disease (De Novo) kidney disease Recurrence of original disease Death Other Data rrom Kohaut et al!

% of Tolal

13 3 2 I I 3 20 27 2 I I I I 7 IO 8

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Renal Transplanlalion

mary vascular thrombosisis a rare event in adult kidney recipients. 2. There was a high incidence of graft loss from acute (20%) and early (4%) rejection. This coincideswith the perception that children, especially young children, have a higher degree of immunologic responsiveness than older patients.sya 3. Graft lossfrom recurrent diseaseis a major and troublesomeproblem in pediatric renal transplantation, particularly in regards to recurrent FC&S IO-13 Risks for Graft

Failure

The principal prognostic variables associatedwith increased risk for graft failure for recipients of cadaveric grafts are depicted in Table 4. With living donor grafts, the relative increased risk for graft failure wasgreatest among black recipients (relative risk, I .9), recipientswith greater than live prior blood transfusions (relative risk, 1.8), and recipients less than two years of age (relative risk, 1.6).” Antibody induction therapy with either ATG, ALG, or OKT3 wasassociatedwith increasedgraft survival (relative risk, 0.75).”

Choice of Donor Kidney and Timing of Transplant Living

Donor

Versus

Cadaver

Donor

There are many factors involved in selecting the optimal donor organ for a prospective pediatric patient with ESRD. The principal factors influencing graft survival and, therefore, selectionof donor graft, include the following: 1. Recipientswith living donor grafts do considerably better than those patients receiving cadaveric grafts. 2. Among cadaverkidney recipients,thosewith grafts Table 4. Relative Risk of Graft Failure for Pediatric Patients Receiving Cadaveric Allografts Relative Risk Increme

Recipient age (~2 years) Donor age (<6 years) Prior transplant No ATG/ALG/OKT3 induction >5 Lifetime transfusions Recipient race (black) No DR matches Data from Kohaut et al.”

P Value

2.35 1.48 I .46

<.OOl coo I .oo 1

1.44

coo1

I .30 1.27 1.25

.007 .03 .02

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from donorslessthan 6 years of agehave the worst graft survival.6 3. Cold ischemia time of greater than 24 hours compromisesgraft survi~al.~ 4. Early acute tubular necrosis(ATN) is associated with poor graft outcomein both living and cadaver donor transplantation.i4 5. Avoidance of the major technical problem in pediatric transplantation, graft thrombosis,is of profound importance. The patients at greatest risk for graft thrombosisappear to be recipients lessthan 6 years of age of living donor grafts, as well ascadaver graft recipients who receive grafts from donors lessthan 6 years of age, particularly thosewith long cold storagetime.7 With the aboveconsiderations,it is clear that the first choicefor a prospectivepediatric recipient should be, if possible,a living donor graft, albeit with the known increasedrisk for graft thrombosisin patients lessthan 6 years of age.But with proper recognition and careful management of the technical issues involved, graft thrombosiscan be almost completely avoided (seesectionon Adult Kidneys in Infants and Small Children). It has been our experience that a small donor flank incision(Fig 1) hasbeenan additional incentive for a medically suitable, prospective kidney donor, which most often will be a parent. In contrast to the surgical recovery of the usual kidney donor to an adult recipient, the parent donor to a child usually hasan additional responsibility, and that is, that the donor parent will most often be responsiblefor the care and important medicationadministration of the pediatric recipient, particularly in the caseof young parents of whom the nondonor parent will need to continue employment. Thus, a smaller flank incision will facilitate surgical rehabilitation and full compliancewith the additional responsibilitiesof the pediatric donor parent. If a medically suitableliving donor is not available, then the strategy would be to use a cadaver donor graft, preferably from a donor greater than 6 years of age and, if possible,greater than IO years of age. It would alsobe important to diligently avoid ATN with its attendant problemsand greater risk of graft loss. One needs to recognize that a child who losesa kidney will likely become sensitized and may be dillicult to transplant later in life. This is an important point becausea child may not do well with long-term dialysis,and additionally, may very well be encumbered with numerous problems related to dialysisaccess.These can becomequite complex and

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Figure

1. Slightly greater than 2-inch donor nephrectomy flank incision.

distressful to, not only the child, but the parents and health care providers. Timing of the Transplant A total of 28% of pediatric renal transplants reported to NAI’RTCS have been pre-emptive and occured before the need for dialysis.6 Graft survival for both live donor and cadaver kidneys is significantly better in the pre-emptive group compared with the dialysis group.‘j A pre-emptive transplant prior, but somewhat close to the time of dialysis requirement appears ideal and will avoid the myriad ofdialysis access problems. The only exception is for the infant in whom a period of peritoneal dialysis, intensive nutritional therapy, and bone management may be beneficial. It has generally been our goal to pursue this course with infants until they reach approximately 10 kg and are 6 months of age. When the infant is not tolerating dialysis, or not growing, then we will proceed with transplantation at a lesser weight. The smallest infant that we have successfully transplanted with good long-term graft survival weighed 4.5 kg.

Adult Kidneys in Infants and Small Children The principal considerations infants and small children aspects relating to the use of (2) the fluid resuscitative ensure good function of such

in transplantation of are (1) the technical adult-sized kidneys, and measures required to a kidney without subse-

quent ATN or possiblegraft thrombosis.More specifically, the vascular anastomosesrequire meticulous attention to ensure that blood flow to the kidney is not compromised,becausethe donor renal artery is often the samediameter or slightly larger than the recipient aorta, and the donor renal vein may have a diameter approximately three times that of the recipient vena cava. In addition, the pediatric medical, surgical, and anesthesia teams need to fully understand the dynamicsof the increasedblood flow demandof the adult kidney on the small child with a small heart, small blood volume, and marked blood vesseldiscrepancies. Aside from the convincing NAPRTCS data showing that children do not do well with small kidneys,6 we ourselves are convinced that an adult-sized or near adult-sized kidney is the most appropriate graft for an infant or small child. One of the authors (OS) had previously beena strong proponent of the useof pediatric cadaver kidneys,t5 but over time it has becomeapparent that they lack the reserve to come back after a severe rejection episode.This observation seemsto be important in children in whom the prevalence of rejection is greater than adults and in whom graft lossfrom rejection also appears to be greater. Important Technical Aspects Implantation of an adult-sized kidney into an infant or small child can be a formidable procedure, but if certain surgical principles are followed, transplantation can be safeand provide the patient with the best

Pediahc

Renal Trmsplanlalion

possible opportunity for long-term graft survival. One of the most important considerations in performing the vascular anastomoses is to ensure that there is a perfect lie of both the renal artery and renal vein without any redundancy, which in turn, can result in kinking and subsequent thrombosis. Great care must be taken to this point because the adult-sized kidney will occupy a good part of the right abdomen (Fig 2A and B), allowing little space for the renal vessels between the kidney and great vessels except for their short, straight, and direct passage. The best way to determine the site of the anastomoses on the aorta and vena cava is to take the kidney temporarily out of cold slush, and place it in the recipient’s right flank to determine, not only the best position of the renal vessels, but where to amputate these vessels to avoid redundancy. One should avoid hooking one renal vessel over the other but provide a straight course fol each renal vessel from the renal hilus to both the aorta and vena cava. Anatomically, the venous structures of the native kidney are anterior to the arterial structures at the hilus. If the kidney being implanted is a donor left kidney, then the renal vein can be amputated and anastomosed to the anterolateral aspect of the vena cava. The left renal artery itself will now be anteriot and allow the surgeon greater latitude in determining the site ofanastomosis to the aorta. With the left kidney, the aortic anastomosis can most frequently be carried out below the inferior mesenteric artery. Implantation of the donor right kidney seems to be more prone to surgical error. Generally, the right renal vein is short and does not need to be amputated. However, the problem is with the placement of the renal artery. Most often, the renal artery will emerge superior to the renal vein so that bringing it over the vein to an aortic position inferior to the inferior mesenteric artery may produce a partial obstruction of the more pliable renal vein and predispose to thrombosis. Thus, we will most often anastomose the right renal artery to the aorta superior to the inferior mesenteric arter)r (Fig 3). Two other technical considerations at the time of vascular anastomoses are worthy of mention to minimize metabolic acidosis and warm ischemia to the kidney graft being implanted. Clamping both the aorta and vena cava for the entire time to accomplish the vascular anastomoses can accelerate acidosis from the ischemic lower extremities. We prefer to initially clamp off the vena cava anastomotic site, perform the anastomosis, and at its completion cross-clamp the renal vein with a fine vascular bull

55

Figure 2. (A) Anterior view of mag-netic resonance (MR) study shows opacificd adult-size kidney occupying most of the right abdomen in this infant. The liver, seen immediately over the kidney and the renal vein, with its two principal tributaries is also seen on this view. (B) Lateral view of MR study in the same patient shows the disproportionate relative size of the adult kiclney to the infant’s abdomen.

dog clamp. Then, the vena cava vascular clamps can be released and cava flow reestablished. Occasionally there may be some bleeding, and this can most easily be managed at this time without the renal artery anastomosis having already been accomplished, which

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Fluid Management

Figure 3. Diagrammatic representation of a right donor, adult-size kidney in an infant. The donor renal artery can be the same size or slightly larger than the aorta, whereas the donor renal vein can be approximately three times the diameter of the vena cava. might restrict surgical maneuverability in the inrant. After this, the aorta is now appropriately crossclamped for the arterial anastomosis. Because the total anastomotic time in an infant or small child can be longer than that in the routine adolescent or adult transplant, we will repeatedly cool the kidney externally at approximately lo-minute intervals with ice cold saline, sucking the solution from the dependent part of the operative field as it is poured onto the kidney, so as not to induce hypothermia. This intermittent surface retooling, therefore, favors a “perfect” vascular anastomoses without the risk of undue warm ischemia. Before reperitonealization and wound closure, it is very important to check the positioning of the adult kidney to make sure the upper pole is not encroaching and obstructing blood flow in the vena cava, which in turn can predispose to venous hypertension and renal vein thrombosis. In addition, the surgeon needs to be aware that some abdominal compression will occur with the wound closure of an infant. With a large kidney now occupying a good portion of the right abdomen, this can easily cause kinking of the renal blood vessels if they are redundant.

An adult kidney transplanted into a small child with a small blood volume, small heart, and small blood vessels will pose blood flow demands that, if not understood, can result in ATN or precipitate later graft thrombosis. In addition, we are aware of a case more than 20 years ago in which a small child developed severe hypotension, cardiac arrest, and brain death on the release of the vascular clamps after anastomoses of the renal vessels to this child’s aorta and vena cava. Clearly, transplantation of an adult kidney into an infant or small child results in the creation of what is probably the largest known, purposehilly constructed arterial-venous Gstula-like conduct in humans. The meticulous attention to intraoperative and immediate postoperative fluid management is absolutely essential to mitigate against arterial hypotension with the reestablishment of blood flow through the adult kidney, as well as to maintain optimum perfusion of this kidney. It is very important to bring the central venous pressure to approximately 18 cm/H10 before releasing the vascular clamps and reperfusing the adultsized kidney, because the latter will cause an immediate drain of a large portion of the child’s relatively small blood volume. With a number of these small children, bilateral nephrectomy and urologic reconstruction for congenital anomalies may be necessary at the same surgery before the actual implantation of the adult kidney. Therefore, normal operative fluid maintenance should be maintained during this part of the surgical procedure until approximately 45 minutes before the anticipated time of release of the aortic clamps and graft reperrusion so as to minimize tissue edema. Excessive use of crystalloid alone to achieve the desired central venous pressure will usually result in extensive tissue edema. Colloid and blood should then constitute most of the fluid administration during the 45 minutes before release of the vascular clamps. Because of the increased blood flow demand of the adult kidney and to maintain good blood pressure and a high cardiac tilling pressure, a relative state of intravascular hypervolemia is also desirable during the early postoperative period. This is most often facilitated by maintaining the infant or small child on mechanical ventilation for approximately 24 to 48 hours after graft revascularization.tG Immediately postoperatively, the transplant recipient’s feet are cool and pedal pulses diminished because of the renal blood steal. In addition, significant tachycardia may be evident, but near normaliza-

Pediatric Renal Transplantation

Lion of these parameters is usually achieved by 48 to 72 hours after transplantation. Our group has been studying the hemodynamic changes in these small transplant recipients with blood flow monitoring preoperatively and postoperatively. Preliminary results of our study indicate that incredible postoperative arterial adaptation occurs, where the aortic blood flow above the renal artery anastomosis is increased at approximately 8 days by more than twofold over the preoperative value. Because of the obvious renal arterial steal, we have also attempted to answer the question as to whether early diminished blood flow to the lower extremities persisted and might result in disproportionate growth of the child. Our studies thus far indicate that along with aortic adaptation, there is also concomitant adaptation of the common iliac vessels with greater than 50% increased flow rates compared with the preoperative values. These hemodynamic changes coupled with the high blood flow demand by the adult kidney, therefore, underscore the critical importance of the fluid resuscitative measures that must be employed in these small children. A recent study by our group of 80 consecutive pediatric patients showed the salient management features of transplant recipients weighing less than I5 kg compared with those weighing I5 kg or more (Table 5). Of the patients in the less than l5-kg group, almost all required blood transfusion and postoperative mechanical ventilation compared with the larger child. Most of the patients weighing between I5 and 20 kg also required blood transfusion, and 42% required postoperative mechanical ventilation. To better understand Table 5, we use a midline, transperitoneal approach in all patients weighing 20 kg or less, and in some weighing beTable 5. Comparison of Smaller (C 15kg) v Larger (2 15kg) Children Undergoing Kidney Transplantation 515kg

n 21 2.9 (0.6-5.9) Age (~4 Surgerylime 6.4 (4.7-7.8) 04 IV fluids 190 (mW) Bloodtransfusion 18/21 Midline incision 21/!21 Postoperative mechanical ventilation 18/2l Datafrom

Hammer

et alI6

215 kg

P Values

59 12.6 (5.0-18.9)

c.001

4.7 (2.3-10.1)

.oo 1

96

coo I

28/59 l9/59

.Ol coo I

8/59

coo I

NA

57

tween 20 and 25 kg. Surgical time can be somewhat prolonged in some of these patients, particularly when bilateral nephroureterectomy and bladder reconstruction is required in patients with severe congenital urologic abnormalitiesand multiple previous surgeries.

Management of Congenital Urologic Abnormalities The Strategy Becausemany potential pediatric kidney recipients have congenital structural abnormalities of the urinary tract as the cause of their ESRD, it becomes useful to develop a strategy for the managementof thesecongenital problems and integrate their management with the performance of the renal transplant. Isolated management of the urinary tract in these patients without any consideration of the future renal transplant surgery can lead to a number of unnecessarysurgeriesand may ultimately result in a very difficult renal transplant operation. To best showthe key principlesof management,we will usea specific caseexample of a patient with prune belly syndromewho was2 years of age and weighed 7.8 kg at the time of transplantation. This patient had multiple congenital abnormalities: bilateral severe hydroureteronephrosis,a patent urachus,an atretic urethra with complete obstruction, bilaterally undescendedtestes,complete absenceof abdominalmusculature, pectus excavatum, and moderate pulmonary hypoplasia(Fig 4). Recognizing the severity of the urinary tract anomaliesand the presenceof renal insufliciency, it was obviousthat any early extensive urologic reconstructive procedureof the ureters would not improve this patient’s renal function but might only hasten the time to end-stage therapy. Our approach to patients suchasthis is to normalize the lower urinary tract asmuch aspossibleand then sterilize the urine so that bilateral nephroureterectomy can be performed as part of the renal transplant surgery. Of course,if urine sterilization cannot be obtained, then preliminary nephroureterectomy needs to be performed before the transplant. The principal advantage of removing the kidneysand ureters at the same transplant operation accruesfrom avoiding extensive dissectionadjacent to the aorta and vena cava,which may then result in moderate surrounding scar reaction and make isolation and skeletonization of these vesselsat the time of later transplantation more diflicult. Becausethese major vesselsin infants and

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Salvatiema

hydronephmtic (enlarged) kidney

et al

ization cannot be achieved, then it also becomes necessary to remove the kidneys and ureters in a separate procedure before transplantation. If we can avoid a midline incision for the removal of these kidneys, we will do so and remove them through two separate small flank incisions. With the current versatile self-retaining retractors, excellent exposure can be obtained to the area of the iliac vessels. When the ureters are not excessively dilated, a small flank incision will allow removal of most of the ureter on the ipsilateral side. When the ureters are very dilated then we will use a midline incision to remove the entire length of each ureter. If the urine can be sterilized before the transplant, we prefer to perform the transplant and remove the right kidney and

bladder patent orachus (opening of bladder to outside)

urethra

Figure 4. Multiple anomalies of urinary tract before reconstructive surgery and kidney transplantation. small children are small compared with the adult donor vessels, any injury from dissection because of scar at the time of the transplant surgery may compromise the subsequent achievement of the desired “perfect” vascular anastomoses. With this in mind, attention in this case was initially directed towards urethral reconstruction and establishment of urethral continuity. Once this was ensured, the patent urachus was repaired and the urinary bladder reconstructed. Satisfactory voiding dynamics were then shown and the urinary tract was sterilized so that bilateral nephroureterectomy and renal transplantation could be accomplished as a single procedure. A midline incision was used for the procedure (Fig 5). At the time of the transplantation surgery, the left testis was also brought down, whereas the right testis was removed because it could not be satisfactorily brought down. The final anatomic outcome in this patient is shown in Figure 6. The basic principles outlined above apply to all patients in whom a midline incision is used. We used a midline transperitoneal approach in all patients weighing 20 kg or less and in some weighing between 20 and 25 kg. In the remaining larger patients, we used the standard curvilinear right or left abdominal extraperitoneal incision. In these larger children the same basic principles outlined would also apply, with the possible exception of the surgical management of the hydronephrotic kidneys and ureters. If urinary steril-

Figure 5. Midline transplant incision from xiphoid to symphysis pubis is seen at the uppermost part of this figure, whereas the hydronephrotic kidneys and severe megaloureters are seen extending from the inferior aspect of the incision. Removal of these dilated systems required extensive dissection around the aorta and vena cava and would have made transplantationat a later date more diflicult if it wasnot performedsimultaneously with the nephroureterectomies.

Pediatric Renal Tramplaniakm

normal

adult

transplanted

kidney

reconstructed urinary bladder

Figure 6. Totally reconstructed urinary tract and transplanted adult kidney. ureter through a right extraperitoneal transplant incision, retracting the posterior peritoneum and colon anteriorly. The left kidney can be removed through a separate small flank incision either before the transplant or at the time of the transplant. Management of the Abnormal Urinary Bladder The strategy for the management of the dysfunctional abnormal urinary bladder in patients undergoing renal transplantation should be to first accept the fact that there is no perfect treatment. With that premise, one can then proceed to employ the simplest, most effective means to achieve good urinary drainage. The goal should be not to encumber the patient with unnecessary morbidity or unnecessary reconstructive surg!ry that will tend to do harm rather than good. For example, it is important not to embark on an extensive procedure, such as bowel augmentation of the urinary bladder, when the patient has proven renal insufficiency, because such a procedure can only enhance the development of true ESRD, and if there is recurrent urinary infection, the augmentation will need to be taken down before transplantation.t7 In patients with obstructive uropathy from posterior urethral valves, the native thickened bladder, although not totally normal, appears to be a much better receptacle for the transplant ureter than an

59

augmented bladder. A number of bladder augmentations are performed because of worsening bladder function and incontinence that often present with the evolvement of renal insufficiency in these patients. A marked polyuria can develop with near end-stage chronic pyelonephritis and hydronephrosis because of loss of renal concentrating ability. This imposes an increased volume burden on these abnormal valve bladders that leave patients frustrated in attempts to maintain satisfactory bladder emptying. This is a transient event that can be managed conservatively until the patient reaches true ESRD, when the hydronephrotic kidneys can be removed and a transplant kidney with normal concentrating ability is implanted. A recent report of long-term follow-up in a large series of patients with posterior valves also makes a strong case for conservative management.‘s The authors conclude that by avoiding diversion in most cases, bladder function is preserved and the need for bladder augmentation is decreased. One of the authors (OS) has long advocated the use of the native bladder for transplantation in children and adolescents who had posterior urethral valves, even when the bladder had been unused and contracted for many years. The principal prerequisites for the use of these small defunctionalized bladders has been (1) that any residual bladder outlet obstruction be ruled out and corrected, (2) that any neurogenic component be ruled out, and (3) the adherence to certain surgical considerations. We have generally found urodynamic studies misleading in these cases. In a personal series (OS) of 37 patients who had kidneys transplanted into. severely contracted urinary bladders (capacity 130 cc), the bladders all subsequently enlarged and were rehabilitated (Fig 7A and B). Three of these patients developed late hydronephrosis (7, 10, and 12 years post-transplant) and required urologic intervention. In contrast, the remaining much larger group of patients were spared extensive pretransplant surgical procedures such as bladder augmentation with bowel. A recent report I9 also indicates that renal transplantation can be performed safely into longterm defunctionalized bladders. An independent report by others, of what was primarily one of our author’s (OS) own experience in this report’s study of patients from 1979 to 1991, disclosed that most of the 23 kidney recipients who had posterior urethral valves had continent urinary drainage with the use of the native bladder after transplantation.20 The incidence of infection and

60

Salvatiera

incontinence were low, 3 patients experienced bladder dysfunction, and only 4 had urinary tract infections post-transplant. Of these 23 patients, 10 received cadaveric and 13 received living related grafts. Patient survival was 100% at 10 years, whereas combined living donor and cadaver graft survival was 69% at 5 years and 63% at 10 years, with a half life

el al

greater than 14 years. All patients with surviving grafts had good kidney function, and a number of patients had transplantation performed before or during the early cyclosporine period. The principal surgical consideration in the use of the defunctionalized contracted urinary bladder is that cicatricial tissue surrounding the bladder detrusser should be excised as much as possible during the transplant surgery. This will allow expansion of the bladder with use after discontinuation of catheter urinary drainage after transplantation. We prefer to .use suprapubic cystostomy drainage with a Malecot catheter for 2 weeks to allow the transplant ureteroneocystostomy to heal well before the small bladder is subjected to large volumes of urine from a good functioning transplant kidney. In a majority of these cases, we will also use a ureteral stent, cutting off a good portion of the stent because these small bladders will not accommodate much more than a short stent stump protruding into the bladder lumen. The bladder end of the stent is then secured to the tip of the Malecot catheter with a 40 monofilament suture, so that the,stent will simultaneously be pulled out when the suprapubic tube is removed. The conservative approach that we have expressed does not mean that if it is pursued, none of these patients will require later urologic intervention. In fact, all patients with abnormal bladders, no matter what tht treatment, need to be monitored throughout the life of the transplant for possible late urologic complications,*’ but it does mean that these patients will have much less surgery and less morbidity than if, for example, urinary bladder augmentation were carried out in every patient. With augmentation, intermittent catheterization at regular and frequent intervals will be absolutely mandatory while under immunosuppression. This can become a real burden to both the child and parents. There can also be additional problems of mucus plugging, diffticulty , Figure 7. (A) Cystogram shows a less than IO-cc capacity, long-term defunctionalized urinary bladder with dilated prostatic urethra and dilated bilateral ureteral stumps. (B) Intravenous pyelogram in the same patient 3 months post-transplantation opacifies the renal collecting system and urinary bladder. With progressive enlargement of the urinary bladder, the ureteral stumps are now high riding and not dilated as previously. By 6 months post-transplantation this patient achieved a bladder capacity of 350 cc. Reproduced with permission from Wiley-I&s. (From Salvatierra, 0: Urologic complications in renal transplantation: Pediatric Renal Transplantation. New York, WileyLiss, 1994,p. 337).

Pedialti

Renal Transplanlahm

in dil&rentiating rejection from the functional ob struction that would occur with incomplete bladder emptying, recurrent urinary infection, and possible sepsis. The latter would undoubtedly lead to further additional surgery, such as takedown of the augmentation and possible urinary diversion. I7

Neurogenic Bladder In patients with neurogenic bladders, we feel that the best alternatives are probably two. In instances where successful intermittent catheterization has already been carried out before ESRD and good compliance has been shown, use of the native bladder can be considered. Otherwise, a short ileal conduit that provides unimpeded urinary drainage might be the best alternative.

Management Diseases

of Other Problematic

Autosomal Recessive Polycystic Kidney Disease Autosomal recessive polycystic kidney disease (PKD) has a spectrum of severity that seems to vary inverselywith the age of presentation. The most severe form of this disease can always be detected by prenatal ultrasonography and is quite obvious at birth with kidneys that are large enough to actually impede delivery. Newborns with the most severe PKD have an enormously hard abdomen, renal failure, severe hypertension, and usually die within hours or days after birth. However, aggressive surgical and dialysis intervention can salvage many of

Figure 8. Kidneys removed from an infant with autosomal recessive PKD. Transverse measurement of both kidneys is 17 cm. A midline incision from xiphoid to symphysis with decompression of this infant’s abdomen is seen in the background.

61

these newborns in whom renal transplantation can later be performed. In other forms of PKD, the same therapeutic urgency is not present, because the disease is of a milder nature and may not present itself until later infancy, childhood, or adulthood with a reasonably good prognosis with respect to renal function.** The most severe forms of PKD demand early removal of the enormous renal masses to decompress the abdomen, initiate peritoneal dialysis, and begin a program of planned high caloric nutrition (Fig 8). Later renal transplantation with an adult-sized kidney can then be performed according to the principles already discussed. Early, aggressive intervention in these newborns with the severe form ofPKD can be extremely important for some parents who have already experienced death of offspring from PKD after delivery. The primary deterent to intervention in these cases is severe congenital pulmonary hypoplasia. However, the determination of the cause of pulmonary insufficiency may be difficult because a significant part of the early pulmonary compromise in these newborns may actually be caused by impaired pulmonatyvolumes from the huge abdominal masses.

Congenital Nephrotic Syndrome Congenital nephrotic syndrome is inherited as an autosomal recessive trait and is characterized by massive proteinuria at or shortly after birth. This will soon evolve into ascites, anasarca, failure to thrive, growth retardation, superimposed serious infectious complications from poor nutrition, and urinary losses of gammaglobulins and complement, as well as

62

Salvalima

signilicant arterial and venous thrombotic episodes because of hypercoagulability. This constellation of problems tends to result in a high mortality rate before the child can be considered for renal transplantations Because of the dismal natural history of this disease, conservative nutritional and pharmacological interventions have usually been unsuccessful. Bilateral nephrectomy and subsequent renal transplantation have really been the only good options available to the child with reasonable results, compared with the overwhelming mortality rate of conservative therapy. NAPRTCS reports overall 72% and 89% l-year graft and patient survival after transplantation, whereas the Finnish experience in a smaller series is even better with 100% graft and patient survival at 1 year.s5 It is, therefore, obvious that the only realistic hope of survival for these children is to prepare them for transplantation by moving quickly to bilateral nephrectomy and peritoneal dialysis, preferably before 6 months of age.24There are few instances in which children have survived to the onset of renal insufficiency with subsequent marked reduction of proteinuria where bilateral nephrectomy may not be needed. However, the high risk of fatal infection and thromboembolism in this group of infants treated conservatively truly justifies early pre-emptive bilateral nephrectomy, dialysis, and restoration of an optimal nutritional state by high caloric nasogastric or gastrostomy feeding, so that the patient can subsequently undergo renal transplantation with a better expectation of surviving.2G Occasionally, transplantation may be considered at the time of bilateral nephrectomy because of extensive abdominal adhesions from prior recurrent peritonitis that preclude peritoneal dialysis and the hypercoagulable state and difficult vascular access that prevent hemodialysis in the small child. However, transplantation at this time is not desirable and should only be performed if satisfactory means to accomplish dialysis are not available. FSGS FSGS is one of the most perplexing problems in pediatric renal transplantation because it is one of the leading causes of renal failure in children and yet has a high incidence of recurrence in the allograft. to-i3 The majority of patients who show recurrence will manifest massive proteinuria, usually by 3 months after transplantation and almost always within the first year.27 From a review of the literature, at least a 20%-recurrence rate with about one

et al

half of these grafts lost in patients transplanted with FSGS now seems to be well established?’ The principal risk factors for recurrence are (1) age, especially less than 15 years, with the greatest risk in those under 6 years of age; (2) a rapid evolution into renal failure that occurs within 3 years of original manifestation; and (3) mesangial expansion in the renal biopsy material. 27 The recurrence rate is approximately 50 O/o10*27in patients less than 5 years of age, and greater than 80% in those less than 15 years at onset who, in addition, go into renal failure within 3 years and have mesangial expansion?’ There has been no proven successful therapy for recurrent FSGS. Recently, there has been interest in obtaining remission with high-dose cyclosporine,2s~2g but there are no other noteworthy confirmatory reports regarding significant therapeutic eflicacy of this approach. Greater interest has been shown with the more recent successes reported with plasma exchange,30-32 and particularly the success with the use of immunoabsorption of immunoglobulin G with a protein Acolumn, suggesting that whatever plasma factor may be responsible for FSGS may be removed by protein A. 32It may be that some of these patients may require long-term plasmapheresis for control. Our program has a patient who is now 3rh years after cadaveric transplantation performed at age 8 with expected and immediate recurrence of FSGS.33 Early plasmapheresis was performed on an almost daily basis and has now been weaned to treatment intervals of approximately 6 weeks. This patient now maintains a creatinine of 1.3 mg/dL, and a low urine protein/creatinine ratio. The outcome and current treatment schedule for this patient are certainly better than losing the kidney graft and returning to frequent dialytic treatments. In retransplantation in patients with FSGS, a study of 64 renal transplants in 46 patients diagnosed with ESRD secondary to FSGS allows some general guidelines. I2 If the primary allograft is lost without recurrence of FSGS, additional renal transplants are likely to be free of recurrent disease, and one can probably use living related donors for second transplants in these patients. However, if there is rapid recurrence of FSGS and subsequent accelerated loss of the primary allograft, further renal transplants carry a high likelihood of recurrent FSGS and graft loss. Future promise of reliable predictability of FSGS recurrence may come from a circulating factor that has been found in some patients with FSGSs4 This circulating factor appears to be associated with recur-

Pediahic

Renal Transplantation

rent disease after renal transplantation and may be responsible for initiating the renal injury of FSGS. Primary

Hypexoxaluria

Type 1

Primary hyperoxaluria type 1 (PHI) is a rare inborn metabolic disorder of the liver that is characterized by diffuse nephrocalcinosis or nephrolithiasis and progressive renal insufhciency. The cause is a deficiency of hepatic peroxisomal alanine: glyoxylate aminotransferase. Nephrocalcinosis is more common in younger children and usual in infants, whereas nephrolithiasis is seen more frequently in older children and adults. Once renal failure occurs, extrarenal deposition of calcium oxalate (systemic oxalosis), will occur in multiple sites such as bone marrow, retina, blood vessels, and heart.35 Therapeutic options for PHI must be individualized to consider the patient as well as the disease.36s37 The principal problem with renal transplantation alone is that subsequent damage of the allograft by oxalate will occur, and once this occurs, systemic oxalosis is ensured. In older children, nephrolithiasis appears more prevalent and seems to be responsive to large doses of pyridoxine (a cofactor for the missing enzyme), as well as hydration for maintenance of high urinary output. In these cases kidney transplantation alone, especially with a living related donor, in combination with the medical measures mentioned, can be performed.37*3s The most severe form of PHI is infantile oxalosis in which diffuse nephrocalcinosis has developed silently and the hepatic enzyme deficiency is essentially complete, thus leaving these patients unresponsive to pyridoxine. This is a fatal metabolic defect for which kidney-liver transplantation is the only viable therapy. The actual decision to perform kidney-liver transplantation, especially in older children and adults, should be made by excluding B6 response, by oxalate and glycolate assay.37 An extensive review of pooled data of the entire United States’ experience in both children and adults was recently reported and showed that results with transplantation are suboptimaLs7 It included 28 renal transplants performed in 22 children. Seventeen living donor transplants were reported in children with eight grafts functioning well and three with borderline function. All six cadaver transplants failed. Combined kidney-liver transplantation was performed in five children, two of whom died within 1 month of transplant. Obviously, transplantation with PHl is problematic and is especially problematic in patients with infantile oxalosis, in which the only

63

chance of survival is combined kidney-liver transplantation. Our program has performed four combined kidney-liver transplants for infantile oxalosis at 15, 16, 20, and 2 1 months of age after a period of aggressive peritoneal dialysis (15 hourly exchanges/day) to control oxalate deposition and nasogastric tube feeding to maximize growth (Fig 9).3gThese patients are now 14 to 32 months post-transplant and all exhibit normal kidney and liver function. The European experience with combined kidney-liver transplants currently results in greater than 80% patient survival at 3 years, but only a few have been performed for infantile oxalosis.3s

Graft Survival, Rejection, and Mortality by Primary Diagnosis Tables 6 and 7 display P-year graft survival, percentage of total patients experiencing rejection, and death for both living and cadaver donor recipients as reported by the NAPRTCS registry.“” The structural category includes congenital obstructive uropathy, renal aplasia/dysplasia, reflux nephropathy, prune belly syndrome (agenesis of the abdominal muscula-

Figure 9. Bilateral renal shadows are easily visualized because of diffuse nephrocalcinosis in this infant with PHI. Peritoneal dialysis catheter is in place.

64

Saluath7a

et al

Table 6. Livine Donor Recioients Grafl Failure Prima9

Cause OfESRLI

from

Number

o/o

107/775

Structural

Glomerulonephritis FSGS Congenital nephrotic syndrome Hemolytic uremic syndrome (HUS) Renal infarction Cystinosis Familial nephritis Other Data

Rate

Kashtan

13.8 16.6 25.7 20.8 19.4 16.7 7.1

33/l99 39/152 1l/53 7i36 4R4 2R8 3R7 36/160

11.1

22.5

% LYear Grafl Sunn’val

89 86 76 84 80 88

93 95 79

Relative Risk Increase

I .oo 1.23 1.91 1.31 1.02 1.22 0.57 0.89 1.71

Patients Experiencing Rejection @)

Patient Mortali& Rate (%)

52 50

3.6 4.0 2.6 11.3 5.6 4.2 0.0 0.0 6.9

59 51 64 58 46 63 54

et aLM

ture), polycystic kidney disease, medullary cystic disease,and chronic pyelonephrotis. Patients with congenital nephrotic syndrome, FSGS, and hemolytic uremic syndrome had the highest graft failure rates, and thosewith congenital nephrotic syndrome had the highest mortality. Of particular note is that cadaver graft recipientswith a primary diagnosisof congenital nephrotic syndrome experienced both the highest mortality rate and the worst graft survival amongall categories.These high mortality and graft failure rates were not simply caused by recipient or donor age, because these factors were controlled by the covariate analysisof the NAPRTCS study.@In part, we believe that these rates in cadaver graft recipients may very well be causedby the need for early transplantation after bilateral nephrectomy becauseof poor dialysisaccess before an optimal nutritional state can be established in these very sick infants. In someof these patients, peritoneal dialysis may not be possiblebecause of abdominal adhesionsfrom prior episodesof recurrent peritonitis. In addition, these patients may not be able to tolerate the immunosuppressionnecessary

becauseof their already debilitated condition. Living donor graft survival is considerably better, perhaps becausemost centers would not proceedwith living donor transplantation unlessthe potential recipient wasin reasonablygood physicalcondition. Nevertheless,the overall high mortality rate in the congenital nephrotic group supports the contention that many of thesesmall children have beendevastatedby their diseases.23,24

Immunosuppression of Rejection

and Prevention

It is not within the scopeof this article to present a detailed discussionof the various immunosuppressive protocols, becausetheseare well covered in the medical literature. However, it is important to indicate that early aggressive,effective immunosuppressionisvery important in pediatric kidney transplantation.‘nq2Within two years of transplantation, 72%of cadaver graft recipients have had a rejection episode, whereas56% of living donor grafts have developed rejection.6Alarmingly, complete reversalof rejection

Table 7. Cadaver Donor Recipients Grafl Failure Primary

Cause ofESRD

Structural Glomerulonephritis FSGS Congenital nephrotic syndrome HUS Renal infarction Cystinosis Familial nephritis Other Data

from

Kashtan

et aI”

Number

207/745 62R34 81/197 24/40 20/48 13140 16/55 14/41 56/183

Rate %

27.8 26.5 41.1 60.0 41.7 32.5 29. I 34.2 30.6

% 2-Year GraJl Sumival

74 75

64 54 62 72 71 70 71

Relative Risk Increase

1.oo 0.98 1.50 1.85 1.70 1.17 1.12 1.33 1.22

Patients Experiencing Rejection &)

68 68 68 65 65 65 56 73 67

Patient Mortality Rate (%)

6.3 3.4 6.1 15.0 8.3 12.5 9.1 7.3

9.3

Pediahic

Renal Transplanlation

occurred in only 50% of all reported rejection episodesG There are a number of reasons why children may be more vulnerable to acute rejections than adults43: Children, particularly young children, seem to have brisk immunologic responsiveness, and this may predispose them to significant rejection.sl“‘+ It may be difficult to establish a diagnosis of rejection in young children, as the clinical manifestations may be hard to recognize.4”,fi Young children may have impaired absorbtion and/or accelerated metabolism of the immunosup pressive agents designed to prevent rejection.43 For example, diarrhea states can precipitate rejection if adequate immunosuppression drug levels are not maintained. Current Principal Immunosuppressive

Agents

The NAPRTCS registry shows that 48% of live donor recipients and 65% ofcadaver graft recipients receive some form of antibody induction therapy during the Grst month post-transplant.‘j Patients who did not receive ATG/ALG/OKT3 were more likely to have experienced an acute rejection episode and also exhibited a greater risk for graft failure (Table 4). Almost all pediatric immunosuppressive protocols are either cyclosporine- or tacrolimus-based, with cyclosporine being administered to 93% of all recipients at 6 months.6 The cyclosporine dosage at I year after transplantation has shown a progressive increase from the start of the NAPRTCS registry in 1987, from 6.5 mg/kg/day to 7.7 mg/lcg/day.” This may reflect a gradual change in attitude towards prevention of rejection, recognizing that the risk and consequences of rejection may be greater than the risk of drug nephrotoxicity. *t*** In fact, a careful review of past cyclosporine experience suggests that evidence for a progressive cyclosporine nephropathy is unconvincing.*’ Tacrolimus-based immunosuppression in pediatric recipients has been primarily used at one center with good results, but still with a rejection incidence of 58%.* Tacrolimus has also been used as rescue therapy with 71% success in patients failing cyclosporine-based immunosuppression.48 Cyclosporine and tacrolimus have possible side effects that are important for the pediatric age group, notably varying hirsutism and gingival hyperplasia for cyclosporine-treated patients and what at this time appears to be a greater incidence of

65

new-onset insulin-requiring diabetes mellitus4s~0~1 and post-transplant lymphoproliferative disorder (PTLD)j* for tacrolimus-treated patients. In adults, a 25% incidence of diabetes has been reportedss and appears to have a particular predeliction for blacks and Hispanics with an almost 30% incidence.53 Whether this will also be true for children will need to await further study, but can be of some concern because 25% of the pediatric dialysis population in the United States is black and 15% Hispanic6 Two immunosuppressive agents recently released by the Food and Drug Administration appear to hold considerable promise for pediatric recipients: the microemulsion formulation of cyclosporine (Neoral) and mycophenolate mofetil (CellCept). The large particle emulsion form of cyclosporine (Sandimmune) has posed great difliculties with pediatric recipients because of its unpredictable pharmacokinetics,j* which, in turn, can be made worse with delayed gastrointestinal mobility from more extensive transplantation procedures in infants and small children, as well as with diarrhea states. In contrast, Neoral has already been shown to provide more consistent absorption and bioavailability of cyclosporine in adults. The same appears true for childrenp3 with optimism that decreased variability of drug blood levels will have an impact on reducing the rejection incidence. Preclinical and clinical experience with mycophenolate mofetil in adult United States and European studies has clearly shown that the incidence of biopsy-proven rejection is significantly reduced?j Early reports are now beginning to show the same efficacy in children as shown in adults.56s57 Steroids and Growth Almost all chronic immunosuppressive regimens in pediatric renal transplantation include maintenance steroids with 96% of patients on steroids at 60 months post-transplant.6 How to best manage steroids to maximize growth of pediatric transplant recipients has been, in part, an enigma. On the other hand, efforts to withdraw steroids have been hampered by fears that such a step might enhance prospects of rejection in a group of patients already exhibiting a high incidence of rejection. However, successful efforts of complete steroid withdrawal have been achieved in selected patients on tacrolimus.ffl Most other efforts at withdrawing steroids in children have been limited to alternate-day dosing. An important recent study by NAPRTCS of 2,001 patients with functioning grafts at 12 months deter-

66

Salvalima el al

mined the effects of alternateday (QOD) steroid dosing(accomplishedin 337 of the 2,001patients) on growth, graft survival, and graft function>s Growth, as measured by change in age- and sex-adjusted height standard deviation scores(SDS), showedthat the QOD group had statistically significant greater positive growth than the daily (QD) steroid group at each 1Zmonth post-transplant interval (12, 24, 36, 48, and 60 months) measured (Fig lo)?” Graft survival and incidence of rejection did not differ on the basisof the steroid dosingpattern and the mean serumcreatinine wasalwayslower in the QOD group at all live 1Zmonth intervals (statistically significant at 12 and 24 months). It is alsonoteworthy that the QD group began to lag in height SDS at 48 and 60 months,with no changein height SDS at 60 months; whereasthe QOD group showedthe greatest positive changein height SDSat 60 months.58In contrast, a NAPRTCS 1Zmonth follow-up of 5 12 pediatric dialysis patients showed negative SDS scoresin all categoriesstudiedat 6 and 12monthscomparedwith baseline.” The data from the NAPRTCS analysis does not appear to support the useof QOD steroid dosing in all patients but rather in selected transplant recipients in whom QOD steroid dosingwould be a safe alternative to complete steroid withdrawal. One could envisionfurther meaningful efforts in this direction, particularly with the advent of mycophenolate mofetil, which might effectively complement cyclosporine-and tacrolimus-basedimmunosuppressive protocols to allow steroid withdrawal or converWQD m

0.81

12

24

36

48

60

MonthsPostTransplant Figure 10. Mean changein heightSDSfrom baselineat 30 days after transplantation.The solid bars indicate patients treated continuously on a QD steroid dosing regimen from 12 months after transplantation and the hatched bars indicate patients treated continuously on a QOD regimen. Dilference between QD and QOD groups, P C .05. Reproduced with permission from Williams and Wilkins. (Jabs y Sullivan JX, Avner ED, Harmon WE: Alternate-day steroid dosing improves growth without adversely tiecting graft survival or long-term graft function. Transplantation 1996,61:3 I)

sion to QOD dosing in more patients and with greater certainty. Malignancies An increased incidence of malignancy is a wellrecognizedcomplication of chronic immunosuppressive therapy. Thirty-eight malignancies have been reported to the NAPRTCS registry.6 Leading cause of malignancieswere lymphoproliferative disorders (23), sarcomas(5), and carcinomas (3). Seventeen percent of these patients have died, 7 within the month that the malignancywasdiagnosed.” One of the most disturbing problems in solid organ transplantation is PTLD. Fortunately, its incidence appearsrelatively low among pediatric kidney recipients when compared with its occurrence with recipients of other solid organ transplants. The NAPRTCS registry revealslessthan a 1% incidence of PTLD in pediatric kidney recipients.G*5” However, the PTLD incidence at one center was 18%(6 of 34) with tacrolimus-basedimmunosuppressionand 8% (2 of 24) with cyclosporine-basedimmunosuppression5*This appearedto conlirm the suspicionof the authors of this article that children managed with tacrolimus may have a greater predisposition to PTLD and require closermonitoring.52

Stanford Experience The pediatric renal transplant program at Lucile Packard Children’s Hospital at Stanford University Medical Center (previouslyat California PacificMedical Center) performed 108 renal transplants in patients age 0 to 18years during a 51/i-yearperiod from mid-l 991 through 1996.mA goal of our program has been to provide a kidney transplant for every child on chronic dialysis,or if possible,just before the need of dialysis.This has beenaccomplishedwith the exception of four smallchildren who died while on maintenancedialysisawaiting a transplant. Twelve percent of the transplant recipients were in the 0 to 1agegroup, and 17%were in the 2 to 5 age group compared with 6% and 16%,respectively, for the NAPRTCS registry. The principal differences in diseasecause from NAPRTCS (Table 1) were a two-times greater incidence (33.3%) of congenital obstructive uropathy compared with 16.8% for NAPRTCS and a 4.6% incidence of oxalosis compared with 0.8% for NAPRTCS. There was only a 7.4%incidence of renal aplasia/hypoplasiafdysplasia comparedwith 17%for NAPRTCS. A total of 72%of

Pediatric

Renal Tranrplantativn

the transplants were from living donors, and 28% were from cadaver donors. All kidneys except nine (92%) were adult-size kidneys, but no kidney was used from a donor less than 2 years of age. The smaller kidneys were used in four patients with oxalosis undergoing combined kidney-liver transplantation and in one patient with an absent vena cava. Twenty-six percent of patients received pre-emptive transplants. Actuarial I-, 2- and 3-year graft survival rates are 99%, 95%, and 93% for living donor transplants and 97%, 92%, and 92% for cadaver donor transplants.ss Overall patient survival for the entire group since the inception of this series in mid-l 99 1 is 97%. Causes of all graft losses and deaths for the entire series are depicted in Table 8.(io The principal causes of graft loss were noncompliance in three adolescents and death in three patients. The death secondary to Epstein-Barr virus sepsis occurred in a patient who had been converted from cyclosporine to tacrolimus. No evidence of Phil> was found in this patient. Only one patient in this series had PTLD, and this patient was on tacrolimus after a combined kidney-liver transplant. Tacrolimus was discontinued and the patient appeared recovered on essentially no immunosuppression. We were fortunate not to lose any kidney from rejection, except for the cases of noncompliance, which occurred at 18 months to 4 years after transplantation. In good part, we believe that this was caused by our early, aggressive immunosuppressive protocol. Our initial 60% of patients in our series were managed with ATG or OKT3 induction. Because of the severe restrictions imposed by the evolving managed health care delivery environment in Northern California, we have subsequently restricted OKT3 induction to sensitized patients and those undergoing retransplantation. Our current basic protocol is ,predicated on intravenous cyclosporine induction, later overlapping with Neoral when

Table 8. Graft Loss and Patient Death Event

Tim Pa.+Tranrplan~

Graft loss Graft loss Graft loss Graft loss Death

1 wk 18mo 22 mo 4Y Id

Death Death

18 mo 3Y

Cause

Recurrent FSGS Noncompliance Noncompliance Noncompliance Hyperkalemia 2” medication error EBV sepsis Pneumonia

67

the patient is able to eat. Cyclosporine levels are closely monitored and patient dosaging is individualized. A trough whole blood cycle level of 350 to 480 ng/mL is maintained during the first month posttransplantation with subsequent gradual tapering, so that at 6 months after transplantation and afterwards the patient is maintained on a trough whole blood cycle level of 200 ng/mL. Almost all of our most recent patients since August 1995 are now on a cyclosporine-based immunosuppressive protocol that includes mycophenolate mofetil and prednisone in tapering doses. With the general immunosuppressive considerations described, our incidences of recipients with acute rejection episodes are 14% and 19% at 1 and 2 years for living donor transplants and 32% and 44%, respectively, for cadaver donor transplants.60 Among the 30 patients on primary triple drug therapy of Neoral, mycophenolate mofetil, and prednisone, there has been only one mild rejection. Our regimen of frequent cyclosporine trough blood level monitoring and dosing by levels, has been designed to prevent even a single rejection episode,@ particularly with the immunologic consequences in the pediatric population. Although our initial immunosuppression is more aggressive than, perhaps, other centers, we believe that the avoidance of recycling of high-dose immunosuppressive therapy for acute rejection episodes obviates any potential benefits of initially using less immunosuppression. In this manner, we have been able to not only enhance graft survival but also minimize the risk of serious infectious complications.

Summary Pediatric renal transplantation poses many challenges, yet successful transplantation is the optimum therapy for children with ESRD. The impediments to success are different and of greater magnitude than seen with adults, primarily because of different and problematic disease causes, distinctly different medical and surgical considerations in small children, and what appears to be an enhanced immune response in smaller children. Nevertheless, excellent results can be obtained in pediatric renal transplantation by strict adherence to surgical detail, tight immunosup pressive management, careful integration of urologic reconstructive surgery with the renal transplant, and aggressive fluid management in the small child.GO Most important to achieving this success is the

68

Salvaliema

management of these patients by an integrated and experienced medical, surgical, and anesthesia team.

Acknowledgment The authors gratelully acknowledge Drs Amir Tejani, Steve Alexander, William Harmon, and Richard Fine for their commitment and leadership in maintaining the NAPRTCS registry, without which many of the results reported would not have been possible. In addition, the authors gratefully acknowledge the invaluable contribution and support or the following individuals who have worked with them: Drs Bruce Tune, Alan Krcnsky, Donald Dabe, Peter Kim, Sheldon OrlofT, Rose Ellen Morrell, Carlos Esquivel, and Amira Al-Uzri; Director ofpediatric intensive care unit Dr Lorry Frankel and the intensive care unit star, Nurse Coordinators Pamela Orlandi, Leigh Page, Laura Cunningham, Debbi Acres, and Roni Callister; and Administrative Assistants Karen ColTey, Stephanie Tsuchida, and Yolanda Thomatis.

References I. Statzl TE, Marchioro TL, Porter KA, et al: The role of organ transplantation in pediatrics. Pediatr Clin North Am 1966, 13:381 2. Ettenger RB: Children are dilTerent: The challenges ofpediatric renal transplantation. Am J Kidney Dis 1992,20:668 3. Fine RN: Renal transplantation of the infant and young child and the use of pediatric cadaver kidneys for transplantation in pediatric and adult recipients. Am J Kidney Dis 1988, 12: 1 4. Najarian JS, Frey DJ, Matas AJ, et al: Renal transplantation in infants. Ann Surg 1990,2 12:353 5. U.S. Renal DataSystem: 1996Annual Data Report. Bethesda, MD, National Institutes orHealth, NIDDKD, 1996 6. Kohaut EC, Tejani A: The 1994 annual report or the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 1996, IO:422 7. Harmon WE, Stablein D, Alexander SR, et al: Graft thrombosis in pediatric renal transplant recipients. Transplantation 1991,51:406 8. Evans E, Ettenger RB: Immune response in pediatric renal transplantation, in Pediatric Renal Transplantation. New York, NY, Wiley-L&, 1994, pl7 9. Fitzpatrick MM, DulIy PC, Fernando ON, et al: Cadaveric renal transplantation in children under 5 years orage. Pediatr Nephmll992,6:166 IO. Senguttuvan P, Cameron JS, Hartley BB, et al: Recurrence ol’ local segmental glomerulosclerosis in transplanted kidneys: Analysis ol’ incidence and risk factors in 59 allograRs. Pediatr Nephrol 1990,4:2 I Il. Ingulli E, Tejani A: Incidence, treatment, and outcome oT recurrent segmental glomerulosclerosis post-transplantation in 42 allografts in children-A single center experience. Transplantation 1991,51:401 12. Stephanian E, Matas AJ, Maurer SM, et al: Recurrence of disease in patients retransplanted for Focal segmental glomerulosclerosis. Transplantation 1992,53:755 13. Tejani A, Stablein DH: Recurrence off&al segmental glomerulosclerosis post-transplantation: A special report of the North

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Pediatric

34.

35. 36.

37.

38.

39.

40.

41.

42.

43. 44.

45.

ffi.

Renal Transplantalion

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