Objectives: Kidney transplant is the treatment of choice for end-stage renal disease, but it is not without complications. We review the medical cause of significant renal impairment and complications that developed after kidney transplant in pediatric patients who required hospital admission and intervention and/or who were followed between 2007 and 2016.
Materials and Methods: A retrospective noninterventional chart review study was conducted in pediatric patients who received a kidney transplant and/or followed at the nephrology clinic at Queen Rania Abdulla Children’s Hospital between 2007 and 2016.
Results: In this study, 101 pediatric patients received a total of 103 transplants. Forty-eight patients (47%) experienced deterioration of kidney function out of a total of 53 episodes of complications; 37 of these episodes occurred early (0-6 mo after transplant), and 26 episodes occurred late. The causes of kidney function deterioration were surgical complications, acute tubular necrosis, cell- or antibody-mediated rejection, diabetes mellitus, urinary leak, recurrence of original disease, and chronic allograft nephropathy. Thirteen patients experienced graft loss; 50% of these losses were secondary to noncompliance to immunosuppressant medication treatment after transplant. A total of six patients died; 2 (23%) of these deaths occurred in the first week after transplant, whereas the other 4 patients died over a period of 10 years.
Conclusions: Pediatric kidney transplant is not without complications; however, most of these complications are treatable and reversible. The most serious complications leading to graft loss and death occur early, in the first week after transplant. Improving immunosuppressant compliance after transplant would prevent 50% of graft losses.
Key words : Compliance, Graft loss, Pediatric kidney transplantation
The first successful pediatric kidney transplant was reported in 1966.1 Since that time, improvements in transplant surgical techniques and immunosuppressant therapy have resulted in kidney transplant as the best treatment for end-stage renal failure for pediatric patients. In Jordan, the first pediatric kidney transplant was performed at Queen Alia Military Hospital in 2004, but it is worth mentioning that the first adult kidney transplant in Jordan was performed in 1971 for a military patient at the hospital of the Jordanian Royal Medical Services. Kidney transplant in Jordan is totally dependent on living donors. According to the most recent data available (2008-2011), the total number of pediatric kidney transplants performed per year in the Arab world is 298; the average pediatric kidney transplant rate was 0.87 PMP per year and the highest rateb(3.1 PMP) was in Jordan.2
The prevalence of chronic kidney disease in Jordanian children was 51 to 75 PMP per year from 2002 to 2004, whereas the incidence of new cases was 10.7 to 14.5 PMP per year,3,4 which is comparable to the rate of renal replacement therapy (15.5 PMP/y) in the United States.5
The distribution of end-stage renal failure at Queen Rania Children’s Hospital and King Hussein Medical Center per cause for the period 2004 to 2016 is shown in Figure 1. According to the 2008 North American Pediatric Renal Trials and Collaborative Studies report, congenital anomalies of the kidney and urinary tract accounted for 48% of cases of renal failure and hereditary nephropathies accounted for 10% of cases, whereas glomerulonephritis accounted for 14% of cases.6
The pediatric transplant program at the hospital of the Royal Medical Services started at Queen Alia Military Hospital and then continued at King Hussein Medical Center. Most of the pediatric kidney transplants in Jordan are performed at King Hussein Medical Center, while a few transplants are done in private practice and under the care of adult nephrologists, especially for adolescent patients. So it is true that when we talk about pediatric transplant at King Hussein Medical Center, we are talking about transplants performed in Jordan.
Materials and Methods
This study used data collected from medical records and the local hospital registry of all patients who were followed at the pediatric nephrology transplant clinic from 2007 to 2016. The data included demographics, cause of end-stage renal failure, number of transplants per year, complications after kidney transplant, cause of graft loss, and graft and patient survival.
From 2004 to 2016, one hundred thirteen pediatric patients received a kidney transplant and/or were followed in the pediatric nephrology clinic. The data available for this study were for 101 patients followed between 2007 and 2016; data for the remaining 12 patients were not included in the analysis. Of the 101 patients, 55 patients (54%) were male and 46 patients (46%) were female. More than half of the patients underwent kidney transplant after the age of 11 years; the youngest patient was 4 years old and had the lowest body weight of 12 kg, as shown in Figure 2.
Most of the transplant patients (> 66%) had renal hypoplasia and reflux nephropathy; the remaining patients had chronic glomerulonephritis, and 50% of these patients had focal segmental glomerulosclerosis (FSGS). Unfortunately, only 5 patients with neurogenic bladder and none with primary hyperoxaluria received a transplant (Figure 3).
Three of the 101 patients received a kidney from a deceased donor, and 33% of the patients underwent a transplant preemptively before starting dialysis. Graft loss occurred in 13 patients. The causal categories are shown in Table 1. After transplant, 57% of the 101 patients did not need to be admitted to the hospital for complications; however, 47% of the patients had more than 1 complication, as shown in Table 2. The complications included cell- and antibody-mediated rejection; recurrence of the original disease; hypertension; infections, including recurrent urinary tract infection, pneumonia, BK virus nephropathy, and cytomegalovirus infection; new-onset diabetes mellitus; posttransplant lymphoproliferative disorder; chronic allograft nephropathy; graft loss; and death.
A total of 12 episodes of acute cell-mediated rejection were diagnosed based on rising serum creatinine levels and kidney biopsy; 4 episodes (28%) were resistant to treatment and the graft was lost as the episodes had presented late. Fortunately, however, 7 episodes (58%) were treated successfully, and creatinine levels returned to normal or near baseline. One patient refused treatment and died as a result of pulmonary edema. The main treatment was pulse methylprednisolone in 3 to 5 doses. In resistant cases, 3 doses of antithymocyte globulin at 3 mg/kg were administered.
Four patients developed antibody-mediated rejection. Three of these patients (75%) were treated successfully and 1 patient (25%) lost his graft function; this patient did not comply with the immunosuppressant medication treatment. The 3 patients who responded were diagnosed early. The treatment for rejection was intravenous immunoglobulin at 1 to 2 g/kg. One patient was resistant to this treatment but responded to rituximab.
Recurrence occurred in patients with FSGS and membranoproliferative glomerulonephritis (MPGN). One of the 12 patients with FSGS experienced recurrence; this patient was treated with plasmapheresis and continued to maintain graft function at 3 months after kidney transplant with normal kidney function and serum albumin level. One of the 3 patients with MPGN experienced recurrence 2 years after kidney transplant. Kidney function continued to deteriorate, and he developed end-stage renal failure that required hemodialysis 5 years after the transplant.
Recurrent pneumonia and urinary tract infection occurred in 3 and 7 patients. None of these patients developed renal impairment and all improved. Five patients developed cytomegalovirus infection that was diagnosed by a positive polymerase chain reaction test; the clinical spectrum ranged from hepatitis to pneumonitis and fever without origin. All 5 of these patients were treated successfully with ganciclovir for 2 weeks or until the infection was resolved as determined by a negative polymerase chain reaction test.
BK virus nephropathy occurred in 2 patients, both of whom experienced deterioration in kidney function. The diagnosis was suggested by the presence of BK virus in urine and blood and was confirmed by kidney biopsy. Antiproliferative treatment (mycophenolate) was discontinued, and intravenous immunoglobin was used as second-line treatment. One of these patients received rapamycin to replace tacrolimus, whereas the other patient continued to receive tacrolimus but with a decreased target to 3 to 5 ng/mL. Creatinine levels and glomerular filtration rates (50, 80 mL/1.73 m2 per min) respectively were stabilized in both of these patients.
Eight patients developed transplant-associated hyperglycemia. The condition resolved in 5 of these patients after a reduction in their immunosuppressant medications, whereas 3 of these patients continued to be insulin dependent.
Two patients developed posttransplant lymphoproliferative disorder; both of these patients died. Four patients developed chronic allograft failure, which was confirmed by biopsy. Two of these patients remained at chronic kidney disease stage 3 with a change in immunosuppressant medication from tacrolimus to rapamycin; the other 2 patients lost graft function and were restarted on hemodialysis.
A total of 6 patients died in the study. Two patients died in the first week after transplant (2009, 2011) owing to surgical complications. Another 2 patients died from posttransplant lymphoproliferative disorder, and 2 patients died after noncompliance to immunosuppressant treatment and development of graft rejection and renal failure. Two patients of 13 received a second transplant for a retransplant rate of 1.7%.
Kidney transplant for pediatric patients with end-stage renal failure offers an improved quality of life over hemodialysis. With a successful transplant, there should be less disruption to family and school life. Diet and fluid restrictions should no longer be necessary, physical growth and mental and psychological development should improve, and there should be a decrease in cardiovascular risk, mortality, and morbidity7; however, this treatment choice is not without complications. Early and late, acute and chronic, and medical and surgical complications can occur.
The medical complications that can occur include delayed graft function, infection, rejection, malignancy, recurrence of the original disease, and chronic allograft failure. Surgical complications include lymphocele, wound infection, thrombosis, renal artery stenosis, urine leak, and ureteric stenosis or obstruction.8
Acute cell-mediated rejection accounts for 10% of graft failures; it occurs in 14% of living-donor recipients and 18% of deceased-donor recipients. A rising creatinine level is a late sign of rejection; however, the most sensitive clinical signs of rejection are hypertension and fever. Biopsy is the standard procedure for confirmation of rejection. Once rejection has been diagnosed, the aim of treatment is reversal of rejection and returning the creatinine level to normal; this is achieved in 50% of cases, whereas partial reversal occurs in 45% of cases. Graft loss occurs in 5% to 10% of cases.9 In our study, two-thirds of the cases of rejection were treated successfully with achievement of the basal creatinine level. One patient died after stopping all immunosuppressant treatment, which highlights the need for follow-up, especially for teenagers and adolescents.
Antibody-mediated rejection is more severe and carries a worse prognosis than cell-mediated rejection, but if it is recognized early and treated promptly, we can usually stop the progression to end-stage renal failure. At our hospital, 50% of cases of rejection were diagnosed early after kidney transplant in patients who received their kidney outside of Jordan from unrelated donors and came in during the first week after transplant with a rising creatinine level. Their condition was recognized early, and they were treated with intravenous immunoglobulin and rituximab in resistant cases. Before 2010, antithymocyte globulin was used as first-line treatment. The resistant case was due to noncompliance with immunosuppressant therapy and presented late.
Recurrence of FSGS occurs in 40% to 60% of cases of primary FSGS. The suggested risk factors for recurrence include the age at onset of disease (14-16 y), a rapid progression to end-stage renal disease (< 48-72 mo), and a history of previous recurrence in an allograft.10 In our study, the recurrence rate was low, possibly because most cases of FSGS are secondary to familial type due to the high rate of consanguineous marriage and are not due to primary FSGS. The recurrence rate of MPGN, especially type II, is high (approaching 80%), which was reflected in our study. Three patients who received a transplant had MPGN: 1 of these patients had MPGN type II, experienced a recurrence, and was restarted on hemodialysis 5 years after his transplant; the other 2 patients had MPGN type I.
BK virus is a small DNA virus that causes clinical disease among immunocompromised patients, mainly tubulointerstitial nephritis, ureteral stenosis in kidney transplant, and hemorrhagic cystitis after bone marrow transplant. BK virus nephropathy occurs in up to 10% of kidney allograft recipients with an incidence of allograft failure of 15% to 50% in affected patients. There are 2 principal approaches to detect and manage BK virus infection: the first is a screening and preemptive strategy and monitoring for viruria or viremia using plasma DNA load, and the second is to decrease the dose of immunosuppressive medications and/or antiviral medications and to perform a biopsy to confirm BK virus nephropathy. At our hospital, we take the second approach, checking for the BK virus in blood and urine and confirming the diagnoses with a biopsy. In this study, we confirmed that 2 patients (2%) had developed BK virus nephropathy. Both patients responded after the discontinuation of mycophenolate and intravenous immunoglobulin. The relatively low rate of BK virus nephropathy in our study is related to the avoidance of induction and heavy immunosuppressant therapy. Most of our pediatric patients received a kidney from a relative, especially a parent; therefore, there is a low rate of mismatching.11
The risk of posttransplant hyperglycemia is high and is secondary to treatment with medications such as prednisolone and tacrolimus more than cyclosporine and to high fluid intake, especially immediately after transplant. Other risk factors include age older than 40 years, black race, obesity, strong family history of diabetes, African or Hispanic ancestry, the presence of concomitant hepatitis C infection, male donor, and human leukocyte antigen mismatching. According to the American Diabetes Association criteria, normal fasting blood glucose is below 100 mg/dL, impaired fasting glucose is 100 to 125 mg/dL, and new-onset diabetes is a fasting blood glucose level above 126 mg/dL. According to the criteria for the 2-hour oral glucose tolerance test, normal glucose tolerance is below 140 mg/dL, impaired glucose tolerance is 140 to 199 mg/dL, and the glucose level for new-onset diabetes is above 199 mg/dL.
It is estimated that 30% of patients will develop hyperglycemia in the absence of pre- or posttransplant diabetes, but only 5% to 10% of these patients will continue to have diabetes. In our study and according to the American Diabetes Association criteria, only 8% of our patients developed hyperglycemia and only 3% developed frank diabetes. The adopted polices for avoidance and treatment of hyperglycemia is to decrease intravenous and oral glucose intake, minimize steroid and calcineurin inhibitor intake to the lowest effective dose, avoid oversuppression, replace tacrolimus with cyclosporine, avoid sirolimus, and use insulin and other hypoglycemic agents.12
The incidence of posttransplant lymphoproliferative disorder is 1% to 2%. Most cases are non-Hodgkin lymphoma of B-cell origin and CD20 positive. It most often presents as kidney dysfunction. There is a high rate of Epstein-Barr virus viral load due to infection and often to reactivation. There is usually extranodal involvement of multiple sites, and the prognosis generally is poor, carrying a high rate of mortality.13,14 In our study, 2 patients (2%) developed posttransplant lymphoproliferative disorder and died.
Chronic allograft failure, which is also known as chronic rejection, transplant nephropathy, chronic renal allograft dysfunction, transplant glomerulopathy, and chronic allograft injury, is the reason for 25% to 30% of patients on the wait list for a donor organ in the United States. Chronic allograft failure could be due to alloantigen-dependent factors, such as a previous acute rejection, the degree of human leukocyte antigen matching, and the presence of antibody sensitization, or due to alloantigen-independent factors, such as the presence of tissue injury, inadequate renal mass, drug noncompliance, posttransplant hypertension, recurrence of the original disease, and whether the patient received a living-donor or deceased-donor kidney.15,16
Kidney transplant is not without complications; however, most of the complications are treatable and reversible, especially if diagnosed early. The most serious complications that can lead to graft loss and death generally occur in the first week after transplant. By improving immunosuppressant compliance, we can prevent 50% of graft losses.
Volume : 15
Issue : 1
Pages : 99 - 103
DOI : 10.6002/ect.mesot2016.O95
From the 1Queen Rania Abdulla Children’s Hospital, Amman Jordan;
Practice; and the 3King Hussien Medical Center, Amman Jordan
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Reham Almardini, Queen Rania Abdulla Children Hospital, Amman Jordan
Phone: +962 799 035 347
Figure 1. Distribution of End-Stage Renal Failure at Queen Rania Children’s Hospital and King Hussein Medical Center for the Period 2004-2016 by Cause
Figure 2. Number of Pediatric Transplant Patients for the Period 2004 to 2016 by Age Group (in Years)
Figure 3. Percentage of Patients Receiving Transplants Versus Dialysis by Causal Category
Table 1. Cause of Graft Loss
Table 2. Number of Posttransplant Complications