Dyslipidemia after pediatric renal transplantation—The impact of immunosuppressive regimens

Dyslipidemia contributes to cardiovascular morbidity and mortality in pediatric transplant recipients. Data on prevalence and risk factors in pediatric cohorts are, however, scarce. We therefore determined the prevalence of dyslipidemia in 386 pediatric renal transplant recipients enrolled in the CERTAIN registry. Data were obtained before and during the first year after RTx to analyze possible non‐modifiable and modifiable risk factors. The prevalence of dyslipidemia was 95% before engraftment and 88% at 1 year post‐transplant. Low estimated glomerular filtration rate at 1 year post‐transplant was associated with elevated serum triglyceride levels. The use of TAC and of MPA was associated with significantly lower concentrations of all lipid parameters compared to regimens containing CsA and mTORi. Immunosuppressive regimens consisting of CsA, MPA, and steroids as well as of CsA, mTORi, and steroids were associated with a three‐ and 25‐fold (P<.001) increased risk of having more than one pathologic lipid parameter as compared to the use of TAC, MPA, and steroids. Thus, amelioration of the cardiovascular risk profile after pediatric RTx may be attained by adaption of the immunosuppressive regimen according to the individual risk profile.     

Prevalence of renal dysfunction in tacrolimus‐treated pediatric transplant recipients: A systematic review

Renal dysfunction after non‐renal transplantation in adult tacrolimus‐treated transplant patients is well documented. Little is known about its prevalence in children. Age‐related changes in both disposition and effect of tacrolimus as well as renal function may preclude extrapolation of adult data to children. To systematically review the literature on renal dysfunction in non‐renal pediatric transplant recipients treated with tacrolimus. PubMed/Medline, Embase, and Google were searched from their inception until April 19, 2012, with the search terms “tacrolimus,” “renal function,” “transplantation,” and “children.” Eighteen of 385 retrieved papers were considered relevant. Twelve dealt with liver, four with heart transplant, one with heart and lung transplant, and one with intestinal recipients. Reported prevalences of mild and severe chronic kidney disease ranged from 0% to 39% and 0% to 71.4%, respectively, for liver, and from 22.7% to 40% and 6.8% to 46%, respectively, for heart and/or lung transplant recipients. Ranges remained wide after adjusting for follow‐up time and disease severity. Possible explanations are inclusion bias and definitions used for renal dysfunction. A considerable proportion of pediatric non‐renal transplant patients who receive tacrolimus‐based immunosuppression, appear to suffer from chronic kidney disease. This conclusion warrants further research into the real risk, its risk factors, and individualization of immunosuppressant therapy.     

BK virus nephropathy in a pediatric heart transplant recipient with post‐transplant lymphoproliferative disorder: A case report and review of literature

BKV is known to cause allograft failure in kidney transplant recipients. It has been recently recognized to cause native kidney nephropathy in non‐kidney transplant recipients. This is a case report BKVN in a 15‐yr‐old HTx recipient who had PTLD and a review of pediatric cases in the literature. The patient was diagnosed with BKVN +189 months after transplantation and died thirty days after diagnosis of BKVN. We identified five other cases of BKVN in pediatric non‐kidney solid organ transplantation, of which all were HTx recipients. Overall, outcome was poor and BKV clearance was not achieved with reduction of immunosuppression and with current therapies. We strongly recommend that pediatric HTx recipients be tested for BKV infection if there is evidence of kidney dysfunction. We also recommend that they have an annual screening for BKV viruria and viremia with the assessment of kidney function.     

Masked hypertension and allograft function in pediatric and young adults kidney transplant recipients

Masked hypertension is a common complication of pediatric kidney transplantation. While office hypertension is known to be associated with worse short‐ and long‐term graft function, the role of masked hypertension in allograft dysfunction is not clear. We conducted a retrospective cross‐sectional analysis of 77 consecutive pediatric kidney transplant recipients who had routine 24‐h ambulatory blood pressure monitoring with the aims to estimate the prevalence of masked hypertension and examine its association with allograft function. Masked hypertension was defined as a 24‐h systolic or diastolic blood pressure load ≥25%. Twenty‐nine percent of patients had masked hypertension. Patients with masked hypertension had significantly lower allograft function estimated using the creatinine‐based Schwartz‐Lyon formula, a cystatin C‐based formula, and combined cystatin C and creatinine‐based formulas than patients with normal blood pressure (all p values <0.05). In a multivariable analysis, masked hypertension remained independently associated with worse allograft function after adjustment for age, sex, race, time post‐transplant, rejection history, antihypertensive treatment, and hemoglobin level. We conclude that in young kidney transplant recipients, masked hypertension is common and is associated with worse allograft function. These results support the case for routine ambulatory blood pressure monitoring as the standard of care in these patients to detect and treat masked hypertension.     

New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney–liver complications

Improved neonatal medical care and renal replacement technology have improved the long‐term survival of patients with ARPKD. Ten‐yr survival of those surviving the first year of life is reported to be 82% and is continuing to improve further. However, despite increases in overall survival and improved treatment of systemic hypertension and other complications of their renal disease, nearly 50% of survivors will develop ESRD within the first decade of life. In addition to renal pathology, patients with ARPKD develop ductal plate malformations with cystic dilation of intra‐ and extrahepatic bile ducts resulting in CHF and Caroli syndrome. Many patients with CHF will develop portal hypertension with resulting esophageal varices, splenomegaly, hypersplenism, protein losing enteropathy, and gastrointestinal bleeding. Management of portal hypertension may require EBL of esophageal varices or porto‐systemic shunting. Complications of hepatic involvement can include ascending cholangitis, cholestasis with malabsorption of fat‐soluble vitamins, and rarely benign or malignant liver tumors. Patients with ARPKD who eventually reach ESRD, and ultimately require kidney transplantation, present a unique set of complications related to their underlying hepato‐biliary disease. In this review, we focus on new approaches to these challenging patients, including the indications for liver transplantation in ARPKD patients with severe chronic kidney disease awaiting kidney transplant. While survival in patients with ARPKD and isolated kidney transplant is comparable to that of age‐matched pediatric patients who have received kidney transplants due to other primary renal diseases, 64–80% of the mortality occurring in ARPKD kidney transplant patients is attributed to cholangitis/sepsis, which is related to their hepato‐biliary disease. Recent data demonstrate that surgical mortality among pediatric liver transplant recipients is decreased to <10% at one yr. The immunosuppressive regimen used for kidney transplant recipients is adequate for most liver transplant recipients. We therefore suggest that in a select group of ARPKD patients with recurrent cholangitis or complications of portal hypertension, combined liver–kidney transplant is a viable option. Although further study is necessary to confirm our approach, we believe that combined liver–kidney transplantation can potentially decrease overall mortality and morbidity in carefully selected ARPKD patients with ESRD and clinically significant CHF.     

Results of early treatment for de novo donor‐specific antibodies in pediatric kidney transplant recipients in a cross‐sectional and longitudinal cohort

The development of dnDSA anti‐HLA antibodies has been shown to be a significant risk factor for graft failure. In 2008, we instituted a routine protocol of standardized monitoring and treatment of dnDSA in pediatric kidney transplant recipients. Of 67 first‐time pediatric kidney transplant recipients, 26 (38%) developed dnDSA after 1.36 (IQ 1‐2.14) years. Coefficient of variance of tacrolimus, a surrogate marker of non‐adherence, was found to be the single most important risk factor for dnDSA development. Overall, there was a significant reduction in dnDSA with treatment in 19 (76%) children. No difference in graft survival and estimated glomerular filtration rate was noted between dnDSA negative and those treated for dnDSA. There was an increased risk of hospitalization in those treated for dnDSA. This study suggests that early detection and treatment of dnDSA can help to prevent graft failure and preserve graft function in the short term. Future studies and longer follow‐up are needed to fully elucidate the effect of early detection and treatment of dnDSA in pediatric kidney transplant recipients.     

Solid tumors following kidney transplantation in children

Kidney transplant recipients have an increased risk of cancer. Data on non‐LPD malignancies (solid tumors) in pediatric renal transplant recipients are limited. We performed a cohort study using the NAPRTCS transplant registry to describe the incidence of non‐LPD malignancy compared with the general pediatric population. The observed incidence rate of non‐LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100 000 person‐years (SIR 6.7; 95% CI, 5.3, 8.5); a 6.7‐fold increased risk compared with the general pediatric population (10.7 cases per 100 000 person‐years). Non‐LPD malignancy was diagnosed in 35 subjects at a median of 726 days post‐transplant. The most common type of malignancy was renal cell carcinoma. The increased risk of non‐LPD malignancy was seen in all patients regardless of age, gender, race, etiology of end‐stage kidney disease, and transplant era. The specific type of immunosuppression was not identified as a risk factor. In this first large‐scale study of North American pediatric renal transplant recipients, we observed a 6.7‐fold increased risk of non‐LPD malignancy compared with the general pediatric population. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk.     

Subclinical cardiovascular changes in pediatric solid organ transplant recipients: A systematic review and meta‐analysis

CV disease is a major cause of morbidity and mortality following solid organ transplantation in adults. While the prevalence of multiple cardiometabolic risk factors is increased in pediatric solid organ transplant recipients, it is not clear whether they have subclinical CV changes. cIMT, central pWV, and CAC are indicative of subclinical CV disease, and, in adults, predict future CV events. The objective of this systematic review and meta‐analysis was to investigate the prevalence of subclinical CV changes, as measured by cIMT, pWV, and CAC among pediatric solid organ transplant recipients. We searched MEDLINE^® and EMBASE and conducted meta‐analysis for studies that evaluated cIMT, central pWV, and CAC among pediatric solid organ transplant recipients (kidney, lung, intestine and liver). The search identified nine eligible studies that included a total of 259 patients and 685 healthy controls. Eight studies reported on kidney transplant recipients and one study on a combined cohort of kidney and liver transplant recipients. The mean cIMT of transplant recipients was significantly higher than that of healthy controls (mean difference = 0.05 mm, 95% CI 0.02–0.07; p < 0.0001) with an estimated pooled prevalence of elevated cIMT of 56.0% (95% CI 17.0–95.0). The one study that assessed pWV showed increased vascular stiffness in transplant recipients compared to healthy controls. No studies assessing for CAC were found. There were limited data regarding subclinical CV disease following pediatric solid organ transplantation. In conclusion, kidney transplantation in childhood is associated with a higher prevalence of subclinical CV changes compared to healthy children. Longitudinal studies are needed to determine whether children have increased CV morbidity and mortality after transplantation.     

Practice recommendations for the monitoring of renal function in pediatric non‐renal organ transplant recipients

The management of non‐renal pediatric solid organ transplant recipients has become complex over the last decade with innovations in immunosuppression and surgical techniques. Post‐transplantation follow‐up is essential to ensure that children have functioning allografts for as long as possible. CKD is highly prevalent in these patients, often under recognized, and has a profound impact on patient survival. These practice recommendations focus on the early detection and management of hypertension, proteinuria, and renal dysfunction in non‐renal pediatric solid organ transplant recipients. We present seven practice recommendations. Renal function should be monitored regularly in organ transplant recipients, utilizing assessment of serum creatinine and cystatin C. GFR should be calculated using the new Schwartz formula. Transplant physicians should also monitor blood pressure using automated oscillometric devices and confirm repeated abnormal measures with manual blood pressure readings and ambulatory 24‐h blood pressure monitoring. Proteinuria and microalbuminuria should also be assessed regularly. Referrals to a pediatric nephrologist should be made for non‐renal organ transplant recipients with repeated blood pressures >95th percentile using the Fourth Task Force reference intervals, microalbumin/creatinine ratio >32.5 mg/g (3.7 mg/mmol) creatinine on repeated testing and/or GFR <90 mL/min/1.73 m².     

Hypertension after pediatric cardiac transplantation: Detection,etiology, implications and management

Roche SL, O’Sullivan JJ, Kantor PF. Hypertension after pediatric cardiac transplantation: Detection, etiology, implications and management.
Pediatr Transplantation 2010:14: 159–168. © 2009 Wiley Periodicals, Inc. Abstract: While it may rescue children with end‐stage heart failure from impending catastrophe, cardiac transplantation leaves 50–70% of pediatric recipients with new‐onset hypertension. Given the unique vulnerability of the heart and kidneys in these children, we can expect long‐term uncontrolled hypertension to shorten both graft and patient survival. In this review we discuss the multi‐factorial etiology of post‐transplant hypertension, highlighting current uncertainties and emphasizing mechanisms specific to cardiac recipients. We consider the optimal means of monitoring BP and in particular, the advantages of 24 h‐ABP over intermittent clinic measurements. We also review BP treatment after cardiac transplantation, drawing attention to specific cautions appropriate when prescribing antihypertensive agents in these circumstances.     

Kidney transplant after hematopoietic cell transplant in pediatrics: Infectious and immunosuppressive considerations

Pediatric patients requiring kidney transplant after hematopoietic cell transplant receive multiple courses of immunosuppression placing them at risk for infection. To elucidate potential risk factors for infection, we compared the immunosuppressive regimens and infectious complications of pediatric kidney transplant recipients at a single institution who had previously undergone hematopoietic cell transplant from different donors to similar patients reported in the literature. Among the initial four post‐hematopoietic cell transplant kidney transplant patients reviewed, viremia episodes were universal, including BK virus, Epstein‐Barr virus, and human herpesvirus‐6, with one death from presumed BK virus encephalitis. No viremia was reported in five similar cases in the literature. Risk factors for increased infection include use of lymphodepleting serotherapy in HCT conditioning, multiple HCTs, limited immune reconstitution time between transplants, increased pre‐KTx viral burden, and use of T‐cell‐depleting versus ‐suppressive induction immunosuppression for KTx. These findings suggest that pediatric post‐HCT KTx recipients are at increased risk for viral infections, likely benefitting from thorough pre‐KTx evaluation of immune reconstitution and preferential use of non‐T‐cell‐depleting induction therapy for KTx. We applied these recommendations to one subsequent post‐HCT patient requiring KTx at our institution with excellent outcomes one year post‐KTx.     

Increased carotid intima‐media thickness in African American pediatric kidney transplant recipients

Early signs of subclinical CV dysfunction can be detected by ultrasound for CIMT. Although A‐A are at high risk for CV disease, CIMT of A‐A kidney transplant recipients has not been previously investigated. The aim of this prospective, controlled, longitudinal study was to investigate determinants of CIMT in a multiracial pediatric kidney transplant population, with a focus on A‐A. Transplant recipients (n = 42) had BMI, waist‐to‐height ratio, fasting glucose, lipid panel, HbA1c%, and CIMT measured at 1, 18, and 30 months post‐transplant. Twenty‐four healthy children (14 A‐A) served as controls. CIMT of A‐A transplant (0.49, 0.49, and 0.48 mm) was higher than non‐AA transplant (0.43, 0.44, and 0.44 mm) at 1, 18, and 30 months and higher than A‐A controls (0.47 mm). Hyperparathyroidism prior to transplant predicted high CIMT‐for‐race. A‐A race was associated with 10% higher CIMT vs non‐A‐A transplant. Metabolic syndrome was associated with 0.03 ± 0.01 mm increase in CIMT among A‐A transplant recipients only. In conclusion, A‐A kidney transplant recipients have increased CIMT. Metabolic syndrome disproportionately affects CIMT of A‐A children post‐transplant. Identification of subclinical CV damage, detected by CIMT, may provide an opportunity for early detection of CV risk in this vulnerable population.     

Overweight,central obesity,and cardiometabolic risk factors in pediatric liver transplantation

PTMS describes the presence of ≥3 cardiometabolic risk factors that include obesity, hypertension, dyslipidemia, and IR. The prevalence of the clustering of ≥3 cardiometabolic risk factors or central obesity has not been studied in pediatric LT recipients. Single‐center, cross‐sectional study. Inclusion criteria: LT recipients 2–18 yr‐old, at least one yr post‐LT. Exclusion criteria: recipients of liver retransplants or multivisceral transplants. Eighty‐seven patients were identified. Median age was 9.8 yr (range 2–18), median time since LT was 6.9 yr (range 1–17). The most common indication for LT was biliary atresia (56%), and the most frequently used immunosuppressant was tacrolimus (80%). The prevalence of overweight and obesity was 21% and 5%, respectively. Central obesity affected 14%, hypertension 44%, IR 27%, low HDL 20%, and hypertriglyceridemia 39% of patients. The prevalence of ≥3 cardiometabolic risk factors was 19%. Fifty percent of the overweight/obese patients had ≥3 risk factors. Time since transplant, immunosuppression and renal function were not different between those with <3 or ≥3 risk factors. Clustering of cardiometabolic risk factors is prevalent in pediatric LT recipients, suggesting an increased risk of future CV events.     

Outcomes of kidney transplantation in children with nephronophthisis: An analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry

Abstract: NPHP is an autosomal recessive chronic tubulointerstitial nephropathy that progresses to ESRD. In the 2006 NAPRTCS report, NPHP was the primary diagnosis in 2.8% of all renal transplant patients. At our pediatric center, that covers a population in which the NPHP1 gene is prevalent, 24% of transplant recipients had a primary diagnosis of NPHP. Since no previous literature reports have documented kidney transplant outcomes in patients with NPHP, a review of the 2006 NAPRTCS database was performed. The results of this review illustrate that patients with NPHP as their underlying kidney disease have a significantly better overall graft survival when compared with all other patients registered in the NAPRTCS database. Sub‐analysis demonstrated that this benefit is statistically significant only for LD kidney transplant recipients. CrCl was better in NPHP at all time points from transplant up to five‐yr follow‐up. Moreover, in NPHP LD transplant recipients the decline of CrCl over five yr was slower compared with non‐NPHP LD transplant recipients. Rates of thrombosis, acute, and chronic rejection as well as causes of graft failure were similar in NPHP patients and all other patients. This review demonstrates that NPHP transplant recipients have excellent outcomes that are shown to be better compared with the general pediatric transplant population.     

A longitudinal retrospective analysis of left ventricular mass in a cohort of pediatric kidney transplant recipients

Childhood end‐stage kidney disease is associated with increased risk for early adulthood cardiovascular (CV) morbidity and mortality. Increased LVM is an early indicator of CV disease. Previous studies have suggested that LVM decreases after kidney transplantation; however, trends have been inconsistent. A single center retrospective longitudinal cohort analysis of LVM, documented annually, starting before kidney transplantation for up to 10 yr after transplantation was performed. BP documented by annual 24‐h ambulatory monitoring studies, and BMI values were also reviewed. Twenty‐seven children followed for a mean period of 5.3 yr were included. Depending on definition of LVH, its prevalence pretransplant and in the first years post‐transplant was up to 33% dropping to 0–25% thereafter. Individual longitudinal LVM z‐score trends were highly variable but generally trended toward the mean immediately after transplant and toward negative values in the following years. BP was stable during the follow‐up period while mean annual BMI increased in the first‐year post‐transplant but declined thereafter. In a cohort of pediatric renal transplant recipients, prevalence of LVH decreased after transplant; however, individual longitudinal LVM trends were highly variable among patients. Prospective studies are needed to correlate individual LVM trends with outcomes.     

Antiviral treatment of chronic hepatitis B with lamivudine in pediatric renal transplantation

Renal transplantation in patients with chronic hepatitis B virus (HBV) infection is known to be associated with an increased risk for exacerbation of liver dysfunction. Lamivudine has been proven to be a potent inhibitor of hepatitis B virus replication in adults after kidney transplantation. Little is known about its efficacy and safety in pediatric renal transplant recipients. Three cases serve for the discussion to demonstrate the complexity of the clinical course and effective treatment of chronic hepatitis B in pediatric patients awaiting renal transplantation. Two patients on dialysis with a high HBV replication rate were treated with lamivudine before transplantation. After the viral load had decreased below the detection limit, they underwent transplantation successfully. Despite intensified immunosuppression to treat a rejection episode in one and a relapse of the nephrotic syndrome in the other patient, the viral load remained <2.5 pg/mL. Both patients developed a mutation in the YMDD motif of the HBV genome associated with an increase in the HBV replication rate >10,000 pg/mL without deterioration of the liver function. In a third patient with a chronic HBV infection with a low replication rate, lamivudine was started about nine months after kidney transplantation due to an increasing viral load after treatment of an acute rejection episode. Six months later, the HBV DNA was no longer detectable. The patient had no signs of liver dysfunction. Lamivudine in the treatment of chronic HBV infection in pediatric renal recipients seems to be safe and effective in preventing acute liver deterioration. Three clinical cases are discussed with regard to current options in monitoring and antiviral treatment of chronic HBV in pediatric renal transplant recipients.     

Long-term care of pediatric renal transplant patients: from bench to bedside

In this review, we discuss current and future issues in the management of pediatric renal transplant recipients, including the optimization of long-term graft function and the minimization of complications caused by immunosuppression. Long-term management involves not only the monitoring of graft function but also the identification of patients at risk for the development of complications. The identification of patients with immunoreactive or immunoregulatory responses can be performed molecular monitoring of the immune response. Also, the use of frequent surveillance kidney biopsies, surrogate markers of chronic rejection, and glomerular filtration rate will be a part of future management. Identifying high-risk patients enables the physician to optimize immunosuppression to limit acute rejection. Short-and long-term management of pediatric transplant patients also includes adequate monitoring of growth and the monitoring for post-transplant lymphoproliferative disease. Ongoing clinical trials are underway that focus on these novel approaches in caring for pediatric transplant recipients.     

Impact of acute rejection on development of chronic rejection in pediatric renal transplant recipients

For pediatric kidney transplant recipients, chronic rejection has become the predominant cause of graft loss. This article reviews risk factors for chronic rejection and what can be done to lower the risk of chronic rejection for future transplant recipients.     

Is ABPM clinically useful after pediatric solid organ transplantation?

When ambulatory blood pressure monitoring (ABPM) is performed in populations with a high risk for secondary hypertension, such as solid organ transplant recipients, hypertension or abnormalities in circadian blood pressure variability are often discovered even in patients with normal office blood pressure (BP). To discuss whether ABPM should be routinely assessed in pediatric solid organ recipients, the available information on pathological findings, association of ABPM abnormalities with outcome parameters, and treatment options is reviewed. ABPM is a useful tool to optimize therapy in the large proportion of transplant recipients with confirmed hypertension. Whether the use of ABPM on a routine basis should be recommended for pediatric transplantation patients without office hypertension remains to be determined.     

Metabolic syndrome: signs and symptoms running together

Brady TM, Parekh RS. Metabolic syndrome: signs and symptoms running together.
Pediatr Transplantation 2010: 14: 6–9. © 2010 John Wiley & Sons A/S.
Abstract:  Children with kidney disease are at increased risk of having several comorbidities such as obesity, dyslipidemia, hypertension, and impaired glucose tolerance, and patients with a constellation of these symptoms are considered to have the MS. Children with kidney disease, and ESRD in particular, are at increased CV risk, as are patients with the MS. To determine the impact MS has on a particularly vulnerable population of children, those who have received a kidney transplant, Wilson et al. explored the prevalence of MS and the association of MS with cardiac abnormalities among this subset of children. They found an overall high prevalence of MS among pediatric transplant recipients and that the risk of left ventricular hypertrophy was higher among children with MS after renal transplant compared to those without MS. Review of the most common definitions of MS and also the clinical implications are discussed. While there is no doubt that children with kidney disease have a high prevalence of CV risk factors and that these children are at risk for CV events early in life, whether the sum of the parts of MS confers increased risk over what is seen with individual risk factors that often run together remains to be seen.