Kidney Transplantation in Children: The Preferred Option But Still No Cure

The paper from White and colleagues1 in this issue of AJKD, based upon data from a single center in British Columbia, Canada, is a timely reminder to clinicians caring for children with chronic kidney disease (CKD),2 that kidney transplantation only means a different stage (CKD-T) and not complete cure from CKD. In children, as in adults, transplantation provides substantially improved quality of life compared with dialysis, reduces the hazard of death by about 70%, and is clearly the optimal mode of renal replacement therapy.3, 4, 5 However, it is not a panacea, it does not remove the CKD state, and mortality for transplanted children remains substantially higher than children who do not have CKD.3 Causes of death are primarily cardiovascular but increased cancer and infection risk are also contributory.3, 6 This paper shows that although this case series of kidney transplant recipients have good kidney function (median glomerular filtration rate of 76 mL/min/1.73 m2), anemia and hypertension, known risk factors for adverse cardiovascular outcomes, occur commonly in this group of children.

What does this study add? The unique feature of this study is the comparison of a prevalent pediatric transplanted population with a native-kidney population with matched glomerular filtration rate values, to estimate the relative frequencies of CKD complications. As the authors acknowledge, the study does have a number of limitations. There were missing data, the sample size was small, the study was cross-sectional and not longitudinal, and because it was retrospective, data on many confounders were not adjusted for. What they do not acknowledge is that it is likely that the comparative analysis is of uncertain validity because the 2 groups, the transplanted and native-CKD groups, are drawn from very different populations, with many more differences than the study factor of interest. For example, although the cause of CKD is matched, it is probable that the severity of the underlying disease is much greater in the transplanted group, given that time to progression to end stage from onset of CKD is likely to be less in this group. Any difference in frequency of CKD complication may be due to differences in duration and/or severity of the underlying kidney disease and not transplantation per se. Duration of CKD was not recorded or adjusted for. Another obvious unequally distributed confounder is immunosuppressant medication, which variably produces bone marrow suppression and hypertension.7, 8, 9 Some descriptive data on immunosuppression use were reported in brief by the authors but dose and level data were not. It could be argued that adjustments for these drugs are unnecessary given that their use is inherent in receiving a transplant, but the side-effect profiles of the different classes of drugs used are variable, and no adjustment for these differences was made by the authors. Finally, being a single-center study, the generalizability of these results to other centers is uncertain.

Despite these weaknesses, the major message remains. Transplantation is a CKD state and the management of a child with a kidney transplant should include both care of the graft and care of the complications of CKD. Unfortunately it remains largely speculative whether correction of anemia, hypertension, and the metabolic disturbances associated with CKD improve long-term outcomes in children who have received a kidney transplant. The recent hemoglobin saga illustrates the perils of extrapolating from information on risk, derived from observational data of exposure and outcomes, to intervention recommendations, which should be obtained from randomized trials in which exposure is systematically modified.10, 11 Accordingly, correction of anemia by erythropoietin-stimulating agents and iron in patients like those described in this paper may be beneficial, or indeed may be harmful. Other strategies like immunosuppression minimization may be more effective. Correction of hypertension is another matter. Randomized trials of blood pressure–lowering agents have almost universally been found to reduce cardiovascular-related morbidity and mortality, irrespective of the population group treated.12, 13 Correction of acidosis and manifestations of CKD-bone mineral disorders is of uncertain benefit.14, 15 Other strategies, not evaluated in this study, such as the detection and management of asymptomatic diabetes (new-onset diabetes mellitus after transplantation) deserve further study.16, 17

Where to from here? Given the cross-sectional design of the study, major changes in the management of children who have received a kidney transplant are not justified, but clinicians who care for these children would do well to heed the call to manage the CKD state of these children as well as care for their grafts. Transplanted children still die more frequently than they should, and randomized trials, international and collaborative in nature, are needed to evaluate the effects of a range of potentially beneficial intervention strategies. Of these, reduction in maintenance immunosuppressive medication and blood pressure lowering look the most promising at the present time,7, 17 but more novel strategies are likely to be needed.