Chronic kidney disease (CKD) is a common complication in long-term survivors of hematopoietic cell transplant (HCT), occurring in 20-60% of adult and pediatric recipients in multiple studies. This proposal studies the natural history of CKD and identifies risk factors for progression of CKD and mortality associated with CKD.
Specific aim 1 will rigorously establish the true prevalence of CKD in this patient population using cystatin C levels and iohexol studies in patients at 3 time points, baseline, prior to conditioning therapy, at day 100 and then again at 1 year after transplant. We will also examine the natural history of CKD and identify risk factors for progression of CKD in patients who develop CKD at 1 year after transplant. We will follow patients with CKD for 5 years after transplant. Using univariable and multivariable Cox regression models, graft vs. host disease, albuminuria, hypertension, post-transplant diabetes and calcinuerin inhibitor use will be analyzed as risk factors for progression to end-stage renal disease.
Specific aim 2 will identify risk factors for mortality in patients with proteinuria at day 100 post-transplant. After adjustment for GVHD, patients with overt proteinuria have an 8- fold greater risk of non-relapse mortality at 1 year post-transplant compared to patients without proteinuria. We propose to determine if increased inflammation in conjunction with other cardiovascular risk factors such as hypercholesterolemia and hypertension, contribute to the increased risk of death in these patients. Increased inflammation will be determined by measuring renal cytokine levels as reflected by urinary levels and determining if these are significantly increased in patients with proteinuria.
Specific aim 3 will use in-depth, quantitative proteomic analysis of urine from patients after HCT to identify a set of proteins which predict the development of CKD by 1 year post-transplant. Urine samples from our prospectively followed cohort of 200 patients at baseline and day 100 and then at the time of diagnosis of CKD will be subjected to fractionation followed by tryptic digestion and shot-gun LCMS/MS analysis to identify proteins associated with CKD development. The most informative proteins identified will be subjected to detailed analysis by ELISA assays to validate their utility as biomarkers. Project Narrative High-dose myeloablative therapy followed by hematopoietic cell transplant (HCT) is an increasingly common treatment for many malignancies and some genetic disorders. Indeed, approximately 20,000 HCTs are now performed annually world-wide and offer the prospect of cures for otherwise fatal or incurable diseases. Ten thousand of these transplants are performed in the United States. With the indications for and the number of transplants increasing and patient survival improving, so, too, will the burden of chronic kidney disease (CKD) on the health care system. Approximately 2000 patients per year in the US alone will develop CKD Stage 3 after HCT and over time these patients are likely to progress to end-stage. Therefore, the care of these patients with CKD will strain our medicare system and add to the growing number of patients on dialysis and on the wait list for a kidney transplant. Studies such as the present one designed to elucidate the risk factors for progression and mortality in this patient population are a critical first step towards the development of targeted interventions to improve patient outcomes.
|Hingorani, S; Gooley, T; Pao, E et al. (2014) Urinary cytokines after HCT: evidence for renal inflammation in the pathogenesis of proteinuria and kidney disease. Bone Marrow Transplant 49:403-9|