Exploring Kidney Disease in Cancer Survivors

In the Division of Nephrology at The Children’s Hospital of Philadelphia (CHOP), investigators are combining research efforts with multidisciplinary clinics to improve kidney outcomes for children with cancer.

Acute kidney injury and chronic kidney disease are common complications in this patient population, especially among those who have received a hematopoietic stem cell transplant (HSCT). Acute kidney injury can range from transient decreases in glomerular filtration rate (GFR) which recover without intervention, to more serious episodes that may or may not completely resolve. Alarmingly, children requiring dialysis for acute kidney injury after HSCT have mortality rates >70%. While the exact prevalence is unknown, estimates suggest that chronic kidney disease probably affects about 1 in 5 long-term survivors of childhood cancer.

The cause of kidney injury in this population is likely multi-factorial and includes ifosfamide and platinum-based chemotherapy, radiation, and calcineurin inhibitors used for graft-versus-host disease prophylaxis in those undergoing HSCT. These treatments have been associated with an increased risk for later hypertension, proteinuria, and tubular dysfunction. The contribution of infections to kidney injury in this population is not well understood. Since completing his pediatric nephrology fellowship training at Cincinnati Children’s Hospital Medical Center (CCHMC) and continuing through the first few years of his appointment at CHOP, Benjamin Laskin, MD, MS, has been exploring novel causes of kidney injury after HSCT. Working closely with his collaborators at CCHMC and CHOP, Laskin has been studying cohorts designed to investigate thrombotic microangiopathy, BK virus infection, and kidney function in children receiving an HSCT.

Laskin’s primary interest is in the study of viral infections, including BK virus infection, in immunosuppressed children after transplant. In a prospective cohort of 88 children undergoing allogeneic HSCT at CCHMC, higher levels of BK viremia predicted the development of later hemorrhagic cystitis. HHV-6 viremia was also associated with an increased risk of hemorrhagic cystitis, an observation that needs further study. Furthermore, the level of BK viremia may provide prognostic information in those already diagnosed with cystitis. In a retrospective cohort of 68 children who received an allogeneic HSCT at CHOP from 2005 to 2011, peak BK viremia >10,000 copies/mL was associated with high-grade hemorrhagic cystitis, defined as the requirement for bladder catheterization or surgical intervention.

BK virus infection may also lead to intrinsic kidney damage after HSCT, as it does in those who have received a kidney transplant. Specifically, children with a peak plasma BK viral load of >10,000 copies/mL had higher peak post-HSCT serum creatinine values relative to baseline and an increased risk of dialysis compared to those with lower levels of viremia. Finally, the estimation of kidney function in this population using serum cystatin C is an active area of research, as creatinine-based methods may overestimate GFR in children with reduced muscle mass, such as can occur after HSCT.

Regarding clinical care, the multidisciplinary Cancer Survivorship Clinic was started at CHOP in 2006 under the guidance of Jill Ginsberg, MD, Division of Oncology. Its overall goal is to offer patients and families access to specialized care during a single clinic visit. The clinic is held once a month and follows long-term survivors of pediatric cancer at least annually. In addition to visits with oncology, other specialists from endocrinology, pulmonary medicine, cardiology, psychology, and nutrition also attend.

Recently, Laskin and Michelle Denburg, MD, Division of Nephrology, joined the Survivorship Clinic team. Prior to clinic visits, children and adolescents are screened for hypertension, proteinuria, and decreased kidney function. At-risk patients are assessed with 24-hour blood pressure studies and serum cystatin C measurements, especially in those with short stature in whom serum creatinine may overestimate GFR.

As mortality for pediatric cancer continues to decrease, more children will become long-term survivors whose healthcare needs will shift to the prevention and treatment of “late effects.” The kidney is increasingly recognized as an organ frequently damaged during the course of cancer treatment. CHOP’s Division of Nephrology hopes its research and multidisciplinary clinical care will serve as a model for the type of collaborative efforts needed to improve the survival, health, and quality of life of this vulnerable patient population.

References

Kidney and bladder outcomes in children with hemorrhagic cystitis and BK virus infection after allogeneic hematopoietic stem cell transplantation. Oshrine B, Bunin N, Li Y, Furth S, Laskin BL. Biol Blood Marrow Transplant. 2013;19(12):1702-1707.

BK viremia precedes hemorrhagic cystitis in children undergoing allogeneic hematopoietic stem cell transplantation. Laskin BL, Denburg M, Furth S, Diorio D, Goebel J, Davies SM, Jodele S. Biol Blood Marrow Transplant. 2013;19(8):1175-1182.

Cystatin C-estimated glomerular filtration rate in pediatric autologous hematopoietic stem cell transplantation. Laskin BL, Nehus E, Goebel J, Khoury JC, Davies SM, Jodele S. Biol Blood Marrow Transplant. 2012;18(11):1745-1752.

Blood, and not urine, BK viral load predicts renal outcome in children with hemorrhagic cystitis following hematopoietic stem cell transplantation. Haines HL, Laskin BL, Goebel J, Davies SM, Yin HJ, Lawrence J, Mehta PA, Bleesing JJ, Filipovich AH, Marsh RA, Jodele S. Biol Blood Marrow Transplant. 2011;17(10):1512-1519.