Serum Soluble Urokinase Receptor Levels as Markers of CKD Progression Risk in Children

Children diagnosed with chronic kidney disease (CKD) face significant comorbidities and reduced life expectancy and quality of life, as well as psychosocial integration during childhood and into adulthood. The ESCAPE (Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients) trial established strict blood pressure control and antiproteinuric pharmacotherapy as the first effective renoprotective strategy in pediatric CKD. Other studies have identified other modifiable conditions, such as metabolic acidosis and vitamin D deficiency, that effect the rate of kidney function decline. Preclinical and clinical research is currently evaluating novel approaches to pharmacological renal protection that may be available for children in the future.

At present, conventional methods to diagnose and monitor CKD in the pediatric population are of limited value. Those methods, including estimated glomerular filtration rate (eGFR) derived from creatinine level and cystatin-C and proteinuria assessment via spot urine samples, do not aid in identification of patients at risk for progressive loss of kidney function.

Incident CKD stage 3 can be predicted with serum soluble urokinase receptor (suPAR) levels in adults; suPAR is a marker of immune activation involved in the pathogenesis of focal segmental glomerulosclerosis. It is unknown whether there is an association between suPAR levels and progression of CKD in children.

Franz Schaefer, MD, and colleagues recently conducted a post hoc analysis of a combined cohort of children with CKD enrolled in two studies: the observational 4C Study (Cardiovascular Comorbidity in Children with Chronic Kidney Disease) and the ESCAPE trial. The researchers sought to test the hypothesis that high levels of serum suPAR in children with CKD may be a biomarker for a more rapid decline in kidney function. Results were reported online in JAMA Pediatrics [doi:10.1001/jamapediatrics.2017.2914].

The primary end point was renal survival, defined as a composite of 50% loss of eGFR that persisted for at least 1 month, initiation of renal replacement therapy, or an eGFR <10 mL/min/1.73 m2. Serum suPAR levels were measured at enrollment, and eGFR was measured every 2 months in the ESCAPE trial and every 4 months in the 4C Study.

The analysis included 898 children from the 4C study (71.5%) and 256 from the ESCAPE trial (28.5%) who had stored serum available for assay of serum suPAR at baseline. Mean age of the eligible participants was 11.9 years and mean eGFR was 34 mL/min/1.73 m2. Median duration of follow-up was 3.1 years (range, 0 to 7.9 years). Primary diagnoses of renal disorders were glomerulopathies, uropathic congenital anomalies of the kidney and urinary tract (CAKUT; reflexive/obstructive CAKUT), other CAKUT, reduced renal mass subsequent to acute kidney injury, tubulointerstitial nephropathies, or other or unknown kidney diseases. Overall, 70.9% of the cohort (n=637/898) were in one of the CAKUT categories, and 7.7% (n=69) had a glomerular disorder.

In the 4C study, patients had more advanced CKD than in the ESCAPE trial: mean eGFR, 29 versus 47 mL/min/1.73 m2, respectively. In 100 participants from the 4C trial and 169 from the ESCAPE trial, mean eGFR at trial entry was >40 mL/min/1.73 m2. Overall, the composite end point was reached by 44.8% of the cohort: 98 in the ESCAPE trial and 304 in the 4C study.

Median suPAR concentration was 5.658 pg/mL in the study (much higher than the 2.082 pg/mL in the healthy control population). In multivariable analyses, there was an inverse association between log suPAR concentrations and eGFR (–0.009; standard deviation [SD], 0.001; P<.001). There was no significant association between suPAR concentrations and sex (female, 0.042, SD, 0.022; P=.06) or age (–0.005; SD, 0.003; P=.09). In addition, suPAR concentrations were not affected by the type of renal disease.

In children with suPAR levels in the highest quartile, 5-year renal survival was 35.9% (95% confidence interval [CI], 28.7-43.0) versus with 64.5% (95% CI, 57.4-71.7) among those in the lowest quartile. In multivariable analyses, there was an association of a significantly higher likelihood of reaching the renal survival end point with older age, the presence of proteinuria, higher systolic blood pressure, glomerular and tubulointerstitial disorders, and initial eGFR.

Following adjustment for traditional risk factors, there was an association of higher log-transformed suPAR levels with a higher risk of CKD progression in patients with baseline eGFR >40 mL/min/1.93 m2 (hazard ratio, 5.12; 95% CI, 1.56-16.7; P=.007). No other covariates (age, sex, diagnosis, or proteinuria) had significant interaction with respect to the association of high suPAR levels with the risk of reaching the renal survival end point.

Limitations cited by the authors included using a single measurement of suPAR, a lack of African American and Asian individuals in the study cohort, and the lack of complete clinical data to eliminate residual confounding. In addition, because the study cohort included only individuals with established CKD, the findings are not generalizable as to the usefulness of suPAR level as a predictive marker in patients at risk for or in very early stages of CKD.

The researchers added, “In conclusion, our findings demonstrate that an elevated serum suPAR level is associated with increased risk of deterioration in kidney function in children with mild to moderate CKD (eGFR, 40-80 mL/min/1.73 m2) secondary to a broad range of renal disorders. Given that suPAR level predicts CKD development in various at-risk populations, it is plausible that measurement of serum suPAR level early in the course of pediatric CKD may identify patients at heightened risk of progression of kidney function loss and adverse clinical outcomes. This is especially relevant in pediatric nephrology practice because at least half of all CKD cases are caused by CAKUT or hereditary disorders that can be identified during infancy or even prenatally. Ongoing mechanistic studies have the potential to define suPAR level as a prime target for renal therapeutics.”