An Empirical Biomarker-Based Calculator for Cystic Index in a Model of Autosomal Recessive Polycystic Kidney Disease—The Nieto-Narayan Formula

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is associated with progressive enlargement of the kidneys fuelled by the formation and expansion of fluid-filled cysts. The disease is congenital and children that do not succumb to it during the neonatal period will, by age 10 years, more often than not, require nephrectomy+renal replacement therapy for management of both pain and renal insufficiency. Since increasing cystic index (CI; percent of kidney occupied by cysts) drives both renal expansion and organ dysfunction, management of these patients, including decisions such as elective nephrectomy and prioritization on the transplant waitlist, could clearly benefit from serial determination of CI. So also, clinical trials in ARPKD evaluating the efficacy of novel drug candidates could benefit from serial determination of CI. Although ultrasound is currently the imaging modality of choice for diagnosis of ARPKD, its utilization for assessing disease progression is highly limited. Magnetic resonance imaging or computed tomography, although more reliable for determination of CI, are expensive, time-consuming and somewhat impractical in the pediatric population. Using a well-established mammalian model of ARPKD, we undertook a big data-like analysis of minimally- or non-invasive blood and urine biomarkers of renal injury/dysfunction to derive a family of equations for estimating CI. We then applied a signal averaging protocol to distill these equations to a single empirical formula for calculation of CI. Such a formula will eventually find use in identifying and monitoring patients at high risk for progressing to end-stage renal disease and aid in the conduct of clinical trials.

An Improved Method for Estimating Renal Dimensions; Implications for Management of Kidney Disease

“…In the CKD patient, functional changes are long preceded by extracellular matrix accumulation within the renal interstitium and parenchymal echogenicity, and abnormalities in renal size often inform presence of some disease [1][2][3]. Autosomal dominant and autosomal recessive PKD is characterized by increased TKV with both TKV, and its rate of increase, a prognostic biomarker for outcome in these populations [4][5][6]. Consequently, there is increasing interest within the nephrology community and pharmaceutical companies to use TKV as a surrogate endpoint in PKD trials to define the efficacy of drug candidates [7].…”

“…Kidneys (Table 1) were retrieved (under ketamine/xylazine anesthesia (25/5 mg/kg intraperitoneal) from adult male and female obese ZSF1 rats (Charles River, New York, NY, USA) at~6 mo of age, and adult male and female PCK rats [6] at~8 mo of age and healthy adult male Sprague-Dawley (SD) rats at~6 mo of age. Separately, adult male SD rats (Charles River, NY, USA) were injected with purumoycin aminonucleoside (PAN, 100 mg/kg, intraperitoneal or vehicle) and left and right kidneys retrieved 2 mo later when animals were~6 mo of age.…”

“…Accurate determination of renal dimensions is important in that it can inform presence and progression of chronic kidney disease (CKD) [1][2][3] and polycystic kidney disease (PKD) [4][5][6], inform inclusion criteria in PKD trials, and assessment of response to drugs in those trials [7]. Measurement of renal dimensions is critical to inform suitability of the donor kidney for implantation in the recipient especially within the pediatric population and patency of the transplanted kidney [8][9][10].…”

Quantitative magnetic resonance imaging assessments of autosomal recessive polycystic kidney disease progression and response to therapy in an animal model

“…In order to minimize this potential variability, all of the segmentation analysis was performed by only one expert rater for this initial study. Quantitative MRI techniques that generate quantitative T1 and T2 relaxation time maps may also be used to facilitate automatic, more objective segmentation of the kidneys and renal cysts (34,35). However, these quantitative acquisitions typically require extended acquisition times, limiting their utility for young pediatric ARPKD patients.…”

Mixed-Unit Lattice Approach for Area Determination of Cellular and Subcellular Structures

“…In patients with focal segmental glomerulosclerosis (FSGS), an increase in glomerular dimensions is directly associated with rapid progression to end-stage renal disease [4]. In polycystic kidney disease (PKD), cyst expansion drives an increase in renal dimensions, which, in turn, precipitates organ dysfunction [5]. Serial determination of changes in the glomerular area and cystic index can thus inform of both the presence and progress of renal disease.…”