Renal growth in isolated methylmalonic acidemia

Abstract

Purpose: We sought to predict renal growth based on clinical and metabolic parameters in patients with isolated methylmalonic acidemia, a group of disorders associated with chronic kidney disease.

Methods: Fifty patients with methylmalonic acidemia, followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared with that of healthy controls and modeled to other clinical parameters using multiple-regression analyses.

Results: Comparisons with age-matched controls showed that renal length in subjects with methylmalonic acidemia was significantly decreased (P < 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C, and serum methymalonic acid concentrations best predicted kidney size. The regression equations used to generate methylmalonic acidemia kidney nomograms were renal length (cm) = 6.79 + 0.22 × age for the controls and 6.80 + 0.09 × age for the methylmalonic acidemia cohort (P < 0.001; constant and slope).

Conclusion: Renal length, reflective of kidney growth, significantly decreased in patients with methylmalonic acidemia over time as compared with controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population.

Figure 1

Renal length (average of left and right) vs. age in methylmalonic acidemia (MMA) and age-matched controls. Mean ± SD. Asterisk denotes p < 0.05.

Figure 2

(a). Renal length vs. age, stratified by serum methylmalonic acid level. Patients with greater than 2000 micromolar serum methylmalonic acid have smaller kidneys. (b). Renal length vs. height, stratified by serum methylmalonic level. Similar to Figure 2(a), more severely affected patients with higher serum methylmalonic acid levels have smaller kidneys across height spectrum.

Figure 2

(a). Renal length vs. age, stratified by serum methylmalonic acid level. Patients with greater than 2000 micromolar serum methylmalonic acid have smaller kidneys. (b). Renal length vs. height, stratified by serum methylmalonic level. Similar to Figure 2(a), more severely affected patients with higher serum methylmalonic acid levels have smaller kidneys across height spectrum.

Figure 3

Serum methylmalonic acid (MMA_S) for all enzymatic subtypes vs. eGFR creatinine - cystatin C. Best fitted linear regression lines are shown for eGFR ≤ 60 and eGFR > 60. MMA_S increases markedly for eGFR values below 60 mL/min/1.73 m².

Figure 4

eGFR creatinine for all enzymatic subtype patients declines with age, reflective of a progressive chronic kidney disease. eGFR calculated using the updated Schwartz equation for children. For adults, the CKD-EPI creatinine equation was used. The solid line represents linear regression for patients with serum methylmalonic acid less than 2000 micromolar and dashed lines represent a linear regression for serum methylmalonic acid greater than 2000. The patients with a higher serum methylmalonic acid show a lower eGFR.