Growth and Nutrition in Pediatric Chronic Kidney Disease

Malnutrition inflammation complex syndrome (MICS) occurs commonly in maintenance hemodialysis (MHD) patients and may correlate with increased morbidity and mortality. An optimal, comprehensive, quantitative system that assesses MICS could be a useful measure of clinical status and may be a predictor of outcome in MHD patients. We therefore attempted to develop and validate such an instrument, comparing it with conventional measures of nutrition and inflammation, as well as prospective hospitalization and mortality. Using components of the conventional Subjective Global Assessment (SGA), a semiquantitative scale with three severity levels, the Dialysis Malnutrition Score (DMS), a fully quantitative scoring system consisting of 7 SGA components, with total score ranging between 7 (normal) and 35 (severely malnourished), was recently developed. To improve the DMS, we added three new elements to the 7 DMS components: body mass index, serum albumin level, and total iron-binding capacity to represent serum transferrin level. This new comprehensive Malnutrition-Inflammation Score (MIS) has 10 components, each with four levels of severity, from 0 (normal) to 3 (very severe). The sum of all 10 MIS components ranges from 0 to 30, denoting increasing degree of severity. These scores were compared with anthropometric measurements, near-infrared-measured body fat percentage, laboratory measures that included serum C-reactive protein (CRP), and 12-month prospective hospitalization and mortality rates. Eighty-three outpatients (44 men, 39 women; age, 59 +/- 15 years) on MHD therapy for at least 3 months (43 +/- 33 months) were evaluated at the beginning of this study and followed up for 1 year. The SGA, DMS, and MIS were assessed simultaneously on all patients by a trained physician. Case-mix-adjusted correlation coefficients for the MIS were significant for hospitalization days (r = 0.45; P < 0.001) and frequency of hospitalization (r = 0.46; P < 0.001). Compared with the SGA and DMS, most pertinent correlation coefficients were stronger with the MIS. The MIS, but not the SGA or DMS, correlated significantly with creatinine level, hematocrit, and CRP level. During the 12-month follow-up, 9 patients died and 6 patients left the cohort. The Cox proportional hazard-calculated relative risk for death for each 10-unit increase in the MIS was 10.43 (95% confidence interval, 2.28 to 47.64; P = 0.002). The MIS was superior to its components or different subversions for predicting mortality. The MIS appears to be a comprehensive scoring system with significant associations with prospective hospitalization and mortality, as well as measures of nutrition, inflammation, and anemia in MHD patients. The MIS may be superior to the conventional SGA and the DMS, as well as to individual laboratory values, as a predictor of dialysis outcome and an indicator of MICS.

Phosphate homeostasis is maintained by a counterbalance between efflux from the kidney and influx from intestine and bone. FGF23 is a bone-derived phosphaturic hormone that acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. FGF23 signals with highest efficacy through several FGF receptors (FGFRs) bound by the transmembrane protein Klotho as a coreceptor. Since most tissues express FGFR, expression of Klotho determines FGF23 target organs. Here we identify the parathyroid as a target organ for FGF23 in rats. We show that the parathyroid gland expressed Klotho and 2 FGFRs. The administration of recombinant FGF23 led to an increase in parathyroid Klotho levels. In addition, FGF23 activated the MAPK pathway in the parathyroid through ERK1/2 phosphorylation and increased early growth response 1 mRNA levels. Using both rats and in vitro rat parathyroid cultures, we show that FGF23 suppressed both parathyroid hormone (PTH) secretion and PTH gene expression. The FGF23-induced decrease in PTH secretion was prevented by a MAPK inhibitor. These data indicate that FGF23 acts directly on the parathyroid through the MAPK pathway to decrease serum PTH. This bone-parathyroid endocrine axis adds a new dimension to the understanding of mineral homeostasis.

Hepcidin is a key regulator of iron homeostasis, but its study in the setting of chronic kidney disease (CKD) has been hampered by the lack of validated serum assays. This study reports the first measurements of bioactive serum hepcidin using a novel competitive ELISA in 48 pediatric (PCKD2-4) and 32 adult (ACKD2-4) patients with stages 2 to 4 CKD along with 26 pediatric patients with stage 5 CKD (PCKD5D) on peritoneal dialysis. When compared with their respective controls (pediatric median = 25.3 ng/ml, adult = 72.9 ng/ml), hepcidin was significantly increased in PCKD2-4 (127.3 ng/ml), ACKD2-4 (269.9 ng/ml), and PCKD5D (652.4 ng/ml). Multivariate regression analysis was used to assess the relationship between hepcidin and indicators of anemia, iron status, inflammation, and renal function. In PCKD2-4 (R(2) = 0.57), only ferritin correlated with hepcidin. In ACKD2-4 (R(2) = 0.78), ferritin and soluble transferrin receptor were associated with hepcidin, whereas GFR was inversely correlated. In PCKD5D (R(2) = 0.52), percent iron saturation and ferritin were predictors of hepcidin. In a multivariate analysis that incorporated all three groups (R(2) = 0.6), hepcidin was predicted by ferritin, C-reactive protein, and whether the patient had stage 5D versus stages 2 to 4 CKD. These findings suggest that increased hepcidin across the spectrum of CKD may contribute to abnormal iron regulation and erythropoiesis and may be a novel biomarker of iron status and erythropoietin resistance.