Newswise — PHILADELPHIA - African Americans have a heightened risk of developing chronic and end-stage kidney disease. This association has been attributed to two common genetic variants – named G1 and G2 -- in APOL1, a gene that codes for a human-specific protein. However, direct evidence showing that these variants definitively cause kidney disease was lacking because APOL1 is widely expressed in different cell types but the gene is present in only some primates and humans. The challenge has been to create an animal model to prove this. Now, a team led by researchers from the Perelman School of Medicine at the University of Pennsylvania has engineered mice with these mutations that cause human-like kidney disease.

“The key missing piece has been whether these variants are true disease culprits,” said senior author Katalin Susztak, MD, PhD, an associate professor of Medicine and Genetics, of the study published online in Nature Medicine. “Our study established that these mutations are definitely disease causing.”

It is well recognized that nutritional monitoring and intervention is indispensable in pediatric CKD management, yet prospectively collected data in this area are scarce. CKiD is one of the largest cohorts of pediatric CKD patients, and the prospectively collected dietary data permits an analysis of the impact of dietary intake on CKD progression and the development of comorbidities. Here we describe our baseline data and compare them with the recommended nutritional levels from the KDOQI and KDIGO guidelines.

CKiD participants consumed much more dietary sodium than the recommended limits. The excessive intake of sodium was most dramatic in the oldest age group. More than 25 % of adolescents aged 14–18 years consumed >5150 mg of sodium daily, which is more than double the top end of the recommended range. Interestingly, sodium intake was similar to data obtained from the general population. Median daily sodium intake reported in the National Health and Nutrition Examination Survey (NHANES) 2011–2012 among those aged 2–5 years, 6–11 years, and 12–19 years were 2295 mg, 3081 mg, and 3593 mg, respectively [14], which is similar to the corresponding levels of 2222 mg, 3028 mg, and 3577 mg among CKiD participants. A significant portion of pediatric CKD diagnoses comprises conditions under the category of congenital anomalies of kidney and urinary tract, which are commonly salt wasting and frequently require sodium supplementation. We found that children with a salt-wasting condition consumed slightly more salt than those without the condition, although this difference was not significant statistically. An analysis of dietary sodium consumption data and its relationship with blood pressure in the CKiD cohort is currently underway. Our results indicate that greater effort is required to reduce dietary sodium consumption in subgroups of children with CKD—such as those with the non-salt-wasting condition or with hypertension—given its potential adverse effects. Most dietary sodium comes from added salt during food processing or cooking [3]. Therefore, behavioral strategies like avoiding processed food and reading food labels should be encouraged. In fact, the National Kidney Foundation provides practical suggestions on how to reduce dietary sodium intake [34].

There is a well-known association between UTI and the presence of VUR in children [11]. However, there is disagreement regarding the management of patients with UTI in regards to screening for VUR. Much of this debate began with the publication of the American Academy of Pediatrics Guideline in 2011 [12, 13]. The controversy is mainly centered around the recommendation that voiding cysto-urethrograms (VCUGs) should not be routinely performed in children between 2 and 24 months of age with first time febrile UTIs [12]. Advocates of this approach are concerned about the invasive nature of VCUGs and the lack of an effective treatment for lower grades of VUR. However, proponents of the routine use of VCUGs cite the outcomes of reflux nephropathy and renal scarring, which have potential to cause significant morbidity, as well as the potential for delay of surgical intervention for patients with high grade VUR [14]. Given the invasiveness of VCUGs, and the potential for morbidity with untreated VUR, a non-invasive marker of VUR would have significant utility in the management of patients with first time UTIs.

It is difficult to comment upon the utility of NGAL in VUR without considering the presence of scarring given the degree of interrelatedness between them. Accordingly, much of the work done on NGAL and VUR also bears on renal scarring. NGAL is a potential candidate marker for VUR, and subsequent scarring, due to its specificity for renal tubular damage. However, the presupposition of this theory is that the damage associated with renal scarring is ongoing, and prior work has shown that uNGAL is not elevated in quiescent forms of chronic kidney disease [15]. Rat models of pyelonephritis show that the upregulation of NGAL gene expression peaks at 2 weeks following pyelonephritis, after which it decreases at both 4 and 6 weeks, but does not return to baseline levels [16]. Immunostaining of rat kidneys suggests that the NGAL upregulation seen at 2 weeks is an inflammatory response to the presence of the bacteria, but that the NGAL upregulation at 6 weeks, which is localized to the renal tubule, is in response to tubular injury rather than infection. Urine NGAL levels correspond to these transcriptome profiling results: uNGAL levels peak at 2 weeks and then decrease by week 6, although not to baseline levels [17]. The differences in these uNGAL values, while of mechanistic interest, likely have little utility in clinical practice when examined at a single point in time. The clinical data in the literature agrees with this notion. While the difference between uNGAL levels in patients with scarring and those without is statistically significant, the values presented to date are all within the normal range of NGAL for age [18, 19]. Further, in a separate cross-sectional analysis of children with pyelonephritis, while there was a statistical difference in uNGAL levels between children who developed renal scarring and those that did not, the mean uNGAL values of patients who developed scarring (9.8 ± 4.5 ng/ml) and those who did not (7.2 ± 3.8 ng/ml) are still within the normal range of uNGAL for age [19, 20]. These results are again interesting from a mechanistic standpoint, but the value of using a single NGAL as a prognostic marker for the development of scarring is limited.

DOI: 10.1007/s00467-016-3406-5