Faculty Bibliography

Interstitial nephritis (IN) is a relatively rare entity in children and adolescents that can be caused by a range of disorders including infection, medications, inflammatory bowel disease, and sarcoid. There is no proven therapy for this condition. We present 2 cases of biopsy-proven interstitial nephritis, of which 1 case was with granulomatous features that presented with unusual sonographic findings of discrete mass lesions in the kidney parenchyma bilaterally. Although a precise cause could not be identified in either case, 1 patient progressed to end-stage kidney disease (ESKD) and the other is in the early stages of treatment. We suggest that recognition of the atypical imaging features of interstitial nephritis may enable early recognition of this condition and avoid confusion with neoplastic or infectious processes.

Background: Chronic illness in children has adverse effects on family members besides the patient and can impact the integrity and function of the family unit. Most previous studies have examined a single disease entity. However, there has been limited assessment comparing the effect of different illnesses on family function.
Method(s): Established patients treated in the pediatric ambulatory Nephrology or DM clinics were included in the study. Their parents were asked to complete the 2-page Pediatric Quality-of-Life Family Impact Module (PedsQL-FIM), version 2.0, a validated survey instrument. Clinical and laboratory data were retrieved from the electronic health record. Data were summarized as mean+/-SD. Disease group and child age were entered as predictors in linear regression analyses with FIM total and subscale scores as outcome variables. Comparisons between groups were assessed using paired t-tests.
Result(s): 96 patients (43 F: 53 M) were evaluated in the Nephrology Clinic and 55 (30 F: 25 M) in the DM Clinic. The mean age of the patients was 13.0+/-3.9 and 10.4+/- 6.3 yr, respectively. Within the KD sample, older age was significantly associated with lower scores on all FIM subscale scores. Gender was not a significant predicator for FIM scores in either disease group. Controlling for age, chronic illness group was a significant predictor of the FIM total and subscale scores. Parents of D patients endorsed significantly lower total FIM scores compared to the KD patients (D 58+/-16; KD 79+/-17 p <0.001) as well as on subscales of physical, emotional, social, and cognitive functioning, communication, worry, daily activities, family relationships, and reports of health-related quality of life (P<0.01).
Conclusion(s): Our findings confirm that chronic illness in childhood adversely affects a wide range of aspects of family function. The impact is greater in older children with KD and varies depending on the disease context. Families with children who have DM manifested greater disturbances than those with children who have isolated KD. Further study is warranted to assess the effects of the underlying renal disease and intensity of medical care and whether there are specific features can be used to identify vulnerable families

Background: Angiogenesis inhibitors have an emerging role in the treatment of pediatric cancers. CNS tumors have high concentrations of pro-angiogenic factors and neo-vascularization. Much of what is known about angiogenesis inhibitors comes from adult studies, where they have been more widely used. Hypertension is a common side effect of this new drug class in adults. Limited information is available about the safety of these medications in children.
Method(s): A single center, retrospective chart review was conducted. Twenty-eight patients under 25 years of age with CNS tumors, who were followed by the Division of Pediatric Hematology and Oncology at NYU Medical Center, were identified who had received angiogenesis inhibitors developed hypertension. Chart review was conducted in 12 cases. The other cases met exclusion criteria or access to full EMR was unavailable.
Result(s): Seven (56%) patients developed hypertension within 9 months of initiation of the drugs, with most occurring in the first 3 months. Four were treated with bevacizumab, 2 axitinib, and 1 pazopanib. While one patient's symptoms resolved, the remaining 6 children required treatment with anti-hypertensive agents. Only two patients were referred to pediatric nephrology and were treated with amlodipine. The remaining patients were all given diuretics by the oncology team, with 3 requiring use of a second antihypertensive agent (ACE inhibitors).
Conclusion(s): Our findings are consistent with the adult literature and indicate that secondary hypertension is a frequent complication of angiogenesis inhibitor therapy. Poorly controlled hypertension in children has the potential to track into adulthood and is a major risk factor for cardiovascular morbidity and mortality. Identification and treatment of pediatric hypertension is an important health focus for pediatric oncology patients. Timely referral to a pediatric nephrologist should be coinsidered for treatment of angiogenesis inhibitor-associated hypertension

OBJECTIVES: Renal manifestations are the second most significant cause of morbidity and mortality in patients with tuberous sclerosis complex (TSC), and include renal cysts, angiomyolipomas, fat-poor lesions, and malignant tumors. These lesions begin in childhood and often lead to chronic kidney disease (CKD). Little is known on the incidence of early modifiable risk factors of CKD, such as proteinuria and hypertension, or subtle decreases in glomerular filtration rate that correspond to the early stages of CKD in children with TSC. The impact of genotype on these early manifestations of CKD has not been investigated. DESIGN: Retrospective chart review of 84 children and young adults with TSC. MEASUREMENTS: This study assessed the prevalence of hypertension, renal impairment, and proteinuria, as well as the genotype-phenotype correlations. RESULTS: Children and young adults with TSC2 mutations had a significantly higher rate of renal lesions, hypertension (36% vs 14%), and decreased renal function than those with TSC1 mutations. CONCLUSION: On the basis of estimated glomerular filtration rate and blood pressure, our findings are consistent with the hypothesis that TSC2 mutations are associated with more severe early renal involvement in children. There is a compelling need for close collaboration of nephrologists and neurologists to provide care to pediatric patients with TSC to improve screening and management of early manifestations of renal disease.

Renal tubule epithelial cells are high-energy demanding polarized epithelial cells. Liver kinase B1 (LKB1) is a key regulator of polarity, proliferation, and cell metabolism in epithelial cells, but the function of LKB1 in the kidney is unclear. Our unbiased gene expression studies of human control and CKD kidney samples identified lower expression of LKB1 and regulatory proteins in CKD. Mice with distal tubule epithelial-specific Lkb1 deletion (Ksp-Cre/Lkb1flox/flox) exhibited progressive kidney disease characterized by flattened dedifferentiated tubule epithelial cells, interstitial matrix accumulation, and dilated cystic-appearing tubules. Expression of epithelial polarity markers beta-catenin and E-cadherin was not altered even at later stages. However, expression levels of key regulators of metabolism, AMP-activated protein kinase (Ampk), peroxisome proliferative activated receptor gamma coactivator 1-alpha (Ppargc1a), and Ppara, were significantly lower than those in controls and correlated with fibrosis development. Loss of Lkb1 in cultured epithelial cells resulted in energy depletion, apoptosis, less fatty acid oxidation and glycolysis, and a profibrotic phenotype. Treatment of Lkb1-deficient cells with an AMP-activated protein kinase (AMPK) agonist (A769662) or a peroxisome proliferative activated receptor alpha agonist (fenofibrate) restored the fatty oxidation defect and reduced apoptosis. In conclusion, we show that loss of LKB1 in renal tubular epithelial cells has an important role in kidney disease development by influencing intracellular metabolism.

BACKGROUND: Perfluoroalkyl acids are synthetic compounds widely used in industrial and commercial applications. Laboratory studies suggest that these persistent and bioaccumulative chemicals produce oxidant stress and damage glomerular endothelial cells, raising concern regarding the impact of these compounds on renal function. METHODS: We performed cross-sectional analyses of data 1960 participants aged 12-19 years of the 2003-2010 National Health and Nutrition Examination Surveys. PFAA exposure was assessed using levels of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid, and perfluorohexane sulfonic acid. Primary study outcomes were estimated glomerular filtration rate (eGFR) and serum uric acid. RESULTS: While adjusting for demographics, cotinine, prehypertension, insulin resistance, body mass index, and hypercholesterolemia, adolescents in the highest PFOA and PFOS quartile had a lower eGFR, 6.84 mL/min/1.73 m2 (95 % CI: 2.19 to 11.48) and 9.69 mL/min/1.73 m2 (95 % CI: -4.59 to 14.78), respectively, compared to the lowest quartile. Highest PFOA and PFOS quartiles were also associated with 0.21 mg/dL (95 % CI: 0.056 to 0.37) and 0.19 mg/dL (95 % CI: 0.032 to 0.34) increases in uric acid, respectively. CONCLUSIONS: PFAAs are associated with a reduction in kidney function and increased uric acid levels in otherwise healthy adolescents. Reverse causation and residual confounding could explain the results. Our study results confirm and amplify previous findings, though longitudinal studies examining prenatal and childhood biomarkers in relationship with robust measures of childhood renal function are needed.

Hemophagocytic lymphohistiocytosis is a hyperinflammatory disorder resulting from primary or secondary immune dysfunction. AKI is frequent in severe hemophagocytic lymphohistiocytosis and has been attributed to multiorgan failure or the use of nephrotoxic drugs, but AKI is rarely considered a direct consequence of the disease process. We describe a child with familial hemophagocytic lymphohistiocytosis type 3 who developed AKI requiring prolonged renal replacement therapy because of severe renal inflammation. There was massive infiltration of the renal parenchyma by activated macrophages and cytotoxic T cells, and acute tubular injury. The patient responded to high-dose intravenous methylprednisolone, which resulted in improvement of renal function and discontinuation of renal replacement therapy. This case confirms the occurrence of reversible AKI due to hemophagocytic lymphohistiocytosis-induced activated macrophage infiltration of the renal parenchyma and inflammation.

Focal segmental glomerulosclerosis (FSGS) is a rare but important cause of end-stage kidney disease in children and adults. Current therapy, consisting of corticosteroids and calcineurin inhibitors, fails to achieve a sustained remission in most patients. Therefore, there is a pressing need to develop new treatments for this glomerulopathy. Traditional approaches have focused on agents that modulate the immune system. In this review, we summarize preclinical and clinical data with newer agents that may ameliorate FSGS. We focus on drugs that inhibit immune injury or inflammation, such as abatacept, rituximab, adalimumab, and stem cells. The potential of agents that block the glomerular action of circulating permeability factors such as soluble urokinase receptor is reviewed. Finally, because fibrosis represents the final common pathway of glomerular damage in FSGS, the experience with a wide range of antifibrotic agents is presented. Despite extensive research on the podocyte dysfunction in the pathogenesis of FSGS, there are few agents that directly target podocyte structure or viability. We conclude that FSGS is a heterogeneous disorder and that intensified translational research is vital to improve our understanding of distinct subtypes that have a defined prognosis and predictable response to targeted therapeutic interventions.

BACKGROUND Recent progress in the identification of Magnesium (Mg) transporters and channels has advanced our understanding of Mg homeostasis. The TRPM6 gene, which encodes an ion channel, contributes to the understanding transepithelial Mg transport. An association was identified between hypomagnesemia with secondary hypocalcemia and the TRPM6 gene. Recently a missense mutation in TRPM6 gene was reported (1). Several othergenes have also been reported in hereditary renal Mg loss. No definite phenotype-genotype correlation has been established. Paracellular transport of magnesium was clarified by the claudin 16-19 mutations. Claudins are tight junctions proteins located in the kidney; mutations in these key proteins are responsible for the condition called familial hypomagnesemia with hypercalciuria and nephrocalcinosis (2). Hypomagnesemia occurs in malabsorption, vitamin D deficiency and hypoparathyroidism. The syndrome of hypomagnesemia with secondary hypocalcemia is a rare disorder characterized by a defect in renal or intestinal Mg absorption, which can result in brain damage if not recognized early. We report a newborn who presented with convulsions, profound hypomagnesemia with hypocalcemia. CASE REPORT A full term male, born to Yemenite parents with no parental consanguinity nor any significant family history, presented at 12 days of life with new onset generalized convulsions. Initial studies showed: Mg <0.6 mg/dL (1.6-2.3 mg/dL), calcium 6.4mg/dl (8.3-10.3 mg/dL), phosphorus 10.3 mg/dl (2.7-4.5 mg/dL), glucose 81mg/dl. Genetic investigation is in progress. The baby was initially treated with anticonvulsants and calcium gluconate. Despite this treatment, seizures persisted. IV Mg boluses (50mg/kg)and Ca (100mg/kg) were then administered. Within 24 hrs serum Ca normalized, but Mg remained below normal. The baby was transitioned to PO Mg and Ca supplements. Serum 25 hydroxy vitamin D was <13ng/mL ergocalciferol 2000 unitswere supplemented. Fractional Mg excretion (FEMg) was elevated at 15% (1-8%) with a low serum Mg 1 mg/dL suggestive of renal loss of Mg. Renal ultrasound was normal. After 24 hrs of IV Ca and Mg, the seizures ceased. However, Mg levels remained suboptimal (highest 1.5mg/dl) despite high PO doses of Mg. The baby was discharged on high doses of Mg (100 mg q 6 hrs), Ca and Vit D supplementation. During follow up calcium and vitamin D were tapered then stopped. Supplemental Mg was increased to200mg q 6hrs to maintain Mg levels at least >1.0 mg/dl. CONCLUSION Primary hypomagnesemia can occur with other electrolyte abnormalities and may be life threatening. The diagnosis can be a challenge, and a high index of suspicion is needed. An inherited disorder should be suspected, and genetic studies are recommended. Despite high doses of Mg levels may remain subnormal. Early diagnosis and appropriate treatment are important to avoid irreversible neurologic damage