Pediatric CKD-MBD: existing and emerging treatment approaches.

The effects of bone and mineral metabolism on skeletal formation, as well as vascular and soft tissue calcifications, define chronic kidney disease-metabolic bone disease (CKD-MBD). Treatment recommendations center on establishing adequate vitamin D status, phosphate control through diet restriction and phosphate binders, and the use of vitamin D analogs for specific indications. Several emerging bone-promoting therapies have now been studied in adults with CKD, including bisphosphonates and denosumab. These approaches are associated with improved bone mass and, in some cases, decreased fracture rates in adults with CKD-MBD and are of potential interest for some children with CKD-MBD. In children with CKD and immobilization and/or muscle weakness, bisphosphonates appear to be an effective treatment to increase bone mass; baseline assessment and careful monitoring of bone density and/or bone biopsy findings are important in consideration of any new bone therapies for children with CKD-MBD.

Beneficial effects of intravenous pamidronate treatment in children with osteogenesis imperfecta under 24 months of age.

Osteogenesis imperfecta (OI) is an inherited disorder characterized by bone fragility and low bone mass. Low bone density and fracture is a cause of morbidity. Limited data exists on bisphosphonate treatment in patients under 24 months of age. The objective of the study was to examine the safety and efficacy of pamidronate in children under 24 months with OI. To do so, we carried out a retrospective chart review and analysis of OI patients started on intravenous pamidronate under 24 months of age. Pamidronate was administered in three-day cycles. Growth, the number of fractures, and lumbar bone mineral densities were recorded both prior to and after treatment initiation. A total of 18 patients were reviewed. Five were classified as OI type I, seven were type III, and six were type IV. The mean age at treatment initiation was 12 months (range 11 days to 23 months). The mean lumbar z score at baseline was -3.63, which improved to -1.53 at one year (P < 0.01) and 0.79 (P < 0.01) at the end of the study. The fracture rate improved from 68 fractures in 209 months (0.32 fractures/patient-month) before treatment to 41 fractures in 1,248 months (0.03 fractures/patient-month) post-treatment (P < 0.05). Height standard deviation score (SDS) was conserved from baseline to end of study (-2.12 ± 2.45 vs. -2.45 ± 2.73) (P = 0.05) with an average follow-up of 73 months. The only adverse effect recorded in six infants was fever during the initial pamidronate infusion. Treatment with intravenous pamidronate is safe, significantly improves lumbar bone mineral density (L-BMD), and reduces fracture rates in young infants with OI while preserving linear growth.

Pediatric nephrolithiasis and the link to bone metabolism.

PURPOSE OF REVIEW: To review the recent publications describing the link between pediatric nephrolithiasis and bone metabolism. RECENT FINDINGS: Nephrolithiasis incidence is increasing in children and is associated with low bone mineral density (BMD). Affected children are conceptually at risk for fractures and osteoporosis. In addition to abnormal calcium metabolism, inflammation, genetic makeup and dietary habits are being recognized as important factors in the pathophysiology of nephrolithiasis and low bone density. Findings from retrospective reviews suggest that low BMD in children may be improved with citrate or thiazide treatment. SUMMARY: The healthcare burden from low BMD with subsequent osteoporosis and fracture risk is immense with potential far-reaching effects in patient quality of life and healthcare expense. Bone mass is acquired in the pediatric age range, thus it is important to identify and treat at-risk children. Retrospective reviews in pediatric patients indicate that citrate or thiazide diuretic treatment may improve BMD. We now understand that a relationship exists between nephrolithiasis and low BMD. To improve healthcare for our current patients as well as protect their future health it is important to identify low BMD and initiate strategies to improve BMD in 'at-risk' children.

Treatment outcome of late steroid-resistant nephrotic syndrome: a study by the Midwest Pediatric Nephrology Consortium.

BACKGROUND: Idiopathic nephrotic syndrome (NS) in children is classified as steroid sensitive or steroid resistant. Steroid sensitivity typically portends a low risk of permanent renal failure. However, some initially steroid-sensitive patients later develop steroid resistance. These patients with late steroid resistance (LSR) are often treated with immunosuppressant medications, but the effect of these additional drugs on the long-term prognosis of LSR is still unknown. METHODS: A retrospective chart review was performed on patients diagnosed with idiopathic NS and subsequent LSR during the 8-year study period from 2002 up to and including 2009, with a minimum of 2 years of follow-up. Primary outcome measures were proteinuria and renal function. RESULTS: A total of 29 patients were classified as having LSRNS. The majority of patients received treatment with calcineurin inhibitors and/or mycophenolate mofetil. Seven patients received three or more non-steroid immunosuppressant medications. Sustained complete or partial remission was achieved in 69 % of patients. Three developed end-stage renal disease, and all others maintained normal renal function. There were 13 episodes of serious adverse events, none of which were fatal or irreversible. CONCLUSION: Most patients with LSRNS responded to immunosuppressive therapy by reduction or resolution of proteinuria and preservation of renal function. The results suggest that immunosuppressive treatment is a viable option in NS patients who develop LSR.

Severe intraoperative hypertension after induction of anesthesia in a child with a neuroblastoma.

Neuroblastomas are the most common, non-central nervous system tumor of childhood. Similar to pheochromocytomas, they are derived from neural crest cells and therefore retain the potential to synthesize catecholamines. Unlike pheochromocytomas, however, perioperative issues related to blood pressure instability with hypertension are uncommon. We report details of a 3-year-old child with a neuroblastoma who developed severe hypertension and end-organ effects after induction of anesthesia. The association of such problems with neuroblastoma is reviewed and options for perioperative care presented.

Trends in hospitalization characteristics for pediatric nephrotic syndrome in the USA.

AIM: The overall aim of the current study was to analyze trends in hospital charges, length of stay (LOS), and mortality for children hospitalized with nephrotic syndrome (NS) in the US. METHODS: Hospitalization characteristics for children ages 0 - 17 years discharged with the principal diagnosis of NS (ICD-9-CM 581.9) in 2000, 2003, and 2006 were evaluated using the Healthcare Cost and Utilization Project (HCUP) Kids' Inpatient Database (KID). RESULTS: The mean number of children hospitalized with a principal diagnosis of NS was 1,869 per year. These discharges accounted for mean total hospital charges that increased from $11,338 to $16,760 and aggregate hospital charges that increased from $21 to $31 million dollars from 2000 to 2006. Compared to non-children's hospitals, children's hospitals had significantly higher mean hospital charges and longer lengths of stay. Importantly, the estimated mortality rate for NS (< 0.5%) was notably lower than prior reports and remained stable throughout the study period. CONCLUSIONS: The national health care expenditures for pediatric NS related hospitalizations are both significant and growing, although mortality is now far lower than previously reported.

Body fat composition and occurrence of kidney stones in hypercalciuric children.

In the last 10 years, the incidence of kidney stones has increased in the pediatric population, and this rise has been paralleled by a significant increase in pediatric obesity rates in the USA. The purpose of this study was to evaluate percentage body fat (%BF) measured by dual energy X-ray absorptiometry (DXA) in hypercalciuric children with and without kidney stones. A retrospective chart review was performed on children with idiopathic hypercalciuria based on a 24-h urine calcium excretion of >4 mg/kg/day or >200 mg/day who had undergone DXA scanning. Patients were then classified by sex and by %BF (3 categories; normal: <27% girls, <21% boys; at risk for obesity: 27-36% girls, 21-30% boys; obese: >36% girls, >30% boys). The 2003-2004 NHANES data were used as a control. Fifty patients (24 males) were analyzed, of whom 26% were assessed as having a normal %BF, 44% as being at risk for obesity, and 30% as being obese. Children with an increased %BF had a significantly higher occurrence of kidney stones (p = 0.03) than those with a normal %BF. No significant differences were noted in 24-h urine chemistries between the groups. In conclusion, an increased %BF was associated with an increased occurrence of kidney stones in children with idiopathic hypercalciuria.

Analysis of the Ribonuclease A Superfamily of Antimicrobial Peptides in Patients Undergoing Chronic Peritoneal Dialysis.

Infectious peritonitis is a common complication in patients undergoing chronic peritoneal dialysis (PD), limiting the duration of PD as a modality for renal replacement therapy and increasing patient morbidity and mortality. Antimicrobial peptides (AMPs) serve critical roles in mucosal defense, but their expression and activity during peritonitis are poorly understood. We hypothesized that AMPs belonging to the Ribonuclease (RNase) A Superfamily are present in peritoneal fluid and increase during peritonitis in patients undergoing chronic PD. In the absence of peritonitis, we detected RNase 3, RNase 6, and RNase 7 in cell-free supernatants and viable cells obtained from peritoneal fluid of chronic PD patients. The cellular sources of these RNases were eosinophils (RNase 3), macrophages (RNase 6), and mesothelial cells (RNase 7). During peritonitis, RNase 3 increased 55-fold and RNase 7 levels increased 3-fold on average, whereas RNase 6 levels were unchanged. The areas under the receiver-operating characteristic curves for RNase 3 and RNase 7 were 0.99 (95% confidence interval (CI): 0.96-1.0) and 0.79 (95% CI: 0.64-0.93), respectively, indicating their potential as biomarkers of peritonitis. Discrete omental reservoirs of these RNases were evident in patients with end stage kidney disease prior to PD initiation, and omental RNase 3 reactive cells increased in patients undergoing PD with a history of peritonitis. We propose that constitutive and inducible pools of antimicrobial RNases form a network to shield the peritoneal cavity from microbial invasion in patients undergoing chronic PD.

Diagnosis, Treatment, and Outcomes in Children With Congenital Nephrogenic Diabetes Insipidus: A Pediatric Nephrology Research Consortium Study.

Background and Objectives: Congenital or primary nephrogenic diabetes insipidus (NDI) is a rare genetic disorder that severely impairs renal concentrating ability, resulting in massive polyuria. There is limited information about prognosis or evidence guiding the management of these patients, either in the high-risk period after diagnosis, or long-term. We describe the clinical presentation, genetic etiology, treatment and renal outcomes in a large group of children <21 years with NDI. Design: A multi-center retrospective chart review. Results: We report on 66 subjects from 16 centers. They were mainly male (89%) and white (67%). Median age at diagnosis was 4.2 months interquartile range (IQR 1.1, 9.8). A desmopressin acetate loading test was administered to 46% of children at a median age of 4.8 months (IQR 2.8, 7.6); only 15% had a water restriction test. Genetic testing or a known family history was present in 70% of the patients; out of those genetically tested, 89 and 11% had mutations in AVPR2 and AQP2, respectively. No positive family history or genetic testing was available for 30%. The most common treatments were thiazide diuretics (74%), potassium-sparing diuretics (67%) and non-steroidal anti-inflammatory drugs (42%). At the time of first treatment, 70 and 71% of children were below -2 standard deviations (SD) for weight and height, respectively. At last follow-up, median age was 72.3 months (IQR 40.9, 137.2) and the percentage below -2 SD improved to 29% and 38% for weight and height, respectively. Adverse outcomes included inpatient hospitalizations (61%), urologic complications (37%), and chronic kidney disease (CKD) stage 2 or higher in 23%. Conclusion: We found the majority of patients were treated with thiazides with either a potassium sparing diuretic and/or NSAIDs. Hospitalizations, urologic complications, short stature, and CKD were common. Prospective trials to evaluate different treatment strategies are needed to attempt to improve outcomes.

Acute Kidney Injury and Atypical Features during Pediatric Poststreptococcal Glomerulonephritis.

The most common acute glomerulonephritis in children is poststreptococcal glomerulonephritis (PSGN) usually occurring between 3 and 12 years old. Hypertension and gross hematuria are common presenting symptoms. Most PSGN patients do not experience complications, but rapidly progressive glomerulonephritis and hypertensive encephalopathy have been reported. This paper reports 17 patients seen in 1 year for PSGN including 4 with atypical PSGN, at a pediatric tertiary care center. Seventeen children (11 males), mean age of 8 years, were analyzed. Ninety-four percent had elevated serum BUN levels and decreased GFR. Four of the hospitalized patients had complex presentations that included AKI along with positive ANA or ANCAs. Three patients required renal replacement therapy and two were thrombocytopenic. PSGN usually does not occur as a severe nephritis. Over the 12-month study period, 17 cases associated with low serum albumin in 53%, acute kidney injury in 94%, and thrombocytopenia in 18% were treated. The presentation of PSGN may be severe and in a small subset have associations similar to SLE nephritis findings including AKI, positive ANA, and hematological anomalies.

Crucial roles of the protein kinases MK2 and MK3 in a mouse model of glomerulonephritis.

Elevated mitogen-activated protein kinase p38 (p38 MAPK) signaling has been implicated in various experimental and human glomerulopathies, and its inhibition has proven beneficial in animal models of these diseases. p38 MAPK signaling is partially mediated through MK2 and MK3, two phylogenetically related protein kinases that are its direct substrates. The current study was designed to determine the specific roles of MK2 and MK3 in a mouse model of acute proliferative glomerulonephritis, using mice with disrupted MK2 and/or MK3 genes. We found that the absence of MK3 alone worsened the disease course and increased mortality slightly compared to wild-type mice, whereas the absence of MK2 alone exhibited no significant effect. However, in an MK3-free background, the disease course depended on the presence of MK2 in a gene dosage-dependent manner, with double knock-out mice being most susceptible to disease induction. Histological and renal functional analyses confirmed kidney damage following disease induction. Because the renal stress response plays a crucial role in kidney physiology and disease, we analyzed the stress response pattern in this disease model. We found that renal cortices of diseased mice exhibited a pronounced and specific pattern of expression and/or phosphorylation of stress proteins and other indicators of the stress response (HSPB1, HSPB6, HSPB8, CHOP, eIF2α), partially in a MK2/MK3 genotype-specific manner, and without induction of a general stress response. Similarly, the expression and activation patterns of other protein kinases downstream of p38 MAPK (MNK1, MSK1) depended partially on the MK2/MK3 genotype in this disease model. In conclusion, MK2 and MK3 together play crucial roles in the regulation of the renal stress response and in the development of glomerulonephritis, which can potentially be exploited to develop novel therapeutic approaches to treat glomerular disease.

Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease.

After infections, thromboembolism is considered by many experts to be the most significant life-threatening complication of nephrotic syndrome. The purpose of this review is to summarize the epidemiology, clinical and molecular pathophysiology, and management of this complication. Children (2.8%) are less likely than adults (26.7%) with nephrotic syndrome to develop thromboembolism. However, infants and children aged >12 years are at much greater risk. Membranous histologic changes increase thromboembolic risk at all ages; in particular, adults with membranous nephropathy have the highest reported risk (37.0%) and children with membranous histology have a rate (25%) that approaches the overall adult rate. There are striking, but variable, pathologic alterations of molecular hemostasis associated with nephrotic syndrome. No clear molecular therapeutic targets have been identified, but most studies show that the major pathologic changes involve antithrombin, fibrinogen, and factors V and VIII. There is inadequate evidence to support routine prophylactic therapy. Therapy includes anticoagulation in all cases, with thrombolysis reserved for those with the most severe thromboembolic disease. Future hemostatic research in nephrotic syndrome should focus on identifying cohorts at highest risk for thrombosis through the use of clinical markers and biomarkers as well as searching for molecular targets to correct the prothrombotic pathophysiology of this disease.