Current Pediatric Reviews (v.10, #2)

Survival of critically ill neonates in the intensive care unit has improved over the past decades reflecting improvementsin obstetric, delivery room and neonatal intensive care, however, morbidity remains significant. Acute kidneyinjury is a common occurrence in these neonates and despite improved understanding of the pathophysiology and managementof acute kidney injury in full term and preterm infants, the mortality remains as high as 61%. Furthermore, thereis growing evidence that despite recovery from the acute injury, these infants are at risk for developing hypertension andchronic kidney disease later in life. Emphasis on improving our capability to detect renal insult and injury early, beforerenal failure occurs, and identification of novel therapeutic agents to prevent and treat acute kidney injury may impactmortality and morbidity. This review focuses on our current knowledge of acute kidney injury in the newborn, approachesto investigating and managing this complication and what future trends in this field may bring.

Inherited Renal Diseases by Jocelyn C. Leung (95-100).
Genetic disorders of the kidney include cystic diseases, metabolic diseases and immune glomerulonephritis.Cystic diseases include autosomal dominant and recessive polycystic kidney disease (ADPKD, ARPKD, respectively).Neonates with enlarged, cystic kidneys should be evaluated for PKD. Patients with ADPKD have cysts and renal enlargement.Most patients present with hypertension, hematuria or flank pain; the most common extrarenal manifestation ispolycystic liver disease. Oligohydramnios, bilaterally enlarged kidneys and decreased urine are featured in utero inARPKD. Medullary sponge kidney is uncommon and features nephrocalcinosis, recurrent calcium stones and a history ofpolyuria/nocturia and/or urinary tract infections. Alport syndrome (AS) is an inherited disease of the glomerular basementmembrane that is usually inherited as an X-linked dominant trait. Most patients with AS present in the first two decades oflife with persistent microscopic or gross hematuria. Later, proteinuria is seen and its presence portends disease progression.Other findings may include sensorineural hearing loss and ocular abnormalities. There are various inherited tubulopathies,including Bartter syndrome, a group of renal tubular disorders that consist of two phenotypes with four genotypes.Patients usually present early in life with salt wasting, hypokalemia and metabolic alkalosis. Other features, dependingon genotype, may include polyhydramnios and premature birth. Gitelman syndrome is also a salt-losing tubulopathycharacterized by hypokalemic alkalosis. The majority of patients with Gitelman syndrome present during adolescenceor early adulthood.

Renal Venous Thrombosis in Neonates by Asha Moudgil (101-106).
Neonatal renal vein thrombosis (RVT) is associated with potentially serious morbidities. Almost 80% of casesof RVT present within the first postnatal month. The most common risk factors for RVT are birth asphyxia/ in utero fetaldistress, being the infant of a diabetic mother, volume contraction and coagulation abnormalities. Thrombus formationmay be initiated by vascular injury, diminished vascular flow, increased blood viscosity, hyperosmolality or underlyingthrombophilia. The classic triad of RVT includes gross hematuria, flank mass (unilateral or bilateral enlargement of kidneys)and thrombocytopenia. Laboratory tests may reveal hematuria, proteinuria, polycythemia, hemolytic anemia,thrombocytopenia and possibly acute kidney injury. The etiology for a hypercoagulable state should be investigated. Renalultrasound with Doppler may show increased size of the affected kidney, increased echogenicity and loss of corticomedullarydifferentiation. Renal venography remains the gold standard for the diagnosis of RVT. Other causes of renalenlargement must be considered. Supportive treatment includes correction of fluid and electrolyte disturbances and treatmentof infection and underlying pathophysiologic abnormalities. Use of unfractionated heparin (UFH) or low molecularweight heparin (LMWH) should be considered if there is evidence of disseminated intravascular coagulation. Conventionalanticoagulants may attenuate hypercoagulability and decrease the risk for thrombus progression and embolism.Surgery is rarely indicated unless there is bilateral involvement with involvement of the IVC. RVT carries the risk of hypertensionand chronic kidney disease.

Renal Development: A Complex Process Dependent on Inductive Interaction by Kiran K. Upadhyay, Douglas M. Silverstein (107-114).
Renal development begins in-utero and continues throughout childhood. Almost one-third of all developmentalanomalies include structural or functional abnormalities of the urinary tract. There are three main phases of in-utero renaldevelopment: Pronephros, Mesonephros and Metanephros. Within three weeks of gestation, paired pronephri appear. Aseries of tubules called nephrotomes fuse with the pronephric duct. The pronephros elongates and induces the nearbymesoderm, forming the mesonephric (Woffian) duct. The metanephros is the precursor of the mature kidney that originatesfrom the ureteric bud and the metanephric mesoderm (blastema) by 5 weeks of gestation. The interaction betweenthese two components is a reciprocal process, resulting in the formation of a mature kidney. The ureteric bud forms themajor and minor calyces, and the collecting tubules while the metanephrogenic blastema develops into the renal tubulesand glomeruli. In humans, all of the nephrons are formed by 32 to 36 weeks of gestation. Simultaneously, the lower urinarytract develops from the vesico urethral canal, ureteric bud and mesonephric duct. In utero, ureters deliver urine fromthe kidney to the bladder, thereby creating amniotic fluid. Transcription factors, extracellular matrix glycoproteins, signalingmolecules and receptors are the key players in normal renal development. Many medications (e.g., aminoglycosides,cyclooxygenase inhibitors, substances that affect the renin-angiotensin aldosterone system) also impact renal developmentby altering the expression of growth factors, matrix regulators or receptors. Thus, tight regulation and coordinatedprocesses are crucial for normal renal development.

Fluid and Electrolyte Disorders in the Newborn: Sodium and Potassium by Marta Suarez-Rivera, Melvin Bonilla-Felix (115-122).
Tubular development continues after birth in full and pre-term infants. As the survival of premature infants increases,serious imbalances in water and electrolytes in this group have become more prevalent. A diminished ability ofthe immature kidney to reabsorb water and respond to mineralocorticoids, a high excretion of filtered sodium, perinatalcomplications affecting tubular function, and the use of medications such as diuretics, indomethacin and amphotericin B,are common factors leading to sodium and potassium imbalances in this age group. Appropriate diagnosis and treatmentshould be guided by a careful assessment of volume status, urine electrolytes and osmolality.

Congenital Anomalies of the Urinary Tract by Hans G. Pohl, A. Barry Belman (123-132).
The upper urinary tract forms as a consequence of the reciprocal inductive signals between the metanephricmesenchyme and ureteric bud. A clue to the timing of events leading to an abnormality of the upper urinary tract can bethe presence also of associated anomalies of internal genitalia since separation of these systems occurs at about the 10thweek of gestation. Prenatal sonography has facilitated the detection of urological abnormalities presenting with hydronephrosis.Hydronephrosis suggests obstruction, but by itself cannot be equated with it. Instead, further radiographic imagingis required to delineate anatomy and function. Now, moreover, non-surgical management of CAKUT should beconsidered whenever possible. Despite the widespread use of prenatal screening sonography that usually identifies themajority of congenital anomalies of the urinary tract, many children still present with febrile urinary tract infection (UTI).Regardless of the etiology for the presentation, the goal of management is preservation of renal function through mitigationof the risk for recurrent UTI and/or obstruction. In the past many children underwent surgical repair aimed at normalizationof the appearance of the urinary tract. Today, management has evolved such that in most cases surgical reconstructionis performed only after a period of observation - with or without urinary prophylaxis. The opinions presented inthis section are not espoused by all pediatric urologists but represent instead the practice that has evolved at Children'sNational Medical Center (Washington DC) based significantly on information obtained by nuclear renography, in additionto sonography and contrast cystography.

Disorders of Mineral Metabolism in the Newborn by Shamir Tuchman (133-141).
Disorders of calcium and phosphorus homeostasis present both acute and chronic clinical consequences fornewborns. The etiologies responsible range from iatrogenic, idiopathic, and inherited metabolic abnormalities. Maintenanceof physiologically normal serum calcium and phosphorus requires complex interactions between the kidneys,gastrointestinal tract, and bone. Calciotropic hormones such as vitamin D and parathyroid hormone, as well as hormonescontrolling phosphorus homeostasis, such as fibroblast growth factor-23 (FGF-23), are essential in controlling these interactions.In newborns, calcium and phosphorus balance must necessarily be positive in order to provide the requisite buildingblocks for growth and maturation. Renal tubular handling of these minerals is a key control point in regulating theoverall body balance in calcium and phosphorus. Adaptive changes in renal calcium and phosphorus reabsorption in newbornsexplain how a net positive total body balance of these minerals is achieved. Monogenetic disorders leading to abnormalrenal handling of calcium and/or phosphorus have immediate clinical consequences in terms of complications associatedwith high or low levels of these minerals. Perhaps more importantly, chronic abnormalities of calcium and/orphosphorus, without treatment, may have serious consequences for growth and development of the growing skeleton. Thisarticle serves to review calcium and phosphorus regulation in the human body, describe differences in handling of theseminerals by the newborn, and review the conditions, both acquired and congenital, that may present with abnormalities incalcium and/or phosphorus in the newborn period.

Assessment of Glomerular and Tubular Function by Kanwal Kher, Kirtida Mistry (142-150).
At birth, GFR and tubular function of neonates is compromised as compared to older children and adults. Thesefunctions are even less developed in premature infants. These facts have a direct bearing on drug dosing, fluid and electrolyteadministration, and maintenance of acid-base balance in neonates. Although many detailed methods of assessing renalfunctions have been provided in this article, laboratory and radiologic studies available in most healthcare facilities are oftensufficient to provide a clinically relevant data in most patients, including neonates.

Nonalcoholic Fatty Liver Disease In Children: Recent Practice Guidelines, Where Do They Take Us? by Ashish Aggarwal, Kanika Puri, Suraj Thangada, Nizar Zein, Naim Alkhouri (151-161).
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children andadolescents in the United States. It is strongly associated with childhood obesity, insulin resistance and metabolic syndrome.Although some children with NAFLD may remain asymptomatic, progression to nonalcoholic steatohepatitis(NASH), and to advanced stages of fibrosis and cirrhosis is well recognized. Unfortunately, despite the increase in awarenessof this disease, there are still no reliable non-invasive diagnostic tests and liver biopsy remains the gold standard forthe diagnosis of NASH and staging of fibrosis. In addition, there are no approved pharmacological treatments currently.Lifestyle modification remains the cornerstone of treatment. Team based multidisciplinary approach involving hepatologists,endocrinologists, exercise physiologist, dieticians, and cardiologists may lead to better outcomes. Recently, theAmerican Association for the Study of Liver Diseases (AASLD) and European Society for Pediatric Gastroenterology,Hepatology and Nutrition (ESPGHAN) committees have made recommendations for the diagnosis and management ofNAFLD in pediatric patients. This review focuses on current literature on epidemiology, natural history, pathogenesisalong with summarizing the recent guidelines on diagnosis and treatment of pediatric NAFLD.

Surfactant replacement therapy is now the standard of care for infants with respiratory distress syndrome. Asthe understanding of surfactant structure and function has evolved, surfactant-associated proteins are now understood tobe essential components of pulmonary surfactant. Their structural and functional diversity detail the complexity of theircontributions to normal pulmonary physiology, and deficiency states result in significant pathology. Engineering syntheticsurfactant protein constructs has been a major research focus for replacement therapies. This review highlights what isknown about surfactant proteins and how this knowledge is pivotal for future advancements in treating respiratory distresssyndrome as well as other pulmonary diseases characterized by surfactant deficiency or inactivation.