Chronic Kidney Disease

Congenital Anomalies of the Kidney and Urinary Tract

Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of birth defects in neonates and infants, with an incidence of 0.4 per 1000 births. They account for approximately 50% to 60% of all cases of ESKD in those children less than 1 year of age. Posterior urethral valves/obstructive uropathy cause 21% of cases, and renal hypo/dysplasia is responsible for an additional 28% of these cases. Historically, the etiology of CAKUT was considered sporadic, polygenic, or non-heritable. However, several genes are associated with CAKUT development, primarily in an autosomal dominant pattern. Additionally, many pediatric patients with CKD have copy number variations. Many of these kidney anomalies occur in the setting of co-existing extrarenal manifestations, and those cases often tend to have a higher rate of associated morbidity and mortality.

Polycystic Kidney Disease and Ciliopathies

Cilia are complex, flagella-like organelles found in most mammalian cell types, which have a wide variety of functions. Due to their wide distribution amongst cell types and their diverse functions, mutations in ciliary proteins lead to a variety of pleiotropic clinical manifestations. Mutations in ciliary proteins cause many different kidney diseases, including polycystic kidney disease (PKD), nephronophthisis, and Bardet-Biedl syndrome. The most common renal ciliopathy is autosomal dominant PKD (ADPKD). It affects about 1 in 1000 people, and most cases are caused by mutations in PKD1 and PKD2. While most cases do not present until later childhood or adulthood, severe cases may present in utero and mimic autosomal recessive PKD (ARPKD). ARPKD, caused primarily by PKHD1, is much less common, affecting about 1 in 10,000 to 1 in 40,000 births. It presents in utero or in the neonatal period with large echogenic kidneys. The severity of kidney disease in ARPKD varies from ESKD at birth to slowly progressive CKD, with most children progressing to kidney failure by 20 years of age. Approximately 30% of patients presenting in the neonatal period die primarily from pulmonary hypoplasia. Other ciliopathies such as Bardet-Biedl and Joubert syndrome often present with extrarenal manifestations. Other causes of neonatal CKD include prune belly syndrome, HNF1B disease, congenital nephrotic syndrome, and neurogenic bladder from spinal cord defects.

Prematurity and Low Birth Weight

Preterm neonates are at high risk for the development of CKD for three reasons: (1) they have a smaller complement of nephrons at birth as a result of disruption of nephrogenesis, which typically continues to 36 weeks; (2) increased risk of acute kidney injury (AKI) due to medications and comorbidities often associated with premature birth; (3) prenatal kidney disease leads to an increased risk of premature delivery either as a result of direct complications such as oligohydramnios, or the presence of extrarenal comorbidities found in syndromic prenatal kidney disease. In a small German study, 53% of children with CKD were premature, a figure significantly higher than the rate experienced by the total infant population of Germany. A publication from the Chronic Kidney Disease in Children (CKiD) cohort also revealed a high prevalence of children with CKD; the lifetime risk for CKD was increased in those neonates who had an abnormal birth history as defined by low birth weight (17%), small for GA (14%), or prematurity defined as GA less than 36 weeks (12%). In a study of more severe CKD, 35% of affected patients were born prematurely, and approximately 50% had a comorbidity, such as cardiopulmonary and/or neurologic involvement.

A systematic review and meta-analysis in 2009 concluded that low birth weight babies (≤5.5 lb) were 70% more likely to develop CKD later in life compared with individuals with normal birth weight. More recent studies show that the incidence of CKD in preterm infants (<37 weeks’ gestation) by mid-adulthood is 9.24/100,000 person-years (py), 5.90/100,000 py for those born at 37 to 38 weeks, and 4.64/100,000 py for those born full term. Low birth weight in the setting of prematurity independently increases the risk for CKD.

Decreased nephron number either due to deranged nephron development and/or scarring leads to an increased risk for CKD regardless of etiology and likely underlies much of the increased risk conferred by premature birth. Total GFR is determined by the filtration rate of single nephrons and the number of nephrons present. When the number of nephrons is diminished, single nephron GFR increases as the kidney works to compensate for the low nephron numbers. This compensatory hypertrophy causes glomeruli to function under increased intracapillary hydraulic pressure, which, over time, causes damage to capillary walls. This abnormal process leads to progressive glomerulosclerosis, proteinuria, hypertension, and CKD. The hyperfiltration hypothesis has been applied and confirmed in autopsy data of hypertensive patients and has been written about at length with reference to infants with intrauterine growth restriction. Nephrogenesis continues through 34 weeks' gestation. Premature infants (even those born appropriate for GA) are therefore born with low nephron numbers compared with term infants. Using computer-assisted morphometry, Rodriguez et al. showed that premature infants who survived to at least 36 weeks' postconception had nephron numbers similar to premature infants with short survival, suggesting that the extrauterine environment does not support normal neoglomerulogenesis. In addition, preterm infants with AKI had fewer nephrons than similar infants without AKI.