By Bradley Warady, MD

End-Stage Renal Disease (ESRD) is the term that refers to severe kidney failure that necessitates the initiation of dialysis therapy or kidney transplantation to maintain life. While ESRD occurs in children and adults, its etiology (cause) in the two populations is very different. Whereas diabetes mellitus and hypertension (high blood pressure) are the leading causes of ESRD in adult patients, two congenital abnormalities, posterior urethral valves and hypoplastic/dysplastic kidneys, and a third disorder, focal segmental glomerulosclerosis (FSGS) are the primary causes of long-term kidney failure in children and are the topic of this discussion.

POSTERIOR URETHRAL VALVES

Posterior urethral valves (PUV) is the most common cause of obstruction of the lower urinary tract in males. This abnormality consists of folds of tissue within the urethra that lead to incomplete or intermittent obstruction to the normal flow of urine. It occurs with an approximate incidence of one case for every 12,000 live births and accounts for 10 to 15 percent of children undergoing kidney transplantation. Overall, nearly 1/3 of children born with PUV progress to ESRD.

The diagnosis of PUV is commonly first suggested by the finding of hydronephrosis (expansion and enlargement of the kidney) on antenatal (before birth) ultrasound in a male fetus. Confirmation of the diagnosis requires the performance of a voiding cystourethrogram (VCUG) in the immediate post-natal period. This radiologic exam characteristically reveals the valve leaflets within the urethra, an enlarged posterior portion of the urethra and a thickened bladder wall, the latter finding the result of elevated bladder pressure that is secondary to the obstruction of urine flow.

Vesicoureteral reflux (backflow of urine from bladder to the kidneys) is present in 35 to 40 percent of patients. Less frequently, PUV is not detected until early childhood (prior to 5 years of age) during the evaluation of a child with recurrent kidney or bladder infections, daytime urinary wetting, voiding difficulties (weak urinary stream) or poor growth secondary to kidney failure.

Once diagnosed, definitive treatment consists of surgically cutting the valves under direct vision by cystoscopy, most commonly performed by a pediatric urologist. In situations in which the child's small size precludes the cystoscopic procedure to be conducted safely, the surgically induced drainage of urine directly from the bladder or kidneys can serve as a temporary measure.

The long-term outlook for children with PUV is largely dependent upon the extent of damage that has occurred to the kidneys in-utero in association with the obstruction, despite surgical relief of the blockage soon after birth. While those with severe damage progress to ESRD (dialysis and transplantation) and have their medical care managed by the combined expertise of their pediatrician, pediatric nephrologist and pediatric urologist, children who maintain normal renal function through puberty have an excellent prognosis and are unlikely to lose significant kidney function as a result of PUV later in life.

FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)

The nephrotic syndrome results from a number of kidney disorders and is characterized by the presence of heavy proteinuria (protein loss in urine), hypoproteinemia (low protein level in blood), hyperlipidemia (elevated cholesterol level) and edema (fluid retention in tissues). While Minimal Change Disease accounts for the majority (greater than 70 percent) of cases of primary (e.g. no known cause) nephrotic syndrome in children, FSGS is unquestionably the most significant of these disorders as a result of its "stature" as the most common acquired cause of ESRD in children.

FSGS accounts for 10 percent of childhood and 15 to 20 percent of adult primary nephrotic syndrome with an overall peak incidence at age six years. (Secondary FSGS can occur as a result of disorders such as sickle cell disease and morbid obesity and will not be discussed further here). The diagnosis is most often made in the setting of a nephrotic syndrome that is unresponsive to prednisone therapy (see below) and requires the kidney biopsy findings of scarring (sclerosis) of parts (focal) of a portion (segmental) of the glomeruli (filters) within the kidney.

Only a minority (20 to 30 percent) of pediatric patients with FSGS respond to treatment with prednisone with complete resolution of proteinuria. This unfortunate, but common scenario, has prompted therapeutic trials with medications such as cyclophosphamide, chlorambucil, methylprednisolone and cyclosporine, with some positive results noted on occasion. The adjunctive (in addition to) use of angiotensin converting enzyme (ACE) inhibitors may further reduce protein loss. Nevertheless, the absence of an uniformed successful approach to therapy has resulted in a National Institutes of Health (NIH) sponsored multicenter study of treatment options, which is scheduled to begin in 2003.

Finally, approximately 1/3 of children diagnosed with FSGS are likely to develop ESRD within five to 10 years. Although the majority of these children will proceed to transplantation, as many as 50 percent of these transplant recipients will suffer a recurrence of the disorder in the transplanted kidney, a "complication" which can compromise the kidney's long-term function. Whereas a circulating factor in blood that is associated with recurrence has been described and studied, its exact identity continues to elude researchers.

Hypoplastic and Dysplastic Kidneys

Hypoplastic kidneys are small kidneys that contain a reduced number of normally developed filtering elements, while dysplastic kidneys contain components that are abnormally developed. Children may manifest either disorder by itself, although the two typically co-exist. Children with a single affected kidney generally do well; in contrast, those with bilateral (two kidneys) hypoplasia/dysplasia characteristically progress to kidney failure and the need for dialysis and transplantation.

Studies have suggested that unilateral renal hypoplasia occurs with a frequency of one case for every 500 persons. A single hypoplastic kidney may be diagnosed by ultrasound when a significant discrepancy between the sizes of the two kidneys is noted. The kidney size can also be compared to normal age-related standards. On the other hand, the presence of a dysplastic kidney is suggested by the finding of increased echogenicity (density) on ultrasound and is associated with abnormalities of the ureters, bladder and urethra (e.g. obstruction, vesicoureteral reflux) in as many as 90 percent of patients.

When not diagnosed with ultrasound, the condition is usually detected during the first few years of life with symptoms of excessive thirst, a large urine output, repeated episodes of dehydration, growth retardation and a failure to thrive. The symptoms may become particularly evident during minor illnesses such as gastroenteritis. Therapy consists of maintaining fluid and electrolyte (sodium, potassium) balance and correcting acidosis. Blood pressure is usually normal, at least partially as a result of salt wasting through the kidney.

Most patients with bilateral disease develop ESRD in mid to late childhood. The registry of the North American Pediatric Renal Transplant Cooperative Study reveals it to be the origin of ESRD in 16 percent of transplant recipients.

Posterior urethral valves, focal segmental glomerulosclerosis and hypoplastic/dysplastic kidneys account for approximately 40 percent of all cases of ESRD that occur during childhood. In turn, the growth, development and quality of life of a substantial number of children are affected by these disorders. While their early recognition is clearly associated with an improved patient outlook, it is hoped that continued research into their origin and treatment will provide methods to ultimately prevent the accompanying progressive loss of kidney function that characterizes them today.

Dr. Warady is the Chief of Pediatric Nephrology and Director of Dialysis and Transplantation at Children's Mercy Hospital in Kansas City, MO and a member of the Pediatric Urology and Nephrology Committee of the National Kidney Foundation.

This article originally appeared in the January 2002 issue of aakpRENALIFE, Vol. 17, No. 4.

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