Grand RoundVesicoureteric reflux: all in the genes?
Section snippets
(S Feather)
A 5-year-old girl first presented in 1975 with an 18-month history of recurrent urinary tract infections. She was hypertensive. A micturating cystourethrogram indicated bilateral vesicoureteric reflux (VUR), and an intravenous urogram showed a small left kidney and bilateral cortical defects suggestive of pyelonephritic scars. Her glomerular filtration rate (GFR) was low (60/mL min-1 1–73 m−2; 80–120). She was treated with antihypertensive medications and prophylactic antibiotics.
By age 9 years
(I Gordon)
VUR is the retrograde passage of urine from the bladder into the ureter and in some cases the renal pelvis, calyces, and collecting ducts.1 VUR can be secondary to high bladder pressure due to anatomical defects or lesions of the urethra (eg, urethral valves), or due to neurological pathology (ie, neurogenic bladder). In primary VUR there is an anatomical defect at the junction of the ureter with the bladder.
The detection of VUR before toilet training requires that either a micturating
(R A Risdon)
Reflux nephropathy describes renal scarring that may accompany VUR. It has been related to the extension of reflux into the renal collecting ducts (intrarenal reflux) which may cause scarring by its hydrodynamic effects alone or, in the presence of urinary tract infection, by allowing ingress of organisms into the renal parenchyma.4, 5 VUR has been diagnosed with increasing frequency in infants by fetal ultrasonography, showing hydronephrosis, and micturating cystourethrography soon after
(A S Woolf)
Renal development is orchestrated by the expression of transcription factors, growth/survival factors, and adhesion molecules. Mutations of genes encoding all classes of these molecules cause urinary tract malformations in mice.8 The transcription factor proteins bind to and regulate the expression of other genes. One family of these proteins contains the paired DNA-binding domain and is encoded by the PAX genes, which show remarkable homology across evolution.9 (PAX stands for ‘paired box’.
(S Feather)
PAX-2 mutations also occur in humans, arising de novo or being inherited in an autosomal dominant manner.15, 16 These heterozygous mutations of the paired or octapeptide domains most likely result in haploinsufficiency–ie, a partial lack of functional protein. The mutations are associated with a syndrome involving eye malformations (optic nerve colobomas), VUR, and small, malformed kidneys. This genetic renal-coloboma syndrome in humans is therefore strikingly similar to the mouse PAX-2
(K Verrier Jones)
VUR is usually diagnosed during the investigation of urinary tract infections. These infections in infants do not give rise to classic symptoms and signs seen in adults (such as dysuria, frequency, urgency) but are associated with non-specific signs such as fever, screaming, malaise, and failure to thrive.
The diagnosis is easily missed unless suspicion is high. When VUR is suggested by prenatal hydronephrosis,21 the newborn infant should be given prophylactic antibiotics until definitive
Conclusion
Isolated primary VUR is an autosomal dominant disorder with incomplete penetrance and variable expression: the genetic defect or defects are unknown. Rarely, VUR can be inherited as part of a syndrome–eg, with optic nerve colobomas. In these cases mutations of PAX-2 have been defined. The long-term prognosis of primary VUR is determined by the presence and severity of associated renal disease, which is a spectrum of renal maldevelopment and pyelonephritic scarring. Given the high familial
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