Reflux Nephropathy

Reflux nephropathy is renal scarring caused by vesicoureteric reflux, in which urine flows back from the bladder to the ureter and kidney, together with infection and congenital dysplasia. It affects 1 to 2% of children, and about 30 to 50% of children presenting with a urinary tract infection have reflux.

The kidney lesion is focal or global cortical scarring with a small, irregular kidney. It develops in early childhood from recurrent pyelonephritis in a kidney with an intrarenal reflux pattern, or from dysplastic kidneys in boys with high grade reflux.

Reflux nephropathy accounts for 10 to 15% of children and 5 to 10% of adults reaching kidney failure. Reflux is familial: 30% of siblings and 35 to 50% of offspring of an affected person have reflux.

Grades of reflux (cystourethrography).

• Grade I: ureter only.
• Grade II: ureter, pelvis and calyces without dilatation.
• Grade III: mild to moderate dilatation with minimal blunting of the fornices.
• Grade IV: moderate dilatation with blunting of the fornices, papillary impressions preserved.
• Grade V: gross dilatation, tortuous ureter, loss of papillary impressions.

• Infants and young children: fever, irritability, poor feeding, vomiting, failure to thrive, febrile urinary tract infection, antenatal hydronephrosis.
• Older children and adults: recurrent urinary tract infection, loin pain, hypertension (in up to 20 to 30% of those with scars), proteinuria, slowly progressive chronic kidney disease.
• Proteinuria above 1 g daily, with secondary focal segmental glomerulosclerosis, signals hyperfiltration injury and progression.
• Pregnancy: bacteriuria, pyelonephritis, pre-eclampsia and decline in function.
• Dysfunctional voiding, constipation and bladder instability coexist and aggravate reflux.

Red flags

• Febrile urinary tract infection in an infant or recurrent infection at any age.
• Hypertension in a child with scars.
• Rising creatinine or proteinuria above 1 g daily.
• Pregnancy with scarring.
• Failure to thrive or growth impairment.

• Urine culture (clean catch or catheter sample in infants), dipstick, microscopy, urine protein:creatinine ratio, creatinine, eGFR, blood pressure measured with the correct cuff size.
• Renal and bladder ultrasound (kidney size, scars, hydronephrosis, ureteric dilatation, bladder wall thickness, residual urine); antenatal ultrasound.
• Technetium-99m dimercaptosuccinic acid scan at least 4 to 6 months after infection to show scars (and at the time of acute infection to show pyelonephritis).
• Micturating cystourethrography to grade reflux after a first febrile urinary tract infection when ultrasound is abnormal, or in recurrent infection, in children; contrast enhanced voiding ultrasound is an alternative.
• Urodynamics for suspected bladder dysfunction.
• In adults: ultrasound, creatinine, urine culture, and cystoscopy or imaging for obstruction.

Differential diagnosis

• Obstructive uropathy (pelviureteric junction obstruction, posterior urethral valves), renal dysplasia, chronic pyelonephritis, renal tuberculosis, papillary necrosis, hypertensive nephrosclerosis, other causes of small scarred kidneys.

Treat acute infection promptly

• Febrile infection in children: oral cefalexin 12.5 to 25 mg/kg twice daily (maximum 500 mg), or co-amoxiclav (dose by age) for 7 to 10 days.
• Give ceftriaxone 50 to 80 mg/kg intravenously once daily (maximum 2 g) if unwell, vomiting or under 3 months.
• Treat early, because delay raises scarring risk.
• Adults: ciprofloxacin 500 mg twice daily for 7 days, or co-trimoxazole 960 mg twice daily for 14 days, or ceftriaxone 1 g intravenously daily when septic. Adjust all doses for eGFR. Avoid nitrofurantoin when eGFR is under 45.

Prevention of infection

• Antibiotic prophylaxis at night for children under 5 years with high grade reflux (grades III to V) or recurrent infection: trimethoprim 2 mg/kg (maximum 100 mg), or cefalexin 12.5 mg/kg (maximum 250 mg), or nitrofurantoin 1 mg/kg (maximum 50 to 100 mg).
• Review every 6 to 12 months. Stop when reflux resolves or by age 5 to 7 years if no breakthrough infection.
• Adults with recurrent infection: nitrofurantoin 50 to 100 mg at night when eGFR is at least 45, or trimethoprim 100 mg at night (monitor potassium, creatinine rise from blocked secretion), or cefalexin 250 mg at night.
• Methenamine hippurate 1 g twice daily where eGFR is at least 30.
• Treat constipation and voiding dysfunction: timed voiding, double voiding, oxybutynin 2.5 to 5 mg twice daily in children over 5 years with overactive bladder.
• Vaginal oestrogen in postmenopausal women.

Surgery or endoscopic correction

• Indications: breakthrough infections despite prophylaxis, high grade reflux with poor renal function, new scars, noncompliance, persisting reflux in older girls.
• Options: endoscopic injection of bulking agent (dextranomer and hyaluronic acid) or open or robotic ureteric reimplantation (success 90 to 98%).
• Posterior urethral valves: endoscopic ablation, with bladder management.

Chronic kidney disease and hypertension

• Blood pressure below 130/80 mmHg in adults and under the 90th centile in children.
• Ramipril 2.5 mg daily increased to 10 mg daily (children 6 mg/m² daily, maximum 10 mg). Check creatinine and potassium at 1 to 2 weeks. Accept a rise up to 30%. Stop if potassium exceeds 6.0 mmol/L.
• Dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20) for persistent proteinuria in adults.
• Sodium under 2 g daily; avoid NSAIDs; maintain hydration.
• Kidney failure: dialysis at eGFR 5 to 10 with symptoms, or transplantation (reflux can be corrected before or during transplantation).

Monitoring. Children: height, weight, blood pressure and urine yearly, and ultrasound every 1 to 2 years. Scans after infection if new symptoms. Adults: creatinine, eGFR, urine protein:creatinine ratio and blood pressure every 6 to 12 months (every 3 months when eGFR is under 45).

Referral and escalation. Paediatric urology and nephrology for every child with high grade reflux or scars. Urgent referral for sepsis, obstruction, pyonephrosis or rapid loss of function.

Special groups

• Pregnancy: screen for bacteriuria monthly, treat promptly, and consider prophylactic cefalexin 250 mg at night. Stop ACE inhibitors before conception. Monitor blood pressure and add aspirin 75 to 150 mg daily from 12 weeks.
• Boys with posterior urethral valves: lifelong urology and nephrology follow up.
• Siblings and offspring: ultrasound screening in infancy.