Reflux Nephropathy

Etiology

The abnormal retrograde flow of urine from the bladder into one or both the ureters leads to vesicoureteral reflux (VUR), which is a direct consequence of incompetent and mislocated ureterovesical valves. Reflux nephropathy is a direct consequence of VUR or other urologic congenital anomalies stemming from chronic high-pressure sterile urine reflux and often leads to recurrent urinary tract infections (UTIs) in early childhood. It is important to understand that not all patients with urinary tract infections and vesicoureteral reflux develop reflux nephropathy.

Epidemiology

The exact incidence and prevalence of RN are not known. It is primarily a disorder of childhood or early adulthood and is more common in females than males. VUR may be a familial disorder affecting 20% of infants who have a parent with a family history of VUR, compared with a 1% to 2% frequency of VUR in the general population.[3] Hypertension occurs in 10% to 30% of children and young adults with RN.[4] It is estimated that RN is responsible for 12% to 21% of all children with chronic renal failure.[5] Reflux nephropathy is the second most common cause of chronic tubulointerstitial disease. Based on the North American Pediatric Renal Transplant Cooperative Study annual report for 2008, 3.5% of the 6491 children on dialysis had RN.[6] It is the fourth most common cause of ESRD in children after focal segmental glomerulosclerosis (FSGS), renal aplasia, hypoplasia or dysplasia and, obstructive uropathy. RN is responsible for the ESRD in 7% to 17% of the children worldwide.[2]

The incidence of ESRD from RN is unknown in the worldwide adult population. About 12% of patients in Europe requiring treatment for ESRD may have RN. In a study of 127 adults (mean age of 41 years) with a diagnosis of VUR in childhood, 35% had unilateral renal scarring, 24% had bilateral renal scarring, 24% had albuminuria, and 11% had hypertension. In the patients with bilateral renal scars, 83% had reduced estimated glomerular filtration rate (eGFR).[7] In countries like Turkey, RN accounts for 18.5% of the causes of chronic kidney disease (CKD). 

In pregnant females with VUR, approximately 40% of the offspring will have the condition, and testing of offspring is highly recommended.

Pathophysiology

VUR leads to high-pressure sterile urine reflux which stunts the normal growth of the kidneys and is often exacerbated by recurrent childhood infections. Not all urinary tract infections with VUR lead to RN because of the architecture of the renal pyramids. Renal pyramids are of two types, simple and compound. Compound pyramids promote intrarenal reflux combined with VUR which leads to RN, given transmission of high-pressure urine and infection to gain access to the renal parenchyma.

VUR ultimately results in chronic interstitial nephritis, tubular atrophy, and renal scarring along with glomerular hypertrophy and secondary FSGS.

Histopathology

Grossly the kidneys are small and irregularly contracted, with renal pelvis and ureteral dilation with thickened walls. In the appropriate clinical setting, the following findings can be seen on the renal biopsy:

• Global glomerular hypertrophy and periglomerular fibrosis
• Chronic interstitial nephritis
• Patchy interstitial scarring
• Extensive tubular atrophy
• Secondary FSGS

History and Physical

The condition is often asymptomatic and frequently diagnosed during routine clinical evaluation or as part of pregnancy workup. The presentation of congenital versus acquired RN in children might help explain the differences in the clinical presentation of RN in adults, with males presenting mostly with hypertension, proteinuria, and progressive renal failure as compared with females who present mostly with recurrent UTI and usually carry a favorable outcome.[8]

Some of the risk factors for RN include:[8]

• The severity of VUR
• Recurrent UTI
• Bladder-bowel dysfunction.
• Younger age
• Delay in the treatment of UTI

Based on the age of presentation, the patients may have the following:

• History of recurrent childhood UTIs
• Prolonged bedwetting
• Complicated urinary infection: Acute pyelonephritis in infants and children
• History of surgical reimplantation of the ureters into the bladder
• Hypertension on presentation[9]
• Abnormal renal function with elevated serum creatinine and reduced eGFR
• Episodes of fluctuating renal function
• Mild to moderate proteinuria
• Severe or nephrotic proteinuria may be from secondary FSGS, which can be confirmed by renal biopsy[10]
• Urinary calculi
• Asymptomatic bacteriuria in pregnancy[11]
• In pregnancy: Urinary infection, hypertension, and preeclampsia[12]
• Approximately 20% of women with reflux nephropathy will develop UTI in pregnancy, with around 6% of these from acute pyelonephritis
• Small kidneys with thinned cortices on renal ultrasonogram (USG) in asymptomatic young patients with hypertension
• Bilateral hydronephrosis on the renal USG
• UTIs may be more common in adults who have had the surgical management of VUR

Evaluation

A thorough history and physical examination along with collateral history from the parents as needed and initial laboratory testing should include:

• Basic metabolic panel (BMP) or comprehensive metabolic panel (CMP)
• Urine analysis
• Complete blood count
• Urine protein to creatinine ratio

Various imaging options are available, and renal ultrasound is the most common and usually first evaluation of postnatal hydronephrosis and UTI in children. Renal USG should be used for siblings of children with VUR. USG is less sensitive for the diagnosis of acute pyelonephritis. Though helpful in renal abscess detection and perinephric space abnormalities, it is not diagnostic for VUR and is not sensitive for renal scars.

Diagnostic voiding cystourethrogram (VCU) is useful in patients with bilateral or unilateral hydronephrosis on renal USG in a patient with the appropriate clinical presentation. It is the primary diagnostic modality for the identification of VUR.

Nuclear cystography can be used to prevent radiation exposure in patients with post-surgical VUR follow-up. It is more sensitive than VCU, but does not aid in the specific grading of VUR or detection of other anatomic defects, for example, ureterocele and diverticulum.

DMSA scan (a radionuclide scan using dimercaptosuccinic acid),[13] is highly sensitive and is the gold standard for the diagnosis of acute pyelonephritis and renal scarring.

Magnetic resonance imaging (MRI), can be used to diagnose renal scarring as it differentiates swelling from scarring, unlike a DMSA scan. It is not practical for use in infants and children, moreover, the cost is a hindrance.

Renal biopsy aids in both diagnosis and prognostication.

Treatment / Management

Low-grade VUR typically resolves spontaneously over time, but in the meantime, it is very important to maintain sterile urine in affected individuals in childhood. In patients with symptomatic VUR, the main treatment modalities include long-term antimicrobial prophylaxis, prompt treatment of UTIs, and surgical correction.

Prophylactic antibiotics should be used depending on the frequency of UTIs, the age of the child, and the severity of the VUR. Appropriate agents include trimethoprim-sulfamethoxazole, trimethoprim alone, nitrofurantoin, and cephalexin. It is crucial to pay attention to the management of bladder and bowel dysfunction, with the following: 

• Laxatives and stool softeners
• Frequent and timed voiding (2 to 3 hours)
• Pelvic floor exercises
• Behavioral modification
• Anticholinergic medications as needed

In chronic and severe VUR, surgical reimplantation of the ureters into the bladder to maintain the competency of the ureters is indicated. It is most beneficial in patients with failed medical management (antimicrobial prophylaxis) to prevent UTIs. Surgery has no role in adolescents and adults with established renal scarring and markers of advanced chronic kidney disease. Surgical indications include:

• Recurrent infections despite compliance with a prophylactic antibiotic regimen
• Worsening of renal scars on DMSA scan
• Non-adherence to the antibiotic prophylaxis

In patients with established RN, it is very important to prevent and aggressively manage hypertension. Appropriate use of renin-angiotensin system (RAS) blockade in patients with glomerular hyperfiltration and patients with established proteinuria.

Various modalities of renal replacement therapies (RRT) can be employed in patients who reach ESRD. Despite the higher incidence of UTIs, there was no significant difference in posttransplantation complications or patient and graft survival rates between RN patients compared with the control group.[14](B2)

Differential Diagnosis

Chronic pyelonephritis with gross findings of the kidney usually distinguishes RN from obstructive pyelonephritis. RN has polar scars, and obstructive pyelonephritis has diffuse hydronephrosis with cortico-medullary atrophy. Advanced VUR may resemble radiographically polycystic kidney disease or unilateral renal cystic disease, a condition that mimics polycystic kidney disease.[15]

Prognosis

Advanced age at presentation and bilateral VUR decreases the probability of resolution. High grade and severity of the VUR have lesser chances of spontaneous resolution.[16] Proteinuria predicts CKD progression in patients with RN.[17]

Complications

The complications of RN are well known but poorly defined because of their insidious onset and slow progression.[8]

• Early growth retardation is observed from recurrent cystitis and pyelonephritis in children affected with VUR and later on with RN. Increased maternal complications are noted.[18]
• Suddenly-accelerated hypertension with associated renal impairment during pregnancy[19]
• Fetal morbidity in women with reflux with renal scarring[20]

Patients with RN will develop hypertension, proteinuria, urine concentration defects, hyperkalemia, acidosis (type 1 renal tubular acidosis), and chronic kidney disease (CKD). Progressive CKD can lead to end-stage renal failure. CKD from RN leads to increased cardiovascular mortality and morbidity.