Reflux Nephropathy

Reflux Nephropathy

Sanjay Jain, MD, PhD

Helen Liapis, MD

Reflux nephropathy with megaureter image shows marked thinning of the cortex and loss of the medulla, especially at the poles image.

Cross-section through full-thickness of cortex image and medulla image in a 7-year-old boy with reflux nephropathy shows the markedly thin parenchyma corresponding to the gross appearance.



  • Reflux: Retrograde urine flow from bladder into ureters or kidney due to functional or physical lower tract defects

  • Reflux nephropathy: Renal parenchymal scarring due to urine reflux



  • Vesicoureteral reflux (VUR)

    • Primary VUR

      • Congenital anomaly, unilateral or bilateral

      • Abnormal insertion of ureter into bladder, abnormal intravesicular tunnel length of ureter

      • Incompetent valve

    • Secondary VUR

      • Distal obstruction, neurogenic bladder: Posterior urethral valves (PUV), multiple sclerosis, spinal cord injury, stroke, diabetic neuropathy, pelvic surgery, B12 deficiency

      • Dysfunctional elimination syndrome: Abnormal holding of urine and voiding pattern

  • Acquired: Urinary tract infections

Pathophysiology Points

  • Reflux due to VUR or lower tract obstruction

  • Reflux nephropathy develops in some patients with VUR

  • Reflux urine enters renal parenchyma via compound papillae (2-3 fused papillae at poles that have round orifice)

  • Reflux gives bacteria access to kidney

  • Continued exposure of kidneys to high-pressure urine reflux or bacteria causes acute or chronic immune response

  • Tubulointerstitial damage ensues with these events leading to edema, ischemia, necrosis, inflammation, tubular atrophy, fibrosis, and scar formation

    • Focal scars in compound papillae

    • Ongoing damage can alter anatomy of simple papillae (dome-shaped with slit-like orifice and drain single lobe) to compound type and cause more diffuse scars

  • Glomerulosclerosis

  • Renin-angiotensin system is activated and causes hypertension

  • Etiology of scar formation is not fully understood

    • Reflux may not be a prerequisite for scar formation as scar can develop in kidneys without intrarenal reflux

    • Bacterial colonization of kidneys may not be necessary to induce kidney damage as scars have been observed in patients without history of urinary tract infection (UTI)

    • New renal scars can develop in presence of reflux and pyelonephritis

  • Intrarenal reflux during development can lead to partial or complete maturation and developmental arrest of developing kidney

  • Genes causing reflux may be similar to those important in kidney development

    • Genes tested and found to be associated with VUR phenotype in humans

      • HLA complex (DNA analysis and serotyping)

      • TNFα (DNA analysis)

      • TGFβ1 (DNA analysis)

      • ACE (DNA analysis, protein and mRNA studies)

      • PTGS2 (protein and mRNA studies)

      • IGF1 (protein and mRNA studies)

      • IGF1R (protein and mRNA studies)

      • EGF (protein and mRNA studies)

      • CCL2 (protein and mRNA studies)

      • ROBO2 (DNA analysis)

      • UPK3A (DNA analysis)

      • UPK1A (DNA analysis)

      • GNB3 (DNA analysis)

      • AGTR2 (DNA analysis)

      • ABO blood group (serotyping)

    • Finding of progression to kidney failure even after correction of reflux suggests ongoing irreversible damage



  • Incidence

    • Reflux nephropathy is a cause of renal failure in 3-5% of renal dialysis or transplant patients

    • Most common cause of severe hypertension in children


  • Hypertension

  • Proteinuria

  • UTI, acute pyelonephritis, chronic pyelonephritis

    • 50-80% of children with febrile UTI have renal scarring

  • Primary or secondary VUR

Laboratory Tests

  • Renal parenchyma scintigraphy: Tc-99m dimercaptosuccinic acid (DMSA) scan; depends on adequate renal blood flow and cellular uptake

  • Voiding cystourethrogram (VCUG) for lower urinary tract disorder

  • Renal function test, urinalysis


  • Surgical repair

  • Antibiotics


  • High-grade reflux more likely to cause nephropathy than low grade; 5% of renal failure in children due to reflux nephropathy

  • Proteinuria, reduced creatinine clearance and GFR, hypertension, high-grade reflux, and bilateral VUR increase likelihood of progression to chronic kidney disease

  • Management criteria are debatable; prophylactic antibiotics and monitoring for nephropathy may be advisable for higher grades of reflux (4 and 5)

  • Functional development of kidney may be affected if reflux in early embryogenesis

  • 20% of renal failure in boys with reflux due to PUV

Urine Reflux Grading

  • 5 grades depending on degree of anatomical changes in the collecting system due to reflux

    • Grade 1: Confined to ureter

    • Grade 2: Involves ureter and pelvis

    • Grade 3: More severe ureter and pelvis involvement with increased tortuosity

    • Grade 4: Grade 3 with blunting of calyces

    • Grade 5: Marked dilatation of pelvis and calyces, tortuosity of ureter

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Reflux Nephropathy

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