Reflux Nephropathy


Article Author:
Narothama Aeddula
Hassam Zulfiqar


Article Editor:
Krishna Baradhi


Editors In Chief:
Laurie Graham
Andrew Wilt
Mary Cataletto


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/24/2019 11:37:48 AM

Introduction

Reflux nephropathy (RN), often presenting in early adulthood with various clinical manifestations of chronic kidney disease, has pathological findings of patchy interstitial scarring, tubular atrophy, and loss of nephron mass. It is often detected during a routine evaluation in early adulthood or during pregnancy, [1]. Reflux nephropathy was previously called chronic pyelonephritis as was believed to result from childhood recurrent urinary tract infections (UTIs). It occurs in approximately 1% to 3% of children and is associated with 7% to 17% of children developing the end-stage renal disease (ESRD) across the globe.[2] RN may account for up to 10% of ESRD etiologies in adult patients.

In children, RN can be acquired or congenital. Acquired UTI is more common among female children and is diagnosed mostly after febrile UTI. Whereas, the congenital RN is diagnosed during antenatally diagnosed hydronephrosis follow-up, with no prior UTI and is more common in male children.

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 the 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 FSGS, renal aplasia, hypoplasia or dysplasia an, obstructive uropathy and 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. 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 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 often exacerbated by the 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 the chronic interstitial nephritis, tubular atrophy, and renal scarring along with glomerular hypertrophy and secondary focal segmental glomerular sclerosis (FSGS).

Histopathology

Grossly the kidneys are small and irregularly contracted, with renal pelves and ureteral dilation with thickened walls. In the appropriate clinical setting, the following findings can be seen in 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 work up. 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 estimated glomerular filtration rate (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 (USG) 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 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 diagnosis.

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

Nuclear cystography can be used to prevent radiation exposure in patients with post-surgical VUR follow up. 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 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. Not practical for use in infants and children, moreover cost is a hindrance.

Renal biopsy aids in both diagnosis and for 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, two 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 aggressive management of 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 UTI's, there was no significant difference in posttransplantation complications or patient and graft survival rates between RN patients compared with the control group.[14]

Differential Diagnosis

Chronic pyelonephritis with gross findings of the kidney usually distinguishing 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.

Consultations

  • Pediatrics
  • Pediatric urology
  • Pediatric nephrology
  • Nephrology (adult)
  • Infectious disease
  • Obstetrics

Pearls and Other Issues

  • Reflux nephropathy (RN) is a relatively common condition and is usually asymptomatic but often presents in early adulthood and women of childbearing age.
  • RN is a direct consequence of abnormal retrograde flow of urine from the bladder into one or both the ureters lead to vesicoureteral reflux (VUR).
  • Reflux nephropathy is the second most common cause of chronic tubulointerstitial disease and fourth common cause of ESRD in children.
  • Patients present with signs and symptoms of chronic kidney disease and hypertension.
  • Pregnant females with RN may have accelerated hypertension, renal impairment and might lead to maternofetal comorbidities.
  • Early diagnosis and appropriate management of reflux nephropathy are important for preserving the renal function.
  • The mainstay of treatment is the prevention and management of hypertension and chronic kidney disease.
  • Various modalities of RRT can be used, but renal transplantation offers better long-term outcomes.

Enhancing Healthcare Team Outcomes

Close coordination is required between obstetricians and nephrologists in pregnant females with high suspicion of RN, for early diagnosis, treatment or prevention of maternal-fetal comorbidities. A coordinated effort between obstetrician and neonatologist is needed to prevent renal damage, as early diagnosis and treatment of VUR are necessary before the neonate develops a UTI. It might be beneficial to offer to screen to infants whose father has VUR.


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Reflux Nephropathy - Questions

Take a quiz of the questions on this article.

Take Quiz
Which of the following is a complication of reflux nephropathy?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which is the criterion standard test for diagnosing reflux nephropathy?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
According to the landmark Randomized Intervention of Children with Vesicoureteral Reflux (RIVUR) trial, antimicrobial prophylaxis after the first episode of a urinary tract infection (UTI) in patients with vesicoureteral reflux does which of the following?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the most common complication of reflux nephropathy that has a significant bearing on the long-term renal outcome?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the most common glomerular lesion in patients with reflux nephropathy (RN)?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 22-year-old male with a history of stage 3 chronic kidney disease (CKD) secondary to reflux nephropathy is referred to a local nephrologist's office for routine CKD management. He had surgical correction of vesicoureteral reflux as an adolescent. The physical exam and vital signs are unremarkable. Laboratory evaluation is notable for a creatinine of 1.7 mg/dL, estimated glomerular filtration rate (eGFR) 56 mL/min/1.73 m2, BUN 28, sodium 136 mEq/L, bicarbonate 18 mEq/L, chloride 102 mEq/L, potassium 3.3 mEq/L, serum albumin of 3.4 grams/dL, calcium 8.4 mg/dL, and phosphate 5.2 mg/dL. His medications include ramipril, omeprazole, and calcium carbonate. What is the most likely etiology for his metabolic acidosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 15-year-old female was evaluated for recurrent urinary tract infections (UTIs) and diagnosed with vesicoureteral reflux (VUR) from the posterior urethral valves. At today's visit, you determine that prophylactic antibiotics have not prevented the recurrent UTIs. She has no complaints except ongoing constipation. The clinical examination is notable for a body mass index of 28 and a blood pressure of 124/76 mmHg. Her laboratory workup is notable for a serum creatinine of 1.2 mg/dL and estimated glomerular filtration rate (eGFR) of 66 mL/min/1.73 m2. A urinalysis shows 2+ protein, three white blood cells, and one red blood cell. Her current medications are lisinopril, sulfamethoxazole/trimethoprim, and inhaled albuterol. Apart from considering surgical intervention for the VUR, which of the following is the best next management option?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Reflux Nephropathy - References

References

Diamond DA,Mattoo TK, Endoscopic treatment of primary vesicoureteral reflux. The New England journal of medicine. 2012 Mar 29     [PubMed]
Mor Y,Leibovitch I,Zalts R,Lotan D,Jonas P,Ramon J, Analysis of the long-term outcome of surgically corrected vesico-ureteric reflux. BJU international. 2003 Jul     [PubMed]
Köhler JR,Tencer J,Thysell H,Forsberg L,Hellström M, Long-term effects of reflux nephropathy on blood pressure and renal function in adults. Nephron. Clinical practice. 2003 Jan     [PubMed]
Phelan ST, Renal disease in pregnancy ambulatory issues. Clinical obstetrics and gynecology. 2012 Sep     [PubMed]
Smellie JM,Prescod NP,Shaw PJ,Risdon RA,Bryant TN, Childhood reflux and urinary infection: a follow-up of 10-41 years in 226 adults. Pediatric nephrology (Berlin, Germany). 1998 Nov     [PubMed]
Morita M,Yoshiara S,White RH,Raafat F, The glomerular changes in children with reflux nephropathy. The Journal of pathology. 1990 Nov     [PubMed]
Roihuvuo-Leskinen H,Lahdes-Vasama T,Niskanen K,Rönnholm K, The association of adult kidney size with childhood vesicoureteral reflux. Pediatric nephrology (Berlin, Germany). 2013 Jan     [PubMed]
Lavocat MP,Granjon D,Allard D,Gay C,Freycon MT,Dubois F, Imaging of pyelonephritis. Pediatric radiology. 1997 Feb     [PubMed]
Torres VE,Velosa JA,Holley KE,Kelalis PP,Stickler GB,Kurtz SB, The progression of vesicoureteral reflux nephropathy. Annals of internal medicine. 1980 Jun     [PubMed]
Elder JS,Peters CA,Arant BS Jr,Ewalt DH,Hawtrey CE,Hurwitz RS,Parrott TS,Snyder HM 3rd,Weiss RA,Woolf SH,Hasselblad V, Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. The Journal of urology. 1997 May     [PubMed]
Lahdes-Vasama T,Niskanen K,Rönnholm K, Outcome of kidneys in patients treated for vesicoureteral reflux (VUR) during childhood. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2006 Sep     [PubMed]
Hollowell JG, Outcome of pregnancy in women with a history of vesico-ureteric reflux. BJU international. 2008 Sep     [PubMed]
Zucchelli P,Gaggi R, Reflux nephropathy in adults. Nephron. 1991     [PubMed]
Jungers P, Reflux nephropathy and pregnancy. Bailliere's clinical obstetrics and gynaecology. 1994 Jun     [PubMed]
Scott JE,Swallow V,Coulthard MG,Lambert HJ,Lee RE, Screening of newborn babies for familial ureteric reflux. Lancet (London, England). 1997 Aug 9     [PubMed]
Deleau J,Andre JL,Briancon S,Musse JP, Chronic renal failure in children: an epidemiological survey in Lorraine (France) 1975-1990. Pediatric nephrology (Berlin, Germany). 1994 Aug     [PubMed]
Hodson EM,Wheeler DM,Vimalchandra D,Smith GH,Craig JC, Interventions for primary vesicoureteric reflux. The Cochrane database of systematic reviews. 2007 Jul 18     [PubMed]
Yazici H,Caliskan Y,Ozturk S,Ozkan O,Turkmen A,Sever MS, Outcome of kidney transplantation following end-stage renal disease due to reflux nephropathy. Transplantation proceedings. 2011 Jun     [PubMed]
Mattoo TK, Vesicoureteral reflux and reflux nephropathy. Advances in chronic kidney disease. 2011 Sep     [PubMed]
Baradhi KM,Abuelo GJ, Unilateral renal cystic disease. Kidney international. 2012 Jan     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of NP-Pediatric Primary Care. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for NP-Pediatric Primary Care, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in NP-Pediatric Primary Care, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of NP-Pediatric Primary Care. When it is time for the NP-Pediatric Primary Care board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study NP-Pediatric Primary Care.