OVERVIEW
Reflux nephropathy is a form of interstitial nephropathy characterized by irregular coarse scarring of the renal surface, hypertrophy and dilatation of the affected calyces, atrophy and regression of the affected cortex, and vesicoureteral reflux (VUR), which was formerly known as “chronic atrophic pyelonephritis”. Vesicoureteral reflux may not be clear or may have disappeared by the time scarring is detected, and some cases are characterized by recurrent urinary tract infections (UTIs). Renal damage can be limited or diffuse, depending on the extent of scarring.
Etiology
The cause of reflux nephropathy is vesicoureteral reflux. Vesicoureteral reflux is the reflux of urine through an unsound vesicoureteral junction. Physiologically, the anatomical integrity of the flap mechanism in the last segment of the ureter prevents this reflux. This flap mechanism consists of an oblique passage of the ureter through the bladder wall; specialized muscular tissue of the ureteral wall; and a mucosal flap at the ureteral orifice. Alterations in the anatomic and functional integrity of the aforementioned flap mechanisms will result in either primary or secondary vesicoureteral reflux.
1. Primary vesicoureteral reflux
Primary vesicoureteral reflux is the most common clinical condition. It is most common in pediatric patients. For the bladder submucosal ureter segment of congenital anomalies, such as congenital bladder submucosal ureter is too short, bladder deltoid muscle tissue dysplasia. As the child grows, the base of the bladder is well developed, and most of the reflux will disappear.
2. Secondary vesicoureteral reflux
Secondary vesicoureteral reflux can be secondary to bladder neck or urethral obstruction (bladder hypertension), neurogenic bladder (bladder muscle weakness), bladder tuberculosis, and after bladder surgery (which causes injury to the ureter) due to various reasons.
3. Grading of vesicoureteral reflux
The grading criteria for the degree of reflux proposed by the International Pediatric Vesicoureteral Reflux Study Group are still widely accepted:
(1) Grade I. Only the ureter is involved.
(2) Grade II Involvement of the ureter and renal pelvis, with no dilatation of the renal calyces and normal calyceal domes.
(3) Grade III The ureter is mildly to moderately dilated and/or curved, the renal pelvis is mildly to moderately dilated, and the dome is absent or only slightly blunted.
(4) Grade IV Moderate dilatation and/or curvature of the ureter, moderate dilatation of the renal pelvis and calyces, disappearance of the acute angle of the dome, but most of the calyx papillae are present.
(5) Grade V Severe dilatation and curvature of the ureter and renal pelvis and calyces, with loss of most of the calyceal papillae.
Symptoms
Clinical manifestations of reflux nephropathy vary. The number of episodes of urinary tract infection and the severity of symptoms are not related to the degree of reflux or the degree of renal scarring, and severe reflux may be present in cases with a history of only one infection. The first urinary tract infection in a child should be investigated regardless of age, gender, and symptom severity. Pediatric patients often present under 4 years of age with recurrent urinary tract infections. Those with medical conditions are mostly young and middle-aged females, and tend to present with unilateral renal atrophy, renal failure, symptoms of urinary tract infections, and hypertension.
The most common clinical manifestations of reflux nephropathy are urinary tract infections and coeliac abdominal pain that mostly occurs during urination. The incidence of urinary tract infection is 63% to 88%; the incidence of proteinuria is 34.5% to 54.7%, which can also be the first symptom of reflux nephropathy, as it often appears after several years of severe scarring, suggesting that vesicoureteral reflux has led to glomerulopathy, which is a poor prognostic indicator. Even if vesicoureteral reflux disappears after surgery, renal function continues to deteriorate. The disease is also characterized by latency, often first detected in pregnancy due to urinary tract infection, proteinuria, hypertension, preeclampsia, or renal failure. Individuals occasionally undergo imaging for other reasons, and the diagnosis of the disease is taken into account by the detection of scarring or atrophy of one or both kidneys or by the finding of asymptomatic bacteriuria. In some cases, the disease may remain asymptomatic for a long period of time and not be diagnosed until renal insufficiency enters the uremic phase.
Hypertension is common in the course of reflux nephropathy and is present in 75% of patients starting dialysis. Hypertension can also occur several years after successful antireflux surgery. The severity of hypertension does not correlate significantly with the degree of reflux or the degree of urinary tract obstruction. The clinical incidence of hypertension ranges from 10.6% to 38.1% and is a common late complication of reflux nephropathy; gestational hypertension (hyperemesis gravidarum) can be the first symptom of reflux nephropathy. About 4% of patients with severe hyperemesis gravidarum have reflux nephropathy; they may have nocturia, polyuria, and abnormal urinary concentrating function; 10.2% to 50% of reflux nephropathy can lead to renal failure, which usually occurs at the age of less than 35 years. About half of the cases have pre-existing azotemia at the time of presentation. Renal failure in unilateral reflux nephropathy is due to concomitant glomerulopathy in both kidneys. The disease may also be associated with a history of enuresis (4% to 20%), kidney stones (2.2% to 18%), and microscopic or gross hematuria.
Examination
1. Laboratory examination
(1) Urine examination In case of urinary tract infection, leukocyturia or pyuria can be seen in sediment examination, and urine bacterial culture is positive; leukocytes, erythrocyte tubular pattern and renal tubular proteinuria, microscopic hematuria, urine specific gravity and urine osmolality are seen in the urine, and renal damage such as obvious decrease of urine specific gravity and urine osmolality, and elevation of urinary NAG enzyme and urinary β2-MG. Decreased concentration function and β2-microglobulin reabsorption suggest that tubular function is impaired, and proteinuria of more than 1 g/day suggests that the disease is secondary to focal segmental glomerulosclerosis.
(2) Blood test can show systemic infectious symptoms such as increased blood leukocytes and left shift of nucleus, positive Tamm-Hosfall antibody, elevated IgG, azotemia and elevated creatinine level in acute renal failure, and hypernatremia when concentrating capacity decreases.
2. Other auxiliary examinations
(1) Renal biopsy The pathological changes in typical cases of this disease are mainly cortical papillary scar formation, dilatation and torsion of renal calyces, with the lesions being most prominent in the lower and upper pole of the kidney, which may be unilateral or bilateral, and the kidneys may be reduced to different degrees, or may be extremely atrophic. If a large amount of reflux continues to exist, the ureter can be seen to be dilated and curved.
(2) histological examination, reflux nephropathy renal histological damage is actually not significantly different from chronic pyelonephritis, can be seen lymphocyte infiltration, interstitial fibrosis, tubular degenerative changes, atrophic tubules often have a gelatinous tubular pattern, some of them are cystic dilatation of the tubules, glomerular vitreous or disappearance of the glomeruli, small arteries and interlobular arteries are blocked due to contraction and intimal thickening, some cases can be seen in the outer medullary band and cortex containing Tamm- Horsfall protein in the outer medullary zone and cortex. Such lesions are often surrounded by aggregates of lymphocytes and plasma cells. In cases with urinary tract infection, cortical atrophy is often accompanied by a severe inflammatory reaction with a radial distribution, which may extend from the damaged medulla to the entire lobule, and the affected kidney is commonly shrunken, with dilated pelvis and calyxes, thinning of the cortex, and focal scarring on the renal surface.
(3) Light microscopy and electron microscopy Light microscopy shows tubular atrophy, interstitial fibrosis, lymphocyte infiltration, and stains containing THP rounds in the cortex and outer medulla, and focal sclerosis of the glomeruli in advanced lesions, and fluorescence microscopy shows IgM, IgG, and C3 deposits in some of the glomeruli. Electron microscopy can see subendothelial electron dense deposits.
3. Imaging examination
(1) Urography The most typical change in this disease is focal cortical scarring corresponding to distorted calyces. The residual lobules may be compensatorily hypertrophied, giving a pseudotumor image. In general, the patient’s urography is typical and gives a “standard” image. The renal scarring corresponds to distorted and pestle-shaped enlarged calyces, alternating with normal cortex.
(2) Ultrasound demonstrates an irregular renal shape, with enhanced reflexes in areas of fibrous scarring and normal reflexes in areas of compensatory hypertrophy. 94% of cases have concordance between ultrasound and excretory urography findings. Ultrasound was not as sensitive as intravenous pyelography in detecting renal papillary morphology, but it was sensitive in detecting renal scarring. Intravenous pyelography is less effective.
(3) Renal scanning Renal scanning can be used as an additional tool in the diagnosis of reflux nephropathy. The most commonly used radionuclide is 99mTc, which has good physical properties. Three different 99mTc-labeled complexes are available for clinical use. (i) 99mTc-labeled DTPA complexes are filtered by the glomerulus with no significant retention in the renal cortex, making them particularly useful for evaluating the function of the collecting system and for determining total and individual glomerular filtration rates. (ii) 99mTc-labeled DMSA is slowly excreted with urine and gradually and slowly accumulates in the functional renal cortex. DMSA scanning defects reflect hypoperfusion at the site due to ischemic damage or reduced radionuclide excretion from the proximal tubules at the site of damage. (iii) 99mTc-labeled glucosinolates have the advantages of the above two: most of them are excreted into the pyelonephric system, but some of them are retained in the renal cortex, and the delayed visualization of 2-3h after injection is particularly advantageous for the detection of acute pyelonephritis as well as cortical scarring, but it is not as effective as intraventricular pyelography in the diagnosis of mild calyceal anomalies.
(4) X-ray voiding cystourethrography (VCUG) VCUG is a traditional method of examining reflux and is valuable in the diagnosis of abnormalities of the urethra and bladder wall as well as in the precise grading of reflux; however, it is invasive and painful and may introduce bacteria into the urethra, and the use of digital subtraction in voiding cystourethrography has increased the sensitivity and precision of diagnosing reflux.
(5) Radionuclide cystography Radionuclide cystography was developed from VCUG, and its radiation dose in the gonads is very low, and it has become one of the optional examination methods in many children’s hospitals abroad. Comparing nuclide cystography and radiologic x-ray voiding cystourethrography (VCUG), the former is now considered the most effective method to screen for reflux and to judge surgical results, with the advantages of low radiation dose; high sensitivity; and the ability to obtain data parameters that cannot be obtained by VCUG, such as residual volume, reflux flow rate, and bladder volume during reflux. The disadvantages of nuclear cystography include the inability to evaluate the condition of the urethra; the inability to grade according to international grading standards; and the inability to show minor bladder wall abnormalities such as small diverticula. The indications for nuclear cystography are as follows: ① Follow-up examination of reflux patients undergoing medical treatment or after surgery. ② Screening of asymptomatic siblings of children with reflux. ③Systematic examination of children susceptible to vesicoureteral reflux (e.g., spinal cord bulge or other functional bladder diseases). (iv) Initial screening of female children with UTI.
(6) Computed tomography (CT) is more accurate in detecting renal cortical scarring, but is more expensive.
Diagnosis
1. Changes on high-dose intravenous pyelography and X-ray tomography
(1) Pestle-like deformity of the kidney and adjacent cortical scarring.
(2) Thinning of the renal cortex, which often occurs unilaterally or bilaterally at both poles of the kidney, with a reduction in renal volume or morphological disproportionality (1.5 cm difference in length between the two kidneys).
(3) Dilatation of the renal pelvis and renal calyces ureter without organic obstruction.
2. Vesicoureteral reflux may be found to varying degrees, but may be absent in about half of adult cases.
3. Rule out secondary vesicoureteral reflux, which is often bilateral in this case.
Treatment
1. Prevention and treatment of urinary tract infection
Regular emptying of the bladder, the most important thing is to urinate twice (the second time within 5 minutes); long course of low-dose bacteriostatic therapy is the most commonly used treatment, every night before bedtime after urination, take sulfamethoxazole/metronidazole (cotrimoxazole) half a tablet for 6 months and then stop observing the drug, if urinary tract infections recur, then restart the treatment, the course of treatment for 1 to 2 years, the person who is allergic to sulfonamides can be used alone with methicarbamol (methicarbazide). Quinolones can also be used, such as ofloxacin (fluorozine acid).
2. Prevention of dehydration
Adequate water should be taken in. Because this patient can not excrete concentrated urine, so, clinically, it is easy to dehydration; in addition, drinking more water can reduce the hypertonic state of renal medulla, which is conducive to the control of infection.
Prognosis
Studies have shown that the prognosis of reflux nephropathy is significantly related to proteinuria, focal segmental glomerulosclerosis and progressive renal decompensation. The degree of proteinuria correlates very significantly with the presence and extent of glomerular injury. Progressive glomerulosclerosis is the most important determinant of the development of chronic renal failure in reflux nephropathy.
Prevention
Reflux nephropathy is a disease caused by multiple etiologic factors, prevention should start from the prevention and treatment of primary diseases, for the diseases that are prone to cause reflux, should be carefully examined, clearly diagnosed and actively treated symptomatically, in order to prevent the occurrence and progressive aggravation of reflux nephropathy.