Reflux Nephropathy

Secondary By A. Najmaldin,

to Intrauterine

Vesicoureteric

Reflux

D.M. Burge, and J.D. Atwell

Southamp ton, England 0 In 107 infants with 182 antenatally diagnosed urinary tract anomalies, 24 had either unilateral (12) or bilateral (12) vesicoureteric reflux (VURJ. The VUR was more common in boys (male to female ratio, 18:s) and usually severe (grades IV [18], Ill [lo], II [4], and I [S]j. Intravenous pyelography showed the changes of atrophic pyelonephritis in 10 refluxing units, and in another two with an associated peiviureteric junctional hydronephrosis. Lateral ectopia of the ureteric orifices was noted in six of these 10 refluxing renal units. Isotopic renography showed a reduction in function in nine of the 14 patients examined, ranging between 9% and 41%. (45% and above was considered within the normal range). Only two patients developed a urinary infection before intravenous pyelography or isotopic renography was performed, suggesting that renal changes noted were primary rather than secondary. Findings support the hypothesis that foetal VUR may be a contributing factor in the causation of atrophic pyelonephritis (foetal reflux nephropathyj observed in these patients. 0 1990 by W.B. Saunders Company. INDEX WORDS: Foetal vesicoureteric reflux; foetal reflux nephropathy: atrophic pyelonephritis; renal dysplasia: renal hypoplasia.

T

HE ORIGIN of reflux nephropathy continues to be a controversial topic. The extent to which urinary infection, genetic factors, and the pressure effects of sterile reflux on a developing kidney interact is debatable. Early diagnosis of urinary anomalies by antenatal sonography has provided an opportunity to study the effects of vesicoureteric rellux (VUR) in the absence of urinary infection in the clinical situation. We have studied 24 patients with evidence of foetal VUR, and present our findings, which support the hypothesis that renal hypoplasia and dysplasia may be a secondary effect’ of intrauterine reflux. MATERIALS AND METHODS

An analysis of 107 consecutive infants with 182 antenataily diagnosed urinary tract anomalies, of whom 24 infants had VUR (36 refluxing renal units) was undertaken. These patients had full urological investigations, including intravenous pyelography (IVP) (24) micturating cystography (24), cystoscopy (16), and isotope renography (14). These patients were given prophylactic chemotherapy following delivery in order to reduce the risks of developing a urinary infection while being investigated. RESULTS

Clinical data on the 24 infants having foetal VUR are given in Table 1. Micturating Cystography

Micturating cystography was performed at a mean age of 7 weeks (range, 1 to 23 weeks). The VUR was Journalof

Pediatric Surgery, Vd 25, No 4 (April), 1990: pp 387-390

bilateral (12) or unilateral (12) and boys predominated (male-female ratio, 16:8). The grades of VUR2 were usually severe; grade IV (16), grade III (lo), grade II (4) and grade I (6) ie, 26 of the 36 refluxing renal units had either grade III or IV VUR. Antenatal upper tract dilatation was seen in 2 1 of the 36 refluxing renal units. The remainder were diagnosed following early postnatal investigations for contralateral dilatation or other urological anomalies. The more severe the VUR, the greater the chance of finding upper tract dilatation. Intravenous Pyelography

IVP was performed at a mean age of 4.5 weeks (range, 4 days to 8 weeks). In 13 patients the IVP was normal. The abnormalities observed included atrophic changes (Fig 1) in 10 kidneys of seven patients. Another two patients had atrophy due to an associated pelviureteric junctional (PUJ) hydronephrosis. Two further patients had renal dysplasia (Fig 2), the second of whom had a septicaemic episode at 3 weeks of age. However, blood cultures, examination of the CSF, and urine were negative, but may have been modified by previously administered antibiotic treatment. In the 10 kidneys observed with atrophic changes, ie, blunting of the pelvicalyceal system and loss of a uniform amount of renal substance but no focal scarring, the degree of VUR ranged from grade IV (7) to grade III (3), and was severe. The pyelographic appearances were normal in eight other kidneys associated with grade IV VUR. Isotopic Renography

In 14 patients, isotopic renography confirmed the loss of functioning renal parenchyma in nine patients and ranged from 9% to 41%. A level of 45% + 5% was considered to be within the normal range. In patients 3, 4, 5, 10, and 16, the reduction in renal function was associated with grade IV VUR, but contralateral grades of VUR were present (grade IV in three, and grade III in two). In patients I7 and 18, reduction in

From the Wessex Regional Centre for Paediatric Surgery, Southampton, England. Presented at the 36th Annual Congress of the British Association of Paediatric Surgeons, Nottingham. England, July 19-21, 1989. Address reprint requests to J.D. Atwell. FRCS. The General Hospital. Tremona Rd. Southampton SO9 IDH, England. 8 1990 by W.B. Saunders Company. 0022-3468/90/2504-0002$03.00/O

387

388

NAJMALDIN,

BURGE, AND ATWELL

Table 1. Clinical Data on the 24 Patients With Vesicoureteric Reflux Vesicoureteric Patient No.

Bilat

IVP

Grade

Unilat of Sex

Refiux Atrophic

R

L

Changes

Ureteric Orifices R

L

Renogrem

-

Associated

Urinary Infection

Anomalies

Prior to Investigations

-

1

M

Bilat

IV

IV

Atrophy

2

M

Unilat

IV

-

NAD

A/O 0l2

Al0 -

3

M

Bilat

IV

IV

Atrophy (R & L)

Cl3

DPTA L 40%

4

M

Bilat

IV

IV

Atrophy (R & L)

Cl3

Cl3 Cl3

DPTA R 27%

-

E coliat 3152

5

F

Bilat

IV

IV

Atrophy (L)

Cl3

Cl3

DPTAL41%

-

None

8

F

Unilat

-

-

Cl3

DPTA, DMSA L 55%.

(RI

None

Cystic dysplasia (Ll -

None None IVP et 5152

I

PUJ (L)

PUJ iL)

None

Cystic dysplasia (R) -

None

no scars 7

M

Bilat

I

I

8

F

Bilat

Ill

IV

NAD

B/l -

9

M

Bilat

II

I

NAD

-

10

M

Bilat

IV

Ill

Shrunken dysplastic?

11

F

Bilat

IV

Ill

Atrophy (R & L)

12

F

Unilat

II

-

NAD

13

F

Unilat

IV

-

NAD

14

M

Unilat

Ill

-

Atrophy (RI

15

F

Unilat

-

16

M

Bilat

17

M

Unilat

Cystic dysplasia (RI

Wl -

DPTA R 9%

012

B/2

B/O Cl1

WO -

DPTA? normal -

None

DPTA R 24%

-

Septicaemia at 3152

DPTA L 45% -

-

None

IVP at 7152

(RI

-

Cl3

I

NAD

-

Ill

IV

NAD

-

II

-

NAD

Cl3 All

B/2

Cystic dysplasia (L)

None

Cystic dysplasia (L) -

None None

DPTA L 35%

Renal agenesis (RI -

DPTA, DMSA R 34%,

Double ureters, ec-

None

-

no scars 18

F

Unilat

III

-

Atrophy (RI

Al0

-

DPTA, DMSA R 27%. no scars

19

M

Bilat

Ill

PUJ (L)

012

20

M

Unilat

Ill

-

NAD

21

M

Unilat

Ill

-

NAD

A/O -

22

M

Unilat

II

-

NAD

-

23

M

Unilat

-

Ill

NAD

-

24

M

Bilat

IV

IV

NAD

-

I

None

-

812 -

None None

topic uretewxele (L) Double ureters, ec-

None

topic ureterocele (L)

DPTA L 18%

PUJ (L)

None

DPTA, DMSA normal -

Megaureter (L) -

None

DPTA normal -

PUJ (L)

None

-

None

-

None

-

None

Abbreviations: Unilat, unilateral, Bilat, bilateral: R, right; L, left; IVP, intravenous pyelography; PIJJ, pelviureteric

junction;

DPTA,

997~

diethylene

triamine pentaacetic acid; DMSA, dimercaptosuccinic acid.

function to 34% was noted with grade II VUR, and 27% with grade III VUR. The most severe reductions in function (patients 7 and 19) were observed in association with cystic dysplasia (9%) and an associated PUJ hydronephrosis (18%); the latter patient had grade III VUR, and the former had grade I VUR.

were ipsilateral in three (PUJ hydronephrosis (2), renal dysplasia (l)), and contralateral in eight (PUJ hydronephrosis (1 ), renal agenesis (l), obstructed megaureter (l), cystic dysplasia (3), and double ureters with associated ureteroceles (2)).

Cystoscopy

Renal parenchymal changes in infants and children who have VUR may be due either to infection producing chronic pyelonephritis, or the renal syndrome of hypoplasia and dysplasia. These two factors often coexist, which makes histological interpretation of excised specimens difficult. In the experimental animal, VUR without infection has been shown to cause renal parenchymal damage.4 The advent of antenatal ultrasonography, which allows the diagnosis of upper and lower urinary tract dilatation in the foetus, has led to urological investigations in the newborn before the complications and sequelae of infection have become evident. In this series of newborns and infants, 10 renal units had atrophic changes with flattening of the renal papillae

Cystoscopy was performed in 16 patients, and the position and configuration of the ureteric orifices was described.3 Severe lateral ectopia with gaping ureteric orifices was seen in five patients (nine renal units), all of whom had renal atrophy, although in one patient it was also associated with a PUJ hydronephrosis (patient 6). Grade III and IV VUR was noted with normal ureteric orifices (patients 1, 18, and 20). Associated Anomalies

Associated anomalies were common. Nonurological anomalies were found in two patients (Turners X0 Syndrome (l), and a ventricular septal defect (1)). Eleven patients had other urological anomalies, which

DISCUSSION

FOETAL VUR AN0

NEPHROPATHY

389

Fig 1. (A) IVP in patient 1, showing marked atrophic changes on the right. The VUR was bilateral grade IV. (B) IVP in patient 4, showing marked atrophic changes on the right. The VUR was bileteral grade IV.

and uniform loss of renal parenchyma (patients 1,3,4, 5, 11, 14, and 18). In these cases, the renal outlines were smooth, which differs from the focal scarring seen in chronic pyelonephritis (reflux nephropathy). In two other patients, the uniform blunting of the renal papillae could be due to PUJ hydronephrosis associated with VUR (patients 6 and 19). It is possible that urinary infection could have been responsible for the changes seen in two other patients

Fig 2. IVP *howing dysplastic right kidney in patient 10, who had bilateral VUR, grade IV on the right and grade III on the left.

(patients 4 and 10). In the former, an E coli urinary infection was diagnosed at 2 weeks of age; it was treated promptly, but an IVP at 5 weeks of age showed bilateral atrophic changes, and on renography, a reduction of function to 27% on the right. In the other patient, a septicaemic episode occurred at 3 weeks of age and an infection screen showed that blood cultures and examination of the cerebral spinal fluid and urine were negative. The IVP and 99mT~diethylene triamine pentaacetic acid renogram at 7 weeks of age showed a shrunken dysplastic kidney (Fig 2), and on renography this kidney contributed 24% of total renal function. Even so, it seems likely that even in these two patients, the short time between the infection and urological investigations would be insufficient to account for the observable changes, thus supporting the concept of foetal VUR being a cause of these changes. Renal dysplasia has a close relationship to obstruction in the urinary tract, and in one large review it was seen in 47 of 49 specimens examined.’ It is possible that VUR occurring during intrauterine life (foetal reflux) may produce parenchymal changes, as a patient with VUR has in effect intermittent obstruction. The back pressure effects on the developing renal tissue may lead to the changes of reflux nephropathy (foetal reflux nephropathy). The extreme example of renal dysplasia is observed in patients with a multicystic kidney with an atretic ureter at the level of the pelviureteric junction; other examples include the cystic dysplasia found in the upper moiety of a duplex pelvicalyceal collecting system with an ectopic ureterocele (patients 17 and 18). The timing of the onset of foetal VUR during intrauterine life may be relevant; the earlier the onset the greater the effect. Other authors have related the high incidence of renal dysplasia to the ectopic position of the ureteral orifices, whether proximal or distal.6 In this series, severe

390

NAJMALDIN,

lateral ectopia was noted in five patients (patients 3,4, 5,6, and 14) and affected nine renal units, all of whom had signs of renal atrophy, although in one patient (6) PUJ hydronephrosis coexisted. In three patients, severe VUR was noted with normally sited ureteric orifices (patients 1, 18, and 20) and in one patient (20) the pyelographic appearances were normal. In patients with double ureters, ectopic ureteroceles, and VUR, the upper and lower moieties are subjected to variable degrees of obstruction; severe with ureterocele, and intermittent and less severe with VUR. Supporting this concept is the report that in seven ectopic ureteroceles, six had severe dysplasia (85%) and in nine refluxing lower units, three had severe and three had mild dysplasia (66%).7 Pyelonephritic changes were observed only in one upper moiety (14%), but in four of nine refluxing units (44%). In the experimental animal it has been shown that obstruction to the foetal kidney late in gestation results in hydronephrosis, whereas if the obstruction occurs in the first half of gestation renal dysplasia occurs.’ We have noted this finding in two others with antenatally diagnosed upper tract dilatation. There was a multicystic kidney and an associated contralateral PUJ hydronephrosis. These findings suggest that anomalies of the ureteric bud are more likely to result in renal dysplasia,

BURGE, AND ATWELL

rather than primary conditions affecting the metanephric blastema. Anomalies of the ureteric bud are influenced by genetic factors, eg, duplex pelvicalyceal collecting system, VUR, paraureteric diverticula, and PUJ hydronephrosis.’ However, complete unilateral renal dysplasias are seen in hereditary and familial dysplasias, such as the Meckel-Gruber and the DandyWalker syndromes, Jeunes thoracic dystrophy, oculocerebral maldevelopment of Zellweger, Laurence-Moon Biedl, and Ivemark Syndromes7 In conclusion, this series of clinical patients with presumed intrauterine reflux (foetal reflux) has evidence of primary atrophic pyelonephritis and/or renal dysplasia (foetal reflux nephropathy). These changes are associated with a loss of functioning renal parenchyma. Such patients are particularly prone to develop urinary infections” and the use of prophylactic chemotherapy is important so that full urological investigations can be carried out safely, and to ensure that the patients remain free of infection and its harmful sequelae. ACKNOWLEDGMENT We thank the staff of the Department of Medical Illustration, University of Southampton, for their assistance with Figs 1 and 2.

REFERENCES 1. Ambrose SS, Parrott TS, Woodard JR, et al: Observations on the small kidney associated with vesicoureteral reflux. J Urol 123:349-351, 1980 2. Smellie JM: Medical aspects of urinary infection in children. J R Cob Physicians, Lond 1:189-196.1967 3. Lyon RP, Marshall S, Tanagho EA: The ureteral orifice: Its configuration and competency. J Urol 102:504-509,1969 4. Hodson CJ, Maling TMJ, McManamon PH, et al: Pathogenesis of reflux nephropathy. Br J Radio1 l-26, 1975 (suppl 13) 5. Risdon RA, Young LW, Chrispin AR: Renal hypoplasia and dysplasia: A radiological and pathological correlation. Pediatr Radial 3:213-225, 1975

6. Mackie GG, Stephens FD: Duplex kidneys: A correlation of renal dysplasia with the position of the ureteral orifice. J UroI 114:274-280, 1975 7. Gartell PC, MacIver AG, Atwell JD: Renal dysplasia and duplex kidneys. Eur Urol9:65-68, 1983 8. Beck AD: The effect of intrauterine urinary obstruction upon the development of the foetal kidney. J Urol 105:784-789, 1971 9. Atwell JD: Familial pelviureteric junctional hydronephrosis and its association with a duplex pelvicalyceal system and vesicoureteric reflux: A family study. Br J Urol57:365-369, 1985 10. Ericsson NO: The small kidney. Prog Pediatr Surg 1:89-98, 1970