Segmental “hypoplasia” of the kidney (Ask-Upmark)

December 1979 The Journal o f P E D I A T R I C S

931

Segmental "'hypoplasia'"of the kidney (Ask- Upmark) Severe segmental renal atrophy with loss of parenchymal elements in small kidneys is commonly known as segmental hypoplasia. The scars are seen as cortical depressions overlying shrunken medullary pyramids and their dilated calyces, and are characterized histologically by colloid-filled tubular microcTsts and a paucity or absence of glomeruli. This lesion has been identified in 1 7 patients, 11 female and 6 male, between 6 and 23 years of age. Eleven patients had hypertension, which developed in six while they were under observation. Thirteen had histories of urinary tract infection, and 16 had evidence of vesicoureteric reflux. Seven patients had impaired renal function (GFR <40 ml/minute/1.73 mS). Abnormal metanephric differentiation (dysplasia) in two specimens, one in association with posterior urethral valves, suggested an occasional intrauterine origin of the abnormality. Twelve patients had radiographic evidence o f decreasing renal size over two to five years of observation, even after surgical correction of reflux, in .four of them unaccompanied by infection. We conclude that segmental "'hypoplasia" is an acquired lesion, although it sometimes has intrauterine origins, and that it is commonly associated with vesicou/eteric reflux, even in the absence of demonstrable infection.

Billy S. Arant, Jr., M.D.,* Ciriio Sotelo-Avila, M . D . , M e m p h i s , Tenn., and Jay Bernstein, M . D , , R o y a l O a k , M i c h .

THE PAPER by Ask-Upmark' in 1929 introduced a distinctive renal abnormality that was associated with hypertension in all but one of eight patients, the exception having had no determination of blood pressure. All but one of his eight patients were female, and the majority were adolescent. Each abnormal kidney was small, containing a decreased number of pyramids. An external circumferential groove marked the site of an elongated calyx that was covered by a very thin band of parenchyma. The attenuated cortex did not contain glomeruli, although it did contain hyperplastic vessels, epitheliallined cysts, and atrophic tubules. The segment lacked a medullary pyramid in relation to the dilated calyx, and it was sharply demarcated from adjacent normal renal tissue. Because of the smallness of the kidneys and the From the Departments of Pediatrics and Pathology, University o f Tennessee Center jor the Health Sciences and LeBonheur Children's Hospital, and the Deparmwnt of Anatomic Pathology, William Beaumont Hospital *Reprint address: 951 Court A re., 538 Dobbs Bldg., Memphis, TN 38163.

0022-3476/79/120931 +09500.90/0 9 1979 The C. V. Mosby Co.

apparently hypoplastic segment, Ask-Upmark considered the lesion to be congenital in origin. Renal microangiographic studies by kjungqvist and Lagergren -~ in specimens from two normotensive adult women with nephrolithiasis and small grooved kidneys indicated that the vascular pattern of the shrunken segment resembled that associated with nephrons of juxtamedullary type, suggesting an arrest of development. Abbreviations used GFR: glomular filtration rate PRA: plasma renin activity VUR: vesicoureteric reflux UTI: urinary tract infection PAS: periodic acid-Schiff They interpreted the findings as confirming the congenital nature of the lesion, and designated it "Ask-Upmark kidney." Batzenschlager et al a in 1962 presented a classification of small kidneys and introduced the term "aglomerular segmental hypoplasia," which they considered to represent segmental absence of glomeruli. However, other

Vol. 95, No. O, pp. 931-939

93 2

Arant, Sotelo-A vila, and Bernstein

The Journal Of Pediatrics December 1979

Fig. 1. An excretory urogram shows the right kidney to be considerably smaller than the left and to have an irregular outline. The lateral margin is indented, and an elongated calyx extends to the capsular surface (arrow). The other calyces are mildly dilated. The pelvis and ureter appear to be of normal caliber. studies demonstrated the variable presence of obsolete glomeruli within the abnormal segment. ~. ~The concept of segmental hypoplasia was developed further by the work of Habib et al? Rudiments of medullary tissue were present and occasionally contained dysplastic structures that ordinarily reflect altered embryonic development. 6 Royer et al ~considered this lesion to be an embryofetopathy resulting from an intrauterine insult to the growing kidney, and most workers have continued to regard it as congenital. The reasons for regarding the abnormality as a malformation or developmental arrest have been less than compelling, however, despite the occasional occurrence of dysplastic structures; the presence of rudimentary corticomedullary tissue in the involved segment could just as well mean that an acquired lesion resulted in severe atrophy of the affected area. 6 The etiology of the associated hypertension has not been indisputably identified. Some patients have had elevated plasma renin activity, whereas others have not. Studies of patients having both diminution of PRA and return to normal of blood pressure following nephrectomy or segmental resection of the lesion demonstrate a presumably causal relationship between the segmental lesion and the hypertension. Recent studies have shown the lesion of segmental hypoplasia to be associated with vesicoureteric reflux. The 9studies of Batzenschlager et al '~ showed the lesions to be strongly associated with ureteropelvic malformation and lithiasis. Mozziconacci et aP had easier found evidence of reflux in one of three patients, and Godard et al '~ in three of 15. Other studies 11-1' indicated that the association held with a high order of frequency. It became apparent,

Fig. 2. Selective right renal arteriogram. The area from which the segmental lesion was resected is indicated by the arrow and the microscopic appearance is shown in Fig. 5. The lobular appearance of the kidney is evidence of multiple scars with interposed hypertrophic parenchyma. A dilated calyx, identified during the study on other films, is located just above the arrow. therefore, that the problem had to be considered together with reflux nephropathy, and that a sharp distinction could not be drawn between segmental hypoplasia and the renal scarring associated with V U R and urinary tract infection. Many studies have demonstrated the relationship o f V U R a n ~ i n f e e t i o n to renal scarring and hypertension in childhood. ~7--~'-If ' a sizeable proportion of patients having a segmental lesion, with or without hypertension, also had VUR, the lesion could be more understandably explained as an acquired form of scarring with its origin in utero or at any time thereafter, and should more properly be identified as segmental renal atrophy. Jn this report we have summarized previously reported cases in which the diagnosis of segmental renal "hypoplasia" was confirmed histologically, and we present the clinical and pathologic findings in 17 new cases. Although many of these patients were young adults, the origins and determinants of the lesion run their course in early childhood.

Volume 95 Number 6 MATERIALS

Segmental "'hypoplasia" of the kidney

AND METHODS

Sixteen patients had hypoplastic kidneys with demonstrable segmental atrophy in a total or partial nephrectomy specimen, and the seventeenth had a radiographically demonstrable lesion that progressed to diffuse atrophy by the time of nephrectomy. The lesion had been shown by excretory urography following a UTI in 11 patients and by selective renal arteriography in the diagnostic evaluation of hypertension in five others; one patient presented with chronic renal insufficiency. Vesicoureteric reflux was documented by low pressure voiding cystourethrography and was graded as mild, moderate, or severe according to the classification of Rolleston et al. ~3 Hypertension was said to exist when diastolic blood pressure, measured with a cuff of an appropriate size on more than one occasion in an upper extremity, was > 2 SD above the mean pressure for the patient's age and sexs 4 Each patient was screened for evidence of UTI, and this diagnosis made o n l y after significant bacteriuria ( > 10~ organisms/ml of the same organism[s]) was found in two separately voided specimens or after bacterial growth occurred in one specimen obtained by suprapubic puncture. Glomerular filtration rate was estimated from endogenous creatinine clearance ~ in 11 patients and from the average of more than one serum creatinine determination in six. ~'~Plasma renin activity was measured by a radioimmunoassay technique in which normal supine adult values were given as 0.6 to 1.6 ng/ml/hour; values were compared to those reported for normal childrens * Radiographic studies were available in all but one patient for measurement of length, the greatest width of each pole and midportion, and the number of papillae in each kidney. Assessment of renal growth was done according to the methods of Hodson et al~; values were compared to expected renal size for body height. The gross dimensions and weights of removed kidneys were compared to normal valuesY' Kidneys that were > 2 SD below the mean for age by either method were said to be hypoplastic. Tissue was embedded in paraffin and sections stained with hematoxylin and eosin, periodic acid-Schiff, Gomori or Masson trichrome, and Verhoeff-van Gieson elastica stains. Sections of scars were evaluated and assigned an arbitrary grade (0 = negative, 1 + = mild, 2 + --- moderate, or 3 + = severe) with regard to cortical hyalinized glomeruli, tubular microcysts, chronic inflammatory cell infiltrates, and vascular sclerosis, medullary chronic inflammatory cell infiltrates and dysplastic ducts, and pelvic chronic inflammatory cell infiltrates; adjacent parenchyma was evaluated for glomerular sclerosis, tubu-

933

Table I. Summary of reported data compared to the current serie~

T

Reviewed case reports ~ Current Adults [ Children 1 series Total no. of patients 87 82 17 Female/male (ratio) 59/28(2.1) 64/18(3.5) 11/6(1.83) Location of lesion(s) Unilateral 79 38 10 Bilateral 8 44 7 Vesicoureteral reflux* 2/2 22/39 16/17 Females 1/1 19/33 10/11 Males 1/l 3/6 6/6 Urinary tract infec13/26 24/56 13/17 tion* Hypertension 53 78 1l Elevated plasma renin activity* Peripheral vein 2/3 18/30 3/7 Renal vein 0/0 15/16 3/3 *No. abnormal/tom[no. studied. lar atrophy, vascular sclerosis, and chronic inflammatory cell infiltrates, and the ureter for hypertrophy and dilatation. CLINICAL OBSERVATIONS Clinical data are summarized and compared to a survey of the literature in Table I. The initial complaints of the 17 patients were related to hypertension in 6 (35%), to urinary tract infection in 7 (41%), and to impaired renal function in 4 (24%). The age (mean _+ SD) at which the lesion was first suspected was 12.2 _+ 4.8 years (range 6 to 23 years). Females were affected nearly twice as often as males (1.8:l); however, the ratio was 5:1 in those with normal blood pressure and 1.2:1 in hypertensive patients. The F:M ratios in the cases culled from the literature were 2.1:1 in adults and 3.5:1 in children. The lesion was unilateral in 12 patients, two of whom had contralateral renal agenesis and therefore might be considered with the five others in whom lesions were identified in both kidneys. The prevalence of bilaterality was less than that reported in the literature for children, but far more than that reported for adults. lpsilateral VUR was demonstrated in all but one patient, considerably exceeding the rate of 58.5% found in the literature. Seven patients, all of them hypertensive, had severe VUR0 and six, two of them hypertensive, had mild or no reflux. Four patients with VUR had no history of UT! prior to the initial presentation and maintained a sterile urine; the rate of infection (13/17) was higher than that found in the literature. Five of 17 patients presented

934

Arant, Sotelo-Avila, and Bernstein

The Journal of Pediatrics December 1979

LEFT KIDNEY

A 3 MONTHS

B

C

D

6 YEARS

7 10/12 YEARS

11 1/12 YEARS

ILEAL BLADDER - RECURRENT INFECTIONS

RENAL LENGTH (CM) RENAL PARENCHYMA (CM2)*

VESICOURETERAL REFLUX - URINARY TRACT STERILE

5,4

7.1

8.7

8,3

16.3

17.9

16.8

9,0

*PLANAR SURFACE AREA OF TOTAL KIDNEY MINUS THE SURFACE AREA OF THE COLLECTING SYSTEM

Fig. 3. Serial tracings from excretory urograms of the renal contour and the pelvocalyceal outline of the left kidney between 3 months and 11V2years of age, when urine flow was diverted (A and B), and following unsuccessful repair of vesicoureteric reflux (C and D). The elongated calyx in the lower pole noted first in B is displaced laterally in C as renal parenchyma hypertrophied. Segmental scars noted during progressive scarring of the kidney appeared as broad scars in D, which was remarkably similar to the gross appearance of the kidney one year later.

with symptoms related to hypertension. In six others, followed from a time they were noted to be normotensive, hypertension appeared to evolve during the time that scar formation became apparent radiographically. The proportions cannot be compared with those in the literature because of differences in the ways of identifying and selecting cases. Since time is considered to be an important factor in scar formation and perhaps the pathogenesis of hypertension, it was expected that hypertensive patients would be older than normotensive ones. There was no difference, however, in the ages of patients when hypertension was first noted (12.2 _+ 3.5 years, mean _+ SD) and those of normotensive patients at the time of their nephrectomies (12.0 _+ 6.5 years). Peripheral PRA was determined in seven untreated hypertensive patients and found to be elevated in only three, a proportion little different from that found in the literature. However, renal vein PRA was increased in each of the three patients studied, one of whom had normal peripheral PRA. Regardless of the PRA, blood pressure returned to normal following nephrectomy in the five hypertensive patients with unilate~al~ lesi0ns and in three patients who had nephrectomies in preparation for renal transplantation. Four of 17 patients in this series have received renal allografts for end-stage renal disease; three others now

have severe impairment of renal function (GFR < 40 ml/minute/1.73 mS). Despite successful surgical correction of the reflux, confirmed by one or more postoperative voiding cystograms, radiographic examinations showed progressive renal scarring, parenchymal loss, and failure of subsequent renal growth in nine patients, six of whom were hypertensive and three normotensive. The urinary tract remained sterile by serial urine cultures at one- to three-month intervals in five patients, whereas four had one or more UTI. One of those presented initially at 9 years of age Nith hypertensive encephalopathy and a creatinine clearance of 37 m l / m i n u t e / 1 . 7 3 mL The hypertension was controlled by medications following successful repair of the VUR, and her urinary tract remained sterile. Renal function deteriorated during the subsequent five years; the dimensions of both kidneys not only failed to increase with body height, but each decreased in length by more than 1 cm and in width by 0.5 cm. One other child had obstructive u r o p a t h j secondary to posterior urethral valves noted at 3 weeks of age (Fig. 3). During the first seven years of life, when urine flow was diverted through an ileal conduit, an increase was observed in renal length from 6.4 to 9.6 cm on the right and 5.4 to 6.6 cm on the left, and in parenchymal planar surface area from 27.5 to 58.3 cm ~ on the right and from 16.3 to 31 cm-'

Volume 95 Number 6

Segmental "hypoplasia" o f the kidney

93 5

Table I1. Morphologic correlations

Renal hypoplasia (weight <-2 SD) Distribution of scars Bilateral Unilateral With contralateral agenesis With multiple scars Ureteropelvic dilatation Chronic inl]ammation Cortical Medullary Pelvic Arterial sclerosis Cortical scar Moderate Severe Adjacent cortex Moderate Severe Adjacent cortical atrophy Gtomerular sclerosis Tubular atrophy

Normotension 6 patients

Hypertension 11 patients

5/5

9/9

1/6 5/6 0 3 4/6

4/l 1 7/11 2 3 6/9

3/6 2/6 2/6

4/11 4/11 3/11

5/6 l/6

6/11 4/11

0/6 0/6

5/l t 0/11

0/6 1/6

3/11 4/l 1

Note: The denominatorsindicate the totals of available data.

on the left. Bilateral reimplantation of the ureters eliminated VUR on the right and the increase in renal length continued to 10.7 cm, but a decrease in renal parenchyma to 26 cm ~ occurred over the next five years. The left kidney increased in length to 8.7 cm, despite persistent V U R and a decrease in renal parenchyma to 16.8 cm 2 during the first six months following surgery; decreases in renal length !o 7.3 cm and in renal parenchyma to 7 cm -~ were observed at the time of nephrectomy five years later. During the fo!low-u p period, however, there was no clinical evidence of urinary tract infection; 22 urine cultures done at regular intervals were sterile, and none was positive. PATHOLOGIC

OBSERVATIONS

The specimens available for pathologic evaluation included three partial resections and 1l unilateral and three bilateral nephrectomies. Each of the kidneys was small, weighing < - 2 SD from the mean for age. Renal dimensions were also small, confirming the radiographic observations. The n u m b e r of pyramids occasionally appeared to be normal and occasionally reduced, but accurate counts were thwarted by scarring an d by hydronephrosis. Pyelocalyceal dilatation was present to a moderate or severe degree in nine specimens and to a mild degree in four specimens. Ureteral dilatation was

Fig. 4. Nephrectomy specimen corresponding to right kidney shown in Fig. 1, A, The kidney weighed only 55 gm ( < - 2 SD), and a deep transverse groove on the midposterior surface extended around the lateral margin. Another, more Shallow indentation lay at the lower pole, and some irregularity was present at the medial aspect of the upper pole. B, Examination of the cut surface showed calyceal elongation and dilatation in the midportion and at both poles of the hemisected kidney. In all three locations the parenchyma over the ectatic calyces was severely atrophic and attenuated, and four separate atrophic segments could beidentified. Hypertrophy of the remaining parenchyma resulted in lobar enlargement and a shift in the axis of the pyramid at the upper pole. The minimally dilated pelvis had a slightly thickened wall. absent or minimal in all but two specimens, only one exceeding 1 cm?" Ureteral muscular hypertrophy was also minimal or mild, and one ureter contained a secondary stricture. Specific identification of the "hypoplastic" segments was sometimes difficult because the scars were commonly multiple and wide. Identification of segmental hypoplasia was based on the recognition of narrow cortical grooves or depressions, beneath which the parenchyma was extremely thin (0.1 to 0.5 cm) and the underlying calyx either elongated or ectatic (Fig. 4). Nine of 14 nephrectomy specimens were thought to contain multiple discrete areas of segmental hypoplasia, and one was severely hydronephrotic with diffuse attenuation of parenchyma. The segmental scars were both polar and central in distribution, and three specimens contained scars in all three

936

Arant, Sotelo-Avila, and Bernstein

The Journal of Pediatrics December 1979

Fig. 5. Microscopic examination of the atrophic segment revealed by excretory urography in Fig. 2 showed a well demarcated segment in which both cortical and medullary remnants could be identified. The atrophic cortex contained a few tubules filled with cf?lloid casts, and glomeruli were not visible. Although the patient was hypertensive, only a few arteries were enlarged and thick walled, and arteriolar sclerosis was mild. The remnant of medulla contaned scattered ducts separated by an abundance of connective tissue. Inflammatory cell infiltrate was sparse. Partial nephrectomy specimen. (PAS stain; magnification 18 x .)

areas. Remaining lobes were often large, suggesting compensatory hypertrophy, with distortion of their usual radial arrangements; the papillae often pointed sideways or outward, rather than toward the hilum. Histopatho!ogic evaluation of the hypoplastic segments showed that a lobar remnant could be identified in all. Several specimens contained only scattered atrophic tubules without glomeruli, but a thin zone of arcuate vessels separated the fibrotic band of cortex from the fibrotic medulla (Fig. 5). The amount of recognizable metanephric tissue varied considerably, some specimens containing large numbers of colloid-filled tubular microcysts and others only few; seven specimens contained a moderate or large number of hyalinized glomeruli (Fig. 6), and in eight they were rare or lacking, despite large numbers of tubular remnants. A single specimen contained several partially patent glomeruli with clusters of tubules. Microscopic examination of the kidney that had undergone progressive hydronephrosis (Fig. 3) showed, despite radiographic evidence of early excretory function, multiple area s of complete cortical atrophy with absence of glomeruli and with only scattered tubular microcysts. Blood vessels in the scars were f f ~ e r o u s and prominent. They were crowded, indicating condensation because of loss of intervening parenchyma, and they were thick walled because of medial hypertrophy and occasional intimal proliferation (Fig. 6). Vascular necrosis and

arteriolar hyalinization Were not seen. Most specimens also contained strikingly dilated, thin-walled vascular structures that were either venous or lymphatic; they imparted a spongy histologic appearance and seldom contained red blood cells. Chronic inflammatory celi infiltration was similarly present in only modest proportions, pelvic inflammation being negligible or lacking in five specimensl Histologic evidence of abnormal metanephric differentiation (dysplasia) was present in two specimens in the form of primitive ducts at or adjacent to the area of segmental hypoplasia. Evaluation of cortical tissue adjacent to the scars showed moderate focal glomerular sclerosis in four, moderate focal t.~bular atrophy in seven, moderate arterial medial hypertrophy in six, and moderate chronic inflammatory cell infiltration in four specimens. These abnormalities frequently coexisted in the same specimen. Juxtaglomerular hyperplasia was present to a mild degree in several specimens. Attempts to do juxtaglomerular counts were thwarted by technical difficulties in doing stains (Bowie) for granules in the material available. The morphologic features did not serve to differentiate sharply between normotensive and hypertensive patients (Table II). The amount of surviving tissue, both cortical and medullary, did not seem to relate to the presence of hypertension, although hypertensive patients more often had bilateral involvement. Hypertensive patients did tend also to have more severe arterial sclerosis, occasionally

Volume 95 Number 6

Segmental "hypoplasia'" of the kidney

937

Fig. 6. The atrophic segment in a normotensive patient contained scattered colloid-filled tubular microcysts, a moderate infiltrate of chronic inflammatory cells, and many thick-walled arteries. Many sclerotic, hyal!nized glomeruli were present. In addition to arteriolar medial hypertrophy, there was mild intimal proliferation. (PAS stain: magnification 60 x .) with intimal proliferation, and to have more glomerular sclerosis, tubular atl-ophy, and arterial sclerosis in adjacent cortical tissue. The vascular and atrophic lesions are attributed to the hypertension, rather than vice yersa. There was no difference bewteen the two groups in severity of renal hypoplasia, the degree of.ureteropelvic dilatation, or degree of chronic inflammatory cell infiltration. DISCUSSION The morphologic lesion of segmental "hypoplasia" is a more or less localized atrophic scar wit h severe parenchyreal attenuation that may involve mu!tiple areas of the kidney, both central and polar. The involved areas contain elements suggesting both shrinkage and retarded growth. The underlying calyx may be either ectatic or simply elongated , and the parenchyma may have shrunken to merely a thin band of connective tissue, without grossly identifiable landmarks. Histologic examination, however, almost always reveals remnants of cortex and medulla, even when nephrons are absent and when only the arcuate vessels remain as indications of previous lobar differentiation. The characteristic lesion includes atrophic, colloid-filled tubules or tubular microcysts without glomeruli, but all variations are possible, including occasional or numerous hyalinized glomeruli. The presence of atrophic metanephr!c elements, even in the absence of recognizable glomeruli, is strong evidence against the simple pathogenetic explanation of glomert~lar agenesis, for metanephric tubules would not have formed without glomeruli. There appears, therefore, to have been a postdevelop-

mental loss of parenchymal elements. The radiographic studies also indicate retarded postnatal growth of the kidney, although hyperplastic and relatively intact lobes can be recognized among the scarred and atrophic segments. The kidney is hypoplastic, in the sense of being smaller than normal, and it is possible that examination prior to "end-stage" scarring would show smaller than normal tubules and glomeru!i in affected areas. It is also possible that nephrogenesis is arrested in the few examples that seem to have had an intrauterine Onset of the process. This process has recently been linked pathogenetically to VUR. Of the cases reported in the literature, 56% had VUR and/or obstructive uropathy whe n appropriate studies were done. The absence of VUR at the time of evaluation cannot be interpreted to mean that it was never present, since VUR is known to occur and to disappear spontaneously prior to puberty. ~~ Hodson et al :~ and Rausley and Risdon ~2 have produced a renal lesion in the pig that is similar to segmental "hypoplasia" in the human. Disagreement persists between ttie two laboratories, however, as to whether the lesion can develop without simultaneous UTI. In our series, ipsilateral VU R was demonstrated in all but one patient, in whom the first cystogram was done at the time of puberty. The primary role of infection could not be evaluated because many patients had radiographic evidence of scarring at initial examination, but four patients had neither history nor findings compatible with UTI before or when the lesion was discovered. Moreover, repair 0fthe reflux, even in the absence of infection, did not appear to interrupt the course of previously initiated scar formation, just as

938

Arant, Sotelo-Avila, and Bernstein

reported previously by Johnston and Mix,3? The ureliability of radiographic assessment of renal growth from kidney length is evident from the data on one patient given in Fig. 3. The reasons for progression of the scar are not clear. It begs the question to say simply that the lesion, having been once initiate d , continues because of vascular damage or tubular disruption. Why is the process not interrupted after removal of the cause? Autoimmune reaction to extravasated tubular protein has been suggested, but the lesion, at least in its complete form, is often lacking in inflammatory cell infiltration. The progressio n to complete parenchymal loss, after removal or alle~(iation of the inciting abnormality, may be without precedent in tissue pathology. Segmental "hypoplasia" has been said to be the most important single cause of hypertension in children/~ and there is convincing evidence that it is renin mediated. Juxtaglomerular cell hyperplasia has been described in the cortex adjacent to the segmental lesion, l~ 3~-~7 and renin granules have been indentified in the thick-walled vessels, hyalinized glomeruli and even the interstitium of the scar? ~ :~ Although PRA in peripheral blood has been abnormal in only 61% of reported and in 43% of our patients, it has been increased in renal venous blood in 94% of cases reported to date and in all of our three patients so studied. Savage et aP ~ reported that PRA in children with VUR and renal scarring may increase prior to clinical evidence of hypertension. This hypothesis is supported further by a return of blood pressure and PRA to normal following segmental resection of the single scar or removal of t h e kidney having the scar. Our studies suggest that hypertension was related neither to renal size nor to multiplicity of scars in one kidney, There was a tendency, however, for hypertension to be associated more often with bilateral scarring. If hypertension should persist following removal of the scarred kidney, it is strongly suggestive that an unidentified scar exists in the contralateral kidney. Although this lesion has been described traditionally in hypertensive patients, the prevalence of associated hypertension is unknown. The more frequent association of hypertension with segmental "hypoplasia" in children and adolescents than in adults can be explained, at least in part, by t h e fact that those patients who develop hypertension are identified earlier in life, whereas scats in individuals that remain normotensive are discovered at a later age as an incidental clinical or autopsy finding. Severe renal scarring is more often assomated with VUR in children under the age of 5 years than in adults, ~~and it is possible that the immature and growing kidney is less tolerant than the mature kidney to the effects of intrarenal reflux. It is more difficult, however, to explain why this

The Journal of Pediatrics December 1979

same lesion can be identified in kidneys of individuals who remain normotensive. The histologic features observed in our patients do not explain why some patients are hypertensive and others remain normotensive. We can only say that, in general, hypertension developed in patients having had a severe degree of reflux in addition to bilateral involvement. One distinct possibility that has yet to be investigated is the altered biosynthesis of prostaglandins in the area of the scar. The recognition that VUR is present in a large proportion of patients strengthens the argument that segmental hypoplasia is an acquired lesion, although the finding of abnormal metanephric differentiation (dysplasia) in a few specimens suggests that VUR may have been present and may have initiated the process in fetal life. The association of segmental hypopiasia with VUR does mean, however, that it is, in a sense, part of the spectrum of "reflux nephropathy," which is well known to be a cause of hypertension and renal failure in childhood. The importance of segmental hypoplasia itself then needs to be critically evaluated both in regard to its frequency in "reflux nephropathy" and in regard to the pathogenesis of hypertension. Whether or not immediate surgical correction of VUR has an advantage over conservative medical management in the prevention of subsequent renal scarring and in the preservation of the normal potential for renal growth is not known. There are reports to support both approaches; however, there has been no report of a prospective, controlled study. Because renal scarring seems to occur with VUR prior to the age of 5 years, it would seem that early detection, regardless of the preferred clinical approach, should be followed by keeping the urine sterile, by serial blood pressure measurements, and by serial assessments of renal function and kidney growth. REFERENCES

1. Ask-Upmark E: Uberjuvenile maligne Nephrosklerose und ihr Verh~iltniszu Storungen in der Nierenentwicklung, Acta Pathol Microbiol Scand 6:383, 1929. 2. Ljungqvist A, an d Lagergren C: The Ask-Upmark kidney, Acta Pathol Microbiol Scand 56:277, 1962. 3. Batzenschlager A, Blum E, and Weill-Bousson M: Le petit rein unilateral. I. Petit rein unilat6ral acquis, Ann Anat Pa,thol (Paris) 7:427, 1962. 4. Habib'R, Courtecuisse V, Ehrensperger J, and Royer P: Hypoplasie segmentaire du rein avec hypertension art~rielle chez l'enfant, Ann Pediatr (Paris) 12:262, 1965. 5. Rauber G, and Langlet M -L: Hypoplasies segmentaires du rein: Distinction de deux formes histologiques, Nouv Presse Med 5:1759, 1976. 6. Bernstein J: Developmental abnormalities of the renal parenchyrna--renal hypoplasia and dysplasia, in Sommers SC, editor: Kidney pathology decennial 1966-1975, New

Volume 95 Number 6

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York, 1975, Appleton-Century-Crofts, pp 11-17 and 3637. Royer P, Habib R, Broyer M, and Nouaille Y: Segmental hypoplasia of the kidney in children, Adv Nephrol 1:145, 1971. Batzenschlager A, Weill-Bousson M, and Guerbaoui M: L'hypoplasie segmentaire agtomdrulaire du rein, Sere H6p Paris 50:601, 1974. Mozziconacci P, Attal C, Boisse J, Pham-Huu-Trung MT, Guy-Grand D, and Durand C: Hypoplasie segmentaire du rein avec hypertension arterielle, Ann Pediatr (Paris) 15:337, 1968. Godard C, Vallotton MB, and Broyer M: Plasma renin activity in segmental hypoplasia of the kidneys with hypertension, Nephron 11:308, 1973. Boccon-Gibod L, Galian P, and Boccon-Gibod L: Le petit rein unilat6ral de l'adulte en dehors des obstructions de la voie excrdtrice: l~tude anatomo-clinique de 37 observations, Ann Urol 6:1, 1972. Olivier C, Broyer M, and Habib R: Hypoplasie segmentaire du rein avec hypertension art6rielle chez l'enfant, XXIV e Congr+s de l'Association des P6diatres de Langue Francaise, Paris, 1975, pp 43-67. Benz G, Willich E, and Sch~irer K: Segmental renal hypoplasia in childhood, Pediatr Radiol 5:86, 1976. Andersen HJ, Jacobsson B, Larsson H, and Winberg J: Hypertension, asymmetric renal parenchymal defect, sterile urine, and high E. coli antibody titre, Br Med J 3:14, 1973. Dein RW, Walker D, and Hackett RL: The Ask-Upmark kidney: A case report, Arch Pathol 96:10, 1973. Javadpour N, Doppman JL, Scardino PT, and Bartter FC: Segmental renal vein renin assay and segmental nephrectomy for correction of renal hypertension, J UrN 110:728, 1973. Still JL, and Cottom D: Severe hypertension in childhood, Arch Dis Child 42:34, 1967. MacGregor M: Pyelonephritis lenta: Consideration of childhood urinary infection as the forerunner of renal insufficiency in later life, Arch Dis Child 45:159, 1970. Stickler GB, Kelalis PP, Burke EC, and Segar WE: Primary interstitial nephritis with reflux: A cause of hypertension, AM J Dis Child 122:144, 1971. Bailey RR: The relationship of vesico-ureteric reflux to urinary tract infection and chronic pyelonephritis--reflux nephropathy, Clin Nephrol 1:132, 1973. Holland NH, Kotchen T, and Bhathena D: Hypertension in children with chronic pyelonephritis, Kidney Int 8(Suppl):243, 1975.

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22.

23.

24. 25.

26.

27. 28.

29.

30. 31.

32. 33. 34. 35. 36.

37. 38.

39. 40.

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