CHRONIC NEPHRITIS IN A NEWBORN INFANTBY

ALBERT E. CLAIREAUX and MORTON G. PEARSONFrom the Bernhard Baron Memorial Research Laboratories, Queen Charlotte's Hospital,

and the Institute of Obstetrics and Gynaecology, Hammersmith Hospital, London

(RECEIVED FOR PUBUCATION MARCH 3, 1955)

Renal disease other than that associated withcongenital malformations is rare in the newborninfant. Formerly syphilis played an important rolein the production of inflammatory renal disease ininfants, but with modern methods of ante-natal carecongenital syphilitic nephritis is almost unknown inthis country.

Glomerular changes, consisting mainly of hya-linization and fibrosis of the glomerular tufts, weredescribed by Herxheimer (1909) and by Schwarz(1928). These lesions were called 'congenitalglomerulosclerosis by Friedman, Grayzel andLederer (1942) who reviewed the subject in somedetail. More recently Swan (1944) and Tedeschi,Halpern and Ingalls (1953) have reported similarlesions in the kidneys of infants whose mothers hadsuffered from rubella during pregnancy. It is felt,however, that these changes are probably vascularrather than infective in origin and are not specificmanifestations of infection by rubella virus.True glomerulonephritis is regarded as being un-

common by Zuelzer, Charles, Kurnitz, Newton andFallon (1951) and according to Potter (1952) isunknown in the newborn infant.

Recently, however, there have been three reportsof glomerulonephritis occurnng in newborn infants(Thompson, 1951; Collins, 1954; Kunstadter andRosenblum, 1954). These authors regarded thecondition as an extreme rarity and were unable tofind reports of similar cases in the literature.Lapage (1932) had described a case of acute haemor-rhagic nephritis in the newborn, but glomerularchanges were absent.

In this paper we describe a case of nephritis in anewborn infant. The renal changes were mostsevere and affected the glomeruli, tubules and inter-stitium.

Case ReportThe mother was a healthy woman of 29 years of age,

and this was her third pregancy. Her first pregnancyin 1948 resulted in the birth of a female child whosubsequently showed pyloric stenosis. She had a

healthy female child as a result of her second pregnancyin 1951.During the pregnancy she seemed quite well until the

beginning of the third month when she had a mild throatinfection. A more severe throat infection occurredduring the fifth month. Similar attacks had occurredduring the previous two years. She was first seen duringthe seventh week of her pregnancy. Blood pressure was115 70 mm. Hg and her urine contained no abnormalconstituents. Wassermann and Kahn reactions werenegative. Her haemioglobin was 13 -5 g. 00 and she wasGroup 0 Rh positive. No abnormality was seen in aradiograph of the chest. The patient thereafter attendedher local county council ante-natal clinic until the 36thweek when she was again seen at hospital. No abnor-mality was found at this examination.Labour began spontaneously on August 9, 1954,

19 days before the estimated date of delivery. Onadmission to hospital a breech presentation of the foetuswas diagnosed. The membranes were still intact but thefoetal heart was irregular. Breech delivery was effectedtwo hours later. The placenta weighed 794 g. Thepuerperium was uneventful. On November 15, 1954,her throat was clear. A swab yielded no pathogens.The anti-streptolysin titre of the blood was 200 units mnl.Blood urea was 22 mg. 100 ml. and uric acid 1-7 mg.100 ml. The patient was a male infant of 6 lb. 13 oz.(3,091 g.) birth weight. He was apnoeic at birth, hada feeble cry and took infrequent gasps. He improvedafter assisted breathing in a servo-respirator but in-drawing of the chest persisted. Crepitations werepresent in both lung fields. On radiological examination,bilateral pneumothorax was found. The infant diedaged 10 hours.

Necropsy. The body was that of a well developedmale infant weighing 3,175 g. No congenital abnor-mality was found on external examination. The ten-torium was tom on both sides and there was severebilateral subdural haemorrhage. The brain was normal.The larynx, trachea and bronchi were healthy. There

was a pneumothorax on the left side. The lungs werecongested and poorly expanded. The right lung wasatelectatic and sank in water. The left lung floated as aresult of gross emphysema. Large emphysematousbullae were present in the interlobular fissures.The heart and great vessels were normal.

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A few petechial haemorrhages were present in the smallintestine. The liver and pancreas were healthy.The kidneys were quite large (each weighed 26 g.).

Their appearance was similar. They showed foetallobulation and the capsule stripped easily. Their surfacewas generally smooth, but a few minute cysts, 0 5-1 mm.diameter, were present. The cysts had smooth wallsand contained a little fluid. Nuumerous petechiae werepresent over the surface of the kidneys. On slicing thecortex and medulla could be easily differentiated. Thecortex was congested and numerous silvery streaks wereseen running at right angles to the surface. Occasionalsmall cysts were seen. The pyramids showed a fewsmall haemorrhages. The calyces and pelvis werehealthy. The renal vessels appeared normal and theureters and bladder were healthy.The spleen appeared normal. The suprarenal glands,

thymus, thyroid and pituitary glands were healthy.

Histology. The left lung showed numerous sub-pleural emphysematous bullae. Patchy intra-alveolarhaemorrhage was seen in both lungs. The right lungwas unexpanded. There was no pneumonia.The liver and spleen showed no abnormality.The capsule of the kidneys showed little change. The

glomeruli were reduced to about one-third of theirusual number. Of the remainder, few were completelynormal. Many were atrophic and showed periglomeru-lar concentric fibrosis (Fig. 1). A few showed prolifera-tion of the cells of Bowman's capsule with striking

crescent formation and in some cases the capsular spacehad been obliterated by this process (Fig. 2). Pseudo-crescent formation was also observed in a number ofinstances (Fig. 3). Here the glomeruli showed partialhyalinization and a neighbouring convoluted tubule wasbecoming adherent to the glomerular capsule. Thelatter showed epithelial proliferation and eventuallythe complex would have become hyalinized and sur-rounded by fibrous tissue. The end-result would there-fore be almost indistinguishable from the crescentdescribed above (Fig. 2). In other glomeruli capsularproliferation was less pronounced, but some adhesionswere present between the glomerular tufts and thecapsule. In a few instances the capsular space containedacidophile material with an occasional polymorpho-nuclear leucocyte. Glomeruli undergoing atrophy werepresent throughout the cortex, but those exhibitingproliferative change were more frequently found near thecortico-medullary junction.The tubular changes were even more striking. The

small superficial cortical cysts seen on macroscopicexamination proved to be grossly dilated tubules con-taining acidophile fluid. About half the cortical tubuleswere dilated and contained colloid casts (Fig. 1). Thisgave the kidney a thyroid-like appearance. The dilatedtubules were lined by flattened atrophic epithelium.The convoluted tubules were more affected than thecollecting tubules but the latter also showed cyst for-mation. A few convoluted tubules showed true hyper-trophy and their epithelium was thrown into papilliform

AEM L; -J 4

FK;. I.-Renal cortex showing glomerular atrophy, tubular dilatationand colloid casts in the convoluted tubules. Large haemopoietic

foci are present on the left. Haernatoxylin and ersin x 75.

FIG. 2.-Glomerulus showing partial hyalinization of the tuft andepithelial cell proliferation of the capsule with crescent formation.

Haematoxylin and eosin x 375.

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folds. In addition to the acidophile colloid materiala number of tubules contained polymorphonuclearleucocytes and cellular debris. Only very few tubules,however, contained purulent material and the majoritycontained no cells at all. A few tubules showed erosionof their walls by an inflammatory process and numerousleucocytes were present.

In addition to cystic dilatation a number of convolutedtubules showed pronounced hyaline droplet degenerationof their lining cells (Fig. 4). Their cells were pale andswollen and in places the epithelium was replaced bybright acidophile droplets. A number of convolutedtubules showed severe hyaline change and their epi-thelium was converted into a hyaline band (Fig. 5). Insome cases two or more such hyalinized tubules hadfused. No cytoplasmic inclusion bodies were seen andno organisms were found in sections stained by Gram'smethod.The interstitial tissue also showed marked alteration.

There were numerous large foci of extramedullaryhaemopoiesis throughout the cortex (Fig. 1). Thesewere mainly normoblastic in character but there was alsoa considerable amount of leucopoiesis. In addition tothese foci small aggregations of polymorphonuclearleucocytes and some lymphocytes were present in theperitubular connective tissue throughout the cortex.This inflammatory cell infiltration was chiefly evidentin the cortex and was minimal in the medulla.

Small haemorrhages were present throughout thecortex. They were situated chiefly in the boundaryzone between the cortex and the medulla. A fewhaemorrhages were also seen in the peripelvic connectivetissue.The interstitial connective tissue was increased in

amount. This fibrosis was mainly cortical. Perivascularfibrosis was most pronounced and long strands of fibroustissue were present in the medullary rays. These wereresponsible for the silvery streaking noted on macroscopicexamination. The convoluted tubules were also sur-rounded by thickened fibrous tissue bands. The collect-ing tubule interstitium showed little change. There wassome increase in the peripelvic connective tissue whichshowed slight polymorphonuclear leucocytic infiltration.The epithelium of the renal pelvis was healthy (Fig. 6).There had been some upset in renal development as aresult of the inflammatory process. The outer cortex,which is the neogenic region of the organ, showed themost pronounced effect. Small groups of tubules weresurrounded by concentric rings of fibrous tissue andglomeruli were absent.The renal vessels were most noticeable for the amount

of perivascular fibrosis. A number of arterioles showedhyperplastic sclerosis. Vessels in other organs werequite normal.

DiscussionIn spite of the signs of glomerulitis and crescent

formation in this case we believe that the funda-mental lesion is a chronic, but still active, pyelo-nephritis. The gross dilatation of the corticaltubules which contained colloid casts, the presence

of pus in a number of tubules, the increase in theinterstitial connective tissue which showed infiltra-tion with polymorphonuclear leucocytes and theglomerular atrophy with concentric pericapsularfibrosis all point to this diagnosis. We feel thatonly a few glomeruli showed truly proliferativelesions and these were insufficient to account forthe gross alteration of the cortical architecture. Theglomerular changes were probably the result of an'alterative glomerulitis'. This change has beendescribed in pyelonephritis by Kimnmelstiel andWilson (1936). These authors have shown that insome cases of pyelonephritis there is hyalinizationof some loops of the glomerular tuft with theformation of capsular adhesions. Occasionally thisis followed by capsular proliferation. They alsodescribe a process of 'invasive glomerulitis' whichprobably explains the pseudo-crescent formationwe observed in the kidneys of our case. In thisinstance there is a direct extension of the inflam-matory process from the interstitial tissue, peri-glomerular lymphatics or tubules through thecapsule into the glomerular space and tuft. Thisprocess was quite clearly demonstrated in our case(Fig. 3). A tubule containing polymorphonuclearleucocytes is seen adhering to the capsule of aglomerulus. The tubular epithelium nearest to thecapsule is undergoing necrosis and will eventuallybecome adherent. A neighbouring glomerulus inthe same field shows a further stage in this process.The tubular lumen is now only a narrow cleft andthe glomerulus and tubules have formed a complexmass. The capsular epithelium undergoes prolifera-tion and eventually the whole mass is hyalinizedand surrounded by concentric rings of fibroustissue. The presence of pus in the tubules and ofpolymorphonuclear leucocytes in the interstitialtissue suggest that the process was still active, butthese findings were not striking features of the case.

Recently Collins (1954) described a case ofchronic glomerulonephritis in a newborn child whodied 90 hours after birth. The illustrations indicatethat the renal changes in his patient were almostexactly similar to those reported above. Collinsfavours a diagnosis of 'chronic and subacuteglomerulonephritis' instead of pyelonephritis. Heexcludes the latter largely on account of the severeglomerular changes in the comparative lack ofinflammatory cell infiltration.Thompson (1951) reported the occurrence of

nephritis in a child who lived for 29 days after birth.The infant during this period suffered from oedemaand albuminuria. Red cells, pus cells, hyaline andgranular casts were present in the urine. Histo-logical examination of the kidneys showed hyaliniza-

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FI,. 3.-Two glomeruli with adherent tubuks. On the top left theconvoluted tubule is a narrow slit attached to the gkomerular capsuleand surrounded by fibrous tissue. On the right the tubule con-tains pus cells and debris. The inner wall of the tubule is becomingattached to the glomerulus. Haematoxylin and eosin 375.

FIG. 4.-Three dilated tubuks showing pronounced hyaline dropletdegencration. Pro-Mallory x 175.

FK;. 5.-Renal cortex showing two completely hyalinized tubuleswith peritubular fibrosis. There is marked haemopoietic activity in

the interstitium. Haematoxylin and eosin x 175.

FIG. 6.-Medulla and pelvis. The stratfied epithelium of the pelvisis intact. The subepithelial connective tissue shows slight infiltrationwith polymorphs. The medulla is congested and dilated tubules

contain cotloid casts. Haematoxylin and eosin x 75.

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tion of some glomeruli while others showed capsularadhesions, crescent formation and increased cellu-larity of the tufts. The proximal convoluted tubuleswere lined by a partially vacuolated epithelium andthe collecting tubules contained casts and leucocytes.There was narked periarterial fibrosis and thearterioles showed hyperplastic sclerosis. The peri-arterial fibrosis was explained on the basis of hyper-tensive change. The author believes that this was acase of glomerulonephritis of some standing. Theconsiderable pyuria and the cellular infiltration ofthe renal stroma suggest that this view may beincorrect and that this was possibly another exampleof pyelonephritis.More recently Kunstadter and Rosenblum (1954)

have described a case of neonatal glomerulo-nephritis and the nephrotic syndrome. The infantwas born prematurely and died 72 days later.During this time the infant had shown pittingoedema over the face and trunk. The infant wasvery anaemic and required several blood trans-fusions. The urine contained albumin, red cellsand casts. At necropsy the kidneys showed red-dening of the cortico-medullary junction and yellowstreaking perpendicular to the cortical surface.On histological examination the glomeruli weresmall, hyperaemic and more cellular than usual.A few glomeruli showed proliferation of the cellsof Bowman's capsule with some adhesions.The tubular epithelium was swollen, granular andvacuolated. The authors believe that this was anexample of subacute glomerulonephritis withnephrosis.Not one of these recent accounts shows that the

diagnosis of glomerulonephritis has been establishedbeyond any reasonable doubt, and Potter (1952) isprobably still correct in her opinion that it does notoccur in the newborn.The pathogenesis of nephritis in the newborn is

obscure. Collins (1954) and Thompson (1951) havesuggested an allergic or hypersensitivity basis for theoccurrence of glomerulonephritis in their patients.

It is interesting to note that the mother of thechild reported by Thompson had suffered from a sorethroat during the sixth month of her pregnancy.The mother of the infant in the present case had athroat infection twice during her pregnancy, at thethird month and again during the fifth month.Whether a hypersensitivity phenomenon followingon these throat infections during early pregnancycould explain the occurrence of a pyelonephritis inthe present case is rather doubtful. There arecertain features which favour such a supposition.The entire histological picture is rather unusual.While we are satisfield that this is not a true glomerulo-

nephritis, the pronounced glomerulitis and tubularhyalinization are peculiar features. Furthermore,the intense perivascular fibrosis and pronouncedperiarterial cellular infiltration bear a faint resem-blance to the appearance found in the healing stagesofpolyarteritis nodosa. The latter has been ascribedto a hypersensitivity reaction. The lack of severeinflammatory change in the renal calyces and pelvisalso suggests that we are not dealing with a typicalbacterial infection of the kidney.

If this pyelonephritis is to be regarded as the resultof a bacterial infection we have to decide the sourceof infection and there seem to be only two pos-sibilities: first, a maternal bacteraemia with trans-mission of the organisms to the foetal blood streamvia the placenta, or secondly an infection of theliquor amnii which is then swallowed by the foetusand absorbed from the gut. The first explanation isimprobable since organisms are unlikely to pass theplacental barrier without causing a placental lesionand there was no evidence of this in the present case.Tlhe second supposition is more plausible, but thereis no evidence that it did occur. The liquor amniiwas not malodorous and no inflammatory lesionswere found in the infant's lungs. There is thus noclear evidence to support the infective origin of therenal lesions and no organisms were found in thesections examined.The changes in the renal cortex which were found

in the present case are of special interest since theywould seem to form the basis of the so-called 'chronicinterstitial nephritis' in older children which wasdescribed by Mitchell (1930). A case of a slowlyprogressive nephritis associated with marked skeletalchanges in a child of 5 years has already beenrecorded by one of us (Claireaux, 1953). Thekidneys in this patient showed marked glomerularhyalinization with pericapsular fibrosis and severeinterstitial fibrosis. A number of tubules containedpus. There was no congenital abnormality of theurinary tract. It is almost certain that this wasan example of a chronic but still active pyelo-nephritis. Weiss and Parker (1939) are firmlyconvinced that all these cases of so-called inter-stitial nephritis associated with renal dwarfism are,in reality, examples of chronic pyelonephritis. Thusolder infants and children who show an osteo-dystrophy associated with advanced renal diseasehave almost certainly suffered from pyelonephritisfor some considerable time. Craig (1935) hasshown that acute pyelitis and pyelonephritis are notuncommon in the neonatal period. The majorityof patients recover but in a few instances the renaldisease may become chronic with the development ofhypertension and bone lesions in later life. The case

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CHRONIC NEPHRITIS IN A NEWBORN INFANT 371

we have described above would seem to indicate thatthe fundamental renal lesion can occur even inutero.

A case is reported of chronic pyelonephritis in anewborn infant. In addition to advanced tubularchanges the kidneys showed unusual proliferativelesions in the glomeruli which may sometimes bemistaken for glomerulonephritis.The pathogenesis of this condition is obscure,

but is possibly the result ofa hypersensitivity reactionto an infection in the mother during early pregnancy.

It is suggested that this unusual form of pyelo-nephritis may form the basis of the so-called chronic

interstitial nephritis found in older children withrenal osteodystrophy.

REFERENCEsClaireaux, A. E. (1953). J. Path. Bact., 65, 291.Collins, R. D. (1954). Amer. J. Dis. Child., 37, 478.Craig, W. S. (1935). Archives of Disease in Childkood, 10, 337.Friedman, H. H., Grayzel, D. M. and Lederer, M. (1942). Amer. J.

Path., 18, 699.Herxheimer, G. (1909). Frankfurt. Z. Path., 2, 138.Kinnmelstiel, P. and Wilson, C. (1936). Amer. J. Path., 12, 99.Kunstadter. R. H. and Rosenblum, L. (1954). Amer. J. Dis. Child.,

38, 611.Lapage, C. P. (1932). Archives of Disease in Childhood, 7, 235.Mitchell, A. G. (1930). Amer. J. Dis. Child., 40, 101.Potter, E. L (1952). Pathology of the Fetus and the Newborn, p. 361.

Chicago.Schwarz, L. (1928). Virchows Arch. path. Anat., 267, 654.Swan, C. (1944). J. Path. Bact., 56, 289.Tedeschi, C. G., Helpern, M. M. and Ingalis, T. H. (1953). New

Engl. J. Med., 249, 439.Thompson, A. C. (1951). W. Va med. J., 47, 16.Weiss, S. and Parker, F. (1939). Medicine, 18, 221.Zuelzer, W. W., Charles, S., Kurnetz, R., Newton, W. A. and Fallon

R. (1951). Amer. J. Dis. Child., 81, 1.

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