thepathology ofrenal ischaemiaischaemic nephrosclerosis associated with hyper-tension. although the...

J. clin. Path., 30, Suppl. (Roy. Coll. Path.), 11, 114-124

The pathology of renal ischaemiaJ. R. TIGHE

From the Department of Surgical Pathology, St Thomas's Hospital, London

The changes of renal ischaemia are amongst thecommonest seen in renal pathology since theyaccompany a great variety of other diseases rangingfrom chronic glomerulonephritis to analgesic abuse,from irradiation to renal transplantation. Unfor-tunately it is not always easy to separate the changesof ischaemia from those of the underlying primarydisease. However, renal artery stenosis provides asuitable model for this study. Many cases of renalartery stenosis are complicated by hypertensionwhich itself produces secondary changes in the kid-ney and so some recognition of this must be given inany discussion of the pathology of renal ischaemia.Renal artery stenosis may affect the main renal

artery, one of its major divisions or one of thesegmental arteries. If only part of the kidney isdamaged nephrectomy specimens provide a usefulcomparison of an ischaemic segment and a controlnormal segment.

It is not the purpose of this study to consider thechanges of acute ischaemia producing renal necrosiswhich will be dealt with elsewhere.

Gross appearance

Following ischaemia, the kidney is reduced in size. Ifa segmental artery is stenosed then the ischaemicarea of the kidney supplied by the narrowed artery isdepressed below the surface of the remainder of thekidney. In young individuals without intrarenalartery disease the capsular surface of the ischaemicpart of the kidney is smooth but in older individualswith arteriolar sclerosis the capsular surface is oftenfinely scarred. If a partial nephrectomy has beenperformed for segmental artery stenosis, the smoothsurface of the kidney may make it appear deceptivelynormal unless an appreciable rim of non-ischaemickidney is included with the specimen. If the patienthas been hypertensive then the area of kidney notsupplied by the stenosed artery may be finely scarred,even in young patients, due to the effects of hyper-tension. The narrowed renal artery protects theischaemic area from the effects of this hypertension.

The cut surface of the ischaemic kidney shows nar-rowing of the cortex and there may be loss ofdemarcation of cortex and medulla.

Glomerular changes

Many of the glomeruli may appear remarkablynormal in spite of severe damage elsewhere in thekidney. The changes of ischaemia in the glomerulartuft and Bowman's capsule were well described byMcManus and Lupton (1960). Although the changesare distributed in the area of supply of the diseasedartery they tend to be more severe in the outercortex (fig 1). The vascular tuft of the glomerulusbecomes compact (fig 2) due to collapse of capil-laries. After staining with periodic acid-methenaminesilver the basement membranes are seen to bewrinkled around the collapsed bloodless capillaries(figs 3 and 4), a pattern confirmed by electronmicroscopy (fig 5). The degree of collapse may varyfrom case to case. This is illustrated in the tablewhere a comparison has been made betweenischaemic and 'normal' glomeruli from two cases ofsegmental renal artery stenosis. In each case blockswere taken across the junction of ischaemic andnormal kidney so that the tissues were subjected toidentical processing and section cutting. In each area20 glomeruli were measured using a Quantimet 720image analyser. In one case the ratio of ischaemicglomerular tufts to normal tufts is not significantlyreduced at 86 per cent, but in the other case theischaemic tufts are only 60 per cent of the area of thenormal tufts. In neither case did the normal zoneappear damaged.

This collapse of the glomerular tufts is usuallyglobal in distribution but in some glomeruli itappears to be segmental (fig 6), suggesting a localfactor within the tuft causing shutdown of capillaryblood flow. There are various possibilities to accountfor the collapse of the glomerular tufts. Global col-lapse may be the result of low perfusion pressurebetween the stenosed renal artery and the glomerulusor it may be due to narrowing of the intrarenal

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The pathology of renal ischaemia

Fig. 1 Ischaemic changes in the kidney are most marked Fig. 2 Collapsed capillaries give the glomerular tuft ain the subcapsular zone (top) of the kidney. Note the solid appearance. The apparent increased cellularity is duetubular atrophy and crowding ofglomeruli (H and E x to concentration of cells into a smaller area (H and E x40). 400).

Fig. 3 Wrinkled, collapsedcapillaries of an ischaemicglomerular tuft. Bowman'scapsule is thickened and split(silver methenamine x 400).

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Fig. 4 A normal glomerulusfrom the same kidney as infig 3 for comparison showingwell filled glomerularcapillaries and smoothbasement membranes (silvermethenamine x 400).

Fig. 5 Ischaemic collapse ofglomerular capillaries outlined by dense wrinkled basement membranes. Capillarylumina are lost but epithelial, endothelial and mesangial cells survive (EM x 4930).

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Total Area (To) (V') Tuft Area (Tu) (v') Tu Tol Tul

Control (C) 14665 ± 2646 11499 ± 2626 78Case 1 65 60

Ischaemic (I) 9525 ± 2575 6908 ± 2282 73(825) (778)

Control 17148 ± 5950 10373 ± 4416 60Case 2 80 86

Ischaemic 13699 + 2588 8931 i 2201 65(1451) (1103)

Table Effects of ischaemia on total glomerular area and tuft areaI

'Average of 20 glomeruli in each group. Figures in parenthesis are the standard errors of the differences between the two means.

arteries and arterioles supplying the glomeruli.Alternatively there may be constriction of thearterioles at the hilum of the tuft, or of capillarieswithin the tuft. The juxtaglomerular cells of theafferent arteriole and the lacis cells at the glomerularhilum are modified smooth muscle cells (Latta andMaunsbach, 1962a) as are mesangial cells within theglomerular tuft (Goormaghtigh, 1942; Tighe, 1975).

The glomerular mesangial cells react strongly withsmooth muscle anti-actomyosin (Becker, 1972) andcells, presumed to be mesangial cells, grown in tissueculture have prominent intracellular fibrils contain-ing actomyosin (Scheinman et al, 1976). The axialdistribution of mesangial cells within the glomerulusand their close anatomical relation to capillaries (fig6) would allow these cells to have an appreciable

Fig. 6 Segmental collapseOfglomerular capillaries. Acapillary in an adjacent

O., s~egment (lower right) is4., w~idely patent and contains

erythrocytes. Mesangialcells occupy the axial regionof the ischaemic segment

~. and are ideally placed to., .ontrol capillary bloodflow

f a Nx3E(EM x 3000).

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effect upon glomerular blood flow. The segmentalcollapse of tuft capillaries without mechanicalobstruction within the lumen is best explained bysuch mesangial contraction. The demonstration ofangiotensin II receptors in mesangial cells (Osborneet al, 1975) points to these cells being liable to thevasoconstrictor effect of this hormone and is furtherevidence for their contractile role. Becker (1962)postulated that closing of peripheral tuft capillariesby mesangial contraction might result in shunting ofblood through anastomoses within and betweenglomerular lobules (Hall, 1954; Boyer, 1956).The cellularity of the collapsed glomerular tufts

(fig 2) may appear somewhat increased but this is duemore to the condensation of cells into a smaller arearather than to cellular proliferation. Hara et al (1975)reported that mesangial cell counts and total glome-rular cell counts are not significantly increased in theischaemic nephrosclerosis associated with hyper-tension. Although the mesangial area appearsexpanded this is, in part, due to condensation ofcapillary basement membranes about the axial coreof the glomerular tuft.As the basement membranes around the col-

lapsed capillaries become thicker, the glomerulartuft becomes converted into a hyaline mass withoutidentifiable capillaries (fig 5). In spite of the apparentloss of blood supply, a few cells remain viable withinthe hyalinized tuft.Meanwhile Bowman's capsule shows changes

which terminate in global sclerosis. Initially Bow-man's capsule contracts around the shrunkenglomerular tuft so that the urinary space is notgreatly increased and the ratio of tuft area/totalglomerular area remains remarkably constant(table). Only later may the urinary space increase dueto disproportionate shrinkage of the tuft. Bowman'scapsular basement membrane (fig 3) becomesthickened and duplicated (Jones, 1974). In someglomeruli, collagen is deposited internal to thecapsular basement membrane. Initially this appearsin the vicinity of the hilum (McManus and Lupton,1960) but later spreads to fill the urinary space sothat the hyalinized tuft and capsular fibrous tissuemerge into one eosinophilic mass. However, usingperiodic acid-Schiff (fig 7) or silver-methenamine thetuft and capsular components of the glomerularmass are readily distinguished. Some cells, ofcapsular origin, are caught up in this proliferatingfibrous tissue. This fibrosis internal to Bowman'scapsule should be distinguished from the peri-glomerular fibrosis seen in chronic pyelonephritis(Heptinstall, 1974).

Late in the disease hyalinized glomeruli undergoresorption similar to that seen in chronic glomer-ulonephritis (Jones, 1963). There is fragmentation of

Fig. 7 The vascular tuft has collapsed to a solid mass ofcapillary basement membranes. Between the tuft andBowman's capsule fibrous tissue has filled the urinaryspace (PAS x 400).

Bowman's capsular basement membrane and fadingof the tuft basement membranes with replacement bycollagen.

Juxtaglomerular apparatus

Much of the interest in ischaemic renal disease stemsfrom the work of Goldblatt et al (1934) who pro-duced hypertension in dogs by constriction of therenal arteries. Goormaghtigh (1940) drew attentionto the hyperplasia of the juxtaglomerular apparatusand the increased granularity not only of thejuxtaglomerular cells but also of interlobar and inter-lobular arteries following clamping of the renalarteries in dogs. Since that time there has beenmuch evidence relating renal ischaemia to hyper-plasia of the juxtaglomerular apparatus and hyper-tension (Tobain et al, 1958; Heptinstall, 1965).The juxtaglomerular apparatus at the hilum of the

glomerulus consists of the afferent and efferent

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Fig. 8 A tangential cut of the afferent arteriole as it enters the glomerulus (left) reveals hyperplastic, large, pale,epithelioid, smooth muscle cells, the juxtaglomerular cells (EM x 2530).

Fig. 9 The juxtaglomerular cells surrounding theafferent arteriole are hyperplastic, causing increasedthickness of the arteriolar wall. Note the increasedgranularity of the JG cells (EM x 1800).

arterioles, the macula densa of the distal convolutedtubule and, between these, the lacis cells which arecontinuous with mesangial cells within the glomerulartuft (Latta and Maunsbach, 1962b). The modifiedsmooth muscle cells of the afferent arteriole shortlybefore it enters the glomerulus become large, paleand epithelioid (fig 8). Within these cells are foundthe juxtaglomerular granules which are now recog-nized as containing renin (Tobain et al, 1959; Cookand Pickering, 1959; Edelman and Hartroft, 1961;Cook, 1968). It is these large epithelioid cells whichshow the initial hyperplasia (fig 9) resulting inappreciable thickening of the arteriolar wall.Turgeon and Summers (1961), studying patientswith hypertension associated with renal arterystenosis, found that there was an inverse correlationbetween the degree of hyperplasia and the durationof the disease, the most prominent juxtaglomerularcells being found in young patients with hyper-tension of short duration. This hyperplasia alsoaffects the lacis cells, so that it may be difficult todistinguish the two types of cells.

Juxtaglomerular granules are rarely as numerousin the human as in laboratory animals. This needs tobe considered when comparing illustrations of thegranularity of hyperplastic juxtaglomerular cells inman with those of laboratory animals. The juxta-

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J. R. Tighe,'~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ w.ny..Fig. 10 Type I dense JG granules in a hyperplastic juxtaglomerular cell. These granules are regardedas specific for this site. Note the dilated rough endoplasmic reticulum (EM x 25 650).

Fig. 11 Type 2 JG granule in a juxtaglomerular cell. Similar granules containing lipid droplets or

myelin are also seen in interlobular arteries and in the mesangium (EM x 31 250).

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Fig. 12 Type 2 JG granule showing laminar and latticecrystalline structure in a coarsely granular matrix (EM x150000).

glomerular granules are of two main types (Biavaand West, 1966) both of which can be demonstratedwith Bowie's stain. The first consists of granulesbounded by a single membrane and filled withhomogeneous or finely fibrillary material (fig 10).Some of these assume a rhomboidal shape. Thesegranules are usually found in the vicinity of Golgicisternae of the juxtaglomerular cells. The secondresembles an autophagic vacuole or residual bodyand consists of a membrane-bound granular matrixwith included lipid droplets (fig 11). The granularmatrix is sometimes arranged in a laminar orhexagonal lattice form (fig 12) and may containmyelin figures. Biava and West (1966) regarded thefirst variety as a specific juxtaglomerular granule andthe latter as non-specific lipofuscin-like, being foundin both the juxtaglomerular cells and in the smoothmuscle cells of arteries. However, the latter granulesincrease progressively in number in arteries ofdecreasing size and are most numerous in afferent

Fig. 13 Autofluorescent granules in hyperplasticjuxtaglomerular cells at the pole of the glomerulus,extending back into the afferent arteriole(unstained x 400).

arterioles (Biava and West, 1965). In spite of themorphological differences, both types of granule arelysosomal (Lee et al, 1966; Fisher, 1966; Cantin et al,1974; Nemes, et al, 1976). The lipofuscin-likegranule is autofluorescent (fig 13) and may also bedemonstrated using thioflavine T (Janigan, 1965).Both types of granule increase in number in ischaemickidneys in juxtaglomerular cells and in lacis cells.The autofluorescent granules are also increased innumber in small arteries and the granules extend intothe proximal mesangium within the glomerular tuft.It is worth recalling that Goormaghtigh (1940)noticed the increased granularity of interlobulararteries in his models ofexperimental renal ischaemia.Heptinstall (1965) has demonstrated in the rat thatthe increased granularity of juxtaglomerular cells isrestored to normal when the ischaemia is relieved.The increased granularity is also associated withincrease in rough endoplasmic reticulum within thejuxtaglomerular cells (fig 10), a change found in cells

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concerned with protein synthesis and secretoryactivity.

Tubules

Ischaemic tubular atrophy is disproportionate to theglomerular damage. The reduction of renal paren-chyma caused by this tubular atrophy results incrowding of glomeruli (fig 1). Counts of glomeruli/mm2 have shown an increase from the normal meanof 65 to a mean of 300 in ischaemic areas.The severity of the tubular atrophy prevents easy

identification of proximal and distal tubules in thecortex (fig 14) but electron microscopy reveals thatmost of the tubules are proximal. The tubular luminaare reduced in diameter and in this respect they differfrom the tubular atrophy of chronic pyelonephritisor of hydronephrosis where there is frequently gross

J. R. Tighe

tubular dilatation. Occasionally some ischaemictubules contain protein casts and the tubular lumenhere is more obvious. The peritubular basementmembranes are thickened (fig 15) and may bedemonstrated using periodic acid-Schiff. This is avaluable way of detecting small foci of ischaemia forthe thickened membranes draw attention to theatrophic tubules.

Interstitial tissues

The degree of interstitial fibrosis in the ischaemicareas is often surprisingly small in spite of the severetubular atrophy. Where there is longstandingarteriosclerosis, as in elderly patients with renalischaemia, there may be more severe interstitialfibrosis.

Fig 14 Figl15Fig 14 An ischaemic glomerulus with hyalinization ofpart of the glomerular tuft. The surrounding tubules areatrophic and cannot be identified as proximal or distal tubules (H and E x 400).Fig 15 Atrophic tubules are surrounded by thickened basement membranes. Interstitial fibrous tissue separatesadjacent tubules (PAS x 400).

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The pathology of renal ischaemia 123

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Fig. 16 Subendothelial hyaline in an arteriole. A fewcoarse lipofuscin-like granules can be seen in the smoothmuscle cells surrounding the hyaline deposit (toluidineblue x 1000).

Interstitial inflammation is also usually slight,being limited to focal collections of lymphocytes.Inflammatory cells in tubules are not a feature ofuncomplicated renal ischaemia.

Arterial disease

In elderly patients both the ischaemic areas of kidneyand that part of the kidney not affected by renalartery stenosis may show fibroelastic intimal pro-liferation of interlobar, arcuate and interlobulararteries. Although this change may be more notice-able in the ischaemic area due to the crowding ofvessels following tubular atrophy and parenchymalloss, analysis of individual arteries shows littlevariation between the ischaemic and less damagedareas of kidney. Arterioles may show hyaline change(fig 16); granules similar to those in juxtaglomerularcells may be found in the smooth muscle cells. Inyoung patients arterial disease is often more severe in

the 'normal'kidney due to the protective effect of therenal artery stenosis in the ischaemic kidney pre-venting the arteries becoming damaged by theassociated hypertension. This is seen particularly inpatients with malignant hypertension secondary torenal artery stenosis. The changes of fibrinoidnecrosis and mucoid intimal proliferation are con-fined to those vessels not protected by the arterialstenosis.

Conclusion

Examination of ischaemic kidneys reveals changeswhich generally correlate well with the patho-physiology of renal ischaemia. Although there is anassociation between renal ischaemia, juxtaglomerulargranulation and hypertension, notable exceptionsare seen from time to time. Improved methods ofidentification of the contents of juxtaglomerulargranules may provide better methods of prediction ofthose patients likely to benefit from nephrectomy forhypertension associated with renal ischaemia.Further studies of the function of mesangial cells andof the smooth muscle cells of the juxtaglomerularapparatus promises to provide information to explainthe collapse of glomerular tufts, and hence ofimpaired glomerular filtration, following ischaemia.

References

Becker, C. G. (1972). Demonstration of actomyosin inmesangial cells of the renal glomerulus. American Journal ofPathology, 66, 97-110.

Biava, C., and West, M. (1965). Lipofuscin-like granules invascular smooth muscle and juxtaglomerular cells ofhumankidneys. Amnerican Journal ofPathology, 47, 287-313.

Biava, C. G., and West, M. (1966). Fine structure of normalhuman juxtaglomerular cells. II. Specific and non-specificcytoplasmic granules. American Journal of Pathology, 49,955-979.

Boyer, C. C. (1956). The vascular pattern of the renalglomerulus as revealed by plastic reconstruction fromserial sections. Anatomical Record, 125, 433-442.

Cantin, M., Veilleux, R., and Desormeaux, P. (1974).Lysosomal function ofjuxtaglomerular granules. Experientia(Basel), 30, 794-797.

Cook, W. F. (1968). The detection of renin in juxtaglomerularcells. Journal of Physiology, 194, 73P-74P.

Cook, W. F., and Pickering, G. W. (1959). The location ofrenin in the rabbit kidney. Journal ofPhysiology, 149, 526-536.

Edelman, R., and Hartroft, P. M. (1961). Localization ofrenin in juxtaglomerular cells of rabbit and dog throughthe use of the fluorescent-antibody technique. CirculationResearch, 9, 1069-1077.

Fisher, E. R. (1966). Lysosomal nature of juxtaglomerulargranules. Science, 152,1752-1753.

Goldblatt, H., Lynch, J., Hanzal, R. F., and Summerville, W.W. (1934). Studies on experimental hypertension. I. Theproduction of persistent elevation of systolic blood pressureby means of renal ischaemia. Journal of ExperimentalMedicine, 59, 347-379.

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124 J. R. Tighe

Goormaghtigh, N. (1940). Histological changes in theischaemic kidney with special reference to the juxta-glomerular apparatus. American Journal of Pathology, 16,409-416.

Goormaghtigh, N. (1942). 1. La doctrine de la cellule muscu-laire, afibrillaire, endocrineen pathologiehumaine. 2. Lereinde l'eclampsie puerp6rale. Bulletin de l'Academie Royalede Medecine de Belgique, 7, 194-217.

Hall, B. V. (1954). Further studies of the normal structure ofthe renal glomerulus. In Proceedings of the Sixth AnnualConference on the Nephrotic Syndromne, edited by J. Metcoff,New York, pp. 1-39. National Nephrosis Foundation.

Hara, M., Meyer, D., and Bohle, A. (1975). The glomerularmesangium in hypertension. A morphometrical com-parison of nephrosclerosis with mesangioproliferativeglomerulonephritis on renal biopsies. Virchows Archiv. A.Pathological Anatomy and Histology, 368, 275-280.

Heptinstall, R. H. (1965). The role of the juxtaglomerularapparatus in experimental renal hypertension in the rat.Laboratory Investigation, 14, 2150-2159.

Heptinstall, R. H. (1974). Pathology of the Kidney, 2nd ed, p.129. Little Brown: Boston.

Janigan, D. T. (1965). Fluorochrome staining of juxta-glomerular cell granules. Archives of Pathology, 79, 370-375.

Jones, D. B. (1963). The nature of scar tissue in glomeru-lonephritis. American Journal ofPathology, 42, 185-199.

Jones, D. B. (1974). Arterial and glomerular lesions associatedwith severe hypertension. Light and electron microscopicstudies. Laboratory Investigation, 31, 303-313.

Latta, H., and Maunsbach, A. B. (1962a). Thejuxtaglomerularapparatus as studied microscopically. Journal of Ultra-structure Research, 6, 547-561.

Latta, H., and Maunsbach, A. B. (1962b). Relations of thecentrolobular region of the glomerulus to the juxta-

glomerular apparatus. Journal of Ultrastructure Research,6, 562-578.

Lee, J. C., Hurley, S., and Hooper, J., Jr (1966). Secretoryactivity of the juxtaglomerular granular cells of themouse: morphologic and enzyme histochemical observa-tions. Laboratory Investigation, 15, 1459-1476.

McManus, J. F. A., and Lupton, C. H., Jr (1960). Ischemicobsolescence of renal glomeruli. The natural history of thelesions and their relation to hypertension. LaboratoryInvestigation, 9, 413-434.

Nemes, Z., Bodolay, E., and Gomba, S. (1976). Evidence forlysosomal matrix in the juxtaglomerular cell granules.Acta Histochemica, 55, 80-88.

Osborne, M. J., Droz, B., Meyer, P., and Morel, F. (1975).Angiotensin II: Renal localization in glomerular mesangialcells by autoradiography. Kidney International, 8, 245-254.

Scheinman, J. I., Fish, A. J., Brown, D. M., and Michael, A. J.(1976), Human glomerular smooth muscle (mesangial)cells in culture. Laboratory Investigation, 34, 150-158.

Tighe, J. R. (1975). The mesangium in glomerular disease.Proceedings of the Royal Society of Medicine, 68, 151-158.

Tobian, L. A., Janecek, J., and Tomboulian, A. (1959).Correlation between granulation of juxtaglomerular cellsand extractable renin in rats with experimental hyper-tension. Proceedings of the Society for ExperimentalBiology and Medicine, 100, 94-96.

Tobian, L. A., Thompson, J., Twedt, R., and Janecek, J.(1958). The granulation of juxtaglomerular cells in renalhypertension, desoxycorticosterone and post desoxycorti-costerone hypertension, adrenal regeneration hypertension,and adrenal insufficiency. Journal of Clinical Investigation,37,660-671.

Turgeon, C., and Sommers, S. C. (1961). Juxtaglomerular cellcounts and human hypertension. American Journal ofPathology, 38, 227-241.

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