INTRARENAL VASCULARALTERATIONS INHEMODIALYSIS PATIENTS

A Semiquantitative Light Microscopic Study

A. Olusegun Fayemi, M.Sc, M.D .,*and Majid Ali, M.D., F.R.G.S. t

Abstract

The intrarenal arterial and ar teriolar changes in the kidneys of 80 pa­tients with chronic renal insufficiency maintain ed on hemodialysis were stud­ied serniquantitati vely by light microscopy and histochemistry. Intimal prolif­eration was common and accounted for thickening of vessel walls and luminalnarrowing. Fibrocollagenous and fibroelastotic intimal changes were locatedpredominantly in the interlobular and arcuate arteries, whereas the fibrornucin­ous intimal lesion was found mainly in the interlobar arteries. Thickening ofthe media was encountered in 25 pe r cent, and adventitial fibrosis in 20 percent of the kidneys. Necrotizing arterial or arteriolar lesions were not seen.The significance of these alterations as a possible cause of renal ischemia andtheir role in the perpetuation of hypertension are discussed.

The pathologic alterations occurringin terminal chronic renal disease, the 50 ­

called end stage kidney disease, have beenth e subject of numerous investigations. I, 2

Most of these studies have been directedtoward the identification of the causativeprimary renal diseases and their pathoge­netic mechanisms.s-:' Studies concerningthe intrarenal vascular ch an ges in chronicrenal disea ses have dealt mainly with be­n ign and malignant hypertension .s" themorphology of renal vascu lar changeshas also been studied , albeit less inten-

sively, in scleroderma, hemolytic-ure micsyndrome, and toxemia of pregnancy.8, 10-14

The intrarenal vascular changes inkidneys of hemolydialysis patients havereceived only passing attention in previ­ou s investigations. Heptinstalf describedconsiderable intimal changes in arteriesof all calibers - from segmental to inter­lobular . Such intimal changes were cellu­lar, cellular with a mucinous background,or fibrous. It was suggested that thesechanges might be related to "disuse en­darteritis." Kincaid-Smith" described

*Assistan t Clinica l Professor of Pathology, Mount Sina i School of Medicine of the City Univer­sity of Ne w York, New York, New York.

tAssistant Professor of Pa thology (Adj .), Colu mbia Uni versity College of Physicians an d Sur-geons, New York, New York. 685

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marked vascular lesions in patients whohad been on hemodialysis for some timeor who had functioning transplants. Thelesions consisted of prominent reduplica­tion of fibrous and elastic layers of arte­ries. This lesion was supposed to repre­sent "disuse" atrophy and was judged tobe similar to that encountered in atrophicpyelonephritic scars. More recentlyMcManus et al." described cellular nod­ules in the intrarenal arteries and ar­terioles in 12 of 40 kidneys from hemo­dialysis patients. The lesions weretraceable to necrotic arteries and ar­terioles and were thought to representsmooth muscle proliferation.

This presentation concerns the renalvascular alterations in 80 autopsy cases inpatients who had been maintained onlong term intermittent hemodialysis. Thestudy provides a semiquantitative evalua­tion and discusses the significance of in­timal proliferative, medial, and adventi­tial changes in arteries and arterioles.

MATERIALS AND METHODS

The autopsy files of Holy NameHospital for the years January 1969through December 1977 were examinedto identify patients with chronic renalfailure treated with or without hemodia­lysis. Ninety-six such cases were identi­fied. Five cases were excluded because ofinsufficient clinical information or inade­quate pathologic material for evaluation.The histologic slides and autopsy reportsof the remaining 91 cases were reviewed.Of these, 80 patients were maintained onhemodialysis for periods ranging fromthree weeks to seven years.

Paraffin sections of the kidneys werecut at 3 to 5 microns and stained with he­matoxylin and eosin, elastica-van Gieson,trichrome, and, when indicated, alcianblue and periodic acid-Schiff stains.Three to six sections were available forstudy in all cases.

The severity of intimal alterationswas graded on a semiquantitative scaleemploying a modification of the methodof Pitcock et al." (Table 1). Similar semi­quantitative grades were used for evalu­ating arteriolar changes except that the

TABLE 1. SEMIQUANTITATIVE GRADING OF

ARTERIOLAR THICKENING AND INTIMAL

PROLIFERATION IN INTRARENAL ARTERIES

o No significant lesions+ Small bur definite patchy intimal or

arteriolar thickening++ Intimal or arteriolar thickening exceeding

two to three times the luminal diameter++ Intimal or arteriolar thickening

approximately equal to or greaterthan the diameter of the lumen of thevessel

thickness of the entire wall of the ar­teriole was substituted for intimal thick­ness. Medial and adventitial alterationswere not quantitated.

Three main patterns of intimal pro­liferation were defined: fibrocollagenous,fibromucinous, and fibroelastotic. In fi­brocollagenous intimal proliferation thelesion was composed predominantly offibroblasts and collagen fibrils. This waseasily demonstrable by the trichromestain and was sometimes associated withmild reduplication of the internal elasticlamina (Fig. 1). In the fibroelastotic pat­tern the duplication of the elastic laminawas prominent and constituted the mostconspicuous change of the intima. Thislesion usually had a minor fibrous corn­ponent (Fig. 2). The third type of intimalalteration, the fibromucinous type, wascharacterized by a faintly bluish hue onhematoxylin and eosin sections andsparse cellularity; the predominant cellwas stellate shaped with a few fibroblasts(Fig. 3). The lesion stained diffusely withalcian blue. The significance of the differ­ence in the distribution of the types ofintimal proliferation in the arteries ofdifferent sizes was determined by chi­square (X2

) analysis. Additionally, the re­lationship of the arterial and arteriolarlesions to the duration of dialysis, thepresence and severity of hypertension,and the primary renal diseases was stud­ied.

Other parameters that were studiedincluded the primary renal disease, thedata for which were derived from boththe gross and the microscopic features ineach case. The criteria employed for dif­ferentiating the various forms of chronicrenal disease were those described by

INTRARENAL VASCULAR ALTERATIONS-FAYEMI, ALI

Figure 1. Arcuate artery showing librocollagenous intimal thickening. There IS reduplication of theelastic lamina. (Elastica-van Gieson stain. X IDO.)

Figure 2. Fibroelastotic intimal thickening in an arcuate artery. Note luminal narrowing. (Elastica-vanGieson stain. x 100.)

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HUM.-\:\ PATHOLOGY-VOLUME I D, ~UMBER fi Not.ember 1979

Figure 3. Longitudinal section of an arcuate artery showing fibrornucinous intimal thickening. Note theabsence of significant elastotic change. (Elastica-van Gieson stain. X 100.)

Heptinstall.v> Special attention was paidto calcification of the various histologiccomponents of the kidneys. The hospitalrecords and clinical summaries that forman integral part of the autopsy protocolprovided information regarding the agesof the patients and the duration of he­modialysis before death.

OBSERVATIONS

Age and Sex Distribution

The ages of the 80 patients in thisstudy ranged from 15 to 84 years with an

average of 55.8 years. There were 43men and 37 women. Fifteen patientswere 40 years old or younger (Fig. 4).

Etiology of Chronic Renal Failure

The underlying renal diseases inthese patients were as follows: chronicpyelonephritis (20), chronic glomerulone­phritis (I3), arterio- and arteriolo­nephrosclerosis (14), diabetic nephropa­thy (I3), polycystic kidney disease (10),end stage renal disease of indetermin­able etiology (4), chronic interstitialnephritis (3), focal sclerosis (1), amyloido­sis (1), and medullary cystic disease (1).

20.------ - - ----------,

Figure 4. Age and sex distribution ofSO patients. Most patients were 50 years orolder.

MolesFema les

o 10-19 20-29 30-39 40-49 50-59 60-69 70·79 80-89AGE

fflI-z 15wi=Cf.~ 100:WCD~ 5::lZ

688

INTRARENAL VASCULAR ALTERATIONS-FAYEMI, ALl

NUMBER OF CASESo 10 15 20 25 30 35 40

FIBROUS

Figure 5. Pattern of intimal thickeningin intrarenal arteries of hemodialysis patients.The lesions in the interlobular and arcuate FIBRO­arteries are generally similar but differ sig- ELASTOTICnificantly from those in interlobar arteries(p < 0.0001).

FIBRO­MUCINOUS

LOBAR ( INTERLOBAR )

INTIMAL CHANGES. The pattern,frequency, and severity of intimal prolif­eration in the intrarenal arteries are de­tailed in Figures 5 and 6. Although thevarious types of lesions do not differ sig­nificantly in their incidence in the arcuateand interlobular arteries, a significant dif­ference exists when these two types ofvessels are compared individually or incombination with the larger interlobar ar­teries (p< 0.0001). The predominant le­sion of the interlobar arteries is fibromu­cinous; fibrous andfibroelastotic intimalchanges occur more frequently in theother arteries. Similarly, statistical analy­sis of the data shows that a predictioncould be made regarding the location ofeach type of lesion. For example, whenthe lesion is fibrous, it is more likely to befound in an arcuate or interlobular thanin a lobar artery. ~ similar conclusioncan be drawn for fibroelastotic and theopposite conclusion for fibromucinous in­timal changes. The intimal changes boreno relationship to the duration of dialysistreatment, the underlying renal disease,or the hypertensive status of the patients.

MEDIAL AND ADVENTITIAL CHANGES.

Meclial hypertrophy was p resen t in 21cases. They usually involved the smallerarcuate and interlobular arteries. In somecases the hypertrophy was cellular; inothers a significant amount of collagenwas present (Fig. 7). There was a definiteincrease in the adventitial fibrous tissuein 16 kidneys. It was characteristicallyacellular and collagenous and involvedarteries of all sizes. Occasionally periven-ous fibrosis was noted. 689

ARCUATE

INT ERLOBULAR

(/) 0wl;{l20uu, 15oa: 10wlD~ 5:JZ O t-J'-"'.-._'-J...-_..L.....L~'--i

20

15

10

5

20

15

10

5

++ +++SE VERITY

Figure 6. Semiquantitative evaluation of in­timal proliferation in intrarenal arteries of hemo­dialysis patients. Fibrornucinous lesions are most.prevalent and most severe in interlobar arteries.

Pathologic Findings

Interlobular and arcuate arterieswere evaluated in all 80 patients. Sectionsof the kidneys from nine patients did notcontain interlobar arteries. The involve­ment of the vessels at different levels wasvariable; interlobar arteries showed nosignificant alterations in II instances, ar­cuate arteries in six, and interlobular ar­teries in another six cases.

HUMAN PATHOLOGY-VOLUME 10, NU~IBER 6 November 1979

Figure 7. Arterial wall showing medial thickening and mild fibromucinous intimal lesion.

ARTERIOLAR CHANGES. The ar-terioles were relatively normal in the kid­neys of 10 patients. The others showedhyperplastic or hyaline arteriolosclerosis.The severity and distribution of thesechanges are detailed in Table 2. Neitherfibrinoid necrosis nor necrotizing arterio­litis was encountered.

MISCELLANEOUS OnSERVATIONS. Thedeposition of calcium in the renal paren­chyma was found in 61 cases. Amongthese, vascular calcification was observedin 10 instances (six mild, four moderate).The larger vessels were more commonlyinvolved. Despite the high frequency andusually severe renal oxalosis in this study,deposition of oxalate crystals in the renalblood vessels was not seen.

TABLE 2. RENAL ARTERIOLAR LESIONS IN

80 HEMODIALYSIS PATIENTS

Type ofLesion Severity of Lesions Total

+ ++ +t+Hyaline

arteriolosclerosis 19 13 3:~

Hyperplasticarteriolosclerosis 9 }[) 12 37

No pathologic

690 alterations 10

DISCUSSION

The present study has shown the dis­tribution and severity of intrarenal vascu­lar lesions in patients with chronic renalfailure on hemodialysis. The entire in­trarenal vascular system from the interlo­bar arteries t.o the arterioles were in­volved by t.hese pathologic changes.Although fibrous, fibroelastotic, and fi­bromucinous intimal proliferative lesionsmay be found in intrarenal arteries of alltypes, we have demonstrated that signifi­cant differences occur in the distributionof these lesions. Thus, fibroelastotic andfibrous lesions are more likely to be en­countered in interlobular and arcuate ar­teries, whereas the fibromucinous varietyis most prevalent in the interlobar vessels.The duration of dialysis and the hyper­tensive status of the patients could not becorrelated with the type or severity of thearterial lesions. Similarly the impact ofthe underlying renal diseases on the vas­cular lesions could not be ascertained.This may be attributed in part to thesmall number of cases in each disease cat­egory.

The pathogenesis of intimal thicken­ing in intrarenal arteries is obscure. Twomechanisms have been proposed. The

INTRARENAL VASCULAR ALTERATIONS-FAYEMI, ALI

'1[~i~;;~':::::~1:ng ----)"J> Endothelial >~ Increased permeabilityof vessels damage of endothelium 1

Vasoconstriction

Organization and ~(~---------___ Insudation of plasmarnyointimal proliferation components

(intimal thickening)

Figure 8. Pathogenetic mechanism for intimal thickening in intrarenal arteries.

more widely accepted view, representedschematically in Figure 8, invokes endo­thelial damage with a subsequent increasein permeability as the initial event. Sup­port for this pathway is derived from ex­perimental work and ultrastructuralstudies. 17•2o Mural thrombosis followed byorganization and endothelialization servesas the basis for the second mechanism ofintimal thickening." In this study recan­alized thrombi were seen in only twocases and in these appeared to be second­ary to the underlying severely thickenedintima.

The literature contains scanty infor­mation about the alterations of the vascu­lar media in chronic renal disease. Obser­vations that have been reported are thoseconcerning the morphology of the arteri­al media in hypertension. Sinclair et al."noted an "attenuated" layer of mediastretched around the intima; Pitcock eta!.5 found that the media was frequentlynormal, occasionally showed thinning,and rarely was completely absent; jones"described a thin layer of hypertrophiedmedial cells stretched over an "onionskin" type of intimal proliferation.

However, divergent data are provid­ed by ~jungqvist,22 who in a microangio­graphic and histologic study of intrarenalarterial patterns in malignant hyperten­sion found hypertrophy of the vascularmedia. The media may be thick in theearly phases of hypertension but maysubsequently become atrophic." The onlyreference to the medial alterations in theend stage kidney disease in hemodialysispatients is provided by McManus et al.,"who found a decrease in the musculaturebut an increase in the ground substanceof the media.

The findings in the present study are

at variance with this conclusion. Aboutone-quarter of our patients showed hy­pertrophy of the smaller arcuate and in­terlobular arteries. These changes wereusually associated with a hyperplastic"onion skin" type of intimal lesion in thearterioles. Unfortunately we did notquantitate the degree of medial thicken­ing in these cases. The discrepancy inthese findings may be explained by sug­gesting that medial hypertrophy occursas an initial response to hypertension.Later, as the elevated blood pressure be­comes more severe or chronic, secondarythinning by dilatation of the vesselsensues. This may be combined with me­dial atrophy resulting from external pres­sure exerted by the severely thickened in­tima. The situation would be similar tothe changes encountered in the vessels ofthe lungs in pulmonary hypertension."

The absence of necrotizing arteriolarlesions in this investigation is of some in­terest. The arterioles showed either hy­perplastic and hyaline arteriolosclerosis inalmost equal proportions. This findingconfirms the observations of others whohave recently studied the renal vascularchanges in hypertensive kidneys." 6,11 Ar­teriolar fibrinoid necrosis, traditionallyconsidered the hallmark of malignant hy­pertension, has been encountered lessfrequently in these studies. The de­creased incidence of this pathologicchange has been linked with better drugcontrol of hypertension.v !' Since hemo­dialysis ameliorates hypertension to aconsiderable extent through a reductionin body electrolytes and extracellularfluid, it would be expected that fibrinoidnecrosis would be less commonly encoun­tered in hemodialysis patients.

The significance of the intrarenal 691

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vascular changes in hemodialysis patientslies in the probability of sustaining hyper­tension, a central problem in the man­agement of patients with end stage renaldisease. The prevailing current opinionholds that hypertension, especially the es­sential type, precedes and induces in­trarenal vascular disease.': 2, 7 This viewhas been vigorously challenged by Gold­blatr'" and Hollenberg et al.,25-27 who inelegant studies have demonstrated theimportant role of the renal vasculature inthe pathogenesis and sustenance of hy­pertension. The latter have shownthrough pharmacologic and radiographicstudies that vasoconstriction of intrarenalvessels may be the primary abnormalityin renal ischemia in a large number ofhypertensive patients ,26 The presentstudy provides anatomic support for thispoint of view. The intrarenal microvascu­lar alteration in patients maintained onhemodialysis reported herein leads tonarrowing of the vascular lumen, whichwould produce and accentuate renal is­chemia. This, in turn, may adversely af­fect the hypertensive status of the pa­tients.

Our observations have led us to con­clude that the vascular alterations inthese patients should not be regarded aspassive lesions emanating from kidneyswhose functions have been usurped byartificial support, but as a probablesource of significant morbidity.

ACKNOWLEDGMENT

We are indebted to Dr. David Korts,Department of Biostatistics, The MountSinai School of Medicine, New York, forthe statistical analysis and to Joyce Yondo­lino for secretarial assistance.

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INTRARENAL VASCULAR ALTERATIONS-FAYEMI, ALI

in rats with intermittent acute angiotensin­hypertension. Acta Path. Microbiol. Scand.,74 :325, 1968.

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Department of PathologyHoly Name HospitalTeaneck, New Jersey 07666 (Dr. Fayemi)

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