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Malignant hypertension (a clinico-pathologic study of 43 cases).
Malignant hypertension is a known complication of hypertension. Primary or secondary hypertension due to renal or non-renal causes can be complicated by development of papilloedema and has a malignantcourse.[1] Aggressive drug therapy with dialysis improves the prognosis in these patients.[10] Fibrinoid necrosis of glomerular capillaries with localised proliferation of endocapillary cells, fibrinoid necrosis of arterioles, and endarteritis of the arterioles and small arteries have been regarded as the characteristic pathological changes in cases of malignant hypertension.[5] These changes would be altered to certain extent by the treatment received. We have studied 43 cases of malignant hypertension (32 autopsies and11 renal biopsies) and tried to correlate the histopathologic findings with the clinical and biochemical data, which forms the basis of the present communication.
Forty-three cases presenting with malignant hypertension (diastolic pressure above 120 mm Hg associated with a grade IV change of retinopathy) were selected for this study. Clinical history with reference to symptomatology, duration of existing benign hypertension, mode of therapy and response to treatment was obtained. Biochemical data regarding renal chemistry was also obtained. Of the 43 cases studied, 32 were fatal and their autopsy material was available. Two sections from each kidney were studied. Eleven cases had recovered and their renal biopsy material was available. All sections were stained with H. & E., P.A.S., elastic van Gieson and Putt's fibrin stain.
Clinical and biochemical findings Nine cases presented for the first time with hypertension and were detected to have malignant hypertension. In 21 cases hypertension was detected less than a year ago while in 10 cases pre-existing hypertension was present for more than a year, maximum duration being 10 years. Thirty-six cases were males. The age range was 10 years to 55 years, with maximum number of patients being in the 26-50 year age group. On analysing the clinical data, oligo-anuria (86.04%), cardiac failure (58.1%), decreased vision (32.5%), and headache (25.5%) were the main presenting symptoms. Uraemic manifestations were noted in 52.2%, Serum creatinine values varied from 1.6 to 19 mg%. Thirty-eight patients were treated with drugs and dialysis, and 5 patients received only drug therapy. According to the response to therapy, patients were grouped as follows: Group I: Consisted of 14 cases where B.P. was fully controlled, their diastolic B.P. being below 100 mm Hg following treatment. Group II: Comprised 4 cases, whose B.P, were marginally controlled; their diastolic B.P. was between 100 and 110 mm Hg. Group III: Comprised 19 cases, whose B.P. were uncontrolled. Group IV: Consisted of the rest 6 cases. Their exact diastolic B.P. after treatment was not known. Thirty-two cases in our series were fatal and autopsy was performed on them, Remaining 11 cases survived and renal biopsy could be done in all of them. Based on the clinical and pathological data, cases were classified as primary or secondary hypertension. Accordingly, there were 14 cases secondary to glomerulo-nephritis; 4 cases due to tubulo-interstitial disease, 7 cases had end stage renal diseases and in the rest 18 cases, no primary cause could be found; hence, they were labelled as having essential hypertension. There was no case of reno-vascular hypertension. Histopathologic findings Glomeruli Wrinkling of basement membrane with shrinkage of the tufts was noted in majority of cases. Deposition of PAS-negative, hyaline material, internal to the Bowman's capsule, was noted in some of the hyalinised glomeruli. Fibrinoid necrosis involving the glomerular tufts was noted in 6 fetal cases. The number of glomeruli showing this change was, however, very low (2-5/100 glomeruli) and was segmental. Focal proliferative change in relation to this necrosis was seen in only 4 cases. Glomerulonephritis There were 14 cases of glomerulo- nephritis with secondary malignant hypertension. There were 3 cases of extra-capillary crescentic glomerulonephritis and 4 cases with membranoproliferative glomerulonephritis with crescents. Remaining 7 cases had chronic glomerulo-nephritis. These glomerular changes due to glomerulonephritis were diffuse while changes due to malignant hypertension were focal. Afferent arterioles Arteriolar hyalinization was a consistent finding and was seen in 24 out of 32 autopsied cases and 5 of the 11 biopsies. Hyaline was variable in amount and was frequently abundant giving rise to a doughnut like appearance. Fibrinoid necrosis was seen in 9 fatal cases. The number of arterioles showing fibrinoid necrosis was small (3-5%). Interlobular arteries Intimal thickening caused by spindle shaped cells arranged circumferentially was noted in 28 cases. The lumen was markedly compromised and in 12 cases it was pin point with apparent disappearance of endothelial cells. The matrix was mucoid, loose and basophilic in 11 cases. Elastic van Gieson stain revealed incomplete elastic fibres in the intima near the lumen. Fibrinoid necrosis was seen in 6 fatal cases. It was scanty in amount and was seen in very occasional arteries, hence detected mainly on fibrin stain. Arcuate arteries Cellular intimal thickening (C.I.T.) was seen in medium-sized arteries in 18 cases. Fibrous intimal thickening (F.I.T.) was a predominant finding and was seen in 21 cases. Fibrinoid necrosis was not seen in any case; Tubulointerstitial changes In 4 cases, evidence of chronic pyelonephritis was found. In one case it was superadded on hydronephrotic kidneys. Tubular atrophy of moderate to severe degree was noted in all cases. None of the cases showed evidence of tubular necrosis. Correlation between histopathologic changes and control of BP following treatment [Table 1] Fibrinoid necrosis was seen in fatal cases only, and majority of them had uncontrolled BP even after aggressive therapy. All 6 cases showing fibrinoid necrosis of the glomerular tufts belonged to group III. Of the 9 cases with fibrinoid necrosis of the arterioles, 8 were from group III and 1, from group II.s In 6 cases, interlobular arteries showed fibrinoid necrosis; 5 of these had uncontrolled BP (group III) while 1 case had marginally controlled B.P. (group II). Changes of cellular intimal thickening in the small arteries too correlated very well with the levels of diastolic BP of the 19 cases in group III; 15 cases (78%) showed cellular intimal thickening. Incidence of cellular intimal thickening in group II was 50% and in group I, 55%. Cellularity seemed to be more in group III as compared to group I. Collagenisation near the periphery of the cellular intima was in group I. Correlation between serum creatinine and histopathology findings [Table 2] This correlation could be done in only thirty-nine cases. About 33% of the cases with serum creatinine above 15 mg% showed evidence of fibrinoid necrosis. No case with serum creatine below 2 mg% showed fibrinoid necrosis. C.I.T. was seen in 88.8% of cases with serum creatinine of more than 15 mg%. However, 50% of cases with serum creatinine of less than 2 mg% also showed C.I.T. There was a rise in the percentage of cases showing the changes of C.I.T. with rising levels of serum creatinine [Table 2]; but this rise was not significant. Correlation of histopathologic changes with age Incidence of fibrous intimal thickening (F.I.T.) increased with age. 43.75% of cases below 30 years showed F.I.T. in medium sized arteries compared to 100% of cases in the 6th decade. Fibrinoid necrosis too showed a slight increase with age (18.8% below 30 years and 50% in the 6th decade). Maximum incidence of C.I.T. was seen in the 4th and 5th decades (69%). It decreased to 50% in the 6th decade and 55% in cases below 30 years. Cause of death in fatal cases Of the 32 fatal cases, B.P. was controlled in 8 cases, it was marginally controlled in 1 case and uncontrolled in 18 cases. In 5 cases, exact levels of B.P. after treatment were unknown. Only in one case was the hypertensive pontine haemorrhage responsible for death. Renal failure was the main cause in the rest of the cases. Associated finding of severe cerebral oedema was noted in 4 cases and cardiac failure in 2 cases.
Malignant hypertension is not a specific disease entity and can complicate benign hypertension, either primary, or hypertension secondary to renal or non-renal causes such as Cushing's disease, pheo chromocytoma and renal artery stenosis and chronic renal disease.[1] Untreated malignant hypertension carries with it an extremely poor prognosis.[6],[8] Aggressive therapy with drugs and dialysis helps in improving the prognosis.10 Though the incidence of benign hypertension increases with age, malignant hypertension is rarely seen beyond the fifth decade.[8] It is also rarely reported below the age of 35 years.[13] In our study, majority of cases, (74.2%) were between the age of 26 and 50 years. 41.9% cases were below 35 years. All these cases below the age of 35 years had secondary hypertension. There was no case beyond the age of 55 years. Fibrinoid necrosis and cellular intimal thickening giving rise to endarteritis proliferans are considered as the characteristic histologic features of malignant hyperension.[5] Prolonged haemodialysis,[11] successful or prolonged anti-hypertensive Ireatment,[3],[9] levels of B.P. at the time of obtaining the tissue for histopathologic. study[13] could all influence histopathologic findings. Controversy exists as to which feature, fibrinoid necrosis or hyperplastic endarteries, correlates better with levels B.P. and hence can be considered as the hallmark of malignant hypertension. Brewer[2] and Heptinstall[4] found a good correlation between the levels of hypertension and fibrinoid necrosis. On the her hand, Kincaid-Smith et al,[8] and Saltz[14] et al found fibrinoid necrosis in hypertensive patients who had no evidence of developing the malignant phase. They felt that fibrinoid necrosis was a terminal event and correlated better with the degree of azotemia and hence was not essential for diagnosis. Pitcock et al[12] did not find fibrinoid necrosis in any of the 25 cases of malignant hypertension in American Black population. Proliferative endarteritis was found to correlate better with levels of hypertension than fibrinoid necrosis.[5],[7],[12] The prominent lesion in thelatterseries[12] was myxoid intimal thickening resembling scleroderma. In our study, changes of fibrinoid necrosis was noted only in autopsied cases; and all cases, had uncontrolled or only marginally controlled BP [Table 1]. All cases with fibrinoid necrosis were from; group III, except 2 cases from group II. Conversely, however, all cases with uncontrolled BP did not show evidence of fibrinoid necrosis. The percentage of glomeruli or arterioles showing fibrinoid necrosis was low, 3-5% of glomeruli or arterioles in comparison with 10-30% reported by other workers.[2],[5] Cellular intimal thickening was a more consistent finding and correlated well with B.P. levels. 78.9% of cases from group III showed C.I.T. compared to 50% from group II and 42.8% from group I. Mucoid change in the intima was noted in 11 cases, 50% of the cases being from group III. Absence of fibrinoid necrosis and collagenisation towards the periphery of the cellular intima was seen in group I. This could be in response to therapy. Similar changes in histopathologic findings after successful treatment were noted by McCormack et al[11] and Harrington et al.[9] The most obvious alteration noted by them was cessation of activity, regression in arteriolar necrosis and appearance of subintimal fibroplasia following treatment. Although the acute lesions of malignant hypertension may be reversible and proceed to healing, the hypertensive state results in damage to large and medium-sized areries which progress to atherosclerosis and fibrous intimal hyperplasia.[11] In our study, the percent- age of cases showing fibrous intimal thickening (F.I.T.) was seen to be equal in those cases with controlled and uncontrolled B.P. Incidence of F.I.T. correlated better with age. There was no correlation between serum creatinine values and incidence of fibrinoid necrosis. C.I.T. was noted in 50% of cases with serum creatinine below 2 mg% and about 88% of cases with serum creatinine above 15%. It suggests that C.I.T. with marked obliteration of vascular lumen may be the cause of renal failure in those cases. As a consequence, acute renal failure was the most common cause of death in our series. Hypertensive intracranial haemorrhage was responsible for death in only 1 case. In summary, 43 cases of malignant hypertension were studied. Changes of fibrinoid necrosis and C.I.T. correlated better with levels of B.P. than with serum creatinine. Treatment had altered the histopathologic findings.
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