Characteristics and Outcome of Biopsy-proven Malignant Hypertension with Severe Kidney Injury: A Retrospective Study

Introduction

Malignant hypertension has a low prevalence in the general population.[12] An exact definition has been waved aside till date. Most recently it was defined as the presence of very high blood pressures (no cut off value) with ischaemic target organ damage (retina, kidney and heart or brain) and so, has digressed from banking on ischaemic retinal changes which can be variably present.[34] Renal abnormalities including elevated serum creatinine, proteinuria (often ≤1 g/24 h) and microscopic haematuria are seen in 60–70% and impaired renal function portends poor renal and patient survival.[5]

Malignant hypertension-related renal changes, thrombotic microangiopathy (TMA) and kidney function often recover upon blood pressure control.[67] Although these acute lesions may proceed to heal, the hypertensive state induces damage to large and medium-sized vessels facilitating atherosclerosis and fibrous intimal hyperplasia.[8] At presentation, 18–40% may require renal replacement therapy (RRT) and over the long term, 6–46% have culminated in end-stage kidney disease (ESKD) with a patient survival rate of 84–90%.[259101112] Death often results from cardiovascular events.[51112] Survival of malignant hypertension has considerably improved with the advent of antihypertensive therapy, but the end-stage kidney disease (ESKD) remains a significant cause of morbidity and mortality.[91314] Initial serum creatinine and control of hypertension were the primary determinants of renal outcome and patient survival.[515] There is only limited information on the clinicopathological profile, renal outcome and patient survival in biopsy-proven malignant hypertension, especially in the current era of potent antihypertensive medications. In most of the existing data, the definition of malignant hypertension is clinical, with emphasis on retinal changes rather than the presence of fibrinoid necrosis on histology. The current study looks into the long-term outcomes of malignant hypertension and its clinical and renal histological correlate.

Materials and Methods

Results

A total of 1180 renal biopsies from January 2014 to December 2018 were screened, 34 (2.9%) of them histopathologically diagnosed as malignant hypertension were identified. Four biopsies were excluded because of incomplete clinical data. Table 1 shows the demographic and clinical parameters at admission. Dialysis at admission was required by 21 (72.4%) subjects.

Discussion

Malignant hypertension is rarely seen beyond the fifth decade and also rarely reported below the age of 35 years, and our cohort had a wide age range of 18 to 65 years (mean 40 ± 11.5 years), with the maximum number of patients being in 35–60 years group.[1518] In contrast to previous literature, the high proportions of dialysis requiring renal failure (72%) might be due to many with rapidly progressive renal failure, with biopsy-proven malignant hypertension.[9519] To our knowledge, patients with this severe degree of renal failure with biopsy-proven malignant hypertension have not been studied till date. Despite biopsy evidence of malignant hypertension, severe neuroretinopathy was confined to only one-third of the patients thereby questioning the reliability of fundal changes as the hallmark of malignant hypertension.[42021] In a retrospective analysis, severe retinopathy was documented in less than 50% of cases with accelerated hypertension.[22]

In cases of renal TMA, the pathology was almost always arterial or arteriolar than glomerular; a feature documented previously in a large study involving 61 cases of biopsy-proven malignant hypertension-induced TMA.[23] Peripheral TMA was less often seen even when there was evidence of the same in target organs. The significant correlations of fibrinoid necrosis, proliferative endarteritis, arteriolar hyalinisation or myxoid intimal thickening with the levels of hypertension evidenced in previous studies were lacking in this cohort.[242526] Fibrinoid necrosis in vessels has been associated with uncontrolled hypertension and death.[27]

There is not too much literature on malignant hypertension patient profile and the detailed renal pathological descriptions are before the 1990s. The classical renal histopathology description of malignant hypertension includes glomerular fibrinoid necrosis, mesangiolysis, endothelial swelling, tuft collapse, ischaemic wrinkling, and vascular changes of fibrinoid necrosis, arteriolar hyalinisation and thrombus and mucoid intimal hyperplasia.[16] The same has been the findings in several clinicopathological studies but findings were variable in each cohort.[272829] Arteriolar hyalinisation, vascular fibrinoid necrosis and mucoid intimal thickening were universally reported, whereas glomerular fibrinoid necrosis is exceedingly rare.[272829] One notable feature among blacks was the absence of arteriolar fibrinoid necrosis.[29] This was also noted in the Japanese series of 12 patients where onion skin lesions and tuft collapse was seen in all in the absence of fibrinoid necrosis. In the current study, there is 100% arteriolar/arterial involvement with a predominance of arteriolar/arterial fibrinoid necrosis, acute vascular TMA, intimal fibrosis and intimal mucoid changes with the sparse incidence of glomerular fibrinoid necrosis and arteriolar hyalinisation. Small vessel fibrinoid necrosis and thrombi are the prominent findings in our cohort though are not universal.

Although we excluded patients with pre-existing documented CKD, the majority of the patients turned out to have chronic changes in renal pathology. The chronicity in the glomeruli may have been either due to long-standing hypertension or due to undetermined pre-existing CKD. One-third of the patients were found to have crescents. As noted above, crescent may be the cue to a glomerular disease-causing hypertension while ischaemic wrinkling and total vessel occlusion were conspicuous in isolated malignant hypertension. In the unique detailed description of pertinent histopathology by Hepinstall, malignant transformation of essential hypertension differed from those secondary to glomerulonephritis in tuft necrosis, focal involvement of glomeruli, arterial necrosis (with less than 5% of vessels involved) and endarteritis fibrosa in the small arteries.[26]

The hypertensive retinopathy of severe grades was seen in only 33.3% (n = 10) cases and only in one case of isolated malignant hypertension. It was more commonly seen in cases of malignant hypertension with evidence of primary glomerular disease and was negatively associated with glomerular ischaemic wrinkling. This was impressively documented in a previous study where hypertensive retinopathy of all grades occurred more frequently in renal parenchymal hypertension than in essential hypertension (P < 0.01). Severe hypertensive retinopathy was seen even in mild hypertension of renal parenchymal disease and was attributed to the increased local vascular permeability and intraretinal leakage of plasma components due to the uremic toxins.[30] Severe retinopathy was also an indicator for non-recovery of renal function, and along with renal dysfunction indicates multiple target organ damage and thence poor renal and patient outcomes.[22]

Recovery of renal function is often incomplete when there is biopsy evidence of malignant hypertension and this is further compromised when kidney injury is severe.[567915] However, even partial renal recovery seems to augur good patient survival. The Bordeaux registry of malignant hypertension, though incomparable about the acute kidney injury (AKI) severity, had noticed worsening of renal function in 14% at 48 months.[12] Successful therapy with antihypertensives do bring about notable histopathological changes with regression of necrosis and appearance of subintimal fibroplasia.[8] As the degree of kidney injury was severe in our cohort the outcomes are not comparable to the existing data on malignant hypertension outcomes.

ESRD rate in malignant hypertension was high at 65.5% and again the severity of kidney injury at presentation determined the long-term renal outcome while none of the acute or chronic vascular changes presaged ESRD.[51012] The presence of TMA also did not predict the long-term renal outcome. This is similar to the large retrospective analysis (1974–2007) wherein those with worse baseline renal function (serum creatinine >3.4 mg/dL), 83.3% finally needed maintenance dialysis.[5] The long-term renal outcome of biopsy-proven malignant hypertension had shown progression to ESRD in 33% even in cohorts with lesser degrees of AKI (serum creatinine 2.27 [1.74-3.14] mg/dL) at presentation.[101123] In contrast, only 3% of patients with severe non-malignant hypertension develop ESRD in long term.[31] Apart from the serum creatinine factor, uncontrolled blood pressure also increases the risk of ESRD by 4–5 folds.[11] Our study also affirms that the severity of renal failure at presentation is the detrimental prognostic factor for renal survival.

The death rate was 50% (n = 13) and the prime predictor was ESRD. Multiple target organ damage primarily renal failure and cardiovascular events are the predictors of death in malignant hypertension, and the survival rate without ESRD is found to be 90% at 5 years.[9101132] There is an increased risk of death in malignant hypertension with every target organ damage (heart, kidney, retina) and severe retinopathy has been associated with mortality.[32] Interestingly, the absence of hypertensive retinopathy was also linked to patient survival in our cohort and this could be analysed further in future studies. The lesser incidence of baseline mild to moderate hypertensive retinopathy, glomerular endocapillary cellularity and tubular atrophy in those who had survived could have been the positive factors for lesser rates of ESRD in these cases.

The two large retrospective analyses of 30 years and 17 years which included 315 and 120 patients with malignant hypertension and follow-up of 1–389 months and 28–108 months, respectively, the renal outcome and patient survival were associated with serum creatinine (>200 μmol/L and 175 μmol/L) and uncontrolled hypertension. The follow-up data was of a very long term and the renal dysfunction in the majority of subjects was not severe at presentation (175 (104–402) μmol/L or 1.2–4.5 mg/dL).[1011] In this respect, our study has included only those with severe renal dysfunction with biopsy-proven malignant hypertension and thorough data in this type of cohort is lacking.

Conclusion

Malignant hypertension is an important cause for rapidly progressive renal failure and clinical description should be all-inclusive of target organs beyond the retina. Vascular microangiopathy and small vessel fibrinoid necrosis were prevalent. The accelerated essential hypertension differs from renal parenchymal hypertension in histology. As in other causes of renal injury, the initial serum creatinine is the principal determinant of renal outcome in cases of severe kidney injury of malignant hypertension. Recovery is often incomplete, and eventually, renal recovery determines patient survival.