Role of complement in so-called benign and malignant nephrosclerosis
Patients presenting with severe hypertension in combination with hypertensive retinopathy, hypertensive encephalopathy and often renal injury with mild signs of thrombotic microangiopathy are labeled to have “malignant hypertension”. Severe hypertension can induce thrombotic microangiopathy in the renal vasculature, the occurrence of which has been linked to mechanical stress to the endothelium. In the majority of patients with arterial hypertension, so-called benign nephrosclerosis or hyaline arteriosclerosis can be found in the kidney. The structural changes of so-called benign nephrosclerosis are characterized by intimal fibroelastosis in arteries including interlobular caliber vessels and sub endothelial hyalinosis in afferent arterioles and pre-arterioles as shown in Figure 2a. The extent of hyalinosis usually correlates with duration and severity of arterial hypertension. Glomeruli show hypertensive injury most likely derived from barotrauma with segmental sclerosis and scarring (Figure 2b).
The histologic changes found in malignant nephrosclerosis are different and malignant nephrosclerosis is more correctly called stenosing arteriosclerosis. It is a form of thrombotic microangiopathy defined by progressive narrowing of interlobular arterial branches and afferent arterioles with intima fibrosis and onion-like appearance of intimal scarring as shown in Figure 2c. In renal biopsies with malignant nephrosclerosis, a pseudo neuroendocrine atrophy pattern can be found. The disease defining change is a progressive narrowing of interlobular arterial branches and afferent arterioles with intima fibrosis and onion-like appearance. The oxygen supply to the glomerulus is reduced resulting in ischemic wrinkling of the glomeruli and atrophic tubules (Figure 2c). The mechanisms causing transition from high blood pressure to malignant hypertension with malignant nephrosclerosis and renal failure are completely unknown. Patient presenting with malignant nephrosclerosis are often young and have a short history of uncontrolled hypertension. It is also unclear, why few patients with hypertension develop malignant nephrosclerosis and several others, with similar levels of blood pressure elevation over much longer time, do not (Wenzel et al. 2017). There must be a certain susceptibility and we argue that changes in the complement system could be among the causes. Malignant nephrosclerosis is hallmarked by complement deposition, inflammation and signs of thrombotic microangiopathy with a renal pathology resembling certain histological features of aHUS (Wenzel et al., 2015). A crucial involvement of the complement system in pathogenesis of thrombotic microangiopathy has been highlighted by numerous studies in the recent years and it has been shown that aHUS can be cured by therapeutic complement inhibition using the C5 cleavage inhibitor eculizumab (Noris & Remuzzi, 2009). The shared clinical and histopathological features between malignant nephrosclerosis and aHUS strongly suggest a role for complement also in the development of malignant nephrosclerosis and point to complement inhibition as a potential therapeutic strategy in malignant hypertension. One may speculate that over activity of complement factors or lack of complement inhibitors defines the subset of hypertensive patients that develop malignant hypertension and nephrosclerosis in response to arterial hypertension (Wenzel et al., 2017). A diagnosis of thrombotic microangiopathy on kidney biopsy in a patient presenting with hypertensive emergency has historically elicited the diagnosis of malignant hypertension-associated thrombotic microangiopathy. Recent studies, however, have raised awareness that a number of these patients may actually represent cases of aHUS. Timmermans and colleagues have published a series of data suggesting that complement defects may be the culprit of disease in patients who present with high blood pressure, severe renal disease, and often progress to end stage renal disease despite blood pressure control. In their first publication, they found genetic defects in the complement system in six out of nine patients with renal thrombotic microangiopathy attributed to severe hypertension from the Limburg Renal Registry. In contrast to patients without genetic defects, patients with complement defects invariably progressed to end-stage renal disease (Timmermans et al., 2017). Moreover, the group showed that serum samples collected at presentation from patients with hypertension associated thrombotic microangiopathy induced abnormal C5b-9 formation on microvascular endothelial cells indicating activation of complement in these patients (Timmermans et al., 2018). In a recent follow up study, the same authors present data showing that assessment of both ex vivo C5b-9 formation and screening for variants in complement genes may categorize patients with hypertensive emergency and thrombotic microangiopathy into two different groups, blood pressure mediated and complement mediated as shown in the upper part of figure 3. Thus, the first group requires blood pressure control whilst the second group should be treated with eculizumab and blood pressure control (Timmermans et al., 2020). However, malignant nephrosclerosis and aHUS presumably represent a continuum of two different diseases as shown in the lower part of figure 3. Laecke et al. recently proposed that variable degrees of the importance of blood pressure versus complement-mediated mechanisms could be found in malignant nephrosclerosis and aHUS (figure 3).
However, the fascinating data from the Limburg Renal Registry are not in agreement with data from Larsen et al .. The latter group performed next-generation sequencing to interrogate the coding regions of 29 genes encoding complement and coagulation cascade members that have been shown to be associated with aHUS.100 patients presenting with severe hypertension, renal failure and a kidney biopsy showing microangiopathic changes limited to the classic accelerated hypertension associated lesion of arterial intimal edema (’mucoid intimal hyperplasia’) without accompanying glomerular microthrombi were analyzed. No pathogenic or likely pathogenic variants were identified in any of the genes analyzed. (Larsen et al., 2018). Data from the Spanish group for the study of glomerular diseases clearly show that severe and malignant hypertension are common among patients with aHUS. However, thrombotic microangiopathy is uncommon among patients presenting with malignant hypertension caused by diseases other than aHUS (Cavero et al., 2019).
Thus, and similar to the ‘C5 situation’, most data suggest a causative complement-nephrosclerosis relationship, but conclusive and irrefutable evidence is still missing.