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.