[OP.LB.02.05] A PATIENT WITH MALIGNANT HYPERTENSION SUCCESSFULLY TREATED WITH ECULIZUMAB AND BOSENTAN - SUGGESTIONS OF SIGNIFICANT INTERACTIONS OF COMPLEMENT AND THE ENDOTHELIN SYSTEM IN BLOOD PRESSURE CONTROL.

OBJECTIVE: Malignant hypertension as borne out by uncontrolled hypertension with accelerated target organ damage has a variable and often dire prognosis. Loss of kidney function is a hallmark of the condition and is frequently accompanied by thrombotic microangiopathy (TMA).

DESIGN AND METHOD: Here we present the case of a patient with malignant hypertension, who was successfully treated using a combination of in-label and off-label medication according to the following pathophysiological concepts: 1) Innate immunity has been identified as a player in blood pressure (BP) control, 2) the complement inhibitor eculizumab has become available for treating atypical hemolytic uremic syndrome (aHUS), which shares many features of malignant hypertension, 3) endothelin (ET) antagonism, although not currently approved for these indications, has been shown to be effective for treating proteinuria and as a possible adjunct for the treatment of resistant hypertension.

RESULTS: A 40year-old man was referred to our hypertension clinic with uncontrolled hypertension and an accelerated loss of kidney function. His history included an excessive use of NSAR. However, serum creatinine had been in the normal range (1,07 mg/dl) six months previously. Two months previously arterial hypertension had been diagnosed at the same time as a serum creatinine of 2,03 mg/dl (MDRD creatinine (cr)-clearance 36 ml/min) with a proteinuria of 600 mg/l. A kidney biopsy had shown stenosing arteriolosclerosis and ischemic glomerular collapse consistent with malignant hypertension. There were signs of former episodes of TMA, but no signs of a fresh TMA. When we saw the patient, there was no laboratory evidence of hemolysis but complement factor C3c was low (0,7 g/l) and CRP was chronically elevated (Fig.1). We refrained from a repeat kidney biopsy because of abnormal platelet function assays. The patient had been admitted to hospital several times for hypertensive urgencies, antihypertensive medication had been stepped up to contain 7 drugs and kidney function deteriorated rapidly (Fig. 1, max. serum creatinine 4,4 mg/dl, MDRD cr-clearance 15 ml/min).(Figure is included in full-text article.)According to the principles outlined above we introduced the dual ET receptor antagonist bosentan (31,25 mg bid, stepped up to 125-0-62,5 mg). An ACE inhibitor was withdrawn. When extended complement analyses showed a discrete elevation of C3d (60 mU/l, reference <40) and sC5b-9 (682 ng/ml, reference <320), we initiated eculizumab (900 mg/week for five weeks, then 1200 mg every two weeks). Serum creatinine started to decrease after 7 days and after 13 months is still in slow decline (2,87 mg/dl, MDRD cr-clearance 25 ml/min, 24 h cr-clearance 46 ml/min/1,73 m2). Proteinuria, having peaked at 3084 mg/g creatinine, decreased to 513 mg/g creatinine. Currently BP is in the upper range of normal according to ambulatory self-measurements. Antihypertensive therapy consists of bosentan plus amlodipin 5 mg bid, torasemide 5 mg, carvedilol 12,5 mg and candesartan 8-0-4 mg. Genetic testing revealed a previously unknown complement factor (CF) I mutation (p.G269V(GGT > GTT)), an equally unknown missense variation in CFH (p.W32Q(TGG > GGC)), a variation with unknown significance in CFB (p.W32Q (TGG > CAG)) together with a portfolio of 16 additional polymorphisms, some of which harbor associations with HUS, membranoproliferative glomerulonephritis (MPGN) and aging related macula degeneration (AMD). A complement screen 9 months into eculizumab treatment revealed nearly complete inhibition of total complement function(CH50, AH50), but C3d (83 mu/l) and sC5b-9 (475 ng/ml) were still elevated. Normalization of CRP was only achieved part of the time. The patient has recently suffered a clinically mild meningococcal plus H1N1 infection during which eculizumab was withdrawn for safety reasons. In view of the complex genetic variations we are currently following a concept of watchful waiting as regards a restart of complement inhibition, while bosentan treatment is being continued.

CONCLUSIONS: This complex case is the first to demonstrate that complement inhibition is a viable approach for the treatment of malignant hypertension if the complement system is involved. We propose that all patients with signs of malignant hypertension should be carefully screened for complement involvement, keeping in mind, that no overt hemolysis has to be present. Data should be collected in a study or a registry. It is difficult to determine the relative contribution of eculizumab and bosentan on reduction of BP and proteinuria. Very limited data on the effects of eculizumab on proteinuria suggest that it has no or little sustained effect. From the existing database it is likely that bosentan has been the drug eliciting proteinuria reduction. Its interactions with complement remain to be further investigated. To name one putative mechanism: Others have described ET to be involved in heparan sulfate shedding of the endothelial glycocalyx and heparan sulfate is the binding site for factor H. Finally we presume that the effects on BP are secondary to structural improvements in the kidneys that might be accessible to a repeat biopsy and may have been caused by either agent or both.