Does Anticomplement Therapy Have a Role in the Management of Malignant Hypertension?

To the Editor:

The conventional management of malignant hypertension focuses on antihypertensive drugs. With this strategy, the annual incidence rate of all‐cause mortality remains 13‐ and 5‐fold, respectively, of normotensive and hypertensive controls, and some patients continue to develop progressive renal failure despite a good degree blood pressure (BP) control.1, 2, 3, 4 Thus, a subset of patients with “malignant hypertension” do not do well with antihypertensive drugs alone and may require different strategies for management.

A 49‐year‐old man presented to his physician for gross hematuria after 2 weeks of cough, shortness of breath, abdominal pain, and vomiting. BP was found to be 220/140 mm Hg and he was immediately referred to the emergency department, where his BP was initially 108/69 mm Hg but soon increased to 232/125 mm Hg. The patient's BP continued to fluctuate after admission and he was intermittently lethargic. Results from laboratory tests showed microangiopathic hemolytic anemia (MAHA) with schistocytes on blood smears, thrombocytopenia, and renal failure (Table).

Table 1.

A Case of Atypical Hemolytic Uremic Syndrome Presenting as Severe or Malignant Hypertension

Months	Chief Complaints	Blood Pressure, mm Hg	Hb, g/dL	Plt, x109/L	LDH, IU/La	Bilirubin, mg/dL	BUN, mg/dL	Cr, mg/dL
−50.5	Anorexia, nausea, abdominal pain	179/136	15.1	261	–	–	19	1.46
−34.7	Anorexia, nausea, abdominal pain	206/136	14.2	203	–	1.7	14	1.2
−33.9	Anorexia, nausea, abdominal pain	125/77	12.1	276	–	1.7	45	2.31
−30.6	Headache, syncope, anorexia	136/84	14	264	–	–	20	1.38
−12.5	Anorexia, nausea, abdominal pain	152/96	13.9	244	–	0.8	21	1.68
−11.3	Headache, anorexia, nausea	180/111	13.1	223	–	–	23	1.81
0	Anorexia, nausea, dizziness, hematuria	232/125	9.5	96	1,471	1.5/<0.1	55	4.84
0.6	None	129/82	10.9	352	491	–	70	5.62
1.5	None	130/85	10.0	275	496	–	58	4.79
2.9	None	122/76	11.2	219	565	–	48	3.50
6.4	None	137/92	11.8	271	647	–	33	2.67

Abbreviations: BUN, serum urea nitrogen; CR, creatinine; Hb, hemoglobin; Plt, platelets. ^aLactate dehydrogenase (LDH): normal <618 IU/L.

Anticomplement therapy with eculizumab, a humanized monoclonal antibody of complement C5, was started for presumed atypical hemolytic uremic syndrome (AHUS) at 900 mg intravenously every week for four doses, followed on week 5 by 1200 mg biweekly. Within 1 week of the first treatment, his mental status cleared, his other extrarenal symptoms subsided, and his platelet count normalized. His BP stabilized at 2 weeks, but his serum creatinine level only began to gradually improve after 6 weeks of anticomplement therapy.

The patient's plasma ADAMTS13 activity, C3, and C4 were normal. Findings from antinuclear antibody, antineutrophil cytoplasmic antibody, antiphospholipid and antiglomerular basement membrane antibodies, and Shiga toxins in stools were negative. Imaging studies and laboratory tests excluded renal artery stenosis, primary hyperaldosteronism, and pheochromocytoma. Results from kidney biopsy showed chronic thrombotic microangiopathy (TMA) with preglomerular arterioles and one interlobular artery exhibiting occlusive intimal proliferation but no active fibrinoid necrosis.

His history prior to this presentation was notable for severe but wildly unstable hypertension for more than 4 years that defied various antihypertensive regimens. The patient also experienced frequent bouts of anorexia, nausea, abdominal pain, and headache that caused him to seek emergency care on several occasions, some, but not all, of which were accompanied by severe hypertension and mild azotemia (Table).

Malignant hypertension may present with the triad of renal failure, MAHA, and thrombocytopenia commonly associated with AHUS2, 3 and TMA in the kidney.5 The similarity in clinical and pathological features suggests that some patients given a diagnosis of malignant hypertension may instead have AHUS that requires anticomplement therapy.6, 7 In one study of 14 cases with “malignant hypertension,” two (14%) were found to have mutations affecting the regulation of the alternative complement pathway.8 This case further demonstrates that AHUS may present with severe hypertension unaccompanied by all the 3 components of the triad of renal failure, MAHA, and thrombocytopenia. The laboratory tests identify only 45% to 75% of the cases with AHUS,6, 8, 9 and the results are often not available for days to months. Therefore, AHUS should be clinically suspected and anticomplement therapy seriously considered for patients with unstable BP despite antihypertensive drugs or prominent extrarenal complications that are not always concurrent with markedly elevated BP.

Initiation of anticomplement therapy does not immediately commit the patient to indefinite treatment. Continuation of anticomplement therapy is not warranted after two weekly doses if hematological and extrarenal complications are not resolved and BP does not stabilize.10 Among patients who show improvement with anticomplement therapy, a gradual tapering of the therapy may be attempted, under close monitoring, after the BP has stabilized, extrarenal symptoms have resolved, and kidney function has maximally improved.