Early recognition of atypical hemolytic uremic syndrome to prevent irreversible kidney injury: cardiac failure and refractory hypertension as critical clues in young patients

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy that predominantly affects the kidneys but may cause severe extrarenal involvement, including cardiac dysfunction. Early recognition and timely complement inhibition are crucial for preventing irreversible organ injury. We report a 27-year-old man with no prior history who presented with hypertensive crisis, acute cardiogenic pulmonary edema with severe global systolic dysfunction and rapidly progressive renal failure. Despite aggressive antihypertensive therapy, diuretics, corticosteroids, hemodialysis, and seven sessions of plasmapheresis, multiorgan dysfunction persisted. Laboratory evaluation showed microangiopathic hemolytic anemia, thrombocytopenia, markedly elevated LDH, and low C3, consistent with complement-mediated TMA. Renal biopsy confirmed TMA compatible with aHUS. Eculizumab therapy was initiated, although delayed due to administrative authorization requirements, and resulted in rapid clinical stabilization and progressive improvement of cardiac function, with complete recovery at 6 months. Renal function, however, did not recover, and the patient remains dialysis-dependent. This case underscores the systemic nature of aHUS and the potential for reversible severe cardiomyopathy when complement inhibition is initiated early. Delayed treatment may permit irreversible renal injury despite full hematologic and cardiac remission, emphasizing the critical importance of timely diagnosis and intervention.

Introduction

Hemolytic uremic syndrome (HUS) together with thrombotic thrombocytopenic purpura (TTP) and the hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, forms part of the broader spectrum of thrombotic microangiopathies (TMAs) [1]. TMAs represent a heterogeneous group of disorders defined by the triad of thrombocytopenia, microangiopathic hemolytic anemia with erythrocyte fragmentation, and elevated serum lactate dehydrogenase (LDH) levels [2]. The characteristic histopathologic hallmark of TMAs is the thickening of arteriolar and capillary walls, accompanied by marked endothelial swelling and detachment, as well as subendothelial accumulation of plasma proteins and cellular debris, which collectively define the underlying vascular lesion observed in all forms of thrombotic microangiopathy [3].

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening form of thrombotic microangiopathy (TMA), associated with an unfavorable prognosis, with mortality rates reaching up to 25% during the acute phase [4]. In current clinical and pathophysiological classification, hemolytic uremic syndrome (HUS) is an umbrella term that includes several distinct entities. The major subtypes of HUS are, Shiga toxin-producing Escherichia coli-associated HUS (STEC-HUS), also referred to as typical HUS, atypical hemolytic uremic syndrome (aHUS), secondary HUS and cobalamin C-associated HUS (rare) [5, 6]. aHUS estimated incidence ranging from 0.23 to 1.9 cases per million population per year, accounting for fewer than 10% of all hemolytic uremic syndrome (HUS) cases [7–9]. The pathology associated with HUS, known as thrombotic microangiopathy, is marked by arteriolar and capillary thickening, endothelial swelling and detachment, thrombosis and blockage of vessel lumens [10, 11] as well as microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury with progression to end-stage renal disease occurring in approximately 50% of cases [7, 12, 13] while compared with typical HUS or STEC-HUS, aHUS is not related to shiga toxin-producing Escherichia coli (STEC), especially serotype O157:H7, and can occur at any age, including adults [14, 15]. The disease results from uncontrolled activation of the alternative complement pathway, leading to formation of C3 convertase, complement deposition, and endothelial injury [12, 16]. Genetic or acquired abnormalities of complement-regulating proteins—such as CFH, CFI, MCP/CD46, C3, and CFB—predispose to complement overactivation [17, 18]. This dysregulation triggers endothelial activation, platelet aggregation, and formation of fibrin-rich microthrombi, resulting in ischemic damage across multiple organs [19].

While these lesions primarily impact the kidneys, extrarenal manifestations occur in approximately 20–30% of cases, particularly affecting the heart, which is among the most frequently involved organs outside the kidneys [18]. Other organs including the brain, lungs, eyes, gastrointestinal tract, liver, and pancreas may also be affected [10, 12, 20]. Cardiac involvement, reported in 3–14% of patients, may present as heart failure, myocarditis, arrhythmias, or myocardial infarction secondary to microvascular thrombosis [21, 22]. Cardiac complications occur in 3–10% of patients with complement-mediated aHUS, as a consequence of microangiopathic injury in the coronary microvasculature, and can cause sudden death [10]. In addition, arrhythmias are likely more prevalent in patients with aHUS, reflecting the widespread nature of systemic microthrombosis [23]. Furthermore, the risk of fatal ventricular arrhythmias in aHUS, such as ventricular tachycardia and torsades de pointes (TdP), escalates due to prolonged QT intervals [24].

We report a 27-year-old male who presented with hypertensive crisis, cardiogenic pulmonary edema, and acute renal failure caused by atypical hemolytic uremic syndrome. Despite maximal antihypertensive therapy, hemodialysis, and plasmapheresis, his hypertensive crisis, heart failure, and renal failure remained refractory until treatment with eculizumab was initiated. Our case highlights the importance of early recognition and timely initiation of complement inhibition to prevent irreversible organ damage.

History of presentation

A 27-year-old, with no prior medical history, presented to a local hospital with increasing shortness of breath, orthopnea, and oedema in the lower limbs from over 2 weeks. No previous hospital admissions, surgeries, or cardiovascular interventions were reported. Upon examination, he had a body temperature of 36.7 °C, patient’s blood pressure was 240/120 mmHg, his heart rate averaged approximately 100 beats/min, a respiratory rate of 28 breaths per minute, and an oxygen saturation of 87% on room air. Auscultation of the chest revealed bilateral basal rales and expiratory wheezing. He also had bilateral pitting edema.

Acute decompensated heart failure with pulmonary edema was impressed. Oxygen supplementation with continuous positive airway pressure (CPAP) was administered, while, furosemide and nitroglycerin were intravenously initiated. Chest radiograph demonstrated increased cardiac silhouette, bilateral central opacities, and small right-sided pleural effusion. The initial electrocardiogram revealed sinus rhythm with nonspecific ST-T wave abnormalities in precordial leads (Fig. 1). Transthoracic echocardiography showed interventricular septal hypertrophy and an acute severe drop in left ventricular ejection fraction to 27% as assessed by the apical biplane Simpson’s rule with global hypokinesis and with a global longitudinal strain (GLS) markedly reduced (9.7%) (Fig. 2). His right ventricle was dilated and impaired (TAPSE 1,6 cm). Patient showed grade II diastolic dysfunction, mild mitral regurgitation and a dilated inferior vena cava (21 mm) without respiratory variation, indicating elevated filling pressures.

Fig. 1.

Patient’s echocardiography, left ventricular hypertrophy (LVH) by voltage criteria: S wave in V2 + R wave in V5 > 35 mm

Fig. 2.

Patient`s transthoracic echocardiography longitudinal shortening of the left ventricle during systole, global longitudinal strain (GLS), showing a markedly drop in left ventricular (LV) systolic function

Subsequent blood examination and uranalysis (Table 1) was performed. Blood examination showed severe anemia (hemoglobin 9.8 g/dL on admission and 8,7 g/dL on day 1) and thrombocytopenia (90 × 10⁹/L on admission and 52 × 10⁹/L on day 1) with schistocytes being present in peripheral smear. Although the patient’s baseline renal function had been normal (documented normal renal function on routine laboratory testing performed approximately 12 months prior to admission, with a serum creatinine of 0.9 mg/dL), admission laboratories revealed acute kidney injury with a creatinine level of 6.4 mg/dL, urea of 178 mg/dL and potasium levels at 3.3mEq/L. His B-type Natriuretic Peptide (BNP) levels was 1281pg/ml, hsTrop 188 pg/ml on admission and 368 pg/ml on day 1, with C-Reactive Protein (CRP) 47,3 U/l on day 1 (Table 1). Given his elevated troponin and family history, patient underwent a left heart catheterization and coronary angiography to evaluate for ischaemic heart disease (Fig. 3) with coronary angiography reveling non-obstructive coronary artery disease. Treatment with high-dose of corticosteroids, diuretics and levosimendan, as well as heart failure therapy with sacubitril-valsartan, empaglifozin, bisoprolol, eplerenone with rapid titration to maximal tolerated dose was initiated. Despite these interventions, cardiac function did not improve, his blood pressure remained high despite multiple antihypertensive medications and renal function continued to deteriorate, necessitating initiation of hemodialysis. There was no evidence of hypertensive retinopathy upon ophthalmological examination while abdominal ultrasonography showed normal renal size and patent bilateral main renal arteries without visible adrenal lesion.

Table 1.

Laboratory findings at presentation and during early hospitalization

Complete blood count (CBC/Whole Blood)	Normal values	On addmission	Day 1
Complete Blood Count (×103/µL)	4.00–11.00	17.09	15,44
Neutrophils (%)	40–70	83.7	86,5
Lymphocytes (%)	20.0–40.0	10.6	7,3
Monocytes (%)	2.0–10.0	5	5,6
Eosinophils (%)	1.00–6.00	0.3	0,3
Basophils (%)	0.3–1.0	0.4	0,3
Neutrophils (×103/µL)	2.0–8.0	14.31	13,36
Lymphocytes (×103/µL)	1.10-4.00	1.81	1,13
Monocytes (×103/µL)	0.10–0.90	0.85	0,86
Eosinophils (×103/µL)	0.04–0.70	0.05	0,05
Basophils (×103/µL)	0.0–0.2	0.07	0,04
Red Blood Cells (RBC) (4.50–5.90 × 106/µL)	4.50–5.90	3.05	2,67
Hemoglobin (HGB) (g/dL)	13.5–17.5	9.8	8,7
Hematocrit (HCT) (%)	41.0–53.0	27.1	24,3
MCV (fL)	76.0–96.0	88.9	91
MCH (pg)	27.0–33.0	32.1	32,6
MCHC (g/dL)	30.0–36.0	36.2	35,8
RDW-CV (%)	11.0–16.0	14.8	14,4
RDW-SD (fL)	37.0–52.0	47.2	47,4
Platlets (x10³/µL)	150–400	90	52
Biochemical Tests (Serum)
Glucose (mg/dL)	60–100	107	182
Urea (mg/dL)	10–50	178	186
Creatinine (mg/dL)	0.5–1.5	6.4	6,6
Alkaline Phosphatase (ALP)	42–128	41	37
Gamma-Glutamyl Transferase (GGT) (U/L)	5–45	43	34
Alanine Aminotransferase (ALT / SGPT) (U/L)	4–45	30	25
Aspartate Aminotransferase (AST / SGOT) (U/L)	4–45	45	40
Lactate Dehydrogenase (LDH) (U/L)	135–225	1000	968
Creatine Kinase (CK / CPK) (U/L)	25–190	220	171
Cholesterol (Total) (mg/L)	125–200	210
Triglycerides (mg/L)	< 150	129
HDL Cholesterol (mg/L)	> 40	47
LDL Cholesterol (mg/L)	< 130	137	26,2
Uric Acid (mg/L)	1.5-7.0	10.2	10,2
Sodium (Na) (mEq/L)	135–148	135	133
Potassium (K) (mEq/L)	3.5–5.3	3.3	3,3
C-Reactive Protein (CRP) (mg/L)	< 6.0	26,2	47,3
B-type Natriuretic Peptide (BNP) (pg/ml)	< 100	1281
High-Sensitivity Troponin I (hsTnI) (pg/ml)	38.00–80.00	188	368
Renin activity (pg/mL)	5.4–34.5	340
Aldosterone (pg/mL)	60–350	334.7
Complement C3 (mg/dL)	88.0-135.0		79.9
Complement C4	16.0–27.0		24.9
Hematology Biochemistry
Haptoglobin (mg/ml)	0.159-2.3		0.13
ACA IgG (U/mL)	<= 48		27.5
ACA IgM (U/mL)	<= 44		5.4
B2GPI IgG (U/mL)	<= 7		0.8
B2GPI IgM (U/mL)	<= 7		0.5
Serological Tests I (Serum)
HSV-1 IgG (S/CO)	< 1		5,80
HSV-2 IgG (S/CO)	< 1		0,04
CMV-IgG (U/ml)	< 6,00		72,9
CMV-IgM (S/CO)	< 0,85		0,46
EBV-IgG (U/ml)	< 0,75		40,35
EBV-IgM (U/ml)	< 0,50		1,99
Urinalysis
Characteristics
Color/Turbidity		Colorless / Clear	Colorless / Clear
pH		6.0	6.0
Specific Gravity (SG)		1008	1008
Urin Chemical Analysis
Protein		++ (100 mg/dL)	++ (100 mg/dL)
Glucose		Negative	Negative
Bilirubin		Negative	Negative
Urobilinogen		Normal, 0.2 mg/dL	Normal, 0.2 mg/dL
Hemoglobin		+++ ( > = Ca200Ery/uL)	+++ ( > = Ca200Ery/uL)
Ketones		Negative	Negative
Nitrites		Negative	Negative
Leukocyte Esterase (L/E)		Negative	Negative
Microscopic Examination
White Blood Cells (WBCs)		Normal, 0–1	Normal, 0–1
Red Blood Cells (RBCs)		Normal, 6–8	Normal, 6–8
Urinary Biochemical Tests
Urea			821
Creatinine			42
Calcium			6 mg/dL
Total Proteins			60.8 mg/dL
24-Hour Urine Volume			2800 ml
24-Hour Urinary Urea			22,988 mg/24 h
24-Hour Urinary Creatinine			1176.0 mg/24 h
24-Hour Urinary Calcium			168.0 mg/24 h
24-Hour Total Urinary Proteins			1702.4 mg/24 h

Fig. 3.

Patient’s coronary angiography. A Right coronary artery (RCA) and B Left anterior descending (LAD) and left circumflex (LCx) arteries. Both figures showing normal vessel course and caliber without evidence of focal obstruction, no apparent pathologic stenosis or lesion

Additional findings included markedly elevated lactate dehydrogenase (> 2000 U/L) and decreased haptoglobin, 0.13 mg/ml (0.159–2.3), consistent with intravascular hemolysis. Low complement C3, 79.9 mg/dL) (88.0-135.0) with normal C4, 24.9 mg/ml (16.0–27.0) (Table 1), and serologic tests for ANA, ANCA, and anti-GBM antibodies were negative. Plasma renin activity measured during the acute phase was markedly elevated at 340 pg/mL (5.4–34.5 pg/mL), and plasma aldosterone was within the upper-normal range at 334.7 pg/mL (60–350 pg/mL) (Table 1), consistent with severe secondary hyperreninemic hypertension. Due to elevated CRP, viral serology was performed, revealing an acute Epstein–Barr Virus (EBV) infection (IgM 1.99 U/mL) (Table 1).

Thrombotic thrombocytopenic purpura (TTP) was considered early in the differential diagnosis due to the presence of thrombocytopenia and microangiopathic hemolytic anemia. Plasma exchange was therefore initiated while the diagnostic evaluation was ongoing. The differential diagnosis was clarified by measurement of ADAMTS13 activity, which was normal at 82% (reference range 80–120%), thereby excluding immune-mediated TTP. Upon admission and throughout hospitalization, the patient reported no history of prodromal diarrhea and stool testing for Shiga toxin was negative [15], thereby excluding Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS).

Patient underwent from day 2 from submmetion; seven sessions of plasma exchange while renal biopsy was performed. Histopathological examination revealed a glomerulus with lobulated architecture, a fibrillar mesangial appearance, and focal thickening of the glomerular basement membrane (Fig. 4). Despite the architectural distortion, a small thrombus was identified within a glomerular capillary loop in the upper right quadrant. The arteriolar wall at the vascular pole appeared edematous with a small intraluminal fibrin thrombus. A central arteriole demonstrated concentric wall thickening with two fragmented erythrocytes embedded in its upper segment. The intima of a small interlobular artery exhibited mucoid change with associated intimal thickening and fibroblastic proliferation within the media, producing an “onion-skin” configuration (Fig. 4C) consistent with a diagnosis of atypical hemolytic uremic syndrome (aHUS) [12, 18].

Fig. 4.

Patient’s renal biopsy. A Glomerulus with lobulation of the architecture, as well as some “fibrillar” appearance of the mesangium and focal thickening of GBM with a small thrombus into a glomerular capillary loop (black arrow), while arteriolar wall of the vascular pole is oedematous, containing a small thrombus of fibrin into the lumen. B Arteriole with thickening of the wall, in the center of the image; two fragmented erythrocytes into the distorted arteriolar wall (upper half of the arteriole, red arrows). C Intima of a small caliber artery (interolobular artery) with “mucoid” changes (“mucoid” intima), in association with thickening of the vessel wall and fibroblastic proliferation into the media (reminiscent of “onion skin”) (H&E X400)

The clinical phenotype-characterized by severe acute kidney injury, malignant hypertension, low C3 with preserved C4 levels, absence of prominent neurological manifestations, and renal biopsy findings consistent with thrombotic microangiopathy—supported the diagnosis of complement-mediated atypical hemolytic uremic syndrome. In addition, the markedly elevated plasma renin activity with aldosterone levels in the upper-normal range indicated activation of the renin–angiotensin–aldosterone system secondary to renal ischemia caused by thrombotic microangiopathy, a well-recognized pathophysiological mechanism underlying malignant hypertension in aHUS. With these findings, treatment with eculizumab, a terminal complement inhibitor, was initiated, although delayed due to administrative authorization requirements. Eculizumab is a long-acting humanized monoclonal antibody targeted against complement C5 inhibiting the cleavage of C5 into C5a and C5b and hence inhibits deployment of the terminal complement system including the formation of membrane attack complex [25].

Following initiation of eculizumab, the patient exhibited a marked improvement in cardiac function, with progressive normalization of blood pressure and rapid resolution of heart failure symptoms within days. In parallel, cardiac biomarkers, including high-sensitivity troponin and B-type natriuretic peptide (BNP), declined significantly in temporal association with the recovery of left ventricular systolic function (Table 1). These findings were consistent with previous clinical reports [19]. Patient was discharged in a stable condition 1 week after his symptoms began to subside. BNP and hsTnI on the day of discharge were 110 pg/ml and 25 pg/ml respectively.

During follow-up, at 3 months, our patient demonstrated improvement with ejection fraction at EF ≈ 55% and GLS at 18%, while after 6 months there was complete myocardial recovery with EF stabilized at 61% and GLS improved to 21.2% (Fig. 5), with BNP levels at 6 pg/ml. However, despite hematologic and cardiac remission, renal function did not recover; the patient remains on chronic hemodialysis and after evaluation by the national transplant committee is listed for kidney transplantation [7, 13].

Fig. 5.

Patient’s transthoracic echocardiography longitudinal shortening of the left ventricle during systole, global longitudinal strain (GLS), showing a significant improvement of left ventricular (LV) systolic function in initial presentation (A) and during follow up after the initiation of eculizumab at 3 months (B) demonstrating significant improvement and complete myocardial recovery at 6 months (C)

Discussion and clinical perspective

In this report, we present a case of complete recovery from atypical hemolytic uremic syndrome (aHUS)–associated heart failure following eculizumab therapy. This case illustrates an unusual presentation of aHUS with simultaneous cardiac and renal failure, emphasizing the systemic nature of complement-mediated TMA [7, 12]. The aetiology of aHUS-associated heart failure is not well-understood although several reports indicates that cardiac dysfunction likely results from microvascular thrombosis and endothelial injury within the myocardium, leading to diffuse ischemia and transient cardiomyopathy [21, 22].

In this case of a young patient with unknown aHUS and new-onset heart and renal failure, we systematically evaluated for common heart failure causes. Heart catheterization ruled out obstructive coronary disease. Hypertension, as observed in our patient, is a key symptom and complication of aHUS [8] as the tiny blood clots can block blood flow to organs like the kidneys, leading to kidney failure, and also cause high blood pressure [26]. Renal biopsy results confirmed the thrombotic microangiopathy, and was the probable cause of aHUS-associated cardiomyopathy. Cardiac microvascular thrombi leading to myocardial ischaemia has been suggested as general aetiology for patients with thrombotic angiopathies [27].

Although chronic hypertensive changes were evident on echocardiography and renal biopsy, the acute presentation—including microangiopathic hemolytic anemia, thrombocytopenia, severe acute kidney injury, low complement C3 levels, and systemic organ involvement—strongly favored complement-mediated aHUS over secondary TMA due to hypertensive emergency. These findings indicate activation of the alternative complement pathway and are consistent with the underlying pathophysiology of aHUS.

Mutations in the complement factor B (CFB) gene can result in enhanced C3 convertase activity or resistance to regulatory inactivation, leading to excessive complement activation and endothelial injury. However, CFB mutations are relatively uncommon, accounting for only 1–2% of aHUS cases [28]. In our case; complement-related genetic testing was not performed due to the urgent need for therapeutic intervention and resource limitations; the diagnosis of aHUS was established based on clinical, laboratory, and histopathologic findings, along with the patient’s rapid response to eculizumab. In addition, upon review of viral serology, the patient was found to have an acute Epstein–Barr Virus (EBV) infection (IgM 1.99 U/mL), which was considered the likely precipitating trigger for the onset of aHUS.

The sunning recovery of systolic function (EF 27% → 61%) after complement inhibitor eculizumab initiation, further supports the diagnosis. Eculizumab is the first-line treatment for patients with aHUS [29] however, plasma exchange should be considered and act as a bridging therapy. Several reports have described similar reversible cardiomyopathy due to complement-mediated microvascular injury, reinforcing the role of complement inhibition in myocardial recovery [21, 22, 30]. In a case, a 49-year-old woman with aHUS and acute renal failure, 1 month after initiation of eculizumab LVEF improved from 20 to 40–45% [30]. In contrast, our case demonstrates a complete recovery of left ventricular systolic function. Eculizumab remains the standard of care, acting as a terminal complement inhibitor that prevents formation of the membrane-attack complex (C5b-9), thereby halting endothelial injury [13, 19]. Early treatment—ideally within 2 weeks of onset—is associated with improved renal outcomes, whereas delayed initiation often results in irreversible nephron loss [13, 16–18]. Despite full cardiac recovery, persistent dialysis dependency in our patient underscores the importance of prompt complement inhibition.

From a clinical perspective, this case emphasizes the importance of timely recognition of the disease and initiation of therapy [7, 12, 16, 31]. Patients with unexplained cardiorenal syndrome, microangiopathic hemolysis, and hypertensive crisis, a diagnosis of aHUS should be highly considered when high blood pressure cannot be controlled by maximum dosages of multiple antihypertensive medications and dialysis. Echocardiographic monitoring with strain imaging may detect early myocardial involvement [31, 32]. This case underscores the paramount importance of early recognition of atypical hemolytic uremic syndrome (aHUS) and prompt initiation of complement inhibition therapy. These measures are crucial to halting disease progression and preventing irreversible organ damage, particularly renal impairment. As highlighted in this case, complement inhibition can lead to full recovery of cardiac function; however, it may fail to reverse advanced renal injury once fibrosis has been established.

Author contributions

All authors have read and agreed to the published version of the manuscript.

Funding

No external funding was received.

Declarations

Conflict of interest

All authors declare no conflicts of interest. All authors declare that they have no conflict of interest. The authors have no competing interests to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. The authors have no financial or proprietary interests in any material discussed in this article.

Informed consent

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