Atypical hemolytic uremic syndrome in infant with solitary kidney

Abstract

Hemolytic uremic syndrome is an acute condition where microvascular thrombi occur in the vasculature of the renal system, resulting in thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. Hemolytic uremic syndrome may originate from either congenital or acquired causes. Hemolytic uremic syndrome is initially treated with supportive care measures; however, if fulminant renal failure ensues, dialysis may be necessary.

Case report

Educational objectives

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) resulting from dysregulation of the alternative complement pathway.

In the absence of infection with Shiga toxin-producing Escherichia coli (STEC), aHUS should be considered in the differential diagnosis of hematuria, as early diagnosis and initiation of complement blockade therapy (e.g. eculizumab) are crucial for favorable renal outcomes.

Consent

Consent was obtained from the patient’s family regarding the use of this case presentation.

Ethical statement

No ethical permission was required and was therefore obtained for this case presentation.

An 8-month-old male infant presented to his primary care physician with parental concern for dark-colored urine over 4 days, most noticeable during the first diaper change of the morning. On the day of presentation, frank hematuria was observed, prompting immediate evaluation.

The patient’s medical history was notable for a full-term birth complicated by antenatal polyhydramnios. At 36 weeks, a prenatal ultrasound showed no structural anomalies. Birth weight was 3.73 kg with normal Apgar scores. Postnatally, the infant experienced persistent hypoglycemia, requiring intravenous dextrose. A left flank mass was palpated on physical examination, and subsequent computerized tomography imaging revealed a large, heterogeneous mass of the left kidney, consistent with congenital mesoblastic nephroma. A radical left nephrectomy was performed on day 3 of life.

At 2 months, the infant developed a perirectal abscess with fistula formation, requiring surgical intervention. He returned to baseline health until the age of 8 months, when gross hematuria occurred. Urinalysis revealed hematuria, proteinuria, bilirubin, and nitrites. Laboratory evaluation showed anemia (Hb 8.9 g/dL), thrombocytopenia (77 × 10³/µL), and elevated blood urea nitrogen (53 mg/dL), creatinine (1.0 mg/dL), AST (94 U/L), and hyperkalemia (6.1 mmol/L). Given the child’s renal history, he was admitted for further evaluation.

Hospital course

On admission, the patient was pale but hemodynamically stable. Laboratory workup revealed proteinuria (urine protein/creatinine ratio of 128,544 mg/g), persistent hematuria, worsening anemia (Hb 8.6 g/dL), thrombocytopenia (63 × 10³/µL), and elevated LDH (1284 U/L). The right kidney ultrasound showed normal structure and flow. Peripheral smear demonstrated schistocytes, elevated reticulocyte count (6%), and low haptoglobin (<8 mg/dL), consistent with TMA.

Pediatric nephrology suspected hemolytic uremic syndrome (HUS). Absence of diarrhea, negative STEC stool studies, and lack of infectious symptoms pointed toward aHUS. ADAMTS13 activity was normal (>61%), and C3 was decreased (67 mg/dL), supporting aHUS over thrombotic thrombocytopenic purpura (TTP).

Despite supportive care, the patient’s renal function declined with a peak BUN and creatinine of 75 and 2.35 mg/dL, respectively. The patient also developed oliguria at this time. Eculizumab was administered on day 3 after meningococcal vaccination, and prophylactic amoxicillin was given. Due to worsening renal failure, he was transferred to a tertiary facility, where renal replacement therapy was initiated. He required IV hydralazine, oral amlodipine, and a nicardipine drip for blood pressure control. Hemodialysis was performed for 8 days, with intubation required due to pulmonary edema.

The patient’s renal function gradually improved. He was discharged after 16 days on antihypertensives and continued eculizumab infusions every 2 weeks. Follow-up showed improved creatinine (0.45 mg/dL) with estimated glomerular filtration rate (eGFR) of 75 mL/min/1.73 m². Complement studies confirmed alternative pathway activation suggested by low CH50 28 Units/mL (n = 41–95 Units/mL), low alternative pathway functional activity 29% (normal 50%–130%), low factor H level 109 mg/L (n = 180–420 mg/L), high Bb level >11.8 mg/L (n < 2.2 mg/L), and high soluble sC5b = 9 0.73 mg/L (n < 0.3 mg/L). Genetic testing revealed a novel pathogenic variant of the complement factor H (CFH) gene: (NM_000186.4:c.2575C>T,p.(Gln859Ter)(1:196706115:C>T located in exon 16 (SCR 14). His mother was found to carry the same mutation. The patient remains on eculizumab with pediatric nephrology follow-up.

Literature review

HUS occurs when thrombi form in the microvasculature of organ systems, most commonly the kidney, resulting in thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury (AKI). ⁴ The causes of HUS can be divided into two categories: STEC HUS and non-STEC HUS, otherwise known as aHUS. ² In children, STEC infection causes around 90% of HUS cases. Approximately 5%–10% of cases are attributed to non-STEC causes, including Streptococcus pneumoniae infection, malignancies, certain medications, transplantation, and autoimmune diseases. ² Given the patient’s history of mesoblastic nephroma, a relapse of malignancy was initially considered a potential cause of HUS; however, further investigations ruled out any concern for recurrence.

aHUS is a rare subset of HUS, accounting for 10% of cases of HUS in children in the United States. ⁴ It is often triggered by infections, malignancy, or pregnancy, leading to an activation of the complement system, which goes unregulated. These individuals may have underlying inherited or acquired dysregulations of the complement pathway. ⁴ Mutations in complement regulatory genes such as CFH, CD46 (MCP), CFI, C3, and CFB, or the presence of autoantibodies against factor H (anti-CFH antibodies), have been implicated in aHUS pathogenesis. ¹ During the initial, acute process of aHUS, the rates of morbidity and mortality are high. ² aHUS has a poor prognosis and can progress to end-stage kidney disease in ~50% of diagnosed cases. ² In addition to renal complications, aHUS can cause systemic damage affecting other organ systems, including the cardiovascular, pulmonary, gastrointestinal, and central nervous systems. ¹

In the absence of acute infections such as STEC or S. pneumoniae, the diagnostic workup for aHUS should include a thorough assessment of complement function along with genetic testing. ⁴ These evaluations are commercially available through several genetic laboratories in the United States. In our case, the infant was found to have a mutation in the CFH gene, which makes up ~25% of genetically confirmed aHUS cases. ¹ CFH is the most commonly mutated gene in aHUS and works as an inhibitor in the complement pathway.^3,4 The genetic abnormality affecting CFH, which leads to aHUS, is associated with the highest risk of developing renal failure within the first year, and in those who receive a kidney transplant, a higher rate of recurrence. ⁴ It is also associated with a higher risk of death within the first year of diagnosis. ⁴

TTP is another form of TMA and should be differentiated from aHUS. TTP typically presents with less renal involvement but more pronounced neurologic symptoms. ² A severe deficiency of ADAMTS13 activity (<10%) confirms the diagnosis of TTP, whereas ADAMTS13 levels are typically normal or only moderately reduced in aHUS.^2,5

The prognosis of aHUS has significantly improved with the introduction of complement inhibitors, particularly eculizumab. Eculizumab is a recombinant humanized anti-C5 monoclonal antibody that blocks cleavage of C5, preventing the formation of C5a and C5b. ⁶ This inhibition effectively halts terminal complement activation, thereby preventing formation of the membrane attack complex. ⁶ Before the availability of eculizumab, treatment options included plasma exchange, kidney transplants, and even the suggested combined renal and liver transplant—especially when the disease was driven by complement regulatory proteins, such as factor H, factor B, factor I, or C3, which are synthesized in the liver.^2,4

Complement blockade has been shown to improve renal outcomes when initiated promptly upon clinical suspicion of aHUS. However, the use of eculizumab carries a risk of life-threatening infections, particularly from Neisseria meningitidis. Therefore, meningococcal vaccination is essential and should be administered at least 2 weeks prior to the first dose. In emergent cases where treatment cannot be delayed, prophylactic antibiotics such as amoxicillin are recommended until vaccine-induced immunity is achieved. ⁷

Ravulizumab, a long-acting C5 inhibitor that offers the advantage of a less frequent dosing schedule compared to eculizumab, has also been approved for the treatment of aHUS in pediatric populations.^8,9

Final diagnosis

aHUS secondary to a CFH gene mutation.

Conclusion

This case highlights a rare but serious cause of gross hematuria and AKI in an infant with a solitary kidney. The child’s initial presentation prompted concern for malignancy recurrence; however, further workup indicated a thrombotic microangiopathic process. Given the absence of STEC infection and negative stool cultures, aHUS was considered early.

The diagnosis was confirmed by complement testing and genetic studies, which revealed a CFH mutation known to confer a poor renal prognosis. The child received prompt treatment with eculizumab, which stabilized and eventually reversed his renal impairment. This case demonstrates the importance of early recognition and intervention in aHUS, particularly in high-risk patients such as this patient with a single kidney.

While literature suggests no established relationship between mesoblastic nephroma and aHUS, this case raises questions about whether prior renal pathology may influence susceptibility to complement-mediated injury. However, current evidence supports a coincidental, rather than causal, association.

This case underscores the importance of maintaining high clinical suspicion for aHUS as a possible cause of TMA in children. Prompt initiation of complement inhibition improves renal outcomes, especially in patients with underlying renal vulnerabilities. Continued long-term management with eculizumab and monitoring by pediatric nephrology are essential in reducing recurrence and preserving renal function in such patients.