Complement-Mediated Thrombotic Microangiopathy with 10 Years of Stable Renal Function After a Year-Long Treatment with Eculizumab with Coincidental Polycystic Kidney Disease

Background

Genetic disease complement-mediated thrombotic microangiopathy (cTMA), is a result of an unchecked alternative complement pathway triggered by an external factor, resulting in endothelial cell injury and organ failure [1]. The 3 main components are microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, though many other organs may be involved [1]. It often results from a combination of an underlying genetic susceptibility with environmental factors triggering unchecked activation of the alternative complement pathway. Pathogenic variants in at least 5 complement genes, coding for complement factor H (CFH), complement factor I (CFI), membrane cofactor protein (CD46), the complement component C3, and complement factor B (CFB), have been shown to be responsible for the majority of the increased risk of developing the disease [1–3]. Typical hemolytic uremic disease (HUS) is an infectious disease most commonly caused by Shiga toxin-producing Escherichia coli (STEC) [2,3]. Because of similarity of presentation, historically, clinicians have labeled cTMA as “atypical” HUS disease, although it is a complement-mediated process with a genetic basis [3]. Individuals with confirmed genetically based cTMA frequently experience relapse, and 60% are at risk for progressing to end-stage renal disease [2–4]. In contrast, classical HUS patients do not have a relapsing disease. There have been successful trials with the complement inhibitor eculizumab, for cTMA. Eculizumab is a humanized, chimeric monoclonal antibody directed against complement component C5 [3,5]. By blocking unchecked complement 3 activation, endothelial injury can be prevented. Eculizumab is very effective in the treatment of cTMA, but based on current scientific data, it is recommended to be taken as a lifelong treatment [5–9].

We present a case of a 5-year-old girl who presented with cTMA and was treated with eculizumab for a year. A decade later, her chronic kidney disease was at stage 3a; the same glomerular filtration rate as the day she came off the eculizumab. We present an alternative approach of intensive monitoring to allow patients to be weaned off eculizumab while maintaining glomerular filtration rate (GFR), as long as there are no relapses. Unfortunately, she developed multiple renal cysts and has been newly diagnosed as positive for PKD1, an autosomal dominant polycystic kidney disease (ADPKD) gene that is unrelated to cTMA. This may lead to progression of the CKD at some point in the future. Genetic tests revealing mutations for cTMA and ADPKD/PKD1 in the same patient have not been reported before, to the best of our knowledge.

Case Report

A previously healthy 5-year-old girl presented with persistent abdominal pain, vomiting, and diarrhea. During the initial workup at an outside hospital, the patient was found to be uremic and thrombocytopenic and was transferred to our hospital. She was negative for E. Coli 0157: H7, a strain of E. coli that produces Shiga toxin, and for other Shiga toxin-producing E. coli (STEC) strains, separately. Uremia continued to worsen with a peak serum creatinine level of 8 mg/dL and blood urea nitrogen (BUN) level of 99 mg/dL. Two days after presentation, the patient became anuric and the decision was made to begin hemodialysis.

At this time a preliminary diagnosis of cTMA was made. Genetic testing was not approved immediately as factor H level was normal, but was later performed and revealed a mutation in the C3 factor H gene. Eculizumab, which was newly approved for this purpose, was offered as the treatment of choice. However, since it is a lifelong therapy, and the family had constraints as they lived 2 hours from the hospital, they were understandably hesitant to start this lifelong treatment, which requires an infusion every 2 weeks and is very expensive. The patient remained hospitalized for 2 weeks on hemodialysis 3 times weekly. She was then transitioned to the outpatient pediatric dialysis unit. During those 2 weeks of hospitalization, plasma-pheresis was offered but the family wanted to consider their options for a while longer, and it was not started. Meningococcal conjugate and pneumococcal conjugate vaccines were given in case the family were to agree to eculizumab, in the future.

After 2 months, the insurance approved the treatment and the family agreed to begin eculizumab infusion. It was started at 600 mg intravenous (IV) for the first dose, followed by 300 mg IV at week 2, then 300 mg IV every 2 weeks thereafter. By then, the need for hemodialysis had decreased to twice a week, which is not uncommon for a 5-year-old child. Eculizumab is a humanized monoclonal antibody targeted against complement C5. It inhibits the cleavage of C5 into C5a and C5b and hence inhibits deployment of the terminal complement system [3–5]. In the first week of illness, the nadir of hemoglobin was 58 g/L (normal for 5 years of age: 120–150 g/L). After 4 blood transfusions over 2 months, before the start of eculizumab, it was 86 g/L, and improved to 114 g/L a month into therapy when hemodialysis was stopped (Figure 1). It leveled off at 126 g/L a year into the illness and has remained normal since. The lac-tate dehydrogenase (LDH) peaked at 8,781 U/L, decreased to 1,340 U/L at the start of eculizumab therapy, normalized after 2 doses when she came off hemodialysis at 284 U/L (normal range, 135–345 U/L) and has remained normal a decade later. The thrombocytopenia improved after the start of eculizumab therapy (Figure 1). The C3, C4, factor H antibody, and A Disintegrin-Like and Metalloproteinase with Thrombospondin (ADAMTS) 13 levels were normal at the onset.

A month after starting eculizumab infusions, serum creatinine was 2.07 mg/dL, LDH was normal at 284 U/L, platelets normalized from 81,000 to 209,000, and hemoglobin was stable at 114 g/L. The patient reported normal urine output and reported that full levels of energy had returned by her sixth birthday. She began full-time school at a local kindergarten and was symptom free. A decision to take her off dialysis was taken. The patient received eculizumab infusions twice monthly for a total of 18 doses and then monthly for 2 more doses, for a total of 20 infusions. On completion of the last infusion, the serum creatinine was 1.23 mg/dL, LDH was 227, hemoglobin was 12.6, and platelet count was 250,000. The GFR by Schwartz formula was 38 mL/min/1.73 m2. The patient has grown in height from 113 cm to a final adult height of 161 cm.

Eight years after the initial admission, the patient had a routine renal ultrasound that showed multiple complicated cysts in the left kidney measuring up to 2.0 cm with internal septations (Figure 2). This finding was confirmed on CT scan. The patient had no known family history of any cystic renal disease including polycystic kidney disease (PKD), but they have not been investigated for this. The patient’s twin sister is healthy.

Currently, the patient is 15 years old; it has been 10 years since the original cTMA episode. At the time of last followup, her serum creatinine was 1.10 mg/dL and her GFR by Schwartz formula was 60 mL/min/1.73 m2. The patient has mild proteinuria that is managed on enalapril 2.5 mg/day (0.05 mg/kg/day). The current urine protein: creatinine ratio is 0.39 (normal <0.2). Blood pressure is normal. The patient has had no relapses of cTMA since the original presentation. She has had over 50 clinic visits and over 60 lab draws in the 10 years since coming off dialysis, but she has had no hospitalizations since then. A Natera Renasight genetic testing panel confirmed a complement factor H mutation, c.2207G>A (p.Arg736Gln), but additionally, showed a PKD1 mutation: c.11801G>C (p.Gly3934Ala). The patient is an identical twin but neither her sister nor any other members of the family have been tested for either genetic variation.

Discussion

We report a case of cTMA in a previously healthy 5-year-old girl who is currently 15. It has been 10 years after her initial presentation, and she has stable chronic kidney disease (CKD 3a). She was treated with eculizumab for a year at the onset of illness. In the pre-eculizumab era, researchers showed that 57–82% of relapses occurred in the first year of followup [9]. In our patient, renal function was slowly recovering before the start of eculizumab, but a month into infusion therapy, after 2 doses for induction, she was able to come off hemodialysis. Now, a decade later, she has a stable GFR and mild proteinuria managed by enalapril. It is unknown whether earlier treatment with eculizumab would have helped her renal function to recover fully and whether it helped her to come off hemodialysis. Eculizumab therapy very effectively reverses unchecked complement activation and reduces death from cTMA [6–8]. Initial guidelines suggested that treatment should be lifelong. However, there is little evidence to support that [9]. A decade ago, discontinuation of eculizumab for cTMA that was rooted in a proven genetic mutation was considered unscientific. The approval reports of the Food and Drug Administration in the USA and similar counterparts abroad emphasize the risks of withdrawal of eculizumab [9].

The efficacy of eculizumab in children was confirmed in a prospective trial [9]. Complete cTMA response was achieved after a median of 8.6 (1–22) weeks [9]. The eculizumab treatment was continued for at least 2 years [9]. No advice was given on how to proceed when a patient was stable and in remission. Lack of proven cTMA disease activity does not denote complete renal recovery [6–9]. In addition, the recurrence or progressive rate of cTMA varies for each mutation, so lifelong continuation may be unnecessary for some. Pathogenic variants in at least 5 complement genes coding for CFH, complement factor I (CFI), MCP (CD46), C3, and complement factor B (CFB) have mainly been shown to increase the risk of developing the disease. The risk of recurrence seemed to be higher in patients with pathogenic mutations in CFH (31–55%), MCP (18–52%), and C3 (50%) [3,9], which often present as a fulminant disease for the first time in adulthood [9]. Theoretically, that could mean there might be a prolonged period between initial presentation and relapse or late initial presentation with a milder disease early in childhood that is missed. Although organ transplantation, pregnancies, and chemotherapy agents, amongst others, have frequently been described as triggers, no specific trigger pattern exists [3–6, 9]. This can create anxiety in patients and the clinicians taking care of them. There is no consensus on the optimal dose and duration of treatment, particularly in view of the high costs and potential life-threatening adverse effects of eculizumab. A limited number of case reports and small number of patient studies suggest a restrictive duration of treatment is an alternative approach [9].

ADPKD is transmitted in an autosomal dominant, fully penetrant fashion, so virtually all individuals who inherit a mutated PKD allele in their germline will develop detectable renal cysts on sonogram by age 30 or possibly later. The majority of ADPKD patients carry a germline mutation in the PKD1 gene on chromosome 16p13, and 15 to 20% of patients harbor a PKD2 mutation on 4q21 [10]. CFH is located in the “regulators of complement activation” cluster on chromosome 1. This gene cluster includes decay-accelerating factor, complement receptor types 1 and 2, membrane cofactor protein, C4-binding protein, clotting factor XIIIb, CFH, and the CFH-related protein genes [3–5]. Therefore, the presence of these 2 mutations in our patient is most likely coincidental, although both diseases have multiple associated, described mutations; for example, PKD1 has >1000 pathogenic mutations described [10]. Scientifically, it will be important to keep a watch if more cases like ours are reported in the future.

Conclusions

We present an alternative method that some have utilized [7,8], of intensive clinical monitoring after completing eculizumab treatment for cTMA for a year and achieving a clinical remission. This intensive followup care strategy was possible because of a reliable family that understood the risks of this illness. Our patient had over 50 visits to a medical provider over a 10-year period and a blood test each time. In a young child, this number of visits is a significant emotional burden and the commitment entailed should not be minimized. Unfortunately, she was found to have a second genetic mutation, PKD1, that was unrelated to CFH, that can affect her renal function in the future. PKD1will in the future increase the risk of deterioration of her renal function, but the resilience of the family portends a slower progression of CKD.