Hemolytic uremic syndrome (HUS) is a type of thrombotic microangiopathy (TMA) characterized by thrombo-cytopenia, acute kidney injury (AKI), and microangiopathic hemolytic anemia [1, 2, 3]. Atypical HUS (aHUS) comprises around 5.0-10.0% of all HUS cases and frequently leads to irreversible kidney injury, often with a worse prognosis [1,2,4]. Atypical HUS is a disease complex characterized by the uncontrolled over-activation of the alternative pathway of the complement system. Activation has been linked to mutations in complement factors in 50.0-60.0% of cases [3]. Atypical HUS cases can be categorized as sporadic or familial. Familial aHUS requires diagnosing at least two aHUS cases in the same family over the past 6 months. Twenty percent of all aHUS patients are familial aHUS cases [5].
Genetic disorders such as gene mutations, rare variants, and risk haplotypes in familial aHUS and sporadic aHUS cases and developmental anomalies such as factor H against autoantibodies are found in 70.0% of patients [6]. The regulator of complement activation gene cluster on human chromosome 1q32 spans over a total of 21.45 cM and contains more than 60 gene codes, 15 of which are complement regulators. This code plays a vital role for both soluble and transmembrane proteins in regulating complement activity. These complement genes are arranged in tandem within two groups. Gene mutations usually occur in complementary genes such as factor H (
Data obtained from familial studies demonstrate that, due to a high level of incomplete penetrance of aHUS, 50.0% of persons carrying
Previous test results of the family members including the values of leukocytes, hemoglobin (Hb), packed cell volume (PCV), platelets, glucose, blood urea nitrogen (BUN), creatinine (Cr), total protein, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transferase, alkaline phosphatase, lactate dehy-drogenase (LDH), total bilirubin, peripheral smear, complement 3 (C3), complement 4 (C4), urine, protein in urine and Cr, haptoglobin, ADAMTS-13 activity, and gene mutation analysis (
The laboratory findings of 13 patients included in the study are presented in Table 1. The test results of our index case at the time of admission were as follows: Hb 7.8 g/ dL, PCV 0.23 L/L, platelets 56000.0 mm3, widespread schistocytes in peripheral blood smear, BUN 126.0 mg/dL, Cr 7.8 mg/dL, ADAMTS-13 activity 99.2%, LDH 2350.0 IU/L and haptoglobin <10.0 mg/dL. Based on these results, the patient was diagnosed with aHUS. Of the 13 patients who were screened, three were diagnosed with CRF, one being our index patient and the other two his siblings. The patient also reported six sibling deaths; three of them died of CRF. Besides, genetic screening results showed that the
Demographic data and laboratory findings of the family members.
Parameters | ST | DT | MNT | NT | FT | MUT | SA | AA | ŞA | FA | AT | CT | MT | Ref. Ranges |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Relationship | Father | Mother | Brother | Brother | AT’s Aunt | AT’s Nephew | Sister | SA’s Husband | AT’s Nephew | AT’s Nephew | Index | Brother | Brother | |
Sex-Age (years) | M-78 | F-66 | M-38 | M-26 | F-26 | M-2 | F-30 | M-48 | M-12 | F-9 | M-28 | M-18 | M-23 | |
WBC (mm3) | 8900.0 | 7600.0 | 10500.0 | 5670.0 | 7400.0 | 19110.0 | 6600.0 | 8200.0 | 5800.0 | 7630.0 | 10300.0 | 5900.0 | 7870.0 | 4000.0-10000.0 |
Hb (g/dL) | 14.5 | 12.7 | 14.2 | 13.7 | 14.6 | 9.1 | 13.0 | 13.2 | 12.6 | 12.8 | 7.8 | 11.9 | 10.7 | 13.0-17.0 |
PCV (L/fL) | 0.43 | 0.38 | 0.43 | 0.41 | 0.44 | 0.29 | 0.39 | 0.40 | 0.38 | 0.39 | 0.23 | 0.36 | 0.32 | 0.37-0.54 |
Platelet count (109/L) | 256.0 | 368.0 | 210.0 | 162.0 | 432.0 | 450.0 | 282.0 | 342.0 | 323.0 | 410.0 | 56.0 | 173.0 | 120.0 | 150.0-500.0 |
BUN (mg/dL) | 32.0 | 58.0 | 36.0 | 19.0 | 25.0 | 23.0 | 21.0 | 24.0 | 26.0 | 21.0 | 126.0 | 113.0 | 122.0 | 18.0-55.0 |
Cr (mg/dL) | 0.78 | 0.92 | 0.84 | 0.82 | 0.67 | 0.25 | 0.76 | 0.48 | 0.64 | 0.72 | 7.80 | 7.67 | 7.60 | 0.72-1.25 |
Total protein (g/dL) | 6.80 | 8.20 | 8.10 | 8.20 | 8.20 | 8.20 | 7.90 | 7.80 | 7.20 | 7.50 | 8.10 | 9.13 | 8.60 | 6.40-8.30 |
Albumin (g/dL) | 4.20 | 4.30 | 4.40 | 4.70 | 4.80 | 4.29 | 4.60 | 4.10 | 4.00 | 4.30 | 4.40 | 5.10 | 4.40 | 3.50-5.520 |
AST (IU/L) | 26.0 | 38.0 | 35.0 | 25.0 | 31.0 | 38.0 | 29.0 | 36.0 | 27.0 | 25.0 | 450.0 | 20.0 | 24.0 | <37.0 |
ALT (IU/L) | 24.0 | 36.0 | 29.0 | 15.0 | 36.0 | 18.0 | 33.0 | 28.0 | 18.0 | 21.0 | 630.0 | 6.0 | 11.0 | <42.0 |
GGT (IU/L) | 8.0 | 12.0 | 17.0 | 14.0 | 16.0 | 13.0 | 29.0 | 14.0 | 12.0 | 17.0 | 14.0 | 9.0 | 28.0 | <64.0 |
ALP (IU/L) | 68.0 | 58.0 | 59.0 | 75.0 | 120.0 | 198.0 | 48.0 | 110.0 | 86.0 | 84.0 | 65.0 | 82.0 | 123.0 | <150.0 |
LDH (IU/L) | 243.0 | 289.0 | 320.0 | 213.0 | 245.0 | 299.0 | 252.0 | 262.0 | 246.0 | 219.0 | 2350.0 | 248.0 | 259.0 | 125.0-220.0 |
Glucose (mg/dL) | 86.0 | 78.0 | 96.0 | 84.0 | 78.0 | 108.0 | 89.0 | 82.0 | 89.0 | 74.0 | 86.0 | 99.0 | 82.0 | 70.0-105.0 |
Total bilirubin (mg/dL) | 0.56 | 0.79 | 0.96 | 0.64 | 0.34 | 0.55 | 0.62 | 0.79 | 0.67 | 0.64 | 1.58 | 0.56 | 0.76 | 0.0-1.2 |
Schistocyte | [–] | [+] | [–] | [–] | [–] | [–] | [–] | [–] | [–] | [–] | [+] | [+] | [+] | – |
C3 (mg/dL) | 134.0 | 124.0 | 124.2 | 158.0 | 112.0 | 186.0 | 154.0 | 134.0 | 142.0 | 132.0 | 98.0 | 95.4 | 136.0 | 90.0-10.0 |
C4 (mg/dL) | 26.2 | 28.2 | 26.4 | 29.5 | 22.0 | 34.6 | 26.3 | 24.2 | 23.4 | 21.3 | 7.7 | 27.3 | 38.3 | 10.0-40.0 |
Proteinuria | [–] | [+] | [–] | [–] | [–] | [+] | [–] | [–] | [–] | [–] | [+++] | anuric | anuric | – |
Hematuria | [–] | [+] | [–] | [–] | [–] | [+] | [–] | [–] | [–] | [–] | [+++] | anuric | anuric | – |
Protein/Cr (mg/mg) | <0.2 | <0.2 | <0.2 | <0.2 | <0.2 | 0.70 | <0.2 | <0.2 | <0.2 | <0.2 | 5.6 | anuric | anuric | <0.2 |
ADAMTS-activity (%) 12 | 97.00 | 96.00 | 84.20 | 77.11 | 94.30 | 120.40 | 67.00 | 88.50 | 92.60 | 102.00 | 99.27 | 98.40 | 83.11 | 40.00-130.00 |
Haptoglobin (mg/dL) | 16.0 | 17.3 | 16.0 | 18.0 | 19.1 | 18.3 | 17.2 | 18.2 | 19.7 | 18.7 | <10.0 | 17.0 | 19.0 | 14.0-58.0 |
NM | H | NM | H | NM | H | NM | NM | NM | NM | H | H | H | – | |
Outcome | healthy | healthy | healthy | healthy | healthy | healthy | healthy | healthy | healthy | healthy | AKI | CRF | CRF | – |
WBC: white blood cell count; Hb: hemoglobin; PCV: packed cell volume; BUN: blood urea nitrogen; Cr: creatinine;
AST: LDH: aspartate lactate dehydrogenase; aminotransferase; C3: ALT: complement alanine aminotransferase, 3; C4: complement GGT: 4;
H: heterozygous; AKI: acute kidney injury; CRF: chronic renal failure.
The family members showing gene mutations included the mother of the index case, three of his brothers, and one of his nephews. The laboratory results of these six cases and seven other family members are shown in Table 1. While all clinical and laboratory findings of the mother (DT), one sibling (NT) and this sibling’s son (MUT), were normal, our index (AT) patient with the heterozygous gene mutation had AKI, and his two siblings (CT and MT) had CRF. These two siblings developed recurrent CRF after they received a renal transplant.
Sibling 1 (MT) developed AKI due to an unknown etiology at the age of 7. He applied to another hospital. His initial symptom was shortness of breath, and he was found to have severe hypertension, AKI with a serum Cr of 8.4 mg/dL, anemia with Hb of 7.8 g/dL, and proteinuria. He underwent a kidney biopsy that revealed non specific findings. As there is a crescent in some areas in renal biopsy, it was thought that there might be rapidly progressive glo-merulonephritis. He received six high-dose pulse steroids and continued with oral steroids and 10 sessions of plas-mapheresis. Despite therapy, the disease progress to CRF, and the patient became hemodialysis-dependent. At that time, aHUS was not considered in this patient. The patient received hemodialysis treatment for 6 months, and then renal transplantation was performed from the father. Renal rejection developed 4 months after transplantation. Hemodialysis treatment was started again. The patient was diagnosed with familial aHUS after the diagnosis of our index case. The patient was taken back to the eculizumab (ECZ) treatment and transplantation program.
Sibling 2 (CT), a 18-year-old male, developed AKI due to an unknown etiology. He was admitted to another hospital with signs of AKI, like his brother. His initial symptom was shortness of breath, and he was found to have severe hypertension, AKI with a serum Cr of 9.1 mg/dL, anemia with Hb of 8.8 g/dL, and proteinuria. Like his brother, he received steroid and plasmapheresis therapy. Despite therapy, the disease progress to the CRF, and the patient became hemodialysis-dependent. After the patient received hemodialysis treatment for 11 months, he underwent a renal transplant (from a 35-year-old male patient who died of a cerebral hemorrhage). Renal rejection developed 3 months after transplantation. Hemodialysis treatment was started again. The patient was diagnosed with familial aHUS after the diagnosis of our index case. The patient was taken back to the transplantation program and eculizumab treatment.
Our index (AT) patient was treated with a total 20 sessions of plasmapheresis (initially, five sessions of plasmapheresis were performed, and then 15 more sessions were performed until the start of ECZ treatment) for 6 weeks and daily fresh frozen plasma therapy. However, upon insufficient response to this treatment, ECZ therapy was initiated. The patient showed a dramatic improvement after treatment with ECZ. The patient’s serum Cr level was reduced to 0.8 mg/dL. Moreover, when the patient became unable to receive ECZ treatment for a while, he once again developed AKI, with his blood Cr level increasing to 6.8 mg/dL. However, the patient’s Hb level decreased to 6.4 g/dL and platelet count to 78000 mm3. Furthermore, the patient developed dilated cardiomyopathy as in some cases reported in the literature [20]. Once the patient received regular ECZ therapy, his AKI symptoms and cardiomyopathy began to improve. The test results on the patient’s last admission were as follows: Hb 13.6 g/dL, PCV 0.40 L/L, platelet 345000.0 mm3, BUN 48 mg/dL, Cr 1.8 mg/ dL, LDH 210.0 IU/L, and haptoglobin 18.2 mg/dL. Longterm follow-up over 1 year showed stable renal function with no relapse. The patient is still being followed by the Departments of Hematology and Nephrology, Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey.
This study reports scanned results of a family who presented at our center. In six of 13 family members, the p.S1191L mutation on the
Some cases with the
In aHUS, patients may be identified as familial or sporadic cases. In inherited cases, genetic mutations in CFH, CFI, C3 convertases, C3 and factor B, thrombomodulin, CD46 and MCP can lead to complement-related HUS. Other factors such as deficiency of metalloprotease activity that cleaves von Willebrand factor (VWF-CP or ADAMTS-13), CFI deficiency, and auto antibodies against CFH may also cause aHUS [25]. These mutations in complement components or regulatory proteins plays an important role in the pathogenesis of aHUS in 50.0-60.0% of patients. These mutations cause mis regulation of the complementary alternative pathway in the endothelium, triggering attacks of thrombotic microangiopathy in the renal microvasculature and other vital organs [26, 27, 28]. A gene mutation in CFH (p.S1191L mutation in the
The history of CRF and renal transplantation resulting in rejection in two patients was also associated with aHUS that might have occurred as a result of a mutation in this gene. No pathologies were detected in the other three family members with gene mutation, including the mother and a 2-year-old child. Therefore, the question arises as to whether factors such as female gender, not having experienced a triggering event, and young age could serve as protective features in the disease. The absence of any pathological findings in the third family member may have resulted from a mechanism that we cannot explain. There exist studies describing this phenomenon in the literature. Despite heterozygous pathogenic variants in complement genes often identified in diseased and healthy parents, the disease is often sporadic, which indicates that genetic mutations give rise to sensitivity, but they do not cause disease [31]. The disease occurred in approximately 50.0% of the family members affected by the gene mutation by the time they reach 45 [32]. Arjona
In addition to our index patient, the
In the treatment of atypical HUS, ECZ, a monoclonal antibody that inhibits complement protein C5, has been demonstrated to be an effective treatment option. In recent years, multicenter studies have shown that ECZ therapy rapidly improves the platelet count and renal functions in most patients after the first dose, eliminating the need for dialysis and plasma treatment. Eculizumab has been reported to be a fast, effective, and life-saving option in treating aHUS [36, 37, 38, 39]. In the present study, our index patient with the
First of all, in our study, we should have performed genetic analysis on more family members, and secondly, we had to determine the causes of death of the deceased individuals of the family more clearly, but we could not.
This study identified six people who were heterozygous for the p.S1191L mutation on the