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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
REVIEW ARTICLE  
Year : 2018  |  Volume : 29  |  Issue : 2  |  Page : 276-283
Atypical hemolytic uremic syndrome: Laboratory characteristics, complement-amplifying conditions, renal biopsy, and genetic mutations


1 Department of Medicine, Jersey Shore University Medical Center, Seton Hall Hackensack-Meridian School of Medicine, Neptune, New Jersey, USA
2 Department of Medicine, Salisbury VA Health Care System, VCOM, North Carolina, USA

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Date of Web Publication10-Apr-2018
 

   Abstract 

Atypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and widespread damage to multiple organs including the kidney. The syndrome has a high mortality necessitating the need for an early diagnosis to limit target organ damage. Because thrombotic microangiopathies present with similar clinical picture, accurate diagnosis of aHUS continues to pose a diagnostic challenge. This article focuses on the role of four distinct aspects of aHUS that assist clinicians in making an accurate diagnosis of aHUS. First, because of the lack of a single specific laboratory test for aHUS, other forms of thrombotic microangiopathies such as thrombotic thrombocytopenic purpura and Shiga toxin-associated HUS must be excluded to successfully establish the diagnosis of aHUS. Second, application of the knowledge of complement-amplifying conditions is critically important in making an accurate diagnosis. Third, when available, a renal biopsy can reveal changes consistent with thrombotic microangiopathy. Fourth, genetic mutations are increasingly clarifying the underlying complement dysfunction and gaining importance in the diagnosis and management of patients with aHUS. This review concentrates on the four aspects of aHUS and calls for heightened awareness in making an accurate diagnosis of aHUS.

How to cite this article:
Hossain MA, Cheema A, Kalathil S, Bajwa R, Costanzo EJ, Cosentino J, Cheng J, Vachharajani T, Asif A. Atypical hemolytic uremic syndrome: Laboratory characteristics, complement-amplifying conditions, renal biopsy, and genetic mutations. Saudi J Kidney Dis Transpl 2018;29:276-83

How to cite this URL:
Hossain MA, Cheema A, Kalathil S, Bajwa R, Costanzo EJ, Cosentino J, Cheng J, Vachharajani T, Asif A. Atypical hemolytic uremic syndrome: Laboratory characteristics, complement-amplifying conditions, renal biopsy, and genetic mutations. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2018 Jun 22];29:276-83. Available from: http://www.sjkdt.org/text.asp?2018/29/2/276/229287

   Introduction Top


Thrombotic microangiopathy (TMA) features widespread microvascular thrombosis, resulting in ischemic injury to multiple organs.[1],[2],[3] In general, there are three distinct forms of thrombotic microangiopathies. These include thrombotic microangiopathies such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) associated with Shiga toxin-producing Escherichia coli (STEC-HUS), and atypical HUS (aHUS). These three entities must be considered in patients presenting with clinical features consistent with TMA. It is worth mentioning that a widespread familiarity with TTP and the traditional thought process that aHUS is a disease of children often lowers the index of suspicion for aHUS as a diagnostic possibility.[3]

A deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), or the presence of autoantibodies against ADAMTS13 can result in TTP. In simple terms, HUS has two distinct sources.[1],[2],[3],[4],[5],[6] An infection with E. coli (serotypes 0157:H7 and 0104:H4) most often results in STEC-HUS. On the other hand, it is the uncontrolled activation of the alternative pathway of the complement system that is involved in the pathogenesis of aHUS.[3]


   Role of Laboratory Data and Clinical Features Top


Microangiopathic hemolytic anemia, thrombocytopenia, and target organ injury are essential clinical features of TMA. Microvascular thrombosis results in ischemic injury to target organs.[5],[6],[7],[8],[9],[10],[11],[12],[13] In patients with aHUS, the kidney is frequently involved.[3],[13] In these patients, hematuria, proteinuria, hypertension, and azotemia can be observed.[3],[13] Important diagnostic elements include thrombocytopenia (platelet count <150,000/μL or 25% decrease from baseline), microangiopathic hemolytic anemia (decreased haptoglobin, decreased hemoglobin, elevated lactate dehydrogenase, and schistocytes on blood film), proteinuria, hematuria, and elevated blood urea nitrogen and creatinine. Abnormal liver function tests and elevated pancreatic enzyme levels can also be seen in patients with liver and pancreatic injury.[3]

Distinct laboratory tests are available to make the diagnosis of TTP and STEC-HUS [Table 1]. However, at present, a single confirmatory test to establish the diagnosis of aHUS does not exist. Shiga toxin test and ADAMTS13 activity are extremely helpful in distinguishing the three forms of TMAs (HUS, TTP, and aHUS) from one another. A deficiency of ADAMTS13 (<5% of normal activity) indicates the diagnosis of TTP, whereas positive Shiga toxin indicates STEC-HUS. Similarly, a normal ADAMTS13 activity and absence of Shiga toxin help establish the diagnosis of aHUS. A major limitation of the ADAMTS13 activity assay test lies in the delay in sample processing, due to which, the results may not be readily available and can take up to several days. This delay in the availability of ADAMTS13 is a major limitation in making a timely diagnosis of aHUS. Improvement in laboratory processing time for ADAMTS13 is urgently needed to improve patient care. A blood sample to determine the ADAMTS13 should be collected before instituting any plasma therapy.[8]
Table 1: Laboratory features of the three forms of thrombotic microangiopathy are presented.

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Surrogate markers for severe ADAMTS13 deficiency can facilitate to establish the diagnosis.[14],[15],[16],[17] Several studies have indicated that a vast majority of patients with severe ADAMTS13 deficiency demonstrate a serum creatinine level <2.26 mg/dL and a platelet count <30 × 109/L.[14],[15],[16],[17] These studies point out that when thrombotic microangiopathy is associated with a serum creatinine level ≥2.26 mg/dL and a platelet count ≥30×10[9]/L, TTP is a highly unlikely diagnosis and aHUS should be strongly considered.[14],[15],[16],[17] Although not confirmatory, clinicians can use this information to help manage their patients.

For the most part, a low C3 level (with normal C4 concentrations in the serum) indicates the activation of the alternative pathway of the complement system. However, a decreased serum C3 level is not specific and cannot be used to establish the diagnosis of aHUS.[3] At the same time, the demonstration of normal C3 and C4 concentrations does not exclude aHUS.[3] A recent study reported on the biomarkers of cellular processes involved in patients with aHUS.[18] These investigators reported that urinary C5a was significantly elevated in patients with aHUS (9.0 ng/mg U-creatinine; a 45-fold increase from healthy subjects) compared to healthy volunteers (0.0–0.7 ng/mg U-Creatinine; P <0.001). Likewise, the urinary C5b-9 was significantly elevated in aHUS patients (30.5 ng/mg U-Creatinine; a 305-fold increase from healthy subjects) compared to healthy volunteers (0.0–0.6 ng/mg U- Creatinine; P <0.0001). In addition, the markers of endothelial damage (thrombomodulin), as well as endothelial activation (VCAM-1) were evaluated. Thrombomodulin was significantly elevated in patients with aHUS (10 ng/mL; a 3.6-fold increase from healthy subjects) compared to healthy volunteers (2.0–3.6 ng/mL; P<0.0001). Finally, VCAM-1 was significantly increased in patients with aHUS (659.8 ng/mL; a 2.0-fold increase from healthy subjects) compared to healthy volunteers (159.2–444.7 ng/mL; P<0.0001).[18]

Clinical presentation of TTP and aHUS has challenged the conventional wisdom.[1],[3],[19] In this context, TTP was thought to predominantly have neurological involvement. Nevertheless, nearly 10% of the patients with aHUS present with altered mental status, focal neurological deficits, and seizure.[8] Almost half of the children with aHUS are reported to have neurological involvement.[19] The presence of diarrhea has been thought to indicate STEC-HUS; however, nearly one-third of the patients with aHUS present with diarrhea.[19],[20] Once considered a disease of the children, aHUS is increasingly diagnosed in the adult population.[19] Conventional methodology of associating certain clinical features with TTP, STEC-HUS, and aHUS is not considered an optimal approach today.

In summary, anemia, thrombocytopenia, and evidence of target organ injury are important in establishing the diagnosis of aHUS. Low haptoglobin, elevated LDH, and schistocytes on the peripheral smear are also important elements that help in establishing the diagnosis. Elevated serum creatinine, proteinuria, and hematuria establish renal injury. ADAMTS13 is a key diagnostic test that must be undertaken in a patient presenting with TMA. Biomarkers of cellular processes are emerging and may serve in the diagnosis and overall management of patients with aHUS.


   Role of Complement Amplifying Conditions Top


As the “multiple-hit” theory,[21] aHUS results from genetic predisposition to alternative complement dysregulation plus the development of states that may induce TMA by activating complement system.[21],[22] The “so-called” complement-amplifying conditions (CACs) include pregnancy complications (preeclampsia, HELLP), autoimmune diseases, malignant hypertension (MHT), infections, major surgery, drugs, and others.[23],[24],[25] CACs can unmask a previously undiagnosed case.[23],[24],[25] At the same time, CACs may lead to a misdiagnosis by taking the focus away from the TMA.[23],[24],[25] For example, MHT is a CAC in which clinicians must investigate the presence of TMA in addition to the optimal treatment of blood pressure control.

Recent data have demonstrated that patients with underlying complement dysregulation are prone to develop TMA when experiencing a CAC.[13],[20] With the development of a CAC, patients with underlying genetic abnormalities are unable to regulate complement, resulting in precipitating aHUS.[20],[26] A large observational study of patients with aHUS showed that 69% of the patients had their first manifestations of TMA while experiencing a CAC.[13] Data from multiple case reports are also emphasizing a similar pattern.[20]

TMA develops in 1/25,000 pregnancies.[27] Approximately 7% of total aHUS cases are pregnancy related.[13],[28],[29] Complement pathway may be activated postpartum (due to maternal circulation of fetal cells, infections, and hemorrhage), resulting in TMA.[29] The diagnosis of pregnancy-related aHUS may be difficult because of similarities between pregnancy-related aHUS, preeclampsia and HELLP syndrome.[27],[30] In a recent study of 21 patients with pregnancy-related aHUS, TMA occurred mostly in the postpartum period and during a second pregnancy.[31] Pregnancy-related aHUS is a serious condition that can lead to rapid deterioration, resulting in poor maternal outcomes.[27]

MHT is another CAC that can result in TMA.[32],[33] In a recent study (n = 45), 71% presented with hypertension.[34] In a separate study, 8% of patients with aHUS also demonstrated MHT.[13] Shear stress on endothelial cells and subsequent injury is known to result in red cell fragmentation, platelet consumption and target organ injury.[32],[33],[35],[36] Patients with MHT may present with TMA.[33] In the absence of accurate diagnosis and optimal treatment, patients with aHUS and MHT may have severe symptoms and poor outcomes.[37],[38] In a retrospective study of 21 patients with TMA and severe hypertension, 86% of patients did not recover kidney function despite adequate antihypertensive therapy, indicating that targeted therapy for TMA is required in addition to controlling hypertension.[39] It has been proposed that a diagnosis of aHUS should be suspected in patients with difficult-to-control hypertension who demonstrate persistent TMA.[40]

Connective tissue diseases can also act as CACs. Systemic lupus erythematosus (SLE) is characterized by the formation of immune complexes that activate complement, leading to cellular injury.[41] Dysregulation of the terminal complement activation has been implicated in the pathogenesis and prognosis of SLE and lupus nephritis.[41],[42],[43] In patients with SLE, TMA is associated with increased SLE activity, infections,[44] decreased long-term kidney function, and poor overall survival.[45],[46],[47],[48],[49] In addition to SLE, multiple case reports of scleroderma-related aHUS have been reported in the literature.[50],[51],[52],[53],[54] Finally, ulcerative colitis can also be associated with aHUS, and two cases of ulcerative colitis-associated aHUS have been recently reported in the literature.[55],[56]

Recurrent and de novo aHUS can develop in patients after kidney transplantation.[57],[58] Likewise, aHUS can develop after the use of certain medications.[57] Data from a recent systematic review of published reports showed that nine medications account for 76% of TMA cases: quinine, tacrolimus, cyclosporine, interferons, gemcitabine, mitomycin, clopidogrel, estrogen/progesterone, and ticlopidine are the most important agents that can result in TMA.[59] The pathogenesis of drug-induced TMA involves both immune-mediated and direct toxicity. As in other conditions, the discontinuation of the offending agent is of primary importance in the overall management of these patients.

Finally, infections of the respiratory and gastrointestinal tracts are particularly important and precede the development of aHUS in nearly 50% of the cases.[13],[28] Common bacterial and viral infections associated with TMA include Streptococcus pneumoniae, cytomegalovirus, H1N1 influenza, human immunodeficiency virus, and parvovirus.[57],[58] The pathogenesis involves activation of the alternative complement pathway, increased production of C5, and deposition of C5b-9.[58]

Taken together, CACs activating the complement pathway are important events in the development of aHUS. These conditions must be recognized in patients presenting with TMA and appropriately addressed to reduce morbidity and mortality. The management of TMA must first focus on the treatment of CAC. If TMA persists despite the optimal management of CAC, complement blockade with a monoclonal antibody (eculizumab) should be considered.


   Role of Renal Biopsy Top


Several changes are observed on renal biopsy in patients presenting with TMA. On light microscopy, the glomerular capillaries demonstrate endothelial swelling with a resultant decrease in the size of the vascular lumen.

Fibrin thrombi in the capillaries occlude the vascular lumen and there may be fragmented red blood cells seen in the glomerular capillary lumen. The afferent and efferent arterioles may also demonstrate fibrin thrombi. Total occlusion of glomerular capillaries and arterioles can be seen in severe cases. In this context, complete occlusion of the arterioles can produce glomerular changes similar to those observed in ischemic injury (glomerular membrane wrinkling and collapse).

Endothelial injury and disruption of the endothelial barrier allow fibrin, fragmented complement factors, fragmented red blood cells, leukocytes, and cellular debris to be deposited in the subendothelial space. During the chronic healing phase, new endothelial cells lay down the basement membrane giving rise to the duplication of the basement membrane. Mesangial sclerosis and increased cellularity give the glomerulus, a nodular pattern (similar to that observed in diabetic nephropathy) giving rise to what is known as membranoproliferative glomerulonephritis. Due to the ischemic insult, tubular necrosis can be seen. In addition, fragmented red blood cells may be observed inside the tubules. In chronic cases, interstitial fibrosis can also be seen. The arteries in the interstitium can demonstrate endothelial swelling, fibrin deposits, thrombosis, and intimal proliferation.

In general, there is an absence of immunoglobulins on immunofluorescence. However, such a scenario may be observed when aHUS is encountered in the presence of another entity (i.e., SLE). Typically, fibrin staining is prevalent in glomeruli and arterioles. C3 can also be found in the glomerulus. Endothelial swelling and subendothelial deposition of fibrin, fragmented complement factors, fragmented red blood cells, leukocytes, and cellular debris are the characteristic findings on electron microscopy. The formation of a new layer on the endothelial side of the basement membrane results in the duplication of basement membrane.

At present, structural histological changes observed on renal biopsy in patients with aHUS, STEC-HUS, and TTP are indistinguishable from each other. There is evidence that the thrombi of HUS predominantly contain fibrin with few platelets, while the thrombi of TTP are composed predominantly of platelets with minimal fibrin.[60] The benefits of obtaining a renal biopsy (in the presence of thrombocytopenia and anemia) must be weighed against its risks and discussed with the patient in detail. It is important to mention that renal biopsy is not required to establish the diagnosis of aHUS. Finally, trauma of biopsy per se in patients with aHUS may serve as an amplifying factor in further triggering the disease activity. However, if renal biopsy has been obtained, it is prudent to review and discuss the findings with a renal pathologist.


   Role of Genetic Mutations Top


Because genetic mutations in the complement regulatory proteins underlie the pathogenesis of aHUS, there has been an increased interest in obtaining genetic studies.[4],[7],[13],[15],[16],[13],[26],[61]

While much progress has been made in our understating of the genetic mutations resulting in aHUS, not all of the mutations are known at this point in time. In addition, multiple coexisting mutations are found in patients with aHUS. It is conceivable that an unknown mutation of a complement regulator may exist in a patient that revealed no mutation on the currently available genetic test. It is for this reason that negative genetic testing cannot be used to rule out the diagnosis of aHUS or to allow a kidney donation from a family member.

Both liver and kidney transplantation has been performed as a strategy to combat aHUS.[5],[6],[26] For the most part, individuals with dysfunction of serum complement proteins can be candidates for combined liver and renal transplantation. On the other hand, patients with dysfunction of membrane-bound complement factors could be recipients of renal transplantation. While this seems to be a good approach, the outcomes of this approach have been disappointing with a failure rate of up to 80% for non-MCP mutations and up to 20% for MCP mutation.[26],[61] In this context, genetic testing may help inform the prognosis.

While genetic testing is not used to establish the diagnosis of aHUS at present, it is emerging as an important component in the overall understating of aHUS. It is worth mentioning that kidney donation from a family member, even if genetic screening reveals no mutation, can be problematic.


   Conclusion Top


Approximately a quarter of the patients die during the acute phase of aHUS and nearly 50% of the patients develop end-stage renal disease at the end of one year.[1],[2],[3],[4] There is a high recurrence of aHUS in the transplanted kidney with subsequent damage to the transplanted kidney and loss of graft. Complement blockade with a humanized monoclonal antibody (eculizumab) has been successfully used for the treatment of aHUS. In this context, timely and accurate diagnosis is of paramount importance to minimize the devastation of aHUS.

 
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Correspondence Address:
Dr. Arif Asif
Department of Medicine, Jersey Shore University Medical Center, Seton Hall Hackensack-Meridian School of Medicine, Neptune, New Jersey
USA
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DOI: 10.4103/1319-2442.229287

PMID: 29657193

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    Abstract
   Introduction
    Role of Laborato...
    Role of Compleme...
   Role of Renal Biopsy
    Role of Genetic ...
   Conclusion
    References
    Article Tables
 

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