The Open Urology & Nephrology Journal




ISSN: 1874-303X ― Volume 12, 2019

A Simplified Approach to the Diagnosis of Atypical HUS: Clinical Considerations and Practical Implications



Arif Asif *, 1, Tushar Vachharajani 2, Loay Salman 3, Ali Nayer 3
1 Division of Nephrology and Hypertension, Albany Medical College, Albany, NY, USA
2 Division of Nephrology and Hypertension W.G. (Bill) Hefner Veterans Affairs Medical Center, Salisbury, NC, USA
3 Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, FL, USA

Abstract

Although rare, atypical hemolytic-uremic syndrome (aHUS) carries a high morbidity and mortality. Widespread microvascular thrombosis, thrombocytopenia and microangiopathic hemolytic anemia are the hallmark of aHUS. Virtually any organ (particularly the kidney) can be a target for the devastating effects of this syndrome. Uncontrolled activation of the alternative pathway of the complement system lies at the heart of the pathogenesis of aHUS. While significant advances have been made in our understanding of aHUS, establishing timely diagnosis of this syndrome has been challenging. This, in part, is due to the absence of a sensitive and specific diagnostic test and a relatively lack of our familiarity with the syndrome. With the recent success and approval of a humanized monoclonal antibody (eculizumab) in the treatment of aHUS, prompt and accurate diagnosis is of paramount importance to limit the target organ injury. This article presents a simplified approach to establishing the diagnosis of aHUS.

Keywords: Atypical hemolytic uremic syndrome, eculizumab, thrombotic microangiopathy, thrombotic thrombocytopenic purpura..


Article Information


Identifiers and Pagination:

Year: 2014
Volume: 7
First Page: 91
Last Page: 94
Publisher Id: TOUNJ-7-91
DOI: 10.2174/1874303X01407010091

Article History:

Received Date: 22/4/2014
Revision Received Date: 1/5/2014
Acceptance Date: 6/5/2014
Electronic publication date: 1 /10/2014
Collection year: 2014

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open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Division of Nephrology and Hypertension, Albany Medical College, 25 Hackett Blvd. Albany, NY 12208, USA; Tel: 518-262-0769; E-mail: asifa@mail.amc.edu




INTRODUCTION

Atypical hemolytic-uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA). It is characterized by endothelial injury leading to vascular thrombosis [1Caprioli J, Noris M, Brioschi S , et al. Genetics of HUS the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006; 108: 1267-79.-3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9.]. Other thrombotic microangiopathies such as thrombotic thrombocytopenic purpura (TTP) and HUS associated with Shiga-toxin producing Escherichia coli (STEC-HUS) also cause vascular thrombosis. While all three diagnostic possibilities must be considered in a patient presenting with TMA, widespread familiarity with TTP (and its successful treatment with plasma therapy) and a conventional wisdom that aHUS is a disease of children lowers the index of suspicion of aHUS on the diagnostic list [3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9.]. In this context, the diagnosis of aHUS can present a diagnostic challenge.

It is worth mentioning that a deficiency of the von Willebrand factor cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) results in TTP. On the other hand, HUS has two different identifiable sources of origin [1Caprioli J, Noris M, Brioschi S , et al. Genetics of HUS the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006; 108: 1267-79.-4Nayer A, Asif A. Atypical hemolytic uremic syndrome a clinical review. Am J Ther 2014; (Eput ahead of print)]. The STEC-HUS is most often seen in the setting of an infection with Escherichia coli (usually E. coli serotypes 0157:H7 and 0104:H4). In contrast, uncontrolled activation of the alternative pathway of the complement system is involved in the pathogenesis of atypical HUS (aHUS) [3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9.]. Of note, there is an intricate reciprocal interplay between complements and the coagulation system and complement activation facilitates vascular thrombosis [5Nayer A, Asif A. Atypical hemolytic-uremic syndrome the interplay between complements and the coagulation system. Iran J Kidney Dis 2013; 7: 340-45.]. In a retrospective autopsy-based study, Hosler et al. conducted a histopathological examination of 56 individuals who succumbed to HUS (n=31) or TTP (n=25) [6Hosler GA, Cusumano AM, Hutchins GM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities.A review of 56 autopsy cases. Arch Pathol Lab Med 2003; 127: 834-9.]. In individuals with TTP, platelet-rich thrombi were present in the heart, pancreas, kidney, adrenal gland and brain, in descending order of severity. In those with HUS, however, thrombi consisted predominantly of fibrin and red cells and were most abundant in the kidney followed by the pancreas (19%), adrenal glands (13%), brain (6%) and heart (3%). No distinction between “typical” and “atypical” HUS was made in this study, however.

From a simplistic standpoint, there are distinct laboratory tests that are available to make the diagnosis of TTP (ADAMTS13 activity assay) and STEC-HUS (PCR or culture-based examination of a stool sample). However, a single confirmatory diagnostic test for aHUS does not exist. Indeed, microangiopathic hemolytic anemia, thrombocytopenia and target organ injury, particularly kidney damage, are essential clinical features of aHUS.

Microvascular thrombosis in atypical hemolytic-uremic syndrome results in ischemic injury to target organs [5Nayer A, Asif A. Atypical hemolytic-uremic syndrome the interplay between complements and the coagulation system. Iran J Kidney Dis 2013; 7: 340-45.-3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9.]. The kidney is the most common organ involved [3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9., 13Asif A, Haqqie SS, Ghate K, Mathew RO, Vachharajani T, Nayer A. Continued eculizumab therapy for persistent atypical hemolytic- uremic syndrome. The Open Urol Nephrol J 2013; 6: 46-8.]. In this context, hematuria, proteinuria, hypertension, azotemia and volume overload can all be seen [3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9., 13Asif A, Haqqie SS, Ghate K, Mathew RO, Vachharajani T, Nayer A. Continued eculizumab therapy for persistent atypical hemolytic- uremic syndrome. The Open Urol Nephrol J 2013; 6: 46-8.]. Important diagnostic elements include thrombocytopenia (platelet count<150,000/ mcL or 25% decrease from baseline), microangiopathic hemolytic anemia (schistocytes on blood film, elevated lactate dehydrogenase, decreased haptoglobin, decreased hemo-globin) and target organ injury (elevated blood urea nitrogen and creatinine, abnormal liver function tests, elevated pancreatic enzyme levels, stroke, myocardial infarction etc.) [3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9.] (Fig. 1).

Fig. (1)

Clinical and laboratory manifestations of atypical hemolytic-uremic syndrome. CNS, central nervous system; GFR, glomerular filtration rate; GI, gastrointestinal; LDH, lactate dehydrogenase; PCR, polymerase chain reaction; STEC, Shiga toxin-producing Escherichia coli; ↑, increased; ↓, decreased; →, unchanged; >, greater than; <, less than.



Laboratory investigations such as Shiga-toxin test and ADAMTS13 activity can be very helpful in distinguishing HUS, TTP and aHUS from one another. A deficiency of ADAMTS13 (less than 5% of normal activity) points to the diagnosis of TTP while the presence of Shiga toxin indicates STEC-HUS. Normal ADAMTS13 activity and absence of Shiga toxin help establish the diagnosis of aHUS in patients presenting with thrombotic microangiopathy. A major limitation of the ADAMTS13 activity assay test is the fact that the results may not be readily available and may take several days. In addition, the test must be performed prior to instituting any plasma therapy. Because TMA can cause rapid and progressive damage to vital organs relatively quickly, the luxury of waiting is not always the best approach [3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9., 13Asif A, Haqqie SS, Ghate K, Mathew RO, Vachharajani T, Nayer A. Continued eculizumab therapy for persistent atypical hemolytic- uremic syndrome. The Open Urol Nephrol J 2013; 6: 46-8.]. In the past, clinicians have heavily relied on plasma therapy for the management of TMA. However, with the advent of eculizumab, a distinction between TTP and aHUS is vital earlier on. Awaiting ADAMTS13 results in the context of aHUS may render the patient vulnerable to the unchecked devastation of aHUS. Plasma therapy (which is often the first intervention) prescribed to TMA patients would not provide targeted and optimal results in patients with aHUS [8Legendre CM, Licht C, Muus P , et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368: 2169-81.].

Recent data have emphasized that surrogate markers for severe ADAMTS13 deficiency can facilitate prompt diagnosis and may serve as a guide to treatment in patients presenting with a TMA [14Ferrari S, Scheiflinger F, Rieger M , et al. French clinical and biological network on adult thrombotic microangiopathies.prognostic value of anti-ADAMTS 13 antibody features (Igistypetiter, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity. Blood 2007; 109: 2815-2.-17Scully M, McDonald V, Cavenagh J , et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood 2011; 118: 1746-53.]. It has been documented that a vast majority of patients with severe ADAMTS13 deficiency demonstrate a serum creatinine level less than 2.26 mg/dL and a platelet count less than 30×109/L (Table 1). In addition, Coppo et al. [15Coppo P, Schwarzinger M, Buffet M , et al. French reference center for thrombotic microangiopathies.predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies the French TMA reference center experience. PLoS One 2010; 5: e10208.] reported antinuclear antibodies in 53% of patients with thrombotic microangio- pathy associated with severe ADAMTS13 deficiency. A prediction model based on these three parameters indicates a specificity of 98.1% and a sensitivity of 46.9% for severe ADAMTS13 deficiency [15Coppo P, Schwarzinger M, Buffet M , et al. French reference center for thrombotic microangiopathies.predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies the French TMA reference center experience. PLoS One 2010; 5: e10208.]. The sensitivity increases to 98.8% and the specificity decreases to 48.1% when only one criterion is present. Therefore, when thrombotic microangiopathy a associated with a serum creatinine level ≥ 2.26 mg/dL and a platelet count ≥ 30×109/L, TTP is a highly unlikely diagnosis and atypical HUS should be strongly considered (Table 1) [14Ferrari S, Scheiflinger F, Rieger M , et al. French clinical and biological network on adult thrombotic microangiopathies.prognostic value of anti-ADAMTS 13 antibody features (Igistypetiter, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity. Blood 2007; 109: 2815-2.-17Scully M, McDonald V, Cavenagh J , et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood 2011; 118: 1746-53.]. This approach can ead to early diagnosis of atypical HUS in the proper context and timely initiation of complement inhibition therapy using a humanized monoclonal antibody (eculizumab).

Table 1

Serum creatinine level, platelet count and antinuclear antibodies in thrombotic thrombocytopenic purpura.




In general, Low C3 and normal C4 concentrations in the serum indicates the activation of the alternative pathway of the complement system with an understanding that decreased serum C3 level is not specific for aHUS [3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9.]. Furthermore, the demonstration of normal C3 and C4 concentrations does not exclude the diagnosis of aHUS [3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9.]. Finally, not all of the individuals who have an abnormality of complement proteins develop aHUS [3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9., 8Legendre CM, Licht C, Muus P , et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368: 2169-81.]. Therefore, the demonstration of complement protein abnormalities is not required to make the diagnosis of aHUS [3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9., 10Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 2012; 8: 622-33.].

It should be noted that clinical presentations of TTP and HUS have challenged traditional wisdom [1Caprioli J, Noris M, Brioschi S , et al. Genetics of HUS the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006; 108: 1267-79., 3Laurence J. Atypical hemolytic uremic syndrome (aHUS): Making the diagnosis. Clin Adv Hematol Oncol 2012; 10: 3-9., 18Neuhaus TJ, Calonder S, Leumann EP. Heterogeneity of atypical haemolyticuraemic syndromes. Arch Dis Child 1997; 76: 518-21.-20Noris M, Brioschi S, Caprioli J , et al. International Registry of recurrent and familial HUS/TTP.familial haemolyticuraemic syndrome and an MCP mutation. Lancet 2003; 362: 1542-7.]. In this context, TTP was thought to predominantly have neurological involvement. Nevertheless, altered mental status, focal neurological deficits and seizure have been reported in approximately 10% of patients with aHUS [8Legendre CM, Licht C, Muus P , et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368: 2169-81.]. Moreover, nearly half of the children with aHUS are reported to have neurological involvement [18Neuhaus TJ, Calonder S, Leumann EP. Heterogeneity of atypical haemolyticuraemic syndromes. Arch Dis Child 1997; 76: 518-21.]. The presence of diarrhea has been thought to indicate STEC- HUS. However, nearly one third of the patients with aHUS present with diarrhea [19Zuber J, Le Quintrec M, Sberro-Soussan R, Loirat C, Frémeaux-Bacchi V, Legendre C. New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol 2011; 7: 23-35.]. Once considered a disease of children, aHUS is increasingly diagnosed in the adult population [21Noris M, Brioschi S, Caprioli J , et al. International registry of recurrent and familial HUS/TTP.familial haemolyticuraemic syndrome and an MCP mutation. Lancet 2003; 362: 1542-7., 22Bresin E, Rurali E, Caprioli J , et al. European working party on complement genetics in renal diseases.Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol 2013; 24: 475-86.]. Consequently, conventional methodo- logy of associating certain clinical features with TTP, STEC- HUS and aHUS is not an optimal approach.

It has been estimated that approximately half of the patients presenting with aHUS progress to end-stage renal disease within one year and a quarter of the patients die during the acute attack of the disease [1Caprioli J, Noris M, Brioschi S , et al. Genetics of HUS the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006; 108: 1267-79.-4Nayer A, Asif A. Atypical hemolytic uremic syndrome a clinical review. Am J Ther 2014; (Eput ahead of print)]. Even when transplanted, aHUS has a high rate of recurrence and subsequent damage to the transplanted organ and loss of graft [23Kavanagh D, Richards A, Goodship T, Jalanko H. Transplantation in atypical hemolytic uremic syndrome. Semin Thromb Hemost 2010; 36: 653-9.-25Waters AM, Licht C. aHUS caused by complement dysregulation new therapies on the horizon. Pediatr Nephrol 2011; 26: 41-57.]. Complement inhibition is emerging as an important strategy in stabilizing the platelet count, halting hemolysis and ameliorating renal injury [8Legendre CM, Licht C, Muus P , et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368: 2169-81., 13Asif A, Haqqie SS, Ghate K, Mathew RO, Vachharajani T, Nayer A. Continued eculizumab therapy for persistent atypical hemolytic- uremic syndrome. The Open Urol Nephrol J 2013; 6: 46-8.]. A humanized monoclonal antibody (eculizumab) has been successfully used for the management of aHUS [8Legendre CM, Licht C, Muus P , et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368: 2169-81.]. In this context, establishing the diagnosis of aHUS in a timely fashion gains importance as eculizumab administration can directly limit the target organ damage. Prompt diagnosis is also important as another form of therapy (such as plasma exchange) is required for the treatment of TTP. At present, eculizumab is not indicated for the treatment of STEC-HUS.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

This work received no funding from public, commercial or not-for-profit organizations.

REFERENCES

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