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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 3  |  Page : 411-416
Renal thrombotic microangiopathy revisited: When a lesion is not a clinical finding

1 The Nephrology Research Group, L'Hotel-Dieu de Quebec Institution (CHUQ), Department of Medicine, Faculty of Medicine, Laval University, Quebec (Qc), Canada and Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA, Canada
2 The Nephrology Research Group, L'Hotel-Dieu de Quebec Institution (CHUQ), Department of Medicine, Faculty of Medicine, Laval University, Quebec (Qc), Canada

Click here for correspondence address and email

Date of Web Publication26-Apr-2010


Despite advances in the field of thrombotic microangiopathy (TMA) and associated syndromes such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), they still leave several issues unresolved. For instance, actual diagnostic criteria on which therapeutic decisions rely are relatively narrow and focused on TTP-HUS, with the consequence that non-idiopathic and atypically-presenting TMA are overlooked. In addition, nosologic classifi­cations of TMA disorders have varied substantially over the years, but are still devised from historical rather than mechanistic data. As such, it is perhaps not surprising that even today TMA is erroneously used as an interchangeable term with TTP-HUS, and missed or inappropriately diagnosed on various occasions. Yet, recognizing TMA is of crucial importance given that this lesion often manifests with potentially reversible renal failure. In this editorial, which is presented from a Nephrologist's perspective, we propose that TMA disorders need to be reclassified to include most types of presentations and confirmed or excluded through more elaborate diagnostic approaches.

How to cite this article:
De Serres SA, Isenring P. Renal thrombotic microangiopathy revisited: When a lesion is not a clinical finding. Saudi J Kidney Dis Transpl 2010;21:411-6

How to cite this URL:
De Serres SA, Isenring P. Renal thrombotic microangiopathy revisited: When a lesion is not a clinical finding. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2022 Oct 3];21:411-6. Available from: https://www.sjkdt.org/text.asp?2010/21/3/411/62689

   Introduction Top

Thrombotic microangiopathy (TMA) is used to describe a pathological lesion that is charac­terized by occluded microvessels due to swe­lling of endothelial cells and to subendothelial aggregation of platelets, proteins and debris. Although it has become the subject of a rapidly growing literature in the recent years, there is still nosological confusion among various dis­orders that can lead to this type of lesion. Such disorders include thrombotic thrombocytope­nic purpura (TTP), hemolytic uremic syndrome (HUS) and secondary forms of TMA, all of which share a number of clinical features as well. Yet, understanding why and how they di­ffer from one another is of high clinical rele­vance to the Nephrologist given that TMA often manifests with acute renal failure and that its treatment or prognosis varies according to presentation and cause.

   TTP, HUS and TMA: Nosological Considerations Top

Both TTP and HUS are clinical syndromes that can be either idiopathic (primary TMA) or etiology-associated (secondary TMA). While TTP was described by Moschowitz in 1924 and presents with non-immune hemolytic ane­mia, thrombocytopenia, renal failure, neurologic impairment and fever, [1] HUS was described by Gasser et al in 1955 and presents with the same hematologic features in addition to renal failure. [2] Since these earlier descriptions, atypical presentations have also been documented. For instance, we and others have reported many individuals in whom TMA lesions were iden­tified in the absence of thrombocytopenia [3],[4] or identifiable causes.

TTP and HUS have been walking hand-in­-hand in the medical literature, to a point where the term TTP-HUS became of common usage, until a duet of landmark papers published in 1998 suggested that these two disorders did not share the same pathophysiological bases. [5],[6] In particular, it was reported that the activity of ADAMTS13, a metalloprotease that cleaves von Willebrand factor in recently formed platelet thrombi, was significantly lower in the plasma of patients with idiopathic TTP com­pared to patients with HUS. These findings were thus in keeping with, and added interest to earlier observations that unusually large von Willebrand factors were also found in the plas­ma of patients with chronic relapsing TTP. [7]

Further evidence have emerged or remerged subsequently to confirm that TTP and HUS are indeed distinct entities. By way of illustration, the prognosis of renal failure is far better in HUS compared to TTP, especially in children and in the setting of viral illnesses or of Echerichia coli O157:H7-associated infections. [1] Along the same line, approximately 50 percent of patients with non diarrheal HUS (sometimes referred to as atypical HUS) have heterozygous mutations in factor H, factor I or membrane co­factor protein CD46, all of which regulate C3 activity by decaying C3convertase (C3bBb), whereas a minority of patients with TTP ap­pear to have genetic defects in their alternative complement pathway. [8],[9]

Such advances in the field of TMA-asso­ciated syndromes (TASs) have led to newer operational definitions of TTP and HUS. In particular, it is now agreed on that idiopathic TTP is defined by microangiopathic hemolytic anemia and thrombocytopenia in the absence of alternative unifying diagnoses and this, re­gardless of end-organ manifestations. [10] On the other hand, H US is now defined as a clinical syndrome that applies mostly to children with microangiopathic hemolytic anemia, thrombo­cytopenia and renal failure, and it is further di­vided into diarrheal and non diarrheal TMA as alluded to earlier. [11]

Despite an array of recent publications in which the classifications and diagnostic crite­ria used for many of the TASs were reviewed, confusion still arises in both the Hematology and Nephrology literature pertaining to con­sensus nomenclature. For instance, it is still widely suggested that TMA is defined by the presence of microangiopathic hemolytic ane­ mia and thrombocytopenia [12],[13] while, as already stated, it corresponds to a pathological lesion, not to a clinical syndrome, and is not always associated with thrombocytopenia. [14],[15] Repeated changes in classifications and diagnostic crite­ria over time in conjunction with some level of hesitation from bedside physicians to rely sys­tematically upon the newer nomenclature might partly account for the ongoing confusion.

In this regard, it should be remembered that the clinical definition of TTP-HUS is still largely tainted by the inclusion criteria used during the large Canadian study to examine the potential benefits of plasma exchange [16],[17] ,and by the observation that the subgroup TTP, as defined in the trial, usually responds posi­tively to this form of therapy. Likewise, dia­rrheal HUS and non diarrheal HUS are now treated according to specific recommendations [9],[18] based on studies in which inclusion criteria consisted primarily of hematologic features. Given that such criteria were quite restrictive and empirical to some degree, the operational definitions that they contributed to bring forth could thus be viewed as arguable from certain perspectives.

By excluding unusual or etiology-associated presentations, for instance, the study designs employed to assess the efficacy of plasma ex­change in TTP and HUS have raised the im­portant issue of how to treat many patients with TMA lesions. This issue is particularly concer­ning if one considers that atypically-manifesting or secondary forms of TMA are not uncom­mon relative to TTP or HUS, have been re­ported to be plasma-responsive on various oc­casions [17],[19] and can also be associated with ADAMTS13 deficiency or other plasma ex­change-responsive abnormalities. [17],[19] During a 30-year period, to this effect, we have provi­ded care for at least 25 athrombocytopenic pa­tients with biopsy-proven TMA whose main manifestation was renal failure in the absence of underlying illnesses, and have observed a number of favorable outcomes following plas­ma exchange. [17],[19]

Another reason for confusion regarding cla­ssifications and diagnostic criteria is the ab­sence of relatively exclusive link between a given clinical syndrome such as idiopathic TTP or non diarrheal HUS and a given etiologic or mechanistic basis. As such, the current ope­rational definitions may appear unsuitable to many physicians from a conceptual perspec­tive as well. As it stands, it might be useful to expand the current classification of TASs so that all clinical syndromes and possible etiolo­gies are represented. A scheme is proposed in [Figure 1] where the novel term atypical TMA­associated syndrome (ATAS) is added and where either of TTP, HUS or ATAS is further subdivided into primary vs. secondary form.

Confusion may have arisen as well when the idea was suggested that disseminated intra­vascular coagulation (DIC) was a form of TAS. Although it might be difficult to distin­guish DIC from TTP, HUS or ATAS in certain cases - these syndromes tend to share common features such as microvascular occlusion, hemolytic anemia, thrombocytopenia, decreased ADAMTS13 plasma activity and end-organ damage - we disagree with this idea. [20] First, the lesion of DIC differs from that of TAS in many respects [Table 1]. Second, protein C, factor V and factor VIII tend to decrease subs­tantially in DIC but not in TAS. [21] Lastly, DIC is almost always associated with severe infec­tion, trauma, leukemia, obstetric complications, systemic inflammatory response syndrome or multiple organ failure.

   TMA from a Nephrologist's Perspective Top

Most of the time, nephrologists will be facing one of three situations when confronted with a histological diagnosis of TMA. In either case, they will often seek consultation from a hema­tologist, but may not always receive the same therapeutic recommendations from case to case.

The first and most typical situation is that of a patient with suspected TTP or HUS on the basis of renal failure, non immune hemolytic anemia and thrombocytopenia. In such cases, the Hematologist is usually involved early on and plasma exchange initiated without or be­fore the result of a renal biopsy. Although a diagnosis may be straightforward according to the initial presentation, it should still not be taken for granted. By way of illustration, Egan et al recently reported 2 cases in whom hemo­lytic anemia and thrombocytopenia were asso­ciated with severe systemic hypertension in the absence of papilledema. [22] In both cases, a cli­nical diagnosis of malignant hypertension was made even though criteria for TTP or HUS were met, and in both cases, a cure was ob­tained through anti-hypertensive therapy in the absence of plasma exchange.

The second situation is that of a patient who presents with renal failure and has known risk factors for developing TMA [Figure 1]. In these cases, thrombocytopenia and anemia may not be present initially or throughout the course of the illness even if organ dysfunction is related to TMA. Again in our center, we have inves­tigated at least 10 athrombocytopenic patients for renal failure in whom TMA was identified through kidney biopsies and occurred in the setting of progressive systemic sclerosis, ma­lignant hypertension or diarrheal HUS. Simi­larly, Zhang et al, reported a series of 21 pa­tients with biopsy-proven renal TMA and se­vere or malignant hypertension but identified thrombocytopenia in only 5 of them [4] , and Le­faucheur et al reported 7 such patients follo­wing lung transplantation but identified hema­tologic criteria in none of them. [3] Although these cases are typically tackled by treating the underlying etiology, they could also be consi­dered for plasma exchange under certain cir­cumstances.

The third situation, which might be more common than suspected, is that of a patient in whom renal failure is associated with TMA on a kidney biopsy in the absence of underlying etiologies or hematologic criteria. [15],[23] According to our own series of patients who were found to have biopsy-proven renal TMA, 22 out of 50 presented in this manner specifically. It is interesting to note here that compared to the 28 other patients who were found to have throm­bocytopenia in the presence or absence of un­derlying etiology, end-stage renal disease or death at 5 years was significantly more pre­valent. These observations are in keeping with those of Schieppati et al who found higher rates of renal dysfunction one year post-diag­nosis, when initial platelet counts were 70 ± 40 compared to 41 ± 16 x 109/L. [23]

   Conclusion Top

Based on this review, it should appear ob­vious that the clinical spectrum, etiologies and pathophysiological mechanisms of TASs are quite varied and that the current classification used to categorize these syndromes are not op­timal. It should also appear obvious that newer clinical trials are warranted to determine whe­ther plasma exchange is beneficial in ATAS and in secondary forms of TASs, and whether certain markers such as ADAMTS13 plasma activity might be helpful in predicting res­ponse to plasma exchange regardless of clinical presentation or etiology.

Based on the case scenarios just presented, one should also be cautious before applying therapeutic algorithms based on current diag­nostic criteria. In particular, acute renal failure associated with thrombocytopenia and hemo­lytic anemia is not always due to TMA le­sions11 and should therefore warrant a diagnos­tic kidney biopsy. One should also contemplate plasma exchange for all cases of TASs in whom substantial organ dysfunction has mani­fested. Although optimal therapeutic strategy still needs to be defined under such circums­tances, this recommendation is based on the following line of reasoning:

  1. Anecdotal evidence suggests that plasma exchange can be beneficial in certain cases of ATASs or secondary TASs.
  2. TAS-related morbidity or mortality is high when TMA lesions do not resolve rapidly.
  3. Plasma exchange is usually a well tole­rated, low-risk procedure.
Controversies that have emerged in the field of TTP-HUS are likely to remind us of those that have emerged in the field of clinicopatho­logy at its beginning. When Laennec (1781­1826) began to correlate auscultation findings with pathological lung lesions at autopsy in the ninetieth century, the establishment objected to the value of his work, arguing for the tradi­tional nosological point of view. [24] Yet, his achievements were a major historical step, allowing medicine to move forward from a science that limited itself at merely defining syndromes based on clinical cases, to a science that exploited refined diagnostic tools from which symptoms and pathological counterparts could be linked together. The importance of a TMA lesion should not be dismissed on the sole basis of a discordant clinical picture.

   Sources of support Top

Sacha A. De Serres is a recipient of the Kidney Research Scientist Core Education and National Training (KRESCENT) Post-Doctoral Fellow Award and a Laval University McLaughlin's Scholarship Award. Paul Isenring is supported by a Research Canadian Chair in Molecular Physiology and by Kidney Foundation of Canada.

   References Top

1.Moake JL. Thrombotic microangiopathies. N Engl J Med 2002;347(8):589-600.  Back to cited text no. 1      
2.Gasser C, Gautier E, Steck A, et al. Hemolytic­uremic syndrome: Bilateral necrosis of the re­nal cortex in acute acquired hemolytic anemia. Schweiz Med Wochenschr 1955;85(38-39): 905-909.  Back to cited text no. 2      
3.Lefaucheur C, Nochy D, Amrein C, et al. Re­nal histopathological lesions after lung trans­plantation in patients with cystic fibrosis. Am J Transplant 2008;8(9):1901-10.  Back to cited text no. 3      
4.Zhang B, Xing C, Yu X, et al. Renal throm­botic microangiopathies induced by severe hypertension. Hypertens Res 2008;31(3):479­-83.  Back to cited text no. 4      
5.Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in throm­botic thrombocytopenic purpura and the hemo­lytic-uremic syndrome. N Engl J Med 1998; 339(22):1578-84.  Back to cited text no. 5      
6.Tsai HM, Lian EC. Antibodies to von Wille­brand factor-cleaving protease in acute throm­botic thrombocytopenic purpura. N Engl J Med 1998;339(22):1585-94.  Back to cited text no. 6      
7.Furlan M, Robles R, Solenthaler M, et al. Defi­cient activity of von Willebrand factorcleaving protease in chronic relapsing thrombotic throm­bocytopenic purpura. Blood 1997;89(9):3097-­103.  Back to cited text no. 7      
8.Jokiranta TS, Zipfel PF, Fremeaux-Bacchi V, et al. Where next with atypical hemolytic ure­mic syndrome? Mol Immunol 2007;44(16): 3889-900.  Back to cited text no. 8      
9.Noris M, Remuzzi G. Atypical hemolyticuremic syndrome. N Engl J Med 2009;361(17):1676­-87.  Back to cited text no. 9      
10.George JN. Clinical practice. Thrombotic throm­bocytopenic purpura. N Engl J Med 2006;354 (18):1927-35.  Back to cited text no. 10      
11.George JN. The thrombotic thrombocytopenic purpura and hemolytic uremic syndromes: eva­luation, management, and long-term outcomes experience of the Oklahoma TTP-HUS Re­gistry, 1989-2007. Kidney Int Suppl 2009; 112):S52-4.  Back to cited text no. 11  [PUBMED]    
12.Ruggenenti P, Noris M, Remuzzi G. Throm­botic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 2001;60(3):831-46.  Back to cited text no. 12      
13.Rieger M, Mannucci PM, Kremer Hovinga JA, et al. ADAMTS13 auto antibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood 2005;106(4): 1262-7.  Back to cited text no. 13      
14.Veyradier A, Obert B, Houllier A, et al. Spe­cific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood 2001;98(6):1765-72.  Back to cited text no. 14      
15.De Serres SA, Isenring P. A thrombocytopenic thrombotic microangiopathy: a condition that could be overlooked based on current diag­nostic criteria. Nephrol Dial Transplant 2009; 24(3):1048-50.  Back to cited text no. 15      
16.Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic throm­bocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med 1991;325(6):393-7  Back to cited text no. 16      
17.Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocyto­penic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med 1991;325(6):398-403.  Back to cited text no. 17      
18.Bitzan M. Treatment options for HUS secon­dary to Escherichia coli O157:H7. Kidney Int Suppl 2009;112:S62-6.  Back to cited text no. 18  [PUBMED]    
19.Bennett CL, Connors JM, Carwile JM, et al. Thrombotic thrombocytopenic purpura asso­ciated with clopidogrel. N Engl J Med 2000; 342(24):1773-7.  Back to cited text no. 19      
20.Ono T, Mimuro J, Madoiwa S, et al. Severe secondary deficiency of von Willebrand factor­cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood 2006;107(2):528-34.  Back to cited text no. 20      
21.Levi M. Disseminated intravascular coagula­tion. Crit Care Med 2007;35(9):2191-5.  Back to cited text no. 21      
22.Egan JA, Bandarenko N, Hay SN, et al. Diffe­rentiating thrombotic microangiopathies induced by severe hypertension from anemia and thrombocytopenia seen in thrombotic throm­bocytopenia purpura. J Clin Apher 2004;19(3): 125-9.  Back to cited text no. 22      
23.Schieppati A, Ruggenenti P, Cornejo RP, et al. Renal function at hospital admission as a prognostic factor in adult hemolytic uremic syndrome. The Italian Registry of Haemolytic Uremic Syndrome. J Am Soc Nephrol 1992; 2(11):1640-4.  Back to cited text no. 23      
24.Roguin A. Rene Theophile Hyacinthe Laennec (1781-1826): the man behind the stethoscope. Clin Med Res 2006;4(3):230-5.  Back to cited text no. 24      

Correspondence Address:
Sacha A De Serres
Service de Nephrologie, L’Hotel-Dieu de Québec du CHUQ, 11, côte du Palais, Quebec (Qc), G1R 2J6
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Source of Support: None, Conflict of Interest: None

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