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Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Alexion Pharma GMBH

Atypical hemolytic uremic syndrome (aHUS) is an extremely rare, complement-mediated disease characterized by acute kidney injury, thrombocytopenia, and microangiopathic hemolytic anemia that occurs with a reported annual incidence for all ages ranging from 0.23 to 1.9 million (1). The disease is in fact a variant of thrombotic microangiopathy, which can manifest as thrombotic thrombocytopenic purpura or HUS (Figure 1). The typical HUS (STEC-HUS) mainly affected children, but more recently a large number of adult patients have also been diagnosed (2). The pathophysiological mechanisms of aHUS include an underlying inherited and/or acquired complement abnormality, which leads to the dysregulated activity of the alternative pathway at the endothelial cell surface, or non-complement inherited abnormalities such as mutations in DGKE, which can result in an aHUS phenotype (1). There are still numerous knowledge gaps regarding this condition, and, until less than ten years ago, a lack of efficient therapeutic regimen to postpone end-stage renal disease was also lacking. Novel monoclonal antibody based therapies contributed to an increase in the number of transplanted cases, and a decline of aHUS patients treated with dialysis (3).

Figure 1. TMA diagnostic flow chart (1)

The 2020 ERA-EDTA first fully virtual conference provided an opportunity to share the latest expert views on the pathophysiological mechanisms and novel treatment strategies in aHUS from leading experts in the field – professor Jean-Michel Halimi and professor Alberto Ortiz, in a virtual panel meeting chaired by professor Eric Rondeau.

Acute kidney injury to chronic kidney disease in aHUS: a progression link?
According to the current KDIGO guidelines, acute kidney injury (AKI) is defined by the presence of either one of the following criteria: an increase in serum creatinine by ≥0.3 mg/dl (≥26.5 µmol/l) within 48 h; an increase in serum creatinine to ≥1.5 times baseline within the previous 7 days; and/or urine volume ≤0.5 ml/kg/h for 6 h (4). The diagnosis is often made late, i.e. after the organ has already been affected and, possibly, irreversibly damaged. The histopathologocal substrate is characterized by necrotic tubular cell death and inflammation, with an additional component of microvascular injury, specific for AKI in TMA (5). The outcome can range from resolution to progression to chronic kidney disease (CKD), eventually leading to end-stage renal disease (ESRD) (6). The cells of the renal vasculature have a poor capacity for repair, resulting in the reduction in vascular density, i.e. ‘capillary rarefaction’ which promotes hypoxia, impairs hemodynamic responses, predisposes to CKD progression and hypertension development ( 7, 8).
CKD is defined as an abnormality of kidney structure, detected by pathohistological analysis; or function, manifested by persistent albuminuria >30mg/g creatinine and/or decrease in glomerular filtration rate <60ml/min/1.73m2; that is present for > 3 months (9). CKD is one the fastest-growing cause of mortality worldwide, with the current incidence of the disease estimated to double by 2040 (10). While mortality of the ESRD patients on renal replacement therapy is affected by a combination of socioeconomic factors, pre-existing medical disorders, renal replacement treatment modalities, and kidney failure itself, a very recent observation that albuminuria per se directly suppresses the production of anti-aging factor Klotho by kidney tubular cells may be the missing link explaining the association between albuminuria, CKD progression and premature death in predialysis patients (11-13). Recent investigations also confirmed that Shiga toxin, responsible for triggering classical HUS, also down-regulates renal klotho expression, thus contributing to renal tissue injury (14).
Before the introduction of the complement inhibitors therapies, the outcome and dialysis-free survival of patients with aHUS largely depended on their genetic background (15). The introduction of eculizmab largely modified the outcomes in adults with AKI caused by aHUS, increasing the prevalence of patients with recovered kidney function, and virtually eradicating the need for dialysis (Figure 2), (16, 17). To achieve such results, appropriate timing of the therapy is of major importance. It appears that introducing eculizumab ≤7 days after first signs of the last aHUS manifestation provides a significantly greater mean improvement in eGFR from month 1 onwards, thus calling for early initiation of therapy to achieve the optimum results (18).

Figure 2. aHUS caused AKI outcomes with different treatment strategies – eculizumab or plasma exchange/plasma infusions (PE/PI), (16, 18)

Nevertheless, introducing eculizumab even in patients already on dialysis may result in renal recovery sufficient to provide dialysis independency (19). The discontinuation of therapy, on the other hand, causes a significant increase in the incidence of renal function decline, and a decrease in the rate of renal function improvement (20).

Malignant hypertension in aHUS: chicken or egg?
Malignant hypertension (MHT) is a condition in which elevated blood pressure (BP) results in target organ damage (21). The disease predominantly presents between 40 and 50 years of age and is more common among Caucasians (22). It is often difficult to identify the main cause of this condition, which can sometimes even be triggered by TMA, while, on the other hand, TMA can present with MHT (23). Even though much more prevalent, the secondary TMAs are less defined than primary, and may develop within several conditions, such as pregnancy, infection, drugs use, transplantation, autoimmune diseases, shiga toxin, MHT and a combination of those. According to the latest research aHUS and/or complement defects are the underlying cause of MHT in 10-15% of the cases, while 30-40% of patients with aHUS present with MHT (23-29). At this point, there seems to be no specific genetic variant associated with the clinical presentation of the disease with MHT (25, 26, 28).
The recent introduction of eculizumab in the treatment of aHUS opened the question of whether the response to this novel therapeutic regimen would differ depending on the presence of MHT. Several studies failed to identify a relationship between the eculizumab effectiveness in preserving renal function and the presence of MHT, concluding that eculizumab treatment provides renal survival regardless of the presence and grade of hypertension (25). In the French cohort, however, renal survival was influenced by MHT phenotype and genetic variants. The patients with no genetic variants and no hypertension had excellent renal survival with or without eculizumab therapy. On the other hand, patients with genetic variants and/or MHT had much worse renal survival rate (26).
Very recently, an algorithm has been proposed to identify patients with the highest risk for defects in complement regulation, but its introduction to practice might be challenging due to unavailability and slow performance of genetic testing (27). The summary of current knowledge on the relationship between aHUS and MHT is presented in Figure 3.

Figure 3. Current insight into the relationship between aHUS and MHT (23-28, 30)


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11. Fernandez-Fernandez B, Valino-Rivas L, Sanchez-Nino MD, Ortiz A. Albuminuria Downregulation of the Anti-Aging Factor Klotho: The Missing Link Potentially Explaining the Association of Pathological Albuminuria with Premature Death. Adv Ther 2020;37 (Suppl 2):62-72

12. Fernandez-Fernandez B, Conception Izquerido M, Valino-Rivas L, et al. Albumin downregulates Klotho in tubular cells Nephrol Dial Transplant 2018;33(10):1712-1722.

13. Ortiz A, Covic A, Fliser D, et al. Epidemiology, Contributors To, and Clinical Trials of Mortality Risk in Chronic Kidney Failure Lancet 2014;383(9931):1831-1843.

14. Feger M, Mia S, Pakladok T, et al. Down-Regulation of Renal Klotho Expression by Shiga Toxin 2 Kidney Blood Pres Res 2014;39(5):441-449.

15. Fremeaux-Bacchi V, Fakhouri F, Garnier A, et al. Genetics and Outcome of Atypical Hemolytic Uremic Syndrome: A Nationwide French Series Comparing Children and Adults Clin J Am Soc Nephrol 2013;8(4):554-562.

16. Cao M, Leite BN, Ferreiro T, et al. Eculizumab Modifies Outcomes in Adults With Atypical Hemolytic Uremic Syndrome With Acute Kidney Injury Am J Nephrol 2018;48(3):225-233.

17. Vande-Walle J, delmas Y, Ardissino G, et al. Improved renal recovery in patients with atypical hemolytic uremic syndrome following rapid initiation of eculizumab treatment J Nephrol 2017;30(1):127-134.

18. Ortiz A. Acute kidney injury to chronic kidney disease in aHUS: a progression link? Presentation at the “Clinical Conundrums in aTypical HUS” – sponsored symposium organised by ALEXION PHARMA GMBH during the 2020 European Renal Association – European Dialysis Transplant Association virtual congress, June 8, 2020. Available at:!resources/clinical-conundrums-in-atypical-hus-organised-by-alexion-pharma-gmbh.

19. Rodriguez-Osorio L, Ortiz A. Timing of eculizumab therapy for C3 glomerulonephritis Clin Kidney J 2015;8(4):449-452.

20. Menne, J., Delmas, Y., Fakhouri, F. et al. Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study BMC Nephrol 2019;20:125.

21. Voldhard F, Fahr KT. Die Brightache Krankheit Klinik Pathologie und Atlas, J. Springer, Berlin, 1914:210, 246.

22. Kimmelstiel P, Wilson C. Benign and Malignant Hypertension and Nephrosclerosis: A Clinical and Pathological Study. Am J Pathol 1936;12(1):45-82.

23. Bayer G, von Tokarski F, Thoreau B, et al. Etiology and outcomes of thrombotic microangiopathies. Clin J Am Soc Nephrol 2019;14(4):557-566.

24. Tostivint I, Mougenot B, Flahault A, et al. Adult haemolytic and uraemic syndrome: causes and prognostic factors in the last decade. Nephrol Dial Transplant 2002;17(7):1228-1234.

25. Cavero T, Arjona E, Soto K, et al. Severe and malignant hypertension are common in primary atypical hemolytic uremic syndrome. Kidney Int 2019;96(4):995

26. El Karoui K, Boudhabhay I, Petitprez F, et al. Impact of hypertensive emergency and rare complement variants on the presentation and outcome of atypical hemolytic uremic syndrome Haematologica 2019; 104(12):2501-2511.

27. Timmermans SAMEG, Werion A, Damoiseaux JGMC, et al. Diagnostic and Risk Factors for Complement Defects in Hypertensive Emergency and Thrombotic Microangiopathy Hypertension 2020;75(2):422-430.

28. Larsen CP, Wilson JD, Best-Rocha A, et al. Genetic Testing of Complement and Coagulation Pathways in Patients With Severe Hypertension and Renal Microangiopathy Med Pathol 2018;31(3):488-494.

29. Timmermans SAMEG, Abdul-Hamid MA, Vanderlocht J, et al. Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities Kidney Int 2017;91(6):1420-1425.

30. Halimi JM. Malignant hypertension in aHUS: chicken or egg? Presentation at the “Clinical Conundrums in aTypical HUS” – sponsored symposium organised by ALEXION PHARMA GMBH during the 2020 European Renal Association – European Dialysis Transplant Association virtual congress, June 8, 2020. Available at:!resources/clinical-conundrums-in-atypical-hus-organised-by-alexion-pharma-gmbh.

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