# Non-Plasmapheresis Approaches for Managing Severe Renal Thrombotic Microangiopathy: A Report of 7 Cases.

Marie Frimat, M. Maanaoui, N. Schwotzer, C. Lebas, A. Lionet, Sylvain

Dubucquoi, Viviane Gnemmi, F. Fakhouri, F. Provôt

► To cite this version:

Marie Frimat, M. Maanaoui, N. Schwotzer, C. Lebas, A. Lionet, et al. Non-Plasmapheresis Approaches for Managing Severe Renal Thrombotic Microangiopathy: A Report of 7 Cases. Am J Kidney Dis, 2024, Am J Kidney Dis, 85 (3), pp.384-388. 10.1053/j.ajkd.2024.06.022. hal-05265004

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# Non-plasmapheresis Approaches for Managing Severe Renal Thrombotic Microangiopathy: A Report of 7 Cases

Marie Frimat, Mehdi Maanaoui, Nora Schwotzer, Celine Lebas, Arnaud Lionet, Sylvain Dubucquoi, Viviane Gnemmi, Fadi Fakhouri, and François Provôt

C5-blockers are the established treatment for complement-mediated hemolytic uremic syndrome (CM-HUS). However, CM-HUS, lacking a definitive test, prompts plasma exchanges as a common first-line therapy, pending further assessments, despite complications and limited evidence in this indication. Recent experts' opinion endorses C5-blockers as the initial treatment for severe renal thrombotic microangiopathy (TMA). This retrospective, single-center study reports a series of 7 patients treated with a plasmapheresis-free approach. All patients presented with severe renal TMA symptoms and low French score and received prompt 900 mg eculizumab within a median of 9 hours from admission. Hematological recovery was rapid, and renal function improved in 6 patients within 6.5 days, with a median hospital stay of 16 days. No rescue plasmapheresis was used. We report 7 cases of an early C5-blocker and plasmapheresis-free strategy in severe renal TMA suspicious for CM-HUS, demonstrating promising initial results. Clinical trials are needed to confirm the efficacy and safety of this approach. Addressing the high cost of C5-blocking therapies and exploring cost-effective alternatives is also crucial for broader implementation and accessibility in targeted therapies for adult renal TMA.

Complete author and article information provided before references.

Am J Kidney Dis.
85(3):384-388. Published
online September 27, 2024.

doi: 10.1053/
j.ajkd.2024.06.022

© 2024 The Authors.
Published by Elsevier Inc.
on behalf of the National
Kidney Foundation, Inc. This
is an open access article
under the CC BY license
(http://creativecommons.
org/licenses/by/4.0/).

## Introduction

Renal thrombotic microangiopathies (TMA) encompass a range of diseases with complex, often multifactorial pathophysiology. Their classification has advanced in tandem with discoveries of underlying molecular mechanisms, such as ADAMTS-13 deficiency in thrombotic thrombocytopenic purpura or uncontrolled activation of the alternative complement pathway in complement-mediated hemolytic uremic syndrome (CM-HUS).¹⁻⁴ With an annual incidence of 0.2-2 per million,⁵ CM-HUS is a rare renal disease but is nonetheless consistently suspected in the more common presentation of renal TMA syndrome (typically involving a triad of acute kidney injury [AKI], thrombocytopenia, and microangiopathic hemolytic anemia), owing to its severe implications and the availability of targeted therapy. Indeed, C5-blockers have revolutionized patient prognosis, resulting a substantial reduction in the incidence of end-stage renal disease at 1 year, from approximately 50% to 10%, particularly when the treatment is administered promptly.³,⁶ However, managing renal TMA syndrome remains challenging, as CM-HUS, in the absence of a positive diagnostic test, remains a diagnosis by exclusion.¹,⁴ Thus, plasma exchanges (PE) are proposed as first-line therapy pending investigation results, particularly ADAMTS13 activity assessment. Nevertheless, PE are complicated in 5%-36%, with 1%-2% potentially life-threatening risk,⁷,⁸ and their benefit is firmly established only in acquired ADAMTS13 deficiency–related TMA and commonly assumed for ticlopidine-induced and anti-factor H autoantibody-mediated HUS.⁹,¹⁰ In other forms of TMA, including Shiga toxin–associated and CM-HUS, the use of PE is not based upon hard evidence. Thus, it has recently been suggested that, in patients with a

first episode of TMA with a French score <2 (a diagnostic tool predicting severe acquired ADAMTS13 deficiency based on a platelet count below 30 G/L [+1] and a serum creatinine level below 200 µmol/L [+1]¹¹) and severe oliguric AKI, considering a C5-blocker as a first-line treatment may be appropriate.⁴ Here, we present a case series of patients admitted with severe renal TMA who underwent treatment with this plasmapheresis-free approach.

## Case Report

From a single-center registry of TMA (Nephrology Department, Lille University Hospital, France, BaMaRa, site S1516), we identified patients treated with a C5-blocker as first-line therapy between January 2022 and April 2023 (minimum 6 months follow-up required). A standardized case-report form was employed to collect baseline and follow-up data. Prior informed consent was obtained from each patient for the use of clinical data.

During the study period, 22 patients with acute renal TMA were registered. Of these, 7 patients, with a median age of 38 years, received a C5-blocker as first-line therapy; the main results are presented in Table 1. Initial symptoms preceded the diagnosis of HUS and admission to the intensive care unit (ICU) by a median of 9 days. Four patients had a recent history of bloody diarrhea, which persisted upon admission in 3 cases. A potential trigger was identified in 4 patients: postpartum (patient 2), third trimester pregnancy (patients 6 and 7), and vaccination 2 weeks earlier (patient 4). Upon admission to the ICU, all patients had a French score of 0, with no evidence of disseminated intravascular coagulopathy or overt secondary HUS. All patients presented with stage 3 AKI¹²; 6 were oligoanuric without immediate fluid overload or metabolic indication for dialysis, while 5 necessitated dialysis within
<table><caption>**Table 1.** Clinical Features of the Patient Presentation Across Cases</caption><thead><tr><th></th><th>P1</th><th>P2</th><th>P3</th><th>P4</th><th>P5</th><th>P6</th><th>P7</th></tr></thead><tbody><tr><td><strong>Features on admission to ICU</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Age, year</td><td>38</td><td>32</td><td>23</td><td>55</td><td>74</td><td>41</td><td>36</td></tr><tr><td>Sex</td><td>M</td><td>F</td><td>F</td><td>F</td><td>F</td><td>F</td><td>F</td></tr><tr><td>Context (interval before admission, weeks)</td><td>0</td><td>PP (9)</td><td>0</td><td>Vaccine (2)</td><td>0</td><td>29-w pregnancy</td><td>38-w pregnancy</td></tr><tr><td>Interval between first symptoms and ICU admission for TMA, d</td><td>9</td><td>30</td><td>10</td><td>7</td><td>8</td><td>12</td><td>1.5</td></tr><tr><td>Hourly urinary output, mL/h</td><td>&lt;10</td><td>100</td><td>&lt;10</td><td>20</td><td>&lt;10</td><td>&lt;10</td><td>&lt;10</td></tr><tr><td>SCr, mg/dL</td><td>18</td><td>4.2</td><td>8.9</td><td>4.8</td><td>10.5</td><td>7.6</td><td>2.3</td></tr><tr><td>Hemoglobin, g/dL</td><td>6.6</td><td>8.9</td><td>11.7</td><td>6.2</td><td>9.5</td><td>9.1</td><td>6.6</td></tr><tr><td>Platelet count, G/L</td><td>83</td><td>102</td><td>66</td><td>45</td><td>67</td><td>103</td><td>58</td></tr><tr><td>Haptoglobin, g/L (N: 0.3-2)</td><td>0.12</td><td>&lt;0.07</td><td>&lt;0.07</td><td>&lt;0.07</td><td>&lt;0.07</td><td>&lt;0.07</td><td>&lt;0.07</td></tr><tr><td>LDH, UI/L (N: 135-225)</td><td>1,209</td><td>483</td><td>3,349</td><td>2,004</td><td>1,427</td><td>919</td><td>3,291</td></tr><tr><td>Schistocyte, %</td><td>2-3</td><td>1-2</td><td>1-2</td><td>3-6</td><td>3-6</td><td>2-3</td><td>2-3</td></tr><tr><td><strong>Extrarenal manifestations</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Neurologic</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td><td>0</td></tr><tr><td>Troponin T, ng/L (N: &lt;50); LVEF, %</td><td>1,475; 40</td><td>18; 38</td><td>8; na</td><td>120; 70</td><td>82;60</td><td>10; 60</td><td>85; na</td></tr><tr><td>History of diarrhea</td><td>0</td><td>0</td><td>1</td><td>1</td><td>1</td><td>1</td><td>0</td></tr><tr><td>Elevated liver enzymes &gt;2 N</td><td>0</td><td>0</td><td>1</td><td>0</td><td>0</td><td>0</td><td>1</td></tr><tr><td><strong>In the first 48 hours</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Interval between ICU admission and C5-blocker administration, h</td><td>6</td><td>24</td><td>6</td><td>9</td><td>7</td><td>24</td><td>30</td></tr><tr><td>Requirement for dialysis</td><td>1</td><td>0</td><td>1</td><td>0</td><td>1</td><td>1</td><td>1</td></tr><tr><td>Major event (interval time from ICU admission, d)</td><td>None</td><td>None</td><td>Seizure (0.5)</td><td>None</td><td>Coma (1.5) CVC-related infection (19)</td><td>None</td><td>None</td></tr><tr><td>ADAMTS-13 activity, %</td><td>45</td><td>86</td><td>114</td><td>61</td><td>79</td><td>78</td><td>49</td></tr><tr><td>Shiga toxin in the stool (PCR)</td><td>0</td><td>0</td><td>1</td><td>0</td><td>1</td><td>0</td><td>0</td></tr><tr><td>C3c, mg/L (N: 800-1,640)</td><td>844</td><td>1,134</td><td>770</td><td>1,130</td><td>616</td><td>897</td><td>761</td></tr><tr><td>Factor Bb, µg/mL (N: 0.49-1.42)</td><td>2.38</td><td>2.51</td><td>4.89</td><td>7.9</td><td>1.61</td><td>na</td><td>5.73</td></tr><tr><td><strong>Kidney biopsy</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Delay, days</td><td>10</td><td>29</td><td>N/A</td><td>7</td><td>N/A</td><td>N/A</td><td>26</td></tr><tr><td>Glomerular/arteriolar TMA</td><td>+/+</td><td>+/+</td><td></td><td>+/+</td><td></td><td></td><td>ES/-</td></tr><tr><td>Thrombi</td><td>+</td><td>+</td><td></td><td>+</td><td></td><td></td><td>-</td></tr><tr><td>Glomerulosclerosis / IFTA (%)</td><td>10 / 70</td><td>15 / 10</td><td></td><td>5 / 10</td><td></td><td></td><td>5 / 10</td></tr><tr><td><strong>Outcome</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Time to platelets increase, d</td><td>1</td><td>3</td><td>1</td><td>1</td><td>1</td><td>1</td><td>3</td></tr><tr><td>Time to platelets &gt; 100 G/L, d</td><td>5</td><td>6</td><td>3</td><td>2</td><td>2</td><td>1</td><td>5</td></tr><tr><td>Time to renal function improvement, d</td><td>ESRD</td><td>6</td><td>11</td><td>6</td><td>26</td><td>3</td><td>7</td></tr><tr><td>Hospital length of stay, d</td><td>16</td><td>8</td><td>21</td><td>14</td><td>34</td><td>15</td><td>16</td></tr><tr><td><strong>Long-term outcome</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Eculizumab regimen: duration, mo</td><td>5</td><td>12</td><td>0.25</td><td>12</td><td>0.5</td><td>7</td><td>1</td></tr><tr><td>Follow-up, mo</td><td>12</td><td>15</td><td>15</td><td>15</td><td>10</td><td>12</td><td>7</td></tr><tr><td>SCr, mg/dL / GFR, mL/min (CKD-EPI) at the last follow-up</td><td>ESRD</td><td>1.4 / 50</td><td>0.78 / 108</td><td>0.8 / 83</td><td>1.09 / 50</td><td>0.8 / 96</td><td>0.77 / 98</td></tr><tr><td>HUS relapse</td><td>0</td><td>0</td><td>0</td><td>1</td><td>0</td><td>0</td><td>0</td></tr></tbody></table>

Abbreviations: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration [equation]; CVC, central venous catheter; ES, endothelial swelling; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HUS, hemolytic uremic syndrome; ICU, intensive care unit; IFTA, interstitial fibrosis and tubular atrophy; LVEF, left ventricular ejection fraction; N/A, not applicable; na, not available; PCR, polymerase chain reaction; P, patient; PP, postpartum; SCr, serum creatinine; TMA, thrombotic microangiopathy.

48 hours. Elevated troponins were found in 4 patients, including 2 with associated left ventricular dysfunction (patients 1 and 2). One patient had an abnormal initial neurological examination (patient 6). Plasma C3c fraction was reduced in 3 patients, and plasma factor Bb fraction was elevated in 6.

Based on a strong suspicion of CM-HUS with severe AKI and/or extrarenal complications, the initial approach included first-line C5-blocker therapy. All patients received a 900 mg eculizumab injection within a median of 9 hours from admission, along with preadministered recommended vaccines and antibiotic prophylaxis. None
underwent plasmapheresis. Hematological recovery was rapid, with platelet counts increasing within 48 hours in 5 patients, and counts were >100 G/L within a median of 3 (1-6) days. Renal function improved in 6 patients within a median of 6.5 (3-26) days (ie, >10% sustained decrease in serum creatinine or cessation of dialysis). ADAMTS13 activity, obtained after the initiation of C5 blockade, was >40% in all patients, and none exhibited anti-factor H antibodies. Shiga toxin was identified with polymerase chain reaction in the stool of 2 patients (patients 3 and 5), and eculizumab was not readministered. Notably, these 2 patients experienced severe neurological symptoms within 48 hours after admission, in the context of exposure to bacteriolytic antibiotics prior to hospitalization. No significant complications occurred in any of the patients, except for a central venous catheter infection related to an indwelling dialysis jugular catheter in patient 5. The median hospital length of stay was 16 (8-34) days. Four out of 7 patients underwent kidney biopsies, detailed in Table 1, within 7-29 days (Fig 1). Among them, patient 1 exhibited severe interstitial fibrosis, suggesting retrospectively a pre-existing chronic kidney disease, and furthermore remained dialysis dependent at the last follow-up. Among the 6 dialysis-free patients, 4 regained prior renal function, while 2 had persistent chronic kidney disease stage 3 (median follow-up 12 months). Though not immediately impacting urgent decisions, suspected CM-HUS presentations prompted genetic assessments. Available results are shown in Table S1 for reference.

Discussion

This retrospective series highlights the feasibility, in the context of a first suspected episode of CM-HUS associated with severe AKI, of promptly initiating C5-blocker therapy. It appears that this therapeutic strategy was only implemented in patients with a French score at admission of 0, indicating a low probability of ADAMTS13 deficiency–related thrombotic thrombocytopenic purpura,

although not completely excluding it.¹¹ As the majority of patients were anuric, it was not possible to obtain a measurement of proteinuria and calculate a modified French score, aiming to enhance the diagnostic accuracy of this score.¹³ It is noteworthy that clinical scores effectively predict ADAMTS13 activity in cases with extreme values, such as a French score of 2 or 0, denoting undetectable or detectable activity, respectively. Uncertainty arises in cases with an intermediate French score of 1 (or a PLASMIC score of 5),¹¹,¹⁴ occurring in up to 25% of cases, prompting consideration of PE until the availability of ADAMTS13. In the present series, the rapid hematological response, particularly characterized by a significant platelet count increase within 24-72 hours, also facilitated the decision not to propose any rescue treatment through PE.

Similarly, renal improvement, when it occurred, was rapid, and hospital lengths of stay were notably brief, except for patient 5, who experienced central venous catheter–related sepsis. Recently, Ryan et al¹⁵ studied the economic impact of early (within 7 days) versus late (day 8 or later) eculizumab initiation in suspected CM-HUS. Early initiation was associated with a shorter length of stay and lower dialysis rates and hospitalization costs compared to late initiation. Together, these aspects could contribute to reducing the risk of post-traumatic stress and improving the quality of life in this population.¹⁶

It should be noted that we treated “by excess” 2 patients in whom Shiga toxin was identified (patients 3 and 5). The use of C5-blockers is controversial in Shiga toxin–producing Escherichia coli (STEC)-HUS, with a dedicated randomized trial providing insights. Thus, in children with STEC-HUS, a 4-week eculizumab treatment was not associated with an improved renal outcome during the acute phase but may have reduced kidney sequelae at 1 year.¹⁷ However, in this trial, patients with severe forms of STEC-HUS were excluded. Given the rare side effects, especially for short-term exposure,¹⁸ the initial use of a C5-blocker was not a missed opportunity for patients 3 and 5. It is noteworthy that both patients exhibited reduced plasma C3 levels and an elevated Bb factor, indicating the activation of the alternative

<figure><img src="image_3.png" /><figcaption>**Figure 1.** Representative renal biopsy images. **Patient 1:** Duplication of the glomerular basement membrane (GBM), mesangiolysis in glomeruli, intimal edema, endothelial swelling, and arteriolar thrombosis (trichrome stain, original magnification ×400); **Patient 2:** Endothelial swelling, GBM duplication in glomeruli, and arteriolar occlusion (*) (PAS stain, original magnification ×200); **Patient 4:** Double contours of the GBM (Jones silver stain, original magnification ×400); **Patient 7:** Double contours (<) in glomeruli (periodic acid–Schiff stain, original magnification ×400).</figcaption></figure>
complement pathway. This highlights the diagnostic challenge and the limited sensitivity of these markers, which indicate activation but do not guarantee the existence of a proven underlying complement regulation abnormality. Additionally, it emphasizes the ongoing debate surrounding the precise spectrum of complement-mediated renal TMA,²,⁴ as illustrated by insights from the use of C5 inhibitors in conditions such as high-risk stem cell transplantation-associated TMA, with promising results from a recent prospective study,¹⁹ or catastrophic anti-phospholipid syndrome with more mitigated outcomes.²⁰

Thus, our experience with early first-line C5 blocker and free-plasmapheresis treatment in patients with a first episode of severe renal TMA and low French score appears favorable and safe. However, the limitations inherent in our retrospective, nonrandomized design, and the small number of patients, preclude an assessment of the superiority of this approach over initiation after day 3 or later, and do not permit its endorsement as standard care without further targeted research. We note that our knowledge regarding the epidemiology of TMAs remains limited, primarily drawn from studies conducted across 2 continents,⁵ and it is possible that the influence of genetics and ethnic background may preclude the generalizability of our findings. Additionally, the high cost of C5 inhibitors is another limitation for implementing the plasmapheresis-free management of adult renal TMA we reported here, particularly in regions with restricted access to such innovative therapies. The potential availability of generic C5 blockers, and the development of other similar drugs, will undoubtedly contribute to reducing these barriers, thus improving the accessibility of targeted therapies for this disease.

## Supplementary Material

### Supplementary File (PDF)

<caption>Table S1: Genetic analysis</caption>

### Article Information

**Authors' Full Names and Academic Degrees:** Marie Frimat, MD, PhD, Mehdi Maanaoui, MD, PhD, Nora Schwotzer, MD, Celine Lebas, MD, Arnaud Lionet, MD, Sylvain Dubucquoi, MD, PhD, Viviane Gnemmi, MD, PhD, Fadi Fakhouri, MD, PhD, and François Provôt, MD.

**Authors' Affiliations:** Nephrology Department, CHU Lille, University of Lille, Lille, France (MF, MM, CL, AL, FP); Inserm, Institut Pasteur de Lille, U1167 - RID-AGE, University of Lille, Lille, France (MF); Service of Nephrology and Hypertension, CHUV, University of Lausanne, Lausanne, Switzerland (NS, FF); Immunology Department, Centre de Biologie Pathologie, CHU Lille, University of Lille, Lille, France (SD); and Pathology Department, University of Lille, Lille, France (VG).

**Address for Correspondence:** Marie Frimat, MD, PhD, Department of Nephrology, Lille University Hospital, 2 avenue Oscar Lambret, F-59000 Lille, France. Email: marie.frimat@chru-lille.fr

**Additional Information:** Dr Frimat's ORCiD is 0000-0002-7461-8298.

**Support:** The research on this topic is supported by a grant from the European Joint Programme on Rare Diseases and Agence Nationale

de la Recherche, France COMPrate ANR-22-RAR4-0007 (to Dr Frimat).

**Financial Disclosure:** Consultancy and/or speaker honoraria: Dr Frimat from Alexion, AstraZeneca, Novartis; Dr Fakhouri from Alexion, Sobi, Apellis, Novartis, Roche, and AstraZeneca; Dr Provôt from Alexion. The remaining authors declare that they have no relevant financial interests for this work.

**Patient Protections:** The authors declare that they have obtained written consent from the patients reported in this article for publication of the information about them that appears within this Case Report.

**Peer Review:** Received December 12, 2023. Evaluated by 2 external peer reviewers and a radiologist, with direct editorial input from the Pathology Editor, an Associate Editor, and a Deputy Editor. Accepted in revised form June 27, 2024.

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