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Table of Contents
BRIEF REPORT
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 41-45

Plasma Infusion versus plasma exchange as first line therapy in atypical hemolytic uremic syndrome: A single centre experience


Department of Pediatric Nephrology, St John's Medical College Hospital, Bengaluru, Karnataka, India

Date of Web Publication17-May-2019

Correspondence Address:
Anil Vasudevan
Department of Pediatric Nephrology, St. Johns's Medical College Hospital, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJPN.AJPN_38_18

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  Abstract 


Plasma exchange (PEX) remains the standard therapy for the management of atypical hemolytic-uremic syndrome (aHUS) in regions where eculizumab is not available. Where even PEX is not feasible or afforded, patients are managed with plasma infusion (PI). This single-center, retrospective study compares the efficacy of PI with PEX and examined for predictors of renal recovery in pediatric patients with aHUS admitted at a single center in a developing country from January 2005 to June 2017. Endpoints for comparison were time to hematological remission, duration of hospitalization, rates of complete and partial renal recovery, time to progression to chronic kidney disease Stage 5, and occurrence of relapses. Of 53 children presenting at 6.3 ± 3.9 years of age, 24 and 22 patients were managed with PI and PEX, respectively. The latter group of patients was sicker at presentation and included 13 children with antibodies to complement factor H. All patients achieved hematological remission, including four patients refractory to PI who were switched to PEX. Patients managed on PI were discharged from hospital earlier than those on PEX and were more often with complete renal recovery (55% vs. 27%). At 1.5 (0.5–72) months of follow-up, similar proportions of 31 patients managed with PI and PEX showed complete and partial renal recovery and had comparable rates of relapse and disease progression. Presentation with acute kidney injury Stage 3 and edema were independent predictors of incomplete renal recovery at discharge. Both PEX and PI are associated with satisfactory short-term outcomes in patients with aHUS lacking access to eculizumab, and PEX might be preferred over PI in patients with severe disease and those with anticomplement factor H antibodies.

Keywords: Acute kidney injury, children, complement, dialysis, plasma therapy, thrombotic microangiopathy


How to cite this article:
Yadav SP, Iyengar A, Vasudevan A. Plasma Infusion versus plasma exchange as first line therapy in atypical hemolytic uremic syndrome: A single centre experience. Asian J Pediatr Nephrol 2019;2:41-5

How to cite this URL:
Yadav SP, Iyengar A, Vasudevan A. Plasma Infusion versus plasma exchange as first line therapy in atypical hemolytic uremic syndrome: A single centre experience. Asian J Pediatr Nephrol [serial online] 2019 [cited 2019 Oct 23];2:41-5. Available from: http://www.ajpn-online.org/text.asp?2019/2/1/41/258562




  Introduction Top


Atypical hemolytic-uremic syndrome (aHUS) results from an inherited or acquired dysregulation of alternate pathway of complement cascade.[1],[2],[3] Complement blockade with eculizumab is the current therapy of choice but is expensive and not available in developing countries.[4],[5] Plasma therapy, as exchanges (PEX) and/or infusions (PI), was used to induce hematological remission in the pre-eculizumab era but was associated with advanced chronic kidney disease (CKD) in a significant proportion of patients.[2],[3],[6],[7] PEX requires technical expertise and equipment and is often not feasible in resource-constrained regions in emergency settings. The present work reports on the relative efficacy of PEX and PI in patients with aHUS in a country lacking access to monoclonal complement blockade.


  Methods Top


This retrospective study included patients, 1–18 years old, diagnosed with aHUS at a tertiary referral hospital between January 2005 and June 2017. aHUS was defined by the triad of microangiopathic-hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI),[8] in the absence of coexisting disease and after exclusions of mimics such as malaria, lupus, sepsis, and HUS secondary to Shigella dysentery or Streptococcus pneumoniae.[4],[5] Clinical information, including investigations, details of management, and outcomes at follow-up, were retrieved from medical records and analyzed after obtaining ethical clearance. The choice of therapy between PEX and PI was primarily on the discretion of the treating physician and was based on patient's size, feasibility of vascular access, and affordability of therapy costs. Plasma therapy was usually instituted within 24 hr of diagnosis of aHUS. PEX involved replacing 1.5–2 times plasma volume with fresh frozen plasma (FFP) and 5% albumin, in a ratio of 3:1, on alternate days, until hematological remission, while PI involved the administration of 10–15 ml/kg of FFP daily until remission.

Outcomes compared between groups were time to hematological remission, duration of hospitalization, renal recovery at the end of hospital stay and at the last follow-up, and occurrence of relapses. Hematological remission was defined as platelet count exceeding 150,000/mm3 in two consecutive readings, with normal serum lactate dehydrogenase.[4],[5] Complete renal recovery was defined as estimated glomerular filtration rate (eGFR) >90 ml/min/1.73 m2 or return to normal eGFR for age,[9],[10] normal blood pressure,[11] and no proteinuria. Partial renal recovery was the persistence of hypertension, nephrotic-range proteinuria, and/or renal dysfunction that was staged for CKD.[12] Dialysis dependence was the persistent need of renal replacement therapy at discharge from the hospital. Hypertension was defined as blood pressure of >95th centile for the corresponding age, sex, and height,[11] and nephrotic-range proteinuria was defined as urine albumin of ≥3+ in urine dipsticks. Testing for antibodies to complement factor H (CFH) (anti-FH) was carried out in a subgroup of 19 patients, on ethylenediaminetetraacetic acid plasma transported to the All India Institute of Medical Sciences, New Delhi, as described previously.[13]

Data were analyzed using Stata version 14 (StataCorp, Texas, USA) and compared between groups using standard parametric and nonparametric tests, as applicable; P < 0.05 was considered statistically significant. Outcomes of four children, who did not respond to PI and received PEX later, were included in the PEX group. Kaplan–Meier analysis was performed to estimate time to progression to CKD Stage 5 and compared between groups using the log-rank test. Univariate and multivariate logistic regression was used to determine predictors of complete or partial renal recovery at discharge.


  Results Top


Presentation and evaluation

Of the 53 patients with aHUS presenting at mean ± standard deviation (range) 6.3 ± 3.9 years (1.6–192 months), 75.4% were boys. Mean platelet count, hemoglobin, and serum creatinine were 62,000/mm3, 5.7 g/dl, and 4.0 mg/dl, respectively; majority of patients presented with AKI Stage 3 [Table 1]. Nephrotic-range proteinuria was observed in 75% of cases and low complement C3 level in 62% of cases. Of 19 patients evaluated for anti-FH antibodies, 13 (68.4%) had elevated titers (>150 arbitrary units/ml). Next-generation sequencing for mutations in relevant genes showed homozygous DGKE mutations in one child and no abnormality in another patient. Kidney biopsy, performed in 22 patients, showed thrombotic microangiopathy in 73%, acute tubular necrosis in 23%, and patchy cortical necrosis in 4% of patients.
Table 1: Comparison between patients managed on plasma infusions and plasma exchanges at presentation

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Management

Forty-one (77%) patients required dialysis. Plasma therapy was administered in 46 (87%) cases; seven patients had mild disease that recovered without plasma therapy. PI was administered in 24 patients for 3.5 ± 2.5 sessions, whereas 22 cases underwent PEX for 5 ± 2.6 sessions. Four children refractory to PI were switched to PEX therapy and responded satisfactorily. All 13 patients with anti-CFH antibody-associated HUS received PEX along with immunosuppression, with prednisolone alone in 8 patients, and with cyclophosphamide or rituximab in 5 and 2 cases, respectively.

Outcomes

One child died during hospitalization while five left against medical advice. At discharge, 19 (40.4%) patients each had complete and partial renal recovery, respectively, while 9 (19.1%) were dialysis dependent. Of the 31 (66%) patients followed for median 1.5 (range 0.5–72) months, 18 (58%) had complete renal recovery, 4 (12.9%) showed CKD Stages 2–4 while 9 (29%) progressed to CKD Stage 5 and this included 4 and 5 patients managed with PI and PEX, respectively. Ten (32.3%) children showed disease relapse, which was managed with PEX in seven cases and PI in three cases, and two children with anti-CFH antibodies also received immunosuppression. Four patients progressed to CKD, of whom two required initiation of dialysis at the last follow-up.

Comparison of groups of patients managed with plasma exchange and plasma infusion

As shown in [Table 1], patients administered PEX were sicker than those receiving PI, with significantly lower levels of hemoglobin and platelet count and higher level of serum creatinine. All children who received PEX achieved remission while only 84% of 24 patients who received PI achieved remission; the time to hematological remission was similar between the two groups of patients [Table 2]. The length of hospital stay was shorter for patients managed on PI [Table 2]. At discharge, an insignificantly higher proportion of patients managed on PI than PEX showed complete renal recovery (55% vs. 26.9%; P = 0.064). However, outcomes were similar between groups at the last follow-up, with complete recovery in 68.8% of patients managed on PI compared to 53.5% of those who received PEX [Table 2]; P = 0.41]. The proportions with relapses were also similar [Table 2]; P = 0.91]. Patients receiving PI or PEX showed similar time to progression to CKD Stage 5 [34.8 vs. 42.5 months; P = 0.7; [Figure 1].
Table 2: Comparison of outcomes between patients managed on plasma infusions and plasma exchanges

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Figure 1: Kaplan–Meier survival analysis showing time to reach chronic kidney disease between plasma infusion and PLEX/PEX (Plasma Exchange)

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Predictors of outcome at hospital discharge

On univariate analysis, predictors of incomplete renal recovery included presentation with Stage III AKI (P = 0.04), presence of edema (P = 0.01), oliguria (P = 0.03), and need for intensive care unit admission (P = 0.02) or dialysis (P = 0.005); type of therapy (PI or PEX; P = 0.2) was not a predictor. On multivariate analysis, presentation with AKI Stage 3 (P = 0.05) and edema (P = 0.03) were the only independent predictors of this outcome.


  Discussion Top


In this unicentric study of 53 children with aHUS, 46 children were managed initially with either PI (n = 24) or PEX (n = 22). PEX was offered to patients who were sicker, as reflected in comparison of baseline characteristics between groups. A higher proportion of patients achieved hematological remission with PEX than PI; further, four patients not responding to PI and switched to PEX, recovered completely. The two groups had comparable time to hematological remission and similar rates of relapse and renal recovery. About one-third of the patients progressed to CKD Stage 5, with the time to adverse outcome being similar for patients managed on PI or PEX.

Information on comparative efficacy of PI and PEX in aHUS is limited. There were insufficient details of plasma therapy in two retrospective cohorts, one of which included adult patients also, making it difficult to draw conclusions about the benefit of one therapy over another.[14],[15] In this study, almost one-third of patients managed on PI or PEX progressed to CKD Stage 5. In a nationwide French series, 6.7% of pediatric patients with aHUS managed with high-dose plasma therapy died, while 16% had progressed to CKD Stage 5, by 1-year follow-up.[15] In contrast, in an Italian study, despite high rates of hematological remission similar to our findings, 50% of children and two-thirds of adults with aHUS progressed to end-stage renal disease or died at the end of 3-year follow-up.[3] Differences in outcomes of plasma therapy between studies may be linked to phenotypic and genetic heterogeneity of aHUS among these populations, and the impact of disease relapses or progression during the varying duration of follow-up.

Two-thirds of patients evaluated for anti-CFH antibodies had autoimmune aHUS. Anti-CFH antibody has emerged as a leading form of aHUS in school-going age group and accounts for more than 50% of aHUS in India.[12],[16] We found high rate of hematological remission and renal recovery in patients with anti-FH antibody-associated aHUS managed with PEX and immunosuppression, similar to findings observed in a large multicenter Indian study.[12],[16] All the patients with antibody-associated aHUS in the present study were managed with PEX, which was shown to be more efficacious than PI in this subgroup of patients.[12] The efficacy of PEX in the subgroup of patients with autoimmune aHUS contrasts with the analysis of outcomes in an International Registry, wherein only two-thirds of 156 children with aHUS achieved complete or partial remission following 2–36 sessions of PEX or PI.[17] Subgroup analysis indicated that plasma therapy was useful in patients with an underlying CFH mutation but did not impact outcomes in those with mutations in gene encoding membrane cofactor protein (MCP).[17] The response to therapy with PEX or PI varies, based on the genetic background and presence of anti-CFH antibody.[17],[18] Other reported predictors of outcome, as listed in a study from China, include age <2 years, oliguria or anuria for more than 1 week, and severe extrarenal manifestations.[19] Similarly, we found that severe AKI at presentation and fluid overload, as suggested by edema, were independent predictors of incomplete or nonrecovery at discharge.

The present study has several limitations. Evaluation for underlying inherited defects or autoantibodies, known to impact outcomes, was not performed in the majority of patients. Therapy with PEX or PI was less intense and abbreviated as compared to previous reports,[13],[14],[15],[16] and only a subgroup of patients were followed for a short duration of time. The groups of patients managed with PI and PEX were not comparable at baseline but had similar outcomes, indicating that lack of demonstration of superior efficacy of PEX compared to PI might be because patients managed with PEX were sicker. The study also has the usual flaws of a retrospective study design, including selection and recall bias, incomplete or selective reporting of outcomes, and high rates of attrition. Within these limitations, plasma therapy, whether as PEX or PI, appears to be feasible and associated with satisfactory short-term efficacy in patients with aHUS in regions lacking access to monoclonal complement blockade. PI might be an acceptable alternative to PEX in emergency settings, especially in patients with mild aHUS or where PEX is not feasible due to patient size or lack of expertise. PEX should be the preferred modality in patients with severe aHUS and in those with anti-FH antibody-associated aHUS.

Acknowledgment

Testing for antibodies to CFH was performed in the Division of Pediatric Nephrology, All India Institute of Medical Sciences, New Delhi, India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844-59.  Back to cited text no. 2
    
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Reid VL, Mullan A, Erwig LP. Rapid recovery of membrane cofactor protein (MCP; CD46) associated atypical haemolytic uraemic syndrome with plasma exchange. BMJ Case Rep 2013;2013. pii: bcr2013200980.  Back to cited text no. 7
    
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Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int 2012;2:S1-38.  Back to cited text no. 8
    
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Heilbron DC, Holliday MA, al-Dahwi A, Kogan BA. Expressing glomerular filtration rate in children. Pediatr Nephrol 1991;5:5-11.  Back to cited text no. 9
    
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Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009;20:629-37.  Back to cited text no. 10
    
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National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114:555-76.  Back to cited text no. 11
    
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Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:S1-50.  Back to cited text no. 12
    
13.
Sinha A, Gulati A, Saini S, Blanc C, Gupta A, Gurjar BS, et al. Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children. Kidney Int 2014;85:1151-60.  Back to cited text no. 13
    
14.
Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, 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.  Back to cited text no. 14
    
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Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaimé F, Dragon-Durey MA, Ngo S, et al. Genetics and outcome of atypical hemolytic uremic syndrome: A nationwide French series comparing children and adults. Clin J Am Soc Nephrol 2013;8:554-62.  Back to cited text no. 15
    
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Khandelwal P, Gupta A, Sinha A, Saini S, Hari P, Dragon Durey MA, et al. Effect of plasma exchange and immunosuppressive medications on antibody titers and outcome in anti-complement factor H antibody-associated hemolytic uremic syndrome. Pediatr Nephrol 2015;30:451-7.  Back to cited text no. 16
    
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Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2007;18:2392-400.  Back to cited text no. 17
    
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Hofer J, Janecke AR, Zimmerhackl LB, Riedl M, Rosales A, Giner T, et al. Complement factor H-related protein 1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2013;8:407-15.  Back to cited text no. 18
    
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Zhao SA, Ning BT, Mao JH. Clinical characteristics of children with hemolytic uremic syndrome in Hangzhou, China. World J Pediatr 2017;13:183-5.  Back to cited text no. 19
    


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