Jesús Camacho-Rodríguez

Dario Colazzo

Melanie Herschel

Ioana Manolescu

Soudip Roy Chowdhury

Reuse-based Optimization for Pig Latin

Keywords: Reuse-based Optimization, Linear Programming, PigLatin

Pig Latin is a popular language which is widely used for parallel processing of massive data sets. Currently, subexpressions occurring repeatedly in Pig Latin scripts are executed as many times as they appear, and the current Pig Latin optimizer does not identify reuse opportunities.

We present a novel optimization approach aiming at identifying and reusing repeated subexpressions in Pig Latin scripts. Our optimization algorithm, named PigReuse, identifies subexpression merging opportunities, selects the best ones to execute based on a cost function, and reuses their results as needed in order to compute exactly the same output as the original scripts. Our experiments demonstrate the effectiveness of our approach.

INTRODUCTION

The efficient processing of very large volumes of data has lately relied on massively parallel processing models, of which MapReduce is the most well known. However, the simplicity of these models leads to relatively complex programs to express even moderately complex tasks. Thus, to facilitate the specification of data processing tasks to be executed in a massively parallel fashion, several higher-level query languages have been introduced.

In this work, we consider Pig Latin [START_REF] Olston | Pig latin: a not-so-foreign language for data processing[END_REF], which has raised significant interest from the application developers as well as the research community. Pig Latin provides dataflow-style primitives for expressing complex analytical data processing tasks. Pig Latin programs (also named scripts) are automatically optimized and compiled into parallel processing jobs by the Apache Pig system [START_REF]Apache Pig[END_REF], which is included in all leading Hadoop distributions e.g., HDP [START_REF]HDP[END_REF], CDH [START_REF] Cdh | [END_REF].

Part of this work was performed while the authors were with Université Paris-Sud and INRIA.

In a typical batch of Pig Latin scripts, there may be many identical (or equivalent) sub-expressions, that is: script fragments applying the same processing on the same inputs, but appearing in distinct places within the same (or several) scripts. While the Pig Latin engine includes a query optimizer, it is currently not capable of recognizing such repeated subexpressions. As a consequence, they are executed as many times as they appear in the script batch, whereas there is obviously an opportunity for enhancing performance by identifying common subexpressions, executing them only once, and reusing the results in every script needing them.

Identifying and reusing common subexpressions occurring in Pig Latin scripts automatically is the target of the present work. The problem bears obvious similarities with the known multi-query optimization and workflow reuse problems; however, as we discuss in Section 6, the Pig Latin primitives lead to several novel aspects of the problem, which lead us to propose dedicated, new algorithms to solve them. Motivating example. A Pig Latin script consists of a set of binding expressions and store expressions. Each binding expression var = op means that the expression op is evaluated, and the resulting bag of tuples is bound to the variable var, which can be used by follow-up expressions in a script.

Consider the following Pig Latin script a1:

Line 1 loads data from a file page_views and creates a bag of tuples that is bound to variable A. Each of these tuples consists of three attributes (user,time,www). Line 2 loads data from a second file, and binds the resulting tuple bag to B. Line 3 joins the tuples of A and B based on the equality of the values bound to attributes user and name. The next line uses the Pig Latin operator FOREACH, that applies a function on every tuple of the input bag. In this case, line 4 projects the attributes user, time and zip of every tuple in R. Then the result is stored in the file a1out1. In turn, line 6 executes a left outer join over the tuples of A and B based on the equality of the values bound to the same attributes user and name, and the result is stored in a1out2.

The following script a2 only executes a left outer join over the same inputs:

The script b that we introduce next produces the same outputs as a1 and a2: However, b's execution time is 45% of the combined running time of a1 and a2. The reason is twofold. First, observe that the joins are rewritten into a COGROUP 1 operation (line 3) and FOREACH operations (lines 4 and 7-8). The interest of cogroup is that through some simple restructuring, one can carve out of the cogroup output various flavors of joins (natural, outer, nested, semijoin etc.) This restructuring operation differs depending on whether we want to generate the join between A and B needed for script a1 (line 4), or the left outer join between A and B for scripts a1 and a2 (lines 7-8). The detailed semantics of these restructuring operations will become clear in Section 4. Thus, the first reason for the speedup of b w.r.t. a1 and a2 is that the COGROUP output is reused to generate the result for both joins. The second reason is that in b, the left outer join is computed only once, and its result is used to produce the desired output of scripts a1 (line 9) and a2 (line 10).

A typical feature of our optimizer is that it works on the algebraic representation of Pig Latin scripts. Thus, it is orthogonal to the Pig Latin query evaluation and execution process. This allows our approach (i) to benefit from the Pig Latin optimizer, and (ii) to apply our optimization independently of the underlying Pig Latin query compilation and execution engines. Contributions. The technical contributions of this work are the following.

• We propose PigReuse, a multi-query optimization algorithm that merges equivalent subexpressions it identifies in Directed Acyclic Graph of algebraic representation of a batch of Pig Latin scripts. PigReuse produces then an optimal merged plan where redundant computations have been eliminated, by relying on Binary Integer Linear Programming in order to select the best plan based on the provided cost function.

• We present techniques to improve effectiveness of our baseline PigReuse optimization approach.

• We have implemented PigReuse as an extension module within the Apache Pig system. We present an experimental evaluation of our techniques using two different cost functions to select the best plan.

Outline. Section 2 is dedicated to preliminaries. Section 3 presents the main techniques over which PigReuse relies on, while Section 4 presents strategies to enhance it. Section 5 describes our experimental evaluation. Finally, Section 6 discusses related work, and then we conclude.

1 COGROUP is a generalization of the group-by operation on two or more relations: for every distinct value of the grouping key occurring in any of the inputs, it outputs a tuple that includes an attribute group bound to the grouping key, and a bag of tuples for each input Ri such that the bag Ri includes all tuples in Ri that contain the value of the grouping key.

PRELIMINARIES

Since our approach strictly depends on rewriting Pig Latin expressions into equivalent ones, we rely on algebraic representation of Pig Latin scripts. Actually, the Pig Latin data model features complex data types (e.g., tuple, map etc.) and nested relations with duplicates (bags). Thus, we rely on the Nested Relational Algebra for Bags [START_REF] Grumbach | Towards Tractable Algebras for Bags[END_REF] (NRAB, for short) to represent Pig Latin scripts. We consider a subset of the NRAB algebra and extend it with other operators, such as cogroup. In turn, we have formalized (and implemented) the entire Pig Latin-to-NRAB translation process. Formal details of the translation are presented in [START_REF] Camacho-Rodríguez | PigReuse: A Reuse-based Optimizer for Pig Latin[END_REF].

We represent a set of NRAB binding expressions obtained from a Pig Latin program as a Directed Acyclic Graph (DAG); each binding is represented as a node, while edges represent the data flow among nodes.

To illustrate, Figure 1.a introduces four different Pig Latin scripts s1-s4; we will reuse them throughout the paper. The scripts read data from the three input relations page_views, users, and power_users; from now on, we denote these relations as A, B, and C.

After connecting the different algebraic expressions generated from s1, we obtain the DAG query q1 shown in Figure 1.b, also including the DAG-based representations of s2-s4. We denote the NRAB projection operator as π, while the selection operation is denoted as σ. In turn, inner join is denoted as 1, while left outer join is denoted as 1.

REUSE-BASED OPTIMIZATION

Based on the previously introduced representation of Pig Latin scripts as NRAB DAGs, we now introduce our PigReuse algorithm that optimizes the query plans corresponding to a batch of scripts by reusing results of repeated subexpressions. More specifically, given a collection of NRAB DAG queries Q, PigReuse proceeds in two steps: Step [START_REF] Agrawal | Scheduling shared scans of large data files[END_REF]. Identify and merge all the equivalent subexpressions in Q. To this end, we use an AND-OR DAG, in which an AND-node (or operator node) corresponds to an algebraic operation in Q, while an OR-node (or equivalence node) represents a set of subexpressions that generate the same result.

A A C A A C B B B
Step [START_REF] Alvaro | Multi-query optimization for parallel dataflow systems[END_REF]. Find the optimal plan from the AND-OR DAG.

Based on a cost model, we make a globally optimal choice of the set of operator nodes to be evaluated. Our approach is independent of the particular cost function chosen.

The final output of PigReuse is an optimized plan that contains (i) the operator nodes leading to minimizing the cummulated cost of all the queries in Q, while producing, together, the same set of outputs as the original Q, and (ii) equivalence nodes that represent result sharing of an operator node with other operators in Q. In the following sections, we describe each step of our reuse-based optimization algorithm in detail.

Equivalence-based merging

To join all detected equivalent expressions in Q, we build an AND-OR DAG, which we term equivalence graph (EG, in short); the construction is carried out in the spirit of previous optimization works [START_REF] Graefe | The Volcano optimizer generator: Extensibility and efficient search[END_REF][START_REF] Roy | Efficient and Extensible Algorithms for Multi Query Optimization[END_REF]. In the EG, an AND-node corresponds to an algebraic operation (e.g., selection, projection etc.). An OR-node o is introduced whenever a set of expressions e1, e2, . . . , e k have been identified as equivalent; in the EG, the children of o are the algebraic nodes at the roots of the expressions e1, e2, . . . , e k . In the following, we refer to AND-nodes as operator nodes, and OR-nodes as equivalence nodes. Formally, we define an EG as follows.

Definition 1. An equivalence graph (EG) is a DAG, defined by the pair (O ∪ A ∪ To, E), with O, A, and To disjoint sets of nodes, and:

• O is the set of equivalence nodes, A is the set of operator nodes, To is the set of sink nodes.

• E ⊆ (O × A) ∪ (A × O) ∪ (A × To) is a set of directed
edges such that: each node a ∈ A has an in-degree of at least one, and an out-degree equal to one; each node o ∈ O has an in-degree of at least one, and an out-degree of at least one; each node to ∈ To has an in-degree of at least one.

Observe that in an EG, O nodes can only point to A nodes, while A nodes can point to O or To nodes. Building the equivalence graph. To build the equivalence graph, we need to identify equivalent expressions within the input NRAB query set Q. We rely on the standard notion of query equivalence, i.e., two expressions are equivalent iff their result is provably the same regardless of the data on which they are computed. Our equivalence search algorithm is sound but not complete; see [START_REF] Camacho-Rodríguez | PigReuse: A Reuse-based Optimizer for Pig Latin[END_REF] for a detailed discussion.

Figure 2 depicts the EG corresponding to the NRAB DAGs q1 to q4 in Figure 1.b. In Figure 2, all the leaf nodes in the NRAB DAGs that correspond to the same scan operation (namely, nodes A, B, and C) feed the same equivalence node. The equi-joins coming from DAGs q1 and q2 on relations A and B over attributes user and name are also inputs to the same equivalence node.

Cost-based plan selection

Once an EG has been generated from a set of NRAB queries, our goal is to find the best alternative plan (having the smallest possible cost) computing the same outputs as the original scripts. We call the output plan a result equivalence graph (or REG, in short). Definition 2. A result equivalence graph (REG) with respect to an EG defined by (O ∪ A ∪ TO, E) is itself a DAG, defined by the pair (O * ∪ A * ∪ TO, E * ) such that:

• O * ⊆ O, A * ⊆ A, E * ⊆ E.
• The set of sink nodes To is identical in EG and REG.

Each sink node has an in-degree of exactly one. • Each operator node in-degree in EG and REG is equal.

Each equivalence node has an in-degree of exactly one, and an out-degree of at least one.

In the REG, we choose exactly one among the alternatives provided by each EG equivalence nodes; the REG produces the same outputs as the original EG, as all sink nodes are preserved. Further, each REG can be straightforwardly translated into a NRAB DAG which is basically an executable Pig Latin expression. The latter expression is the one we turn to Pig for execution.

The choice of which alternative to pick for each equivalence node is guided by a cost function, the overall goal being to minimize the global cost of the plan. We assign a cost (weight) to each edge n1 → n2 in the EG, representing all the processing cost (or effort) required to fully build the result of n2 out of the result of n1.

Figure 3 shows a possible REG produced for the EG depicted in Figure 2. This REG can be obtained by using a cost function based on counting the operator nodes in the optimized script. In Section 5, we consider different cost functions and compare them experimentally.

Cost minimization

We model the problem of finding the minimum-cost REG relying on Binary Integer Programming (BIP), that has already been used to solve database optimization problems [START_REF] Karanasos | Delta: Scalable data dissemination under capacity constraints[END_REF][START_REF] Yang | Algorithms for materialized view design in data warehousing environment[END_REF]. Broadly speaking, a linear programming problem can be expressed as: given a set of linear inequality constraints over a set of variables find value assignments for the variables such that the value of an objective function depending on these variables is minimized. 2) ensures that every output is generated exactly once. [START_REF] Camacho-Rodríguez | PigReuse: A Reuse-based Optimizer for Pig Latin[END_REF] states that if the (only) outgoing edge of an operator node is selected, all of its inputs are selected as well. This is required in order for the algebraic operator to be capable of correctly computing its results. Finally, (4) states that if an equivalence node is generated, it should be used at least once, which is modeled by means of a max expression (details about its BIP encoding can be found in [START_REF] Camacho-Rodríguez | PigReuse: A Reuse-based Optimizer for Pig Latin[END_REF]).

Minimize C = e∈E Cexe subject to: xe ∈ {0, 1} ∀e ∈ E (1)
e∈E in to xe = 1 ∀to ∈ To (2) e∈E in a xe = x E out a × |E in a | ∀a ∈ A (3) e∈E in o xe = max e∈E out o xe ∀o ∈ O (4)

EFFECTIVE PIGREUSE

In the following, we present three extensions to the basic PigReuse algorithm which allow for identifying and exploiting additional factorization opportunities (formal details can be found in [START_REF] Camacho-Rodríguez | PigReuse: A Reuse-based Optimizer for Pig Latin[END_REF]). Normalization of the input NRAB DAGs is carried out by reordering π operator nodes as follows: we push them away from scan operators or closer to store operators. We do this by visiting all operator nodes in a NRAB DAG, starting from a scan, and by moving each π operator up one level at a time if possible. Although pushing projections up through a plan is counterintuitive from the classical optimization point of view, it increases the chances to find equivalent subexpressions, as we will shortly illustrate. Further, after our reusebased algorithm produces the optimized REG, we push the π operators back down to avoid the performance loss incurred by manipulating many attributes at all levels.

Since cogroup nests the input relations, reordering π with this operator requires complex rewriting. Specifically, we use the NRAB restructuring operator in the rewriting, denoted as map ϕ , which applies a function ϕ to all tuples in the input. Thus, we rewrite the project π into a map that applies π on the corresponding bag of tuples in the input relation.

To illustrate the advantages of this phase, Figure 5.a shows the EG generated by PigReuse over the normalized NRAB DAGs q1 to q4. Comparing this EG with the one shown in Figure 2, we see that due to the swapping of the π operator corresponding to q2, our algorithm can identify an additional common subexpression between q2 and q4, by determining the equivalence between the joins over A, B, and C; the corresponding equivalence node is highlighted. Join decomposition. The semantics of Pig Latin's join operators e.g., 1, 1, 1 , or 1 allow rewriting these operators into combinations of cogroup and map operators. The advantage of decomposing the joins in this way is that the result of the cogroup operation, which does the heavy-lifting of assembling groups of tuples from which the map will then build join results, can be shared across different kinds of joins. The map will be different in each case depending on the join type, but the most expensive component of computing the join, namely the cogroup, will be factorized.

Figure 5.b shows the EG generated by PigReuse after applying normalization and decomposition to the NRAB DAGs q1 to q4. One can observe that the decomposition of the 1 operators from q1 and q2, and the 1 operator from q3 leads to an additional sharing opportunity, as the result of the cogroup on attributes user and name can be shared by the subsequent map operations (highlighted equivalence node).

Observe that 1 operators were rewritten into two operators. The first one is a cogroup on the attributes used by the join predicate. The second one is a map that does the following for each input tuple: (i) project each bag of tuples corresponding to the cogroup input relations; (ii) apply a NRAB bag destroy operation, denoted as δ, which unnests one level those bags; and (iii) perform a cartesian product × among the tuples resulting from unnesting those bags. If a bag is empty, e.g., the input relation did not contain any value for the given grouping value, the δ operator does not produce any tuple, and thus the tuples from the other bags for the given tuple are discarded. Thus, the rewriting produces the exact same result as the original operator.

For the left outer join 1 rewriting, cogroup is followed by a map operator that (i) unnests the bag associated to the left input of the cogroup; (ii) if the bag associated to the right input (var 2 ) is empty, it replaces it with a bag with a null tuple, otherwise it keeps the bag as it is; (iii) unnests the bag resulting from the previous operation; and (iv) performs a cartesian product on the tuples resulting from the δ operations in order to generate the 1 result. Aggressive merge is based on the observation that it is possible to derive the results of a join or cogroup operator from the results of a cogroup operator, as long as the former relies on a subset of the input relations and attributes of cogroup . This means that these rewritings rely on the notion of cogroup containment. In particular, this entails checking the containment relationship between respective sets of input relations and attributes. Then, in order to generate the result of the original 1 or cogroup operator, we add the appropriate operator on top of cogroup . Differently from previous extensions, aggressive merge is applied while creating the EG.

EXPERIMENTAL EVALUATION

We have implemented PigReuse in Java 1.6. The source code amounts to about 8000 lines and 50 classes. It works on top of Apache Pig 0.12.1 [START_REF]Apache Pig[END_REF], which relied on the Hadoop platform 1.1.2 [START_REF]Apache Hadoop[END_REF]. The cost-based plan selection algorithm uses the Gurobi BIP solver 5.6.2 (www.gurobi.com). Deployment. All our experiments run in a cluster of 8 nodes connected by a 1GB Ethernet. Each node has a 2.93GHz Quad Core Xeon processor and 16GB RAM, runs Linux CentOS 6.4, and has two 600GB SATA hard disks where HDFS is mounted. Setup. For validation, we used data sets and scripts provided by the PigMix [20] PigLatin performance benchmark. We created a page_views input file of 250 million rows; the benchmark includes other input files, which are based on the page_views file, and are much smaller than this one. The total size of the data set amounted to approximately 400 GB before the 3-way replication applied by HDFS.

We run our algorithm with two different workloads, denoted W1 and W2, containing 12 and 20 Pig Latin scripts, respectively. Details about these workloads are given in [START_REF] Camacho-Rodríguez | PigReuse: A Reuse-based Optimizer for Pig Latin[END_REF]. Cost functions and experiment metrics. Currently we have implemented two cost functions in PigReuse, focusing on reducing the number of logical operators, and the number of MapReduce jobs, respectively. Beyond these two cost functions used by our PigReuse algorithm, we also quantify the performance of executing a PigLatin workload through the following standard metrics: the Execution time is the wall-clock time measured from the moment when the scripts are submitted to the Pig engine, until the moment their execution is completely finished; the Total work is the sum of the effort made on all the nodes, i.e., the total CPU time as returned by logs of the MapReduce execution engine. Experimental results. We now study the benefits brought by the optimizations proposed in this work. The reported results are averaged over three runs.

Figure 6 shows the effectiveness of our baseline PigReuse algorithm (PR), PigReuse with normalization (PR+N), Pi-gReuse with normalization and decomposition (PR+ND), and PigReuse applying all our extensions including aggres- sive merge (PR+NDA). The figure shows relative values for the execution time and total work metrics. The cost function that minimizes the total number of operators in the EG is denoted by minop, while the cost function that minimizes the total number of MapReduce jobs is denoted by minmr.

In Figure 6.a, we notice that the total execution time is reduced by more than 70% on average among our PigReuse algorithms. Two alternative executions without PigReuse are shown. In the first one (NoPR/S), we execute sequentially every script in each workload using a single Pig client. In the second one (NoPR/M), we use multiple Pig clients that send concurrently the jobs resulting from the scripts to MapReduce. As it can be seen, the execution time for the second variant is lower as jobs resulting from multiple scripts are scheduled together, and thus the cluster usage is maximized. However, observe that the total work (Figure 6.b) increases for the multi-client alternative. The reason is that the scheduler cannot overlap significantly the map phases of multiple queries since there are too many map tasks. Thus, their execution remains quite sequential.

For the workloads we considered, our extensions reduced the total work over the baseline PigReuse algorithm (Figure 6.b). However, this was not always the case for the execution time (Figure 6.a). The reason is that some of the resulting plans requiring more effort had less sequential ex-ecution steps, thus they could be parallelized easier by the MapReduce engine. When aggressive merge was applied, the execution time and the total work decreased only if the minmr cost function was used. The reason is that if the minop function is used, PigReuse generates the same REG for PR+ND and PR+NDA, namely, the REG with the minimum number of operators. However, with minmr, PigReuse chooses a plan with more operators but that runs faster.

RELATED WORK

Relational multi-query optimization. Our work directly relates to multi-query optimization (MQO). The early works [START_REF] Jarke | Common subexpression isolation in multiple query optimization[END_REF][START_REF] Sellis | Multiple-query optimization[END_REF] proposed exhaustive, expensive algorithms which were not integrated with existing system optimizers. The technique presented in [START_REF] Roy | Efficient and Extensible Algorithms for Multi Query Optimization[END_REF] was the first to integrate MQO into a Volcano-style optimizer, while [START_REF] Zhou | Efficient exploitation of similar subexpressions for query processing[END_REF] presents a completely integrated MQO solution accounting also for the usage and maintenance of materialized views. The approach of [START_REF] Silva | Exploiting Common Subexpressions for Cloud Query Processing[END_REF] takes into account the physical requirements of the consumers of common sub-expressions in order to propose globally optimal execution plans. While all of these works deals with the relational algebra, our approach optimizes workloads expressed in terms of the richer NRAB algebra including nesting. Further, differently from these approaches, ours can be directly applied to alternative implementations of Pig Latin or of any other language based on NRAB.

The above considerations still hold for the approach proposed in [START_REF] Giannikis | Shared workload optimization[END_REF], which relies on sharing physical operators in large SQL workloads. The approach presented in [START_REF] Neumann | Generating optimal dag-structured query evaluation plans[END_REF] also addresses both global optimization and sharing possibilities at once, but it aims at optimizing a single query, while extensions to multi-query are not trivial and not explored so far. As pointed out in [START_REF] Giannikis | Shared workload optimization[END_REF], the global optimization plus sharing problem can not be expressed by a linear program and thus a branch-and-bound heuristic solution is proposed, whereas our sharing problem can be solved optimally through BIP. [START_REF] Nagel | Recycling in pipelined query evaluation[END_REF] optimizes SQL workloads at runtime and tries to maximize recycling opportunities of intermediary results. Due to the complexity constraints of considering multiple rewritings for each query, [START_REF] Nagel | Recycling in pipelined query evaluation[END_REF] only considers the optimized plan for each of them, in contrast to PigReuse. This design choice comes at the price of missing sharing opportunities. Reuse-based optimizations on MapReduce. Recent works have sought to avoid redundant processing for a batch of MapReduce jobs by sharing their scans or intermediary results. Since the semantics of the computation is not visible at the level of MapReduce programs, these works are either limited to detecting identical inputs and outputs of MapReduce tasks (without being able to reason on task equivalence) [START_REF] Agrawal | Scheduling shared scans of large data files[END_REF][START_REF] Nykiel | MRShare: sharing across multiple queries in MapReduce[END_REF][START_REF] Wang | Multi-Query Optimization in MapReduce Framework[END_REF], or need some annotations to the jobs to inform about sharing opportunities [START_REF] Elghandour | ReStore: reusing results of MapReduce jobs[END_REF][START_REF] Lefevre | Opportunistic Physical Design for Big Data Analytics[END_REF]. Our PigReuse algorithm works on the higher-level semantic representation of Pig Latin scripts. This enables more complex reuse-based optimizations, e.g., through algebraic expression rewriting.

MQO for higher-level languages based on MapReduce has been considered in [START_REF] Alvaro | Multi-query optimization for parallel dataflow systems[END_REF][START_REF] Olston | Automatic optimization of parallel dataflow programs[END_REF]. For Hive workloads, [START_REF] Alvaro | Multi-query optimization for parallel dataflow systems[END_REF] shows by example that improving replication of frequently used data, re-ordering queries in a workload, and scheduling queries in parallel can improve performance. In turn, [START_REF] Olston | Automatic optimization of parallel dataflow programs[END_REF] studies how to schedule Pig Latin programs in order to best profit from the shared computations. The core of our work, instead, is concerned with identifying common sub-expression of a workload, and examining the global sharing problem, which are not addressed in [START_REF] Olston | Automatic optimization of parallel dataflow programs[END_REF].

CONCLUSIONS

We have presented a novel reuse-based optimization approach for Pig Latin scripts. Our PigReuse algorithm identifies sub-expression merging opportunities, and selects the best ones to merge based on a cost-based search process implemented with the help of a linear program solver. Pi-gReuse allows plugging any cost function and its output is a merged script reducing its value. Our experimental results demonstrate the effectiveness of our optimization strategies.

1

  A = LOAD 'page_views' AS (user, time, www); 2 B = LOAD 'users' AS (name, zip); 3 R = COGROUP A BY user, B BY name; 4 S = FOREACH R GENERATE flatten(A), flatten(B); 5 T = FOREACH S GENERATE user, time, zip; 6 STORE T INTO 'a1out1'; 7 U = FOREACH R GENERATE flatten(A), 8 flatten (isEmpty(B) ? {(null,null,null)} : B); 9 STORE U INTO 'a1out2'; 10 STORE U INTO 'a2out';

Figure 1 :

 1 Figure 1: Sample Pig Latin scripts (a) and their corresponding algebraic DAG representation (b).

Figure 2 :

 2 Figure 2: EG corresponding to NRAB DAGs q1-q4.

Figure 3 :

 3 Figure 3: Possible REG for the EG in Figure 2.

Figure 4 :

 4 Figure 4: BIP reduction of the problem.

Figure 5 .

 5 c depicts the new EG produced by PigReuse using aggressive merge; the new connections are highlighted. The figure shows how the results for the cogroup, 1, and 1 operators on A and B relations are derived from the cogroup operator on A, B, and C.

Figure 5 :

 5 π<user,time,zip> cogroup<user,name,id> cogroup<user,name> map<δ(A)×δ(B)×δ(C)> map<δ(A)×δ(B)> map<δ(A)×δ(empty(B)?{{⊥}}:B)> cogroup<user,id> map<δ(G1)×δ(C)> cogroup<user,name> cogroup<user,name> map<δ(A)×δ(B)> π<user,time, π<user,time,zip> cogroup<user,name,id> cogroup<user,name> map<δ(A)×δ(B)×δ(C)> map<δ(A)×δ(B)> map<δ(A)×δ(empty(B)?{{⊥}}:B)> cogroup<user,id> map<δ(G1)×δ(C)> EG generated by PigReuse on (a) the normalized DAGs q1-q4, (b) the normalized and decomposed DAGs q1-q4, and (c) applying aggressive merge on the normalized and decomposed DAGs q1-q4.

Figure 6 :

 6 Figure 6: PigReuse evaluation using workload W1 (left) and W2 (right).

  Many years of research and development efforts have led to the implementation of extremely efficient BIP solvers. Generating the result equivalence graph. Given an input EG, for each node n ∈ O ∪ A ∪ To, we denote by E in respectively. For each edge e ∈ E, we introduce a variable xe, denoting whether or not e is part of the REG. Since in our specific problem formulation any xe takes values in {0, 1}, our problem is formulated as a BIP problem. Further, for each edge e ∈ E, we denote by Ce the cost assigned to e by some cost function C. Importantly, the model we present next is independent of the chosen cost function. Our optimization problem is stated in BIP terms in Figure 4. Equation (1) states that each xe variable takes values in {0, 1}. (

n and E out n the sets of incoming and outgoing edges for n,

A = LOAD 'page_views' AS (user, time, www);

B = LOAD 'users' AS (name, zip);

R = JOIN A BY user, B BY name;

S = FOREACH R GENERATE user, time, zip;

STORE S INTO 'a1out1';

T = JOIN A BY user LEFT, B BY name;

STORE T INTO 'a1out2';

A = LOAD 'page_views' AS (user, time, www);

B = LOAD 'users' AS (name, zip);

R = JOIN A BY user LEFT, B BY name;

STORE R INTO 'a2out';


Picard Camille

Burtey Stéphane

Bornet Charleric

Curti Christophe

Montana Marc

Patrice Vanelle
email: patrice.vanelle@univ-amu.fr

PATHOPHYSIOLOGY AND TREATMENT OF TYPICAL AND ATYPICAL HEMOLYTIC UREMIC SYNDROME

Keywords: Hemolytic uremic syndrome, Urtoxazumab, Eculizumab, Shigatoxin receptor analogues Hemolytic uremic syndrome, Urtoxazumab, Eculizumab, Shigatoxin receptor analogues Syndrome hémolytique urémique, Urtoxazumab, Eculizumab, Analogue des récepteurs aux shigatoxines

Hemolytic uremic syndrome is a rare disease, frequently responsible for renal insufficiency in children.

Recent findings have led to renewed interest in this pathology. The discovery of new gene mutations in the atypical form of HUS and the experimental data suggesting the involvement of the complement pathway in the typical form, open new perspectives for treatment. This review summarizes the current state of knowledge on both typical and atypical hemolytic uremic syndrome pathophysiology and examines new perspectives for treatment.

RESUME

Le syndrome hémolytique urémique est une maladie rare, souvent responsables de l'apparition d une insuffisance rénale chez les enfants.

Des découvertes récentes ont conduit à un regain d'intérêt dans cette pathologie. La découverte de nouvelles mutations génétiques dans la forme atypique et les données expérimentales suggérant l'implication de la voie du complément dans la forme typique ouvrent de nouvelles perspectives pour le traitement.

Cette revue résume l'état actuel des connaissances sur la physiopathologie du syndrome hémolytique urémique typique et atypique et présente les nouvelles perspectives de traitement.

Introduction.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) like thrombotic thrombocytopenic purpura (TTP). Typically, TMA histology includes intimal proliferation and/or endothelial swelling with luminal fibrin deposition in arterial or capillary beds. The clinical manifestations associated with TMA are non-immune mechanical haemolytic anaemia, thrombocytopenia and organ dysfunction. TTP mainly affects the central nervous system, whereas HUS has a renal tropism that does not exclude damage to other organs like the central nervous system. As a consequence, differential diagnosis between TTP and HUS can be difficult.

There are two categories of HUS: typical and atypical.

Typical HUS is generally preceded by an episode of diarrhea mainly due to pathogens producing shigatoxin or verotoxin.

Atypical HUS (aHUS) is familial or sporadic. Abnormal activation of the alternative complement pathway is a key event in the physiopathology of aHUS. The efficacy of eculizumab confirmed the role of the complement in aHUS.

The aim of this review is to present recent progress in the understanding and management of the pathology.

Typical hemolytic uremic syndrome.

Etiology

Typical HUS average annual incidence ranges between 0.6 and 1.4 cases per 100,000 children under 16. [START_REF] Bertholet-Thomas | Syndrome hémolytique et urémique post-diarrhéique: Quand y penser? Quel suivi?[END_REF][START_REF] Schifferli | Hemolytic-uremic syndrome in Switzerland: a nationwide surveillance 1997-2003[END_REF] Most cases occur during summer between June and September and particularly at age 1 [START_REF] Bertholet-Thomas | Syndrome hémolytique et urémique post-diarrhéique: Quand y penser? Quel suivi?[END_REF].

In developed countries, the HUS mortality rate is less than 5%. Shigatoxin Escherichia coli (STEC) were isolated in 60% of cases of infection. [START_REF] Schifferli | Hemolytic-uremic syndrome in Switzerland: a nationwide surveillance 1997-2003[END_REF][START_REF] Walker | Haemolytic-Uraemic Syndrome as a Sequela of Diarrhoeal Disease[END_REF] Often, the O157:H7 strain is involved (15%), but other strains can be identified, in particular O104:H4 which caused an epidemic near Bordeaux, France in June 2011 and a German outbreak. [START_REF] Blaser | Deconstructing a lethal foodborne epidemic[END_REF] About 5% of HUS is due to other pathogens such as Shigella dysenteriae type I or Streptoccocus pneumoniae, which represent 40 to 50% of non Escherichia coli cases. In these cases the disease is caused by N-acetyl neuraminidase, also found in another possible trigger of HUS, the influenza virus. [START_REF] Loirat | Management of hemolytic uremic syndrome[END_REF] Less than 10% of Escherichia coli and Shigella infections and less than 1% of pneumococcus infections result in HUS, [START_REF] Walker | Haemolytic-Uraemic Syndrome as a Sequela of Diarrhoeal Disease[END_REF][START_REF] Blaser | Deconstructing a lethal foodborne epidemic[END_REF] suggesting that genetic or environmental risk factors to develop HUS remain to be identified.

HUS is a frequent cause of renal insufficiency in children. Four years after an episode, 3% of children develop end-stage renal disease and 25% suffer from reduced renal function. [START_REF] Walker | Haemolytic-Uraemic Syndrome as a Sequela of Diarrhoeal Disease[END_REF] According to a 1996 study conducted by the French Institut de Veille Sanitaire (InVS), dialysis is required to treat 46% of children [START_REF] Bertholet-Thomas | Syndrome hémolytique et urémique post-diarrhéique: Quand y penser? Quel suivi?[END_REF] and, during the acute phase of the disease, is associated with a poor prognosis. [START_REF] Walker | Haemolytic-Uraemic Syndrome as a Sequela of Diarrhoeal Disease[END_REF] 2.2. Pathophysiology STEC, the primary cause of typical HUS, is a commensal of the cattle digestive tract.

Contamined food is the most frequent source and contamination rarely occurs via interhuman transmission or after contact with cattle. The incubation period ranges from 1 to 10 days. [START_REF] Bertholet-Thomas | Syndrome hémolytique et urémique post-diarrhéique: Quand y penser? Quel suivi?[END_REF] After ingestion, bacteria colonize the host colon and adhere to the enterocyte brush border via the protein intimin, a virulence factor encoded by the eae gene. [START_REF] Orth | What makes an enterohemorrhagic Escherichia coli?[END_REF] Then the bacteria release toxins called Shigatoxins (Stx) or Verotoxin that cause damage to the intestinal wall, already harmed by Escherichia coli colonization.

The binding of Stx and the action of hemolysin, another virulence factor, lead to the synthesis by enterocytes of IL-8 and other proinflammatory cytokines, attracting neutrophils and macrophages into the infection site. These phenomena cause the bloody and profuse diarrhea characteristic of the pathology. [START_REF] Mariani-Kurkdjian | Syndrome hémolytique et urémique : aspects microbiologiques[END_REF] Stx is the key element in the pathophysiology with two main types of toxins: Stx1 and Stx2. Stx2 is 50 to 60% identical in sequence to Stx1. Stx1 has a greater affinity for its receptor but Stx2 is more often associated with the development of HUS. [START_REF] Liu | Shiga toxin (Stx) 1B and Stx 2B induce von Willebrand factor secretion from human umbilical vein endothelial cells through different signaling pathways[END_REF] They are composed of one A subunit with N-glycosidase activity and of five B subunits enabling them to bind to their receptors: Gb3 (globotriosyl ceramide).

After its release from the bacteria, Stx joins the general circulation. While the epithelium crossing mechanism is not yet fully understood, several hypotheses exist. Toxins could pass through spaces left by destroyed enterocytes or through intracellular junctions made permeable by the disorganization of the intestinal epithelium, or they could pass by translocation through intact enterocytes. [START_REF] Acheson | Translocation of shigatoxin across polarized intestinal cells in tissue culture[END_REF] The toxin has never yet been found circulating freely in the blood of patients with HUS. Either the amount of toxin freely circulating is too small to be detected by the usual techniques (which are not sensitive enough) [START_REF] Acheson | Translocation of shigatoxin across polarized intestinal cells in tissue culture[END_REF][START_REF] Macleod | Reproduction of edema disease of swine with purified Shiga-like toxin II variant[END_REF] or toxin circulation occurs via a transporter. This is the hypothesis most often put forward in the literature. However, there is still uncertainty as to the transporter: polymorphonuclear leukocytes, [START_REF] Brigotti | Interactions between Shiga toxins and human polymorphonuclear leukocytes[END_REF][START_REF] Exeni | Role of polymorphonuclear leukocytes in the pathophysiology of typical hemolitic uremic syndrome[END_REF][START_REF] Griener | Differential binding of Shiga toxin 2 to human and murine neutrophils[END_REF][START_REF] Loo | Binding and transfer of verocytotoxin by polymorphonuclear leukocytes in hemolytic uremic syndrome[END_REF] monocytes, [START_REF] Geelen | Interactions of shiga-like toxin with human peripheral blood monocytes[END_REF][START_REF] Van Setten | Effects of verocytotoxin on nonadherent human monocytes: binding characteristics, protein synthesis, and induction of cytokine release[END_REF] or platelets have been suggested. The toxin is supposed to be transported via its binding to a non-Gb3 receptor with a much lower affinity than that of Gb3 receptors, which explains why the toxin detaches from its transporter to join its target. [START_REF] Keir | Shigatoxin-associated hemolytic uremic syndrome: current molecular mechanisms and future therapies[END_REF] Stx target organs express Gb3 receptors, particularly kidney endothelial cells; brain, liver, heart, pancreas and hematopoietic cells are also involved.

Once an organ is reached, toxin binds to Gb3 via its pentameric B subunit. It is internalized by endocytosis and retrogradely transported to the endoplasmic reticulum where the A subunit is split into two parts A1 and A2. A1 inhibits protein synthesis via division of ribosomal ARN, which ultimately causes cell death by apoptosis. [START_REF] Keir | Shigatoxin-associated hemolytic uremic syndrome: current molecular mechanisms and future therapies[END_REF] The damage suffered by the renal endothelium exposes subendothelium along with its tissue factor and von Willebrand factor, respectively involved in coagulation and platelet aggregation. Thus, the key event is microthrombosis, responsible for the classic triad of HUS: platelet consumption, mechanical destruction of erythrocytes and acute renal insufficiency. [START_REF] Bertholet-Thomas | Syndrome hémolytique et urémique post-diarrhéique: Quand y penser? Quel suivi?[END_REF][START_REF] Keir | Shigatoxin-associated hemolytic uremic syndrome: current molecular mechanisms and future therapies[END_REF] Thrombosis and tissue damage are aggravated both by ischemia [START_REF] Loirat | Management of hemolytic uremic syndrome[END_REF] and by pro-inflammatory cytokines, from the injured endothelium, attracting neutrophils, monocytes and activated macrophages that in their turn release cytokines (NFB, TNF, Il-1, Il-6, Il-8, etc…).

Cytokines can also increase Gb3 expression on the surface of endothelial cells, selfperpetuating apoptosis. [START_REF] Keir | Shigatoxin-associated hemolytic uremic syndrome: current molecular mechanisms and future therapies[END_REF] P-selectin expression at platelet and endothelium surfaces increases, [START_REF] Ståhl | Shiga toxin and lipopolysaccharide induce platelet-leukocyte aggregates and tissue factor release, a thrombotic mechanism in hemolytic uremic syndrome[END_REF] binding in particular to neutrophils and thus favoring their extravasation toward the infection site, which causes tissue factor expression on cell surfaces. [START_REF] Ståhl | Shiga toxin and lipopolysaccharide induce platelet-leukocyte aggregates and tissue factor release, a thrombotic mechanism in hemolytic uremic syndrome[END_REF][START_REF] Mcgregor | Rôle de la sélectine P (CD62P) dans les interactions des cellules endothéliales et des plaquettes activées avec les leucocytes[END_REF] Thrombosis is also favored by B subunits via stimulation of the secretion of von Willebrand factor. [START_REF] Liu | Shiga toxin (Stx) 1B and Stx 2B induce von Willebrand factor secretion from human umbilical vein endothelial cells through different signaling pathways[END_REF] The rapid worsening of the disease appears not to be due solely to the direct action of toxins.

It has recently been suggested that the complement could play a role in the typical HUS physiopathology. Up to now, the complement had only been shown to affect familial or sporadic atypical HUS. However, patients with typical HUS were shown to have activation products of the alternative complement pathway and low concentrations of C3 in their plasma and serum. [START_REF] Orth | Complement in typical hemolitic uremic syndrome[END_REF] The presence of C3 on platelet/leukocyte complexes was also revealed.

During HUS, these complexes release microparticles covered with C3 and C9, indicating complement activation. [START_REF] Ståhl | Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coliinduced hemolytic uremic syndrome[END_REF] Previously, P-selectin expression was thought to increase during HUS, and P-selectin has been proved to be able to activate complement, as a fixation site for C3. [START_REF] Morigi | Alternative pathway activation of complement by Shigatoxin promotes exuberant C3a formation that triggers microvascular thrombosis[END_REF] The complement cascade induces formation of C3a and C5a, thereby increasing expression of P-selectin and decreasing synthesis of thrombomodulin, which favors clotting.

Anaphylatoxins C3a and C5a are also mediators of inflammation and activators of leukocytes and platelets. [START_REF] Orth | Shiga toxin activates complement and binds factor H: Evidence for an active role of complement in hemolytic uremic syndrome[END_REF] Kidney damage is linked to complement activation by Stx as well as to the negative control inhibition exercised on the complement cascade. The principal drivers of this regulation are factor I and its cofactor, factor H. Stx 2 binds to factor H, without destroying it, preventing it from binding to cell surfaces and playing its role. [START_REF] Orth | Shiga toxin activates complement and binds factor H: Evidence for an active role of complement in hemolytic uremic syndrome[END_REF] (fig. 1) Shigatoxin affects not only protein synthesis but also gene expression, leading most often to an up-regulation of transcripts by increasing their lifetime. Activation of the CXCR4/CXCR7/SDF-1 pathway could play a role in HUS. These results were observed in mice by RT-PCR and microarray analysis. A disorder of this pathway causes glomerulonephritis and hemostatic disorders in mice. The hypothesis that this pathway plays a role in the HUS pathophysiology is confirmed in animals, with a survival rate of 57.7% in mice treated by a CXCR4 inhibitor against 23.1% of mice without inhibitor treatment. Similar results were obtained humans with a four times higher rate of SDF-1 detected in children with typical HUS than in healthy children. [START_REF] Petruzziello-Pellegrini | The CXCR4/CXCR7/SDF-1 pathway contributes to the pathogenesis of shiga toxin-associated hemolytic uremic syndrome in human and mice[END_REF]

Treatments

There is no specific treatment for HUS, only symptomatic treatment to prevent complications from renal failure. [START_REF] Loirat | Management of hemolytic uremic syndrome[END_REF] 2.3.1. Currently approaches 2.3.1.1. Volume expansion.

Patients developing HUS frequently present a reduction of their plasmatic volume secondary to loss of fluids in the stool. Correction of hypovolemia is critical. A cohort study on 29 children < 10 years old with HUS suggests that early parenteral rehydration during E.coli O157:H7 infection could help to conserve diuresis, thereby improving renal prognostic, avoiding dialysis and long-term sequelae and shortening patients hospital stay. [START_REF] Ake | Relative nephroprotection during Escherichia coli O157:H7 infections: association with intravenous volume expansion[END_REF] In a study of 50 patients of whom 64% were anuric, 84% of those who did not receive parenteral rehydration developed anuria. Without volume expansion, the risk of developing anuric HUS is multiplied by 1.6 compared to the risk of developing anuric HUS with volume expansion. [START_REF] Hickey | Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome[END_REF] 2.3.1.2. Plasma therapy Plasma therapy is recommended in the treatment of TTP [START_REF] Georges | How I treat patients with thrombotic thrombocytopenic purpura: 2010[END_REF] and of atypical HUS. [START_REF] Waters | aHUS caused by complement dysregulation: new therapies on the horizon[END_REF][START_REF] Kim | Plasma therapy for atypical haemolytic uraemic syndrome associated with heterozygous factor H mutations[END_REF] However plasma therapy has not been shown to be effective in treating typical HUS. Plasma therapy is not indicated in HUS associated with streptococcus pneumoniae infection.

Antibiotics

Antibiotherapy during Enterohaemorrhagic Escherichia coli (EHEC) infections is not recommended. The stress caused by the treatment may increase the synthesis and liberation of toxins by bacteria and could therefore lead to higher risk of developing HUS.

A study conducted on 259 patients infected by Escherichia coli O157:H7 found that 36% of children who received antibiotics (all type of antibiotics) developed HUS, versus 12% of children no receiving antibiotics (p<0,001). [START_REF] Wong | Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157[END_REF] In vitro studies of the O157:H7 strain showed that subinhibitory levels of antibiotics targeting DNA synthesis (ciprofloxacin…) lead to increased production of toxins, whereas antibiotics targeting the membrane, transcription or translation do not affect the synthesis of toxins in any way. [START_REF] Mcgannon | Different classes of antibiotics differentially influence Shiga toxin production[END_REF] The O104:H4 strain does not appear to release Stx in the presence of therapeutic concentrations of ciprofloxacin, meropenem, fosfomycin and chloramphenicol. [START_REF] Corogeanu | Therapeutic concentrations of antibiotics inhibit Shiga toxin release from enterohemorrhagic E. coli O104:H4 from the 2011 German outbreak[END_REF] Moreover, treatment by azythromycin during the German outbreak of Escherichia coli O104:H4 (dispensed to prevent meningitis during the eculizumab trial) decreased the length of time bacteria were carried: 4.5% carried long-term in the azithromycin arm versus 81.4% in the arm without antibiotics (p<0,001). However, the frequency of HUS and of its symptoms were not decreased; patients were simply contagious for a shorter period, and could return to normal professional and social activity more quickly. [START_REF] Nitschke | Association between azithromycine therapy and duration of bacterial shedding among patients with Shiga toxin-producing enteroaggregative Escherichia coli O104 : H4[END_REF] Antibiotics could have a beneficial effect if the bacterial strain is quickly identified. Randomized trials will be essential to determine whether antibiotics offer promise for the treatment and prevention of HUS. Until such studies are realized, antibiotherapy is not recommended.

Others treatments

Supportive care also includes anemia management by transfusion or by erythropoietin to reduce blood transfusion.

Treatments by antithrombotic drugs, diuretics and anti-inflammatory drugs have not proved efficacy and are not recommended. [START_REF] Loirat | Management of hemolytic uremic syndrome[END_REF] 2.3.2. Potential future approaches.

VEGF (vascular endothelial growth factor)

Anti-VEGFs are antiangiogenic agents used in the treatment of some cancers. Unexpected side effects can occurr, especially for bevacizumab for which thrombotic microangiopathy is reported. [START_REF] Eremina | VEGF inhibition and renal trombotic microangiopathy[END_REF] The comparison with HUS is made by some researchers, who demonstrated that VEGF is synthesised by renal podocytes and that injection of Stx may inhibit this synthesis causing microangiopathy in mice. [START_REF] Psotka | Shiga toxin 2 targets the murine renal collecting duct epithelium[END_REF] This discovery concerning the mechanism of action of toxins opens new research perspectives for the treatment of HUS.

Shigatoxin receptor analogues

To the best of current knowledge, Stx appears to be the key element in the physiopathology of HUS.

Research could usefully begin with oral administration of toxin receptors to block Stx before it enters the general circulation. In this context, trisaccharides linked to an inert polymer matrix were developed in Canada as Synsorb Pk®. This resin acts as a toxin binder before toxin fixation to enterocytes. The phase I study showed an absence of side effects in healthy adults and the conservation of the resin's binding activity even after exposure to the extreme pH of the gastrointestinal tract. [START_REF] Armstrong | A phase I study of chemically synthesized verotoxin (Shiga-like toxin) Pk-trisaccharide receptors attached to chromosorb for preventing hemolytic-uremic syndrome[END_REF] Phase II studies were unfortunately less promising. In the experimental and placebo groups respectively, the prevalence of serious extrarenal events was 18% versus 20% (p = 0.82) and dialysis was required in 42% against 39% of cases (p = 0.86).

The trial failed to demonstrate reduced severity of the disease in children treated by Synsorb Pk®. [START_REF] Trachtman | Effect of an oral shiga toxin binding agent on diarrhea associated hemolytic uremic syndrome in children: a randomized controlled trial[END_REF] Treatments may have started too late; some authors put forward the hypothesis that such oral treatments will only be effective if administered during incubation or during the appearance of symptoms and up to 2 or 3 days after the onset of diarrhea. [START_REF] Karmali | Prospects for preventing serious systemic toxemic complications of Shiga toxin-producing Escherichia coli infections using Shiga toxin receptor analogues[END_REF] A tetravalent peptide (PPP-tet) having a great affinity (Kd = 0.13 µM) for B subunits of Stx 2 was recently designed. The binding of the toxin to the peptide does not block its internalization by the cell, but causes an aberrant retrograde transport. The transport is normal up to the Golgi and then the toxin is redirected to an acid compartment, where it will be destroyed instead of proceeding to the endoplasmic reticulum. The molecule is acetylated to prevent its degradation by gastrointestinal proteolysis. After this transformation, the peptide retains its efficacy in terms of mice survival even after that infection becomes established (p < 0.005). [START_REF] Nishikawa | A multivalent peptide library approach identifies a novel Shiga toxin inhibitor that induces aberrant cellular transport of the toxin[END_REF] Another therapeutic hypothesis is using parenteral administration to block the effects of the toxin after it penetrates the systemic circulation. Remarkably, when administered intravenously, PPP-tet protected mice from HUS (p<0.0001). [START_REF] Nishikawa | A multivalent peptide library approach identifies a novel Shiga toxin inhibitor that induces aberrant cellular transport of the toxin[END_REF] Another study used the same molecule intravenously in baboons, with similar results to those in mice: 100% survival not only after concomitant injection of peptide and toxins (p<0.01) but also when the peptide was administered 6 hours after the toxins (p<0.01). The survival rate for an injection of the peptide 24 hours after the infection was 3 monkeys out of 4 (p<0.03), suggesting the possibility of long-term benefit. [START_REF] Stearns-Kurosawa | Rescue from lethal Shiga toxin 2-induced renal failure with a cell-permeable peptide[END_REF] Other Shigatoxin receptor analogues have been designed, such as "Starfish", which was able to protect mice from Stx 1 but not from Stx 2 and its modified version "Daisy", which was able to protect them from both toxins. [START_REF] Mulvey | Assessment in mice of the therapeutic potential of tailored, multivalent Shiga toxin carbohydrate ligands[END_REF] 2.3.2.3. Anti-shigatoxin antibody.

Circulating toxins may be neutralized by antibodies directed against them, and this appears a promising avenue to explore: various monoclonal antibodies tested first on mice and then on pigs permitted the survival of 90% of the animals. [START_REF] Mukherjee | Human Stx2-specific monoclonal antibodies prevent systemic complications of Escherichia coli O157:H7 infection[END_REF] The most advanced example is urtoxazumab, currently in phase III. The molecule demonstrated great efficacy in mice (100% survival with the effective dose) only when it was administered at maximum 24 hours after the beginning of the infection. [START_REF] Yamagami | Efficacy of postinfection treatment with anti-Shiga toxin (Stx) 2 humanized monoclonal antibody TMA-15 in mice lethally challenged with Stx-producing Escherichia coli[END_REF] In phase I in healthy adults and infected children, urtoxazumab was well tolerated. [START_REF] Lopez | Safety and pharmacokinetics of Urtoxazumab, a humanized monoclonal antibody, against Shiga-like toxin 2 in healthy adults and in pediatric patients infected with Shigalike toxin-producing Escherichia coli[END_REF] Other antibodies in phase I were also well tolerated by healthy volunteers [START_REF] Dowling | Phase 1 safety and pharmacokinetic study of chimeric murine-human monoclonal antibody cαStx2 administered intravenously to healthy adult volunteers[END_REF][START_REF] Bitzan | Safety and pharmacokinetic of chimeric anti shiga toxin 1 and anti shiga toxin 2 monoclonal antibodies in healthy volunteers[END_REF]. The phase III results will tell whether or no these antibodies have a place in the therapeutic arsenal against HUS. 2.3.2.4. Eculizumab: complement inhibitor.

The role of the alternative complement pathway during typical HUS was introduced by experimental data, and it has been suggested as a way to evaluate eculizumab, an anti-C5 monoclonal antibody. A study involving 3 children with poor prognosis was conducted.

Improved clinical outcomes 24h after the first injection were observed and patients recovered normal renal function after 6 months of treatment. No mutation of genes involved in the alternative complement pathway was observed, which rules out the differential diagnosis of atypical HUS. [START_REF] Lapeyraque | Eculizumab in severe Shiga-toxin-associated HUS[END_REF] These case-reports provide new and encouraging possibilities for the treatment of typical HUS.

However, the findings should be compared to other studies. A comparison of conventional treatment with plasma therapy accompanied or not by eculizumab during the German outbreak did not show greater efficacy for eculizumab. Blocking the complement pathway active in the digestive system could even increase bacterial carrying time and contact with toxins. [START_REF] Kielstein | Best supportive care and therapeutic plasma exchange with or without Eculizumab in Shigatoxin-producing E. coli O104:H4 induced haemolytic-uraemic syndrome: an analysis of the German STEC-HUS registry[END_REF] In contrast, during the French epidemic, eculizumab was used on 9 patients with extra-renal complications. Improvement of renal and neurological function as well as biochemical parameters was obtained in all patients. Even so, it was not a comparative and randomized trial and the authors were unable to conclude on the benefit of using eculizumab to treat typical HUS. [START_REF] Delmas | Outbreak of Escherichia coli O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab[END_REF] Additional randomized trials are needed to determine the efficacy, the targeted population, the duration and the best time to start treatment by eculizumab. It would also be interesting to determine how the treatment affects the length of time that Escherichia coli is carried.

Recombinant thrombomodulin

Thrombomodulin (TM) has an anticoagulant effect, an anti-inflammatory effect and the capacity to supress complement activity. Recombinant TM is currently validated to treat disseminated intravascular coagulation.

Recombinant TM appears effective in typical HUS as an anticoagulant and an antiinflammatory. TM was tested at the posology of 380 U/kg per day in 3 young patients.

Symptoms improved after treatment began, with increased haemoglobin and platelets and decreased creatinine, LDH level and complement activity. [START_REF] Honda | A novel strategy for hemolytic uremic syndrome: successful treatment with thrombomodulin α[END_REF] The effects of TM were confirmed in another similar study. [START_REF] Kawasaki Y | Efficacy of recombinant human soluble thrombomodulin for childhood hemolytic uremic syndrome[END_REF] 2.3.2.6. Manganese MnCl 2 manganese salt was reported to block the intracellular trafficking of Stx1 of HeLa cells, apparently inhibiting the toxic effects of Stx1. [START_REF] Mukhopadhyay | Manganese blocks intracellular trafficking of Shiga toxin and protects against Shiga toxicosis[END_REF] However, manganese did not affect nor the trafficking nor the toxic effects for Stx2, probably because of divergence in toxin trafficking mechanisms. [START_REF] Gaston | Failure of manganese to protect from Shiga toxin[END_REF][START_REF] Mukhopadhyay | Shiga toxin-binding site for host cell receptor GPP130 reveals unexpected divergence in toxin-trafficking mechanisms[END_REF][START_REF] Tewari | Manganese induces oligomerization to promote down-regulation of the intracellular trafficking receptor used by Shiga toxin[END_REF] Despite these results, manganese could be a promising therapy for Stx1-induced HUS. Its toxicity needs to be carefully evaluated, [START_REF] Gaston | Failure of manganese to protect from Shiga toxin[END_REF] even if only brief manganese exposures are required. [START_REF] Mukhopadhyay | Shiga toxin-binding site for host cell receptor GPP130 reveals unexpected divergence in toxin-trafficking mechanisms[END_REF]

Atypical hemolytic and uremic syndrome

Atypical HUS is mainly caused by a dysregulation of the alternative complement pathway.

3.1. The complement system.

The complement system is essential to innate immunity. There are 3 different pathways activating the complement cascade: the classical, lectin and alternative pathways.

In healthy patients, the alternative pathway involves low quantities of C3 being cleaved into

C3a and C3b, indicating permanent activation of the system. However, it is finely restrained by negative feedback to prevent its attacking host tissues.

During HUS, the alternative pathway gets out of control leading to the formation of the Membrane Attack Complex (MAC) and various anaphylatoxins responsible for the endothelial damage, platelet activation, inflammatory reaction, thrombus, [START_REF] Nester | Atypical hemolytic uremic syndrome: what is it, how is it diagnosed, and how is it treated?[END_REF] thrombocytopenia, anemia and renal insufficiency characteristic of the pathology.

After the cleavage of C3, C3b binds to factor B, which is then cleaved by factor D to Bb. The C3Bb complex also known as C3 convertase is formed, creates an amplification loop and generates more C3b. New C3b fragments bind to the C3 convertase, forming C5 convertase.

Then, C5 is cleaved into C5a (inflammatory particle) and C5b. C5b finally binds with C6, C7,

C8, and C9 to form the MAC. (fig 2.)

This cascade is regulated by several proteins, such as Factor I and its co-factor, factor H, thrombomodulin and the Membrane Cofactor Protein (MCP).

Epidemiology.

Atypical HUS accounts for 5 to 10% of HUS in children and the majority of HUS in adults. [START_REF] Loirat | Atypical hemolytic uremic syndrome[END_REF] The total incidence remains unknown, and has been estimated at 2 cases out of 1.000.000 in the USA. [START_REF] Maga | Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome[END_REF] Extra-renal symptoms occur in 20% of patients. The estimated mortality rate is from 2 to 10%, a third of patients suffering from end-stage renal failure after the first episode. At least one mutation in the complement system (factor H (CFH), MCP, factor I (CFI), thrombomodulin (TM), C3 convertase and factor B (CFB)) is documented in 70% of pediatric or adult patients. [START_REF] Salvadori | Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations[END_REF] These mutations are most frequently heterozygous and hypomorphic [START_REF] Caprioli | Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome[END_REF] One third of patients did not develop the disease until adulthood, and HUS onset is associated with an infectious event in all MCP-mutated, 70% of CFH-mutated, and 60% of CFI-mutated patients. These observations suggest that mutations should confer a predisposition to develop HUS, and that onset of the disease should be correlated to complement activation caused by infectious event or endothelial insult.

Genetic rearrangements between factor H and CFH-related proteins (CFHR1 and CFHR3)

were also identified in several aHUS patients, resulting in a hybrid gene factor H/CFHR1 or factor H/CFHR3. [START_REF] Skerka | Complement factor H related proteins (CFHRs)[END_REF] In the addition to the influence of these mutations, patients who do not carry CFH mutations can be predisposed to HUS by common polymorphic variants of CFH gene. Moreover, polymorphism may also help the full manifestation of the disease for patients with CFH mutations. [START_REF] Caprioli | Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease[END_REF] Anti-factor H antibodies were also found in several patients (tab.1) [START_REF] Loirat | Atypical hemolytic uremic syndrome[END_REF] and are often associated with the homozygous deletion of genes coding for CFHR1/CFHR3. [START_REF] Skerka | Complement factor H related proteins (CFHRs)[END_REF] Recently DGKE mutation was described in aHUS. DGKE is involved in the control of haemostasis [START_REF] Lemaire | Recessive mutations in DGKE cause atypical haemolytic-uremic syndrome[END_REF] and its link with the identification of mutation in thrombomodulin highlights the role of the coagulation cascade in the pathophysiology of aHUS. Patients with DGKE mutation have a better prognosis, while factor H mutations lead to the worst prognosis, with 60 to 70% of aHUS patients dying or suffering end-stage renal disease. Familial aHUS form were identified in 20% of cases but genetic counselling is difficult because the penetrance of the disease is estimated at 50%. [START_REF] Loirat | Atypical hemolytic uremic syndrome[END_REF] Secondary atypical HUS is defined when a causative agent can be identified. Among infective agents, HIV has been frequently reported. Other causes identified for secondary HUS are connective tissues diseases, pregnancy and post-transplantation. [START_REF] Loirat | Atypical hemolytic uremic syndrome[END_REF] Many different drugs were also reported to induce syndromes of thrombotic microangiopathy (TMA). According to the level of kidney injury, these reports were described as HUS or thrombotic thrombocytopenic purpura (TTP). Level of evidence for these drug-induced HUS borderline syndromes pointed out 22 drugs with a definite association with TMA. [START_REF] Zl | Drug-induced thrombotic microangiopathy: a systematic review of published reports[END_REF] Quinine, cyclosporine and tacrolimus were most reported. Interferons  and , sirolimus and anticancer agents as mitomycin, gemcitabine, bevacizumab were also frequently implied.

Treatment

Plasma therapy

Plasma therapy is the first-line treatment for atypical HUS in adults. [START_REF] Loirat | Plasmatherapy in atypical hemolytic and uremic syndrome[END_REF] Its clinical use is based on empirical data and expert recommendations; to date there are no clinical trials. Its efficacy was observed in several cases. [START_REF] Waters | aHUS caused by complement dysregulation: new therapies on the horizon[END_REF][START_REF] Kim | Plasma therapy for atypical haemolytic uraemic syndrome associated with heterozygous factor H mutations[END_REF][START_REF] Lapeyraque | Efficacy of plasma therapy in atypical hemolytic uremic syndrome with complement factor H mutations[END_REF] The aim of plasma therapy is to replace mutant elements of the complement by normal elements in order to eliminate proinflammatory and thrombogenic factors responsible for symptoms. [START_REF] Loirat | Management of hemolytic uremic syndrome[END_REF] It is considered that injections of fresh frozen plasma alone are sufficient in case of quantitative deficits, while plasma exchange is more indicated in cases of qualitative deficits. [START_REF] Loirat | Plasmatherapy in atypical hemolytic and uremic syndrome[END_REF] All complement mutations seem to react positively to plasma therapy except for MCP mutation, because MCP is not a circulating protein. [START_REF] Loirat | Plasmatherapy in atypical hemolytic and uremic syndrome[END_REF][START_REF] Loirat | Complement and the atypical hemolytic uremic syndrome in children[END_REF] Recent European guidelines recommend starting plasma therapy as soon as possible, in parallel with symptomatic treatments (dialysis, transfusion, antihypertensive treatment…). Plasma therapy sessions should initially be administered at a rate of one per day, then progressively spaced out from 5 to 3 sessions per week. [START_REF] Loirat | Complement and the atypical hemolytic uremic syndrome in children[END_REF] Longterm treatment seems to be more effective than discontinuous treatment in preventing progression toward end-stage renal disease. [START_REF] Loirat | Plasmatherapy in atypical hemolytic and uremic syndrome[END_REF] The long-term outcomes for this treatment are still little known. [START_REF] Lapeyraque | Efficacy of plasma therapy in atypical hemolytic uremic syndrome with complement factor H mutations[END_REF] A case of therapeutic failure was reported after 4 years of treatment, with no cause of plasma resistance determined. [START_REF] Nathanson | Secondary failure of plasma therapy in factor H deficiency[END_REF] During treatment, even short term, potentially serious side effects can occur. However, side effects are more frequent in children than in adults, which justifies the management of young patients in specialized units. Main side effects are hypotension that may require a fluid bolus, symptomatic hypocalcemia, allergy and thrombosis or infection of the catheter. [START_REF] Michon | Complication of apheresis in children[END_REF] 3.3.2. Complement inhibitor: eculizumab.

In the mouse, C5 was found to be essential to the development of HUS. This led to the demonstration of the potential of eculizumab to treat atypical HUS. [START_REF] De | The development of atypical hemolytic uremic syndrome depends on complement C5[END_REF] Eculizumab was first used for the treatment of paroxysmal nocturnal hemoglobinuria, another disease involving the alternative complement pathway. French marketing authorization AMM for use in atypical HUS was obtained in 2011, based on two non comparative trials.

In these two studies, patients received eculizumab for 26 weeks. The first study included 20 patients sensitive to plasma therapy and the second included 17 patients with plasma therapy resistance. Both showed an amelioration of hematologic parameters and an absence of thrombotic microangiopathy. All secondary end-points were also improved, and in particular, early use of eculizumab was shown to be associated with a greater increase in glomerular filtration rate (GFR). It should be notified that patients without identified complement mutations were also successfully treated by eculizumab therapy. [START_REF] Legendre | Terminal complement inhibitor eculizumab in atypical haemolytic-uremic syndrome[END_REF] Eculizumab is being proposed as a first-line treatment [START_REF] Legendre | Terminal complement inhibitor eculizumab in atypical haemolytic-uremic syndrome[END_REF] and an algorithm of therapeutic options indicates that eculizumab could become the new gold-standard of atypical HUS management, replacing plasma therapy. [START_REF] Zuber | French Study Group for aHUS/C3G. Use of Eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies[END_REF] Given the cost of the treatment, however, this must be clearly determined by a cost/efficiency analysis.

A more recent publication [START_REF] Maga | Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome[END_REF] recommends eculizumab for children where plasma therapy is not possible. It is also considered an effective treatment of the prophylaxis of atypical HUS recurrence after transplantation. [START_REF] Maga | Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome[END_REF][START_REF] Ranch | Prophylactic eculizumab for kidney transplantation in a child with atypical hemolytic uremic syndrome due to complement factor H mutation[END_REF][START_REF] Matar | Atypical hemolytic uremic syndrome recurrence after kidney transplantation[END_REF] Nevertheless, treatment parameters remain to be determined, particularly optimal treatment duration, on which there is no consensus and which needs to be clarified.

It should be noted that the recently described DGKE mutation has no incidence on the complement cascade, so eculizumab may have no benefit for newborn patients with this type of mutation. [START_REF] Lemaire | Recessive mutations in DGKE cause atypical haemolytic-uremic syndrome[END_REF].

Specific treatment of patients with anti-factor H antibodies

Atypical HUS secondary to anti-CFH antibodies has a poor prognosis. Anti-CFH antibodies are found in 6 to 10 % of patients with aHUS. The frequency is higher in children than in adults.

Contrary to the other anomalies, which appear in children under 2 years of age, patients with anti-CFH antibodies are older than 5. This abnormality is also characterized by severe hemolysis, renal failure and high frequency of extra-renal manifestations including hepatic and neurological failure.

Treatment recommendations are [START_REF] Loirat | Anti-factor H autoantibody-associated hemolytic uremic syndrome: the earlier diagnosed and treated, the better[END_REF][START_REF] Sinha | Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children[END_REF][START_REF] Khandelwal | Effect of plasma exchange and immunosuppressive medications on antibody titers and outcome in anti-complement factor H antibody-associated haemolytic uremic syndrome[END_REF] to rapidly start plasma exchanges coupled with prednisone and IV cyclophosphamide or rituximab until the rate of anti-CFH antibodies decreases and then continue with maintenance treatment with prednisone and mycophenolate mofetil. Efficacy/tolerance comparisons were rarely reported for cyclophosphamide or rituximab therapy in anti-CFH HUS. One case report suggested efficacy of cyclophosphamide in relapse following rituximab therapy, [START_REF] Boyer | Pulse cyclophosphamide therapy and clinical remission in atypical haemolytic uremic syndrome with anti-complement factor H autoantibodies[END_REF] but a non-randomized retrospective study including 45 patients showed similar outcomes for the two therapies. [START_REF] Khandelwal | Effect of plasma exchange and immunosuppressive medications on antibody titers and outcome in anti-complement factor H antibody-associated haemolytic uremic syndrome[END_REF] Eculizumab too can be used in cases of extra-renal symptoms, reducing the risk of relapse from 21 to 8% at 1 year. [START_REF] Loirat | Anti-factor H autoantibody-associated hemolytic uremic syndrome: the earlier diagnosed and treated, the better[END_REF] Because of the poor prognosis and the existence of an effective specific treatment, it is important to look for antibodies quickly after symptoms appear. Early treatment is associated with a better prognosis.

Transplantation.

In patients with stage 5 chronic kidney disease, the possibility of renal transplantation must be considered. However, because of the high rate of recurrence, the genetic profile must be explored in depth. For mutations of factor H, I and C3, risk of disease recurrence and of graft rejection are respectively 75 to 90%, 45 to 80% and 40 to 70%; consequently, transplantation is not recommended for carriers of these mutations [START_REF] Salvadori | Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations[END_REF]. For the MCP mutation, the prognosis for transplant conservation is much better with a lower than 20% risk of relapse. [START_REF] Loirat | Management of hemolytic uremic syndrome[END_REF] For patients with anti-factor H antibodies, the risk of relapse is lower if the antibody level is maintained low after the transplantation by immunosuppressant treatment. Transplanting these patients is difficult because of their multiple transfusions. [START_REF] Loirat | Complement and the atypical hemolytic uremic syndrome in children[END_REF] Calcineurin inhibitors are considered as the best immunosuppressant currently available. Preventive plasma therapy is also recommended to avoid HUS recurrence after transplantation. [START_REF] Salvadori | Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations[END_REF] Living-related kidney donation is not recommended because of the high probability of graft loss. The donor has also a risk to develop the disease because of the probability of carrying the same mutation as the recipient. [START_REF] Loirat | Complement and the atypical hemolytic uremic syndrome in children[END_REF][START_REF] Taylor | Clinical Practice Guidelines for the management of atypical Haemolytic Uraemic Syndrome in the United Kingdom[END_REF] To avoid relapse after the transplantation, combined liver and kidney transplantation has been proposed. Factors H, I, B as well as C3 are synthesized by the liver, so, the graft would allow the synthesis of normal factors, thus correcting complement anomalies and preventing relapses. [START_REF] Saland | Liver-kidney transplantation to cure atypical hemolytic uremic syndrome[END_REF] The first attempts, despite improving renal function, led to patients deaths from hepatic graft failure. [START_REF] Cheong | Attempted treatment of factor H deficiency by liver transplantation[END_REF][START_REF] Remuzzi | Hemolytic uremic syndrome: a fatal outcome after kidney and liver transplantation performed to correct factor H gene mutation[END_REF] It was suspected that the stress caused by the ischemia then the reperfusion of the liver led to major activation of the complement, which could not be regulated and which caused hepatic microthrombosis. [START_REF] Koskinen | Complement activation during liver transplantation -Special emphasis on patients with atypical hemolytic uremic syndrome[END_REF] Intensive preoperative plasma exchange and transfusion of fresh frozen plasma during the operation, in order to supply a maximum of functional factors and to limit attacks by the complement on the transplant liver until it could synthesize non-mutated factors, [START_REF] Saland | Liver-kidney transplantation to cure atypical hemolytic uremic syndrome[END_REF] was proposed with success. [START_REF] Wilson | Successful simultaneous liver-kidney transplant in an adult with atypical hemolytic uremic syndrome associated with a mutation in complement factor H[END_REF][START_REF] Saland | Successful split liver-kidney transplant for factor H associated hemolytic uremic syndrome[END_REF][START_REF] Jalanko | Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H[END_REF] The pre-transplantation use of eculizumab appears promising, [START_REF] Forbes | Changing strategies for organ transplantation in atypical haemolytic uraemic syndrome: a tertiary case series[END_REF] encouraging results have already been obtained in preventing relapse in cases of isolated renal transplantation. [START_REF] Nester | Pre-emptive Eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome[END_REF][START_REF] Weitz | Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome[END_REF] These successful uses of combined liver-kidney transplantation raise new questions. For example, in cases of HUS where the kidney is not yet altered, why not carry out an isolated liver transplantation to protect the kidney from relapses? This was attempted successfully in a five-year-old child for whom renal and hepatic function as well as remission were maintained at least 2 years. [START_REF] Haller | Successful isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in complement factor H[END_REF] However, there is not yet enough evidence to understand the long-term evolution of the kidney after an isolated liver transplantation. Furthermore, the benefit/risk balance needs to be carefully considered by clinicians, especially in the light of the encouraging results with eculizumab.

3.3.5. Future therapies New treatment, for example other anti-C5 antibodies which could be absorbed per os and are less immunogenic than eculizumab, are in phases I or II of clinical trials. Anti-C3 antibodies are also currently under investigation. [START_REF] Salvadori | Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations[END_REF] Infusion of recombinant complement regulatory proteins could be an interesting treatment. aHUS caused by an alteration of factor H could be treated by administering purified factor H, a less expensive technique than plasma exchanges. It would also avoid the use of central venous lines, a gateway for infections. The process of purification using human plasma has been developed and is compatible with industrial production, but no clinical trials have yet been conducted. [START_REF] Brandstätter | Purification[END_REF]

Conclusion

This is renewed interest in HUS as a result of the German outbreak and the extension of the AMM for eculizumab in 2011.

The discovery of the role of the complement in typical HUS opens new treatment perspectives. However, the very complex pathophysiology of typical HUS remains unclear. The efficacy of the complement inhibitor, Stx receptor analogues and anti-toxin antibodies should be evaluated to determine their place in the therapeutic arsenal.

Table 1:

Mutation type Frequency

For

  atypical HUS, eculizumab appears the best candidate for treatment of reference, both preventive and curative, for kidney failure. Nevertheless, clinical studies on new potential treatments such as purified factor H or isolated liver transplantation are needed. Isolated liver and biochemical characterization of functional complement factor H from human plasma fractions. Vox Sang 2012; 103(3): 201-12.

Figure 1 :

 1 Figure 1: Main stages in the pathophysiology of HUS.

Figure 2 :

 2 Figure 2: Alternative complement pathway

transplantation, though a very risky procedure in the short term, could be a the treatment of choise for increased quality of life and decreased cost of care in the long-term.

Conflict of interet : none.