KIDNEY FOUNDATION FOR CHILDREN
SAVING YOUNG LIVES
Aypical Hemolytic Syndrome continues to be a disease in evolution .It is caused by complement dysregulation- leading to complement induced endothelial damage..Hereditary or acquireed deficiencies of alternalte complement pathway proteins have been implicated as also the presence of anti complement factor H antibodies.(anti CHF abs).Anti CHF ab are held responsible for 10% of aHUS in European Children..The present study brings to attention that antiCFH ab account for 56% of all aHUS in Indian children.This has major implications for therapy and outome.
Data from India published as original article in clinical Investtigation in Kidney Internationa
;earns an exhaustive commentary in the same issue.
Prompt plasma exchange and immunosuppressive treatment improves the outcome of anti factor H autoantibody associated hemolytic uremic syndrome in children.
Kidney Int 2014 (85) 1151-1160 Aditi Sinha,Ashima Gulati,Savita Saini, Caroline Blanc,Arti Gupta,,Bahadur Singh Gurjar,,Himanshu Saini Shambuprasad T Kottresh, Uma Ali, Divya Bhatia, Alpana Ohri,Manish Kumar,Indira Agarwal,,Snajeev Gulati, Kanav Anand, M Vijaykumar, Rajiv Sinha,SIddharth Sethi,Maud Salmona,Anna George,Vineeta Bal, Geetika Singh,Amit K Dinda, Pankaj Hari,,Satyajit Rath,,Marie-Agnes-Dragon-Durey and Arvind Bagga for the Indian HUS registry
This study describes the clinical features,therapies and outcome in patients with HUS from 26 centres in India..Of the 246 children with HUS, 138 (56.1%) were found to have anti CHF ab..This percentage is much higher than in patient cohorts described earlier from Europe..(5 - 25%)..The fact that the study population included 109 patients from one centre (AIIMS) that also showed a similar proportion of antibodies suggest a truly increased prevalence of the condition in Indian children rather than just a selection bias.Consistent with literature the investigators found that 88.2% of patients with anti CFH antibodies had homozygous deletions in CFHR1 gene.The CHFR gene deletion in healthy controls was 9.5% as reported in Europe, the high prevalence of antibody associated HUS in Indian Children was attributed to additional genetic factors or environmental influences in the pathogenesis.
The findings of the study support the early initiation of treatment.Delayed initiation of plasma exchanges 2-3 weeks after onset predicted adverse outcomes.Using risk estimates the authors demonstartae that 1 adverse outcome was prevented for approximately 3 patients receiving combined plasma exchange and immunesuppresssion. Predictors of adverse outcome were anti CFH antibodiy titres > 48000 AU/ml and low C3 during the acute phase..Maintenance treatment with prednisolone and mycophenolate mofetil or azathioprine significantly reduced the risk of relapse.
The commentary concludes with an emphatic recommendation that where economics permit rapid anti CFH antibody assays should be available for patients with aHUS so as to allow early initiation of treatment and to guide therapy
Loirat C, Fremeaux Bacchi V. Anti factor H autoantibody associated hemolytic uremic syndrome- the earlier diagnosed and treated the better.Kidney Int 2014 (85); 1019-1022
Current pediatric nephrology literature is inundated with articles reflecting experiencce with use of CD20 monoclonal antibody Rituximab(RTX) in the treatment of nephrotic syndrome (NS) As with all emerging therapies since its introduction in 2004 results of prospective studies are rapidly adding information to the cluster of case reports from various parts of the world..There are 2 consecutive review articles in the journal of pediatric nephrology.RTX has proved useful in children with SDNS..In steroid resistant nephrotic syndrome (SRNS), it can be used as combination therapy.It is not clear whether these children achieve long term remission or become RTX dependent or there are some in both categories. Interestingly some patients with SRNS become sensitive to high doses of steroid if relapses occur after RTX treatment..RTX also has a role in preventing graft loss in cases where FSGS recurs post transplant. by inducing complete or partial remission.in recurrrent FSGS.Adverse reactions during RTX infusions including Acute Lung Injury and in the long term progressive mutifocal leucoencephalopathy has been reported after RTX therapy..In India RTX therapy will have two additional implications.1) Cost of therapy. 2) Increased risk of infections
A Decade Later
I s there a ray of hope for some children with Nephrotic Syndrome.
Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid resistant nephrotic syndrome
. Kamei K Okoda M, Sato M, Fujimaru T, Ogura M, Nakayama M, Kaito H, Iijima K,,Ito S. Pediatr Nephrol 2014 :29: 1181 -1187-
Based on the surmise that RTX may weaken disease activity and patients with SRNS may acquire improved sensitivity to conventional treatments such as Methyl prednisolone (MPT) Kamei et al admiministered RTX to 10 patients with calcineurin and MPT resistant NS. RTX was followed by MPT for 3 consecutive days once every 2 to 4 weeks,until complete remission (CR)...Seven patients (70%) achieved CR,1 achieved partial remissio and two showed no response..RTX was infused atotal of 27 times..Infusion reactions were observed 11 times (41%); 2 patients showed late onset adverse events;agranulocytosis in 1 with upper respiratory tract infection and severe pneumonia requiring mechanical ventilation in another..The authors conclude that RTX combined with MPT is an option for overcoming refractory SRNS.
Other recent articles of interest
1. Is Rituximab effective in childhood nephrotic syndrome ? Yes and No.Markus J, Kemper & Anja Lehnhardt, Anna Zavischa,Jun Oh; Pediatr Nephrol (2014) 29: 1305-1311
2 Rituximab in nephrotic syndrome-does it make sense? Gabriel Cara-Fuentes G,John A Kairalla, Takuji Ishimoto, Christopher Rivard, Richard J Johnson, Eduardo H Garin.Pediatr Nephrol (2014) 29 : 1313 -1319
3. Retreatment with high dose prednisolone after Rituximab infusion for childhood onset steroid -resistant nephrotic syndrome.Fujinaga S, Hara T. Pediatr Nephrol (2014) 29:1291-1292
4 Impact of Rituximab on height and weight in children with refractory steroid resistant nephrotic syndrome. Sato M, Ito S, Ogura M,Kamei K . Pediatr Nephrol (2014) 29 : 1373- 1379.
5 .Efficacy of Rituximab in children with refractory steroid resistant nephrotic syndrome.A prospective observational study in Shanghai..Li Sun,Hong Xu, Qian Shen, Qi Cao, Jia Rao, Hai- Mei Liu, Xiao -Yan Fang,Li-Jun Zhao. World J Pediatrics (2014) 10 (1): 59- 63
Two reviews (1,2) compile data from studies that have used RTX in children with SDNS, SRNS and have explored the possible mechanism of action ie.role of B cells on T cell activation and regulation and the cross reactivity of RTX with sphingomyelin phosphodiesterase acid - like 3b (SMPDL-3b) protein. RTX preserves the podocyte sphingolipid related enzymes and thereby prevents actin cytoskelton remodelling in these cells and subsequent proteinuria.
Always in the news!
Identification of children and adolescents at risk for renal scarring after a first urinary tract infection;A metanalysis with individual data
Nader Sheikh MD, MPH, Jonathan C Craig MD MBChB PhD, Maroeska M Rovers PhD, Liviana Da Dalt MD,Stefanos Gardikis MD, Alejandros Hoberman MD,Giovanni Montini MD,Carlos Rodrigo MD,Seppo Taskinen MD,David Tuerlinx MD,Timothy Shoppe MD,MPH JAMA Pediatr 2014 ; 168 (10) 893-900
The recurrent theme with respect to UTI remains unchanged.The continuing search for features of early identification of children with UTI who are at high risk for scarring and its consequences emphasizes its its importance as a preventable cause of CKD in children.
The authors performed an individual patient data metanalysis of 1280 children with first UTI from 8 studies and developed aprediction model that provides clinicians with a method of identifying the subgroup of children with first UTI who are at risk for renal scarring.They have demonstrated that children with 1.an abnormal renal ultrasonographic finding or 2. a temperature of 39 degrees C and 3. an etiologic organism other than E Coli represent ahigh risk group in whom the risk for renal scarring is twice the baseline risk ( model 1 score of 2 or more represent a particularly high-risk group in whom the risk for renal scarring was 30.7%).At this cut-off model 1 identified 44.9% patients with eventual renal scarring.These children merit close follow up and consideration for late 99m Tc succimer scan.
In addition polymorphonuclear cell count greater than 60%, C reactive protein level greater than 40 mg/l were all associated with the development of renal scars. Sheikh et al confirm the importance of high grade VUR as the most important risk factor for renal scarring;however,rue the fact that they are unable to resolve the difficult question of how to idnetify this small but impportant subgroup of children without subjecting all children to a VCUG..The overall predictive ability of model 1 with 3 non-invasive variables was only 3% to 5% less than the predictive ability of models requiring a blood draw and/or a