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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 13  |  Issue : 4  |  Page : 252-258

ABO-incompatible kidney transplantation: Indian working group recommendations


1 Department of Nephology, Sir Ganga Ram Hospital, Bengaluru, Karnataka, India
2 Department of Nephology, BGS Gleneagles Global Hospitals, Bengaluru, Karnataka, India
3 Department of Nephology, Max Super Speciality Hospital, Mohali, Himachal Pradesh, India
4 Department of Nephology, Rabindranath Tagore International Institute of Cardiac Sciences, Kolkata, West Bengal, India
5 Department of Nephology, Breach Candy Hospital; Department of Nephology, Sir HN Reliance Foundation Hospital, Mumbai, Maharashtra, India
6 Department of Nephology, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, India
7 Department of Nephology, Aditya Birla Memorial Hospital, Pune, Maharashtra, India
8 Department of Nephology, Medanta-The Medicity, Gurugram, Haryana, India
9 Department of Nephology, Primus Super Speciality Hospital, Chankyapuri, Delhi, India
10 Department of Nephology, Century Hospital, Hyderabad, Telangan, India
11 Department of Nephology, PGIMER, Chandigarh, India
12 The George Institute for Global Health, UNSW, New Delhi; Manipal Academy of Higher Education, Manipal, India

Date of Submission26-Aug-2019
Date of Acceptance26-Nov-2019
Date of Web Publication31-Dec-2019

Correspondence Address:
Dr. Vivekanand Jha
The George Institute for Global Health, 311-312, Third Floor, Elegance Tower, Plot No. 8, Jasola District Centre, New Delhi - 110 025
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_39_19

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  Abstract 


Expanding use of ABO-incompatible kidney transplant (ABOiKT) globally and in India demands harmonized protocols. With an aim to provide unified and standardized consensus for ABOiKT in Indian setting, a 14-member working group formulated this document on key critical areas to guide ABOiKT. The recommendations include the following: (i) Gel column agglutination test is a method of choice for antibody (Ab) titer assessment with tube method as acceptable alternative. Immunoglobulin G measurement is advised for clinical decision making. (ii) Assessment of one Ab titer before subjecting patient to Ab removal is recommended. Postplasmapheresis (PP) titers to be monitored anywhere between 2 and 12 h. (iii) Target Ab titer recommended is ≤1:16 irrespective of the method used for titer assessment. (iv) If cost and availability are not a concern, immunoadsorption (IA) should be preferred. (vi) Choice of replacement fluid depends on the method employed for Ab removal. (vii) Donor or AB-positive plasma transfusion can be considered to avoid coagulopathy and bleeding in posttransplant period. It also decreases the risk of coagulopathy associated with greater number of PP cycles performed during and after transplant. (viii) IA column can be reused if cleaned, sterilized and stored properly. (ix) Intravenous immunoglobulin (IVIG) is optional for use in ABOiKT. Choose IVIG batch with lowest ABO- Ab titers and use in low dose (~ 100 mg/kg). (x) Rituximab in a low dose of 100–200 mg is effective and its use (at-least 2 weeks prior to transplant) is at the discretion of treating renal transplant physician. (xi) Avoid, if possible, the combined used of antithymocyte globulin and rituximab as it increases risk of infections significantly. (xii) Posttransplant PP is needed if there is Ab mediated rejection with increasing titers. (xiii) Standard immunosuppression should be followed. These recommendations are first of a kind that aims to standardize the practice of ABOiKT, serve as a guiding tool to the transplant physicians in India.

Keywords: ABO-incompatible kidney transplant, antibody, immunoadsorption, India, plasmapheresis, recommendations


How to cite this article:
Bhalla A K, Anil Kumar B T, Chauhan M, Das P, Gandhi B, Hegde U, Jeloka T, Mali M, Jha PK, Kher A, Mukkavilli KK, Ramachandran R, Jha V. ABO-incompatible kidney transplantation: Indian working group recommendations. Indian J Transplant 2019;13:252-8

How to cite this URL:
Bhalla A K, Anil Kumar B T, Chauhan M, Das P, Gandhi B, Hegde U, Jeloka T, Mali M, Jha PK, Kher A, Mukkavilli KK, Ramachandran R, Jha V. ABO-incompatible kidney transplantation: Indian working group recommendations. Indian J Transplant [serial online] 2019 [cited 2020 Apr 8];13:252-8. Available from: http://www.ijtonline.in/text.asp?2019/13/4/252/274610




  Introduction Top


Globally, the ability for eligible patients with end-stage kidney failure to receive the life-saving kidney transplantation is limited by a shortage of organ donors. It is estimated that in India, nearly 220,000 individuals require kidney replacement therapy annually, which remains unmatched with a current number of 7500 kidney transplants being performed at approximately 250 centers across the country.[1] Most of these are from living donors. In some families, suitable voluntary living donors are available, but are unable to donate because of blood group incompatibility (ABO incompatible [ABOi]). This has been considered to be an absolute contraindication for kidney transplant (KT) since long.[2] In recent years, the ability of the global transplant community to overcome this barrier has allowed thousands of patients to receive a kidney.[3],[4]

In India, early attempts for ABO-incompatible kidney transplants (ABOiKT) were made in the late 1980s. However, this procedure remained poorly utilized until a few years back, largely because of cost and perceived cumbersome nature of the desensitization protocol. As per the literature, the first reported case of successful ABOiKT from India was in a 19-year-old male with initial anti-B antibody (Ab) titer of 1:512, which was reduced to <1:8 after 11 sessions of plasmapheresis (PP) and 100 mg/kg of intravenous immunoglobulin (IVIG) after each PP. There was no rejection of the graft at 6 months.[5] A single-center study in 2016 comparing ABOiKT and ABO-compatible KT (ABOcKT) reported comparable patient and graft survival, biopsy-proven acute rejection (15% vs. 16.29%), and infection rates (15% vs. 9.7%), respectively.[6] Anecdotal experience suggests that approximately 200–250 ABOiKT are performed annually in India. However, the protocols for working up and desensitization are not uniform. With more centers wanting to start ABOiKT, there is a need to standardize the clinical practice and protocols and provide guidance to new centers on ABOiKT in India. There is a concern about the right method of Ab detection, acceptable Ab titer at the time of transplant, desensitization and immunosuppression protocol, need for posttransplant monitoring and desensitization and diagnosis and treatment of Ab-mediated rejection. This consensus document is intended to assist transplant centers in the clinical approach to setting up ABOiKT program.


  Materials And Methods Top


A group of 14 nephrologists and transplant surgeons representing a range of kidney transplant services from across India came together to develop this document. A set of key points of discussion [Table 1] was developed and circulated to the group. After preparatory work over Email, the working group met in New Delhi, India to review the current practice in India, to reconcile the differences and harmonize with current recommendations from elsewhere in the world. The specific protocols that were reviewed included the following.
Table 1: Points of discussion

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  • Tokyo Women's Medical university protocol (Japan)[7]
  • John Hopkins protocol (USA)[8]
  • Mayo Clinic protocol (USA)[9]
  • Friedberg University Hospital protocol (Germany)[10]
  • Stockholm Group protocol (Sweden)[11]
  • Rabindranath Tagore hospital protocol (India).[12]



  Recommendations Top


Method of determination of antibody titers

Gel column agglutination test is recommended as a method of choice for Ab titer assessment. Tube method is an acceptable alternative.

The currently available methods of assessment of ABO Ab titers include hemagglutination method, room temperature incubation method and indirect antiglobulin test. Tube agglutination test, although crude, is used commonly. In recent years, it has been overtaken by gel agglutination test, which is more sensitive, quantitative, easy to perform, and is less time-consuming.[13],[14] Knowing the method of estimation is important as titers differ according to the method.[15] Evidence also demonstrate that gel column agglutination test has greater reproducibility compared to tube test.[16] Flow cytometry has demonstrated comparable analytical performance to that of gel column agglutination test but it is more expensive.[17],[18] Considering wide availability, higher sensitivity, and ease of use,[14],[19] the working group recommended gel agglutination method for determination of Ab titers. In case of nonavailability of gel method, tube method is an acceptable alternative.

Target pretransplantation antibody titers

  • Assessment of one Ab titer before subjecting patient to Ab removal is recommended
  • Immunoglobulin (Ig) G measurement should be used to make clinical decisions. IgM measurement is discretionary
  • Pretransplant IgG Ab titer of 1:16 should be taken as cut-off to go ahead for ABOi-KT irrespective of the methods used for titer assessment
  • Outcome of ABOi-KT depends on many factors and therefore patient and caregiver need to be counseled that titers are not the sole factors in determining outcome.


Both IgG and IgM antibodies are present in the circulation of ABOi recipient; however, IgG is more relevant for clinical outcomes because IgM remains confined to vascular space which makes it amenable to easier removal. Higher pretransplant titers of IgG are associated with lower rate of graft survival and increased likelihood of graft rejection. This was demonstrated by Shimmura et al.[20] who reported 8-year graft survival rate at of 66.8% and 79.7% for 1:16 (n = 21) and 1:32–1:64 (n = 33) IgG Ab titer whereas it was 28.6% for titers 1:128 and higher (n = 7). Furthermore, there was no association between IgM titers and graft survival. Another study in Korean patients observed frequent Ab rebound, difficulty to reach target titers of 1:16, higher rate of acute rejection, infection, and reduced allograft function in the group with higher titers (≥1:512) compared to those with lower titers (≤1:256). Multivariate analysis in this study proved that baseline Ab titers were independent predictors of acute rejection.[21]

Target Ab titers have been evolving [Table 2]. The British Transplantation Society guidelines recommend that baseline titer of <1:8 is acceptable.[22] Evidence from Japan suggests that some investigator even performed the transplant at a titer of 1:128. However, the risk of adverse outcomes at such baseline titers was high when compared to the lower titers.[20] In the initial years, most working group members suggested that initially they started with a very stringent titer of <1:4 or <1:8. However, Indian centers are still conservative given the importance of successful transplant, the extra expense incurred by the patient in desensitization leading to the expectation of near certain success and lack of viable options for long-term dialysis. Hence, the consensus was to recommend bringing down the titer to ≤1:16 before proceeding with transplant. A relatively low titer was also thought to provide a safety margin for laboratory variations.
Table 2: Target antibody titers in various protocols

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Antibody removal and preconditioning protocol

  • Selection of method should be decided by availability, cost, and experience
  • Immunoadsorption (IA) is the method of choice for lowering Ab titers but is expensive
  • IA is more cost-effective compared to other methods when it is predicted that more than 4 sessions of PP will be required, such as a starting Ab titer of >1:128
  • PP should be performed if IA and Double-filtration PP (DFPP) are not possible. Frequency of PP should be individualized based on initial titres
  • In DFPP, crystalloids with or without albumin should be used for replacement. Using donor group or AB positive plasma should only be considered in case of coagulopathy or if the number of PP cycles exceed four
  • IA columns can be reused depends on methods employed for cleaning. Saline wash and sterilization with ethylene oxide with storage in dark at 2–8°C can provide reuse of IA columns for 3–4 sessions.


Working group members opined that to decide on choice of method of Ab removal, five factors should be considered – cost, the predictability of the method, initial Ab titer, complications associated with the procedure, and the manufacturer. Methods that are followed include the following.[17]

  • Plasmapheresis
  • Regular plasma exchange
  • Double filtration plasmapheresis
  • Immunoadsorption.


Plasmapheresis

Therapeutic PP is widely employed for Ab removal in ABOiKT. An individual plan should be developed for the patients undergoing ABOiKT based on expected date of transplant, and the baseline Ab titers. Usually, PP is given on alternate days. Duration of PP depends on baseline titers. Approximately, number of cycles required to reach a target titer of <1:16 will be 1–2, 2–3, 3–4, 4–5, 5–6, and >6 for baseline titers of <32, 64, 128, 256, 512, and >512, respectively.[8]

In each session of PP, one plasma volume exchange is replaced at 100% volume with 5% human albumin. Calcium gluconate 0.465 mEq in 4 ml quantity is added to 500 ml of 5% albumin. Acid citrate dextrose-A or heparin is used as the anticoagulant (ratio of 13:1).[18]

As part of moving away from target Ab levels, fixed cycle protocols can be adopted, and it has been suggested that four pretransplant PP sessions may be adequate. Narumi et al. performed four and two cycles of PP those with baseline titers of ≥1:32 and ≤1:16, respectively. Rituximab at a low dose (100–200 mg) was given in patients with high titers. Graft survival rate at 3 and 5 years was 96.1% and 90.7% in high-titers group and 95.8% and 95.8% in low-titers group. The difference in graft survival was nonsignificant (P = 0.6456).[23] However, it was argued that Indian centers were not ready to accept such fixed protocols and would resort to additional sessions to achieve target Ab titers of <1:16.

Double-filtration plasmapheresis

DFPP selectively removes the Ig fraction from the serum and helps in minimizing the volume of substitution fluid required. In DFPP, plasma is first separated by a plasma separator, and in the second filtration, the gamma globulin fractions are separated by plasma fractionator. The process removes concentrated serum globulin fraction including antibodies.[17] The advantages with DFPP include selective removal of Igs, requirement of smaller volumes of substitution fluid and better reduction of Ab titers in one session (70% and 60% removal of IgM and IgG, respectively).[24]

Immunoadsorption

IA has been used for removal of agglutinins since the early 1980s. IA can be antigen-specific or nonspecific.[25] Multiple procedures can be performed in a single column with different types of columns available for different type of agglutinins. Glycosorb column in first treatment reduces donor specific IgM and IgG antibodies by 81% and 56% respectively. Multiple IA treatments may become necessary depending on the baseline titers.[26] A study reported need of seven IA treatments for baseline titers ranging up to 1:1024.[27] An important advantage with this method is that no substitution is required.

The major downside of this method is the high cost of columns, which makes this method less attractive if the initial Ab titers are low enough to not require >4 PP sessions. However, based on current market process, the working group estimated that that IA becomes more efficient in reducing Ab titers if >4 sessions are needed. Hence, it makes sense to use this method if the initial Ab titres are >1:128.

Reuse of IA columns is not recommended. However, reuse has been practiced, reducing cost of treatment. Some authors have used saline rinsing of the Glycosorb column followed by sterilization using ethylene oxide and storage in 2–8°C. The column was reused for total three procedures.[28] With immunosorba column, Schiesser et al. used 1000 mL of Buffer PA pH 7.0 to wash the plasma, a citrate solution with 1000 mL eluate PA pH 2.2 to remove antibodies and 1000 mL. buffer PA pH 7.0 for neutralization. In the end, the column was rinsed and filled with 250 mL Immunosorba Preservation Solution containing 0.04% polyhexamethylene biguanide and stored in the dark at +2°C–+8°C.[29] A comparative evaluation of three procedure discussed by the working group is presented [Table 3].
Table 3: Comparison of methods for antibody removal

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Intravenous immunoglobulin

  • IVIG use is not routinely recommended in ABOiKT
  • IVIG contains anti-ABO antibodies and can lead to increase in titers
  • When needed, it should be used in low dose (~ 100 mg/kg), after PP cycles, with a batch having low Ab titres.


IVIG has been traditionally considered an important component in ABOiKT desensitization protocols. However, enthusiasm for its use has declined because of its association with rising Ab titers, likely due to the presence of anti-ABO IgG antibodies in the IVIG preparations.[2],[30] In some situations, IVIG use may be needed. In such cases, the group recommended selection of IVIG batch with the lowest Ab titers and minimizing the volume of antibodies.

Replacement fluid after antibody removal

  • The selection of replacement fluid depends on the method employed for Ab titer reduction
  • For IA, crystalloid replacement is enough
  • Albumin and crystalloids are recommended for PP and DFPP
  • If the number of PP or DFPP sessions exceed four, fresh frozen plasma (FFP) may be added to mitigate the risk of coagulopathy.


For each method of Ab removal, the type of replacement fluid is different. For PP, there is need of albumin and crystalloids administration. FFP may also be necessary to reduce coagulopathyassociated complications if number of cycles exceeds four. A study from Yoo et al. reported use of 5% albumin and FFP as 100% replacement fluid in each PP. The number of PP cycles varied from 3 to 5 to reach target titers of <1:8.[31] A study from India also reported that one plasma volume exchange was done with 5% albumin and two units of AB group FFP.[32] In DFPP, there is no removal of albumin from the system and thus consequent need of albumin may be less. Tanabe utilized only 0.5–1.0 L of 8% albumin solution as the replacement fluid during DFPP. This was observed to be equivalent to 2.5–5.0 L of albumin solution or fresh plasma used in regular plasma exchange.[24] Additionally, crystalloid with or without FFP administration may be necessary. Donor plasma may be considered in PP and DFPP to avoid coagulopathy and bleeding in posttransplant period. However, with IA, there are no specific replacement fluids are necessary and only crystalloid substitution may be enough.[33]

Rituximab

  • Rituximab should be used in a dose of 100–200 mg/m2 approximately 2 weeks before transplantation
  • PP, if required, should be performed at least 1-week after rituximab administration
  • All induction therapies can be combined with rituximab
  • The increased risk of infections associated with combined Rituximab- Anti-thymocyte globulin (ATG) use should be explained to patients and caretakers
  • CD19 counts are not recommended for routine assessment.


ABOiKT desensitization protocols employ the anti-CD20 Ab rituximab along with PP or IA.[24] The dose and initiation duration of rituximab before transplant among different protocols is shown in [Table 2]. The British Transplantation Society guidelines recommend use of rituximab in addition to IVIG. However, in absence of specific data on dose and outcomes, no treatment recommendations have been provided. Guideline also identified that the duration before which rituximab started varied from 30 to 1 day before transplant.[22] Genberg et al. reported similar outcomes at 3-years of ABOiKT using IA and rituximab to that of ABOcKT. They administered a single dose of rituximab 375 mg/m2 body surface area on day-30 of transplant.[34] Jha et al. reported using rituximab in the dose of 200 mg 2 weeks prior to transplant.[6] Ravichandran and Kannan had also used rituximab in the dose of 200 mg on day-7.[35] Working group, therefore, opined that rituximab should be used in low doses as it can be effective from 100 to 375 mg/m2 dose but effectively 100–200 mg dose can be used. Optimally, rituximab should be given 2 weeks before transplant or 1-week before PP. Emerging evidence suggests that complete avoidance of rituximab may not have adverse effect on outcomes.[36] However, more data is needed before this course of action can be recommended.

Working group strongly agreed that rituximab when used concomitantly with ATG increase the risk of infections, although few studies found no differences in rate of infection.[37] Working group advised to discuss the possibility of infectious complications with the patients and caretakers when the two agents are being used together.

Postoperative plasmapheresis and antibody titers

Routine measurement of titers after transplantation is not recommended.

Working group unanimously agreed that postoperative titers may not be essential and these do not alter the outcomes of the patient. Posttransplant PP may be necessary if there is graft dysfunction with increasing titers (>1:64 or 4-fold increase from baseline).

Immunosuppression

  • Immunosuppression should be followed as per usual standard as currently practiced for ABOcKT.


Triple therapy with steroids, mycophenolate mofetil and cyclosporine, or preferably tacrolimus (Tac) is the standard approach in renal transplant.[38],[39] The 2017 National Institute for Health and Care Excellence guidelines and the 2009 Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline provide recommendations for immunosuppressive therapy in renal transplant cases.[40],[41] Use of 12 h trough levels (5–15 ng/ml – mean 10 ng/ml) has been suggested by KDIGO guidelines for monitoring Tac levels. Initiation of immunosuppressants has been variable in different studies but it has been suggested initiation 7–14 days prior to transplant is helpful in adequate inhibition of Ab production.[42] There is no evidence to suggest any change in the immunosuppression schedule for ABOiKT.


  Summary of Recommendations Top


Method of determination of antibody titers

  • Gel column agglutination test is recommended as a method of choice for Ab titer assessment. Tube method is an acceptable alternative


Target pretransplantation antibody titers

  • Assessment of one Ab titer before subjecting patient to Ab removal is recommended
  • IgG measurement should be used to make clinical decisions. IgM measurement is discretionary
  • Pretransplant IgG Ab titer of ≤1:16 should be taken as cut-off to go ahead for ABOi-KT
  • Outcome of ABOi-KT depends on many factors and therefore patient and caregiver need to be counseled that titers are not the sole factors in determining outcome.


Antibody removal and preconditioning protocol

  • Selection of method should be decided by availability, cost and experience
  • IA is the method of choice for lowering Ab titers but is expensive
  • IA is more cost-effective compared to other methods when it is predicted that more than 4 sessions of PP will be required, such as a starting Ab titer of >1:128
  • PP should be performed if IA and DFPP are not possible. Frequency of PP should be individualized based on initial titers
  • In DFPP, crystalloids with or without albumin should be used for replacement. Using donor or AB positive plasma should only be considered in cases of coagulopathy or if the PP cycles exceed four
  • IA columns can be reused depends on methods employed for cleaning. Saline wash and sterilization with ethylene oxide with storage in dark at 2–8°C can provide reuse of IA columns for 3–4 sessions.


Intravenous immunoglobulin

  • IVIG use is not routinely recommended in ABOiKT
  • IVIG contains anti-ABO antibodies and can lead to increase in titers
  • When needed, it should be used in low dose (~ 100 mg/kg), after PP cycles, with a batch having low Ab titers.


Replacement fluid after antibody removal

  • Replacement fluid depends on the method employed for Ab titer reduction
  • For IA, crystalloid replacement is enough
  • Albumin and crystalloids are recommended for PP and DFPP
  • If the number PP or DFPP sessions exceed 4, FFP may be added to mitigate the risk of coagulopathy.


Rituximab

  • Rituximab should be used in a dose of 100–200 mg approximately 2 weeks before transplantation
  • PP, if required, should be performed at least after 1-week of rituximab administration
  • All induction therapies can be combined with rituximab
  • The increased risk of infections associated with combined Rituximab-ATG use should be explained to patients and caretakers
  • CD19 counts are not recommended for routine assessment.


Immunosuppression

  • Triple immunosuppression should be followed as per standard currently practiced for ABOcKT.



  Conclusion Top


ABOiKT is a viable alternative to improve donor pool and provide relief to the patients on waitlist for renal transplantation who have otherwise suitable living donors. ABOiKT is emerging in India but there the currently employed protocols are not standardized or uniform. This document provides a standard and unified approach that can be adopted by the renal transplant community in India to harmonize the practice of ABOiKT to achieve better patient outcomes. We hope that this will also contribute to stimulating research in ABOiKT in India.

Acknowledgments

We thank Dr. Vijay M Katekhaye (Director, Quest Medpharma Consultants, Nagpur, India) for his contribution in drafting, editing and reviewing the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr Vivekanand Jha reports consulting or paid advisory board fees from BaxterHealthcare, ZydusCadila, and NephroPlus and grant support from BaxterHealthcare, GlaxoSmithKline Pharmaceuticals Ltd, Biocon, Department of Biotechnology (India), UK MRC, and ICMR.

Dr Vijay Kher have consultancy agreements with Torrent Pharmaceuticals Ltd., India; Novartis, India; Roche, India; Panacea Biotec, India; Sanofi Aventis, India; Intas Pharmaceuticals Ltd., India; Biocon pharmaceuticals, India. Has received research funding from Novartis India, Sanofi Aventis India, Astellas India. Has received honoraria from Novartis, India; Roche India; Astellas, India; Torrent Pharmaceuticals Ltd., India; Dr. Reddy's Laboratories, India; Intas Pharmaceuticals Ltd., India; J.B. Chemicals and Pharmaceuticals Ltd, India. Is the scientific advisor for Roche, India; Novartis, India; Torrent Pharmaceuticals Ltd., India; Sanofi Aventis, India; Dr. Reddy's Laboratories, India; Biocon pharmaceuticals, India; Medtronics, India; Wockhardt Ltd., India. Is associated with speakers bureau for Novartis, India; Roche, India; Panacea Biotech, India; Sanofi Aventis, India; Intas Pharmaceuticals Ltd., India; Biocon pharmaceuticals, India; Pfizer, India; Johnson and Johnson, India; J.B. Chemicals and Pharmaceuticals Ltd., India. Other Interests/Relationships: Kidney Health, Education and Research Society, India; Kidney education and research network: nonprofit NGOs.

Dr. Umapati Hedge was the part of advisory board for Wockhardt Ltd., India and has consultancy agreements with Biocon pharmaceuticals, India; Novartis, India. He has received lecture fees from Roche, India; Dr. Reddys Laboratories, India.

Dr. Pranaw Kumar Jha was the part of advisory board for Wockhardt Ltd., India. And consultant for Biocon pharmaceuticals, India.

Dr. Ajay Kher was the part of advisory board for Wockhardt Ltd., India. Was speaker for Sanofi Aventis, India and consultant for Biocon pharmaceuticals, India.

Dr. Manish Mali was the part of advisory board for Wockhardt Ltd., India. He was the guest lecturer for Astellas Pharma, India; Sanofi Aventis, India.

Dr. Tarun Jeloka was part of advisory board for Wockhardt Ltd., Zydus and Lupin Ltd.

Other authors have no conflicts of interest to declare.



 
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