Indian TrANslational GlomerulonephrItis BioLogy nEtwork (I-TANGIBLE): Design and Methods

Why a South Asian registry is important?

Unique population characteristics can influence disease behavior including presentation and response to treatment. Unlike in other major geographies and ethnic populations, the clinical course and outcomes of glomerular diseases in South Asia have not been well studied. A few studies have documented the clinical and pathological patterns of MN, IgAN, C3 glomerulopathy, and postinfectious GN from India. These descriptions are limited to single-center studies with short follow-ups, but highlight a number of unique features. They include identification of high-risk genetic loci in MN,[16] identification of M-type phospholipase A2 receptor (PLA2R) as being important to MN pathogenesis, a marker of disease activity, and a therapeutic target, and complementary and alternative medicine-related MN.[1718192021] Glomerular Research And Clinical Experiments-IgA Nephropathy in Indian}s (GRACE-IGAI)[22] and other studies[2324] from India showed an overabundance of chronic lesions and lack of features indicating active disease in the kidney biopsy in IgAN. Arivazhagan et al.[25] showed poor therapeutic response to corticosteroids in patients with postinfectious GN, whereas Kumar et al. showed that infection had a role in predisposing to C3 glomerulopathy. Kumar et al.[26] also showed that there was a high prevalence of tubular atrophy and interstitial fibrosis in patients with C3 glomerulopathy, which portends a poor prognosis. The impact of other unique determinants, such as dietary protein intake (related to vegetarianism), air and chemical pollution, and the high prevalence of infections in the community, has yet to be studied. The dietary protein intake (related to vegetarianism) influences disease progression (faster development of hypoalbuminemia and related complications and impact on the level of proteinuria), whereas prevalent infections have a role in disease development and course (IgAN, IC (Immune complex), and complement-mediated MPGN and postinfectious GN) and have an impact on risks with immunosuppressive therapies. In the Indian setting, it is also crucial to study the influence of access to care and develop and test cost-effective treatment approaches. The emerging precision therapeutic approaches are centered around biological agents, which are significantly more expensive. This makes it even more important to target their use to the population where the cost-effectiveness of their use is justified. There have been calls to test low-cost treatment strategies, including drug repurposing, where feasible. However, testing the newer or low-cost treatment therapies requires setting up of an efficient infrastructure. Randomized controlled trials (RCTs) are at the forefront of the evidence generation hierarchy and inform guideline recommendations. However, RCTs in nephrology, especially those involving patients with glomerular diseases, need to catch up to many internal medicine specialities. Unfortunately, even among the reported RCTs, representation from a limited-resource setting, especially among South Asians, is poor, despite them representing one-fifth of the world’s population.

To address the challenges mentioned above, we conceptualized the I-TANGIBLE network with the aim of developing a collaborative, integrated glomerular disease investigation infrastructure network for the following:

• Carrying out clinical and translational studies in primary glomerular diseases

• Identifying the risk factors and biomarkers of primary glomerular disease associated with poor short-term and long-term outcomes, including progressing to ESKD and death

• Promoting new and improved strategies for diagnosis, individualized therapies, and prevention through collaborative research

• Identifying factors determining adverse nonrenal outcomes like cardiovascular, bone health, and infections

• Developing additional projects using the I-TANGIBLE database and biological sample storage framework

• Setting up a clinical trial network for glomerular disease in alignment with global glomerular disease networks to conduct high-quality clinical trials.

Study design and objective

The I-TANGIBLE network consists of 13 participating institutions [Figure 1] in India, with George Institute for Global Health, New Delhi, India, being the coordinating center for the network, with responsibility for overall operational and quality control aspects of the study. At the end of the first year, we will contact other like-minded institutions in India to join the study network. A biorepository will be set up at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh. Adults (>18 years) with biopsy-proven MCD, FSGS, MN, IgAN, or MPGN (immune complex- and complement-mediated), with a first biopsy taken within 2 years of enrollment, who provide informed consent will be included in the study. Patients with estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m² for >3 months at the time of screening, kidney or bone-marrow transplant recipients, and patients with active malignancy or active hepatitis B/C replication or HIV-I/II will be excluded. This study will be conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for Good Clinical Practice and the applicable local regulatory requirements for India. Ethical and governance approval has been obtained from The George Institute (TGI) India and from all network institutions.

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Figure 1

Map of India showing location of study centers and geographic distribution: (1) Postgraduate Institute of Medical Education and Research, Chandigarh, (2) Safdarjung Hospital, New Delhi, (3) Institute of Postgraduate Medical Education and Research, Kolkata, (4) Nil Ratan Sircar Medical College, Kolkata, (5) Osmania Medical College, Hyderabad, (6) Nizam Institute of Medical Sciences, (7) Madras Medical College, Chennai, (8) Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, (9) Madurai Medical College, (10) Government Medical College, Calicut, (11) Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, (12) AIIMS Bhubaneshwar, (13) AIIMS, Raipur

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Data collection and biobank

Participants will be recruited prospectively from the out-/in-patient lists of the participating centers. Study staff will screen renal biopsy lists, medical records, laboratory reports, and other existing site databases for participants who fit the study criteria. Participants will be approached to taken a written informed consent to provide their clinical data. Participants will also be approached for their willingness to contribute blood and urine samples for biorepository and for future research use including genetic research, linking their preliminary data and their willingness to be involved in any upcoming clinical trials by the site staff. Once written consent has been obtained, research staff will review the patients’ hospital record to gather their demographics, medical history, and glomerular disease diagnosis details. Data items to be collected at baseline and on follow-up are shown in Supplementary Material (Annexure I and II). The study participants will be managed by their treating teams as per the prevailing standard of care. Follow-ups will be synchronized with their routine follow-up [Supplementary Material, Annexure II] at 3 months, 6 months, 12 months, 18 months, 2 years and annually thereafter. All clinically relevant events will be recorded. We will store blood and urine samples at the time of diagnosis from patients who consent to this aspect of the study. Ten milliliters of blood samples will be collected at the sites using site-specific collection forms (specific to this project) and divided into aliquots. Samples will be processed and stored at −80°C.

Study and data governance

A steering committee (SC) is already formed, whose members are the principal investigators (PIs) and key leaders in glomerular disease research in India. SC would be responsible for the general oversight of the study and provide scientific advice regarding all aspects of the study design, protocol development, conduct, and data collection. It will review the study progress and have a lead role in the study analysis and publication of results. Participant identifiers will be collected within the registry, and the data will be stored electronically in an electronic data capture system within the secure servers of TGI at New Delhi. All the sites will have access to their site-specific data. The ancillary studies’ applications will be scrutinized by the subcommittee of SC before submitting to the funding agencies.

Preliminary work

The study recruitment started in July 2022, and till 10 May 2023, we have recruited 745 participants: MCD (n = 190), FSGS (n = 206), MN (n = 302), and MPGN (n = 47).

Challenges

Although the network is promising, we anticipate multiple challenges; they include loss of patients to follow-up, logistical challenges in collecting data in unprecedented situations like the coronavirus disease 2019 (COVID-19) pandemic, inability to recruit enough patients to the network, and loss of interest by the site investigators. Given that patients with GN often travel large distances to specialized centers for care, we expect dropouts because of patient movement. We will use an electronic retention system to collect essential data, including source data, remotely. During unprecedented situations like COVID-19 pandemic, we will try to engage the patients with telephone-based follow-up visits, with adjudication by site PI. Although slow recruitment can be a challenge, the preliminary work conducted during the last year suggests we should enroll a reasonable number of participants. Systematic long-term follow-up will help in assessing clinically relevant endpoints. Loss of interest among site investigators over time is a concern. To mitigate this risk, we will support the sites with study assistants, engage them through quarterly conferences, and encourage them to initiate and lead projects. Finally, sustainability is a challenge. The network has been set up with initial funding from the Indian Council of Medical Research (ICMR). We hope to both renew the funding and generate additional funding through clinical trials and additional discovery research grants that will support the network infrastructure. Though not foolproof, we believe our mitigation plans will address most of the concerns.

Strengths and limitations

This is the first formal registry of primary GN from a resource-limited setting, where the environment influencing the disease course may vary from the developed world. It will also provide data on health-related quality of life (HRQoL) assessment, a quintessential part of patient-reported outcomes. The proposed network aims to create a supportive framework that will serve as a basis for numerous clinical and translational studies in the future. Although the network does not directly answer fundamental questions, it will pave the way for research that can address important issues related to patient care and basic as well as translational research. Other limitations include the lack of protocolization of treatment, heterogenicity of recruited population, and a lack of representation from the pediatric population.

Abbreviations

ID: identity, PIN: postal index number, CVD: cardiovascular disease, PE: physical examination, HRQoL: health-related quality of life, RPRF: rapidly progressive renal failure, AUA: asymptomatic urinary abnormalities, WBCs: white blood cells, HPF: high-power field, RBCs: red blood cells, ANA: antinuclear antibodies, ANCA: anti-neutrophil cytoplasmic antibodies, PLA2R: M-type phospholipase A2 receptor, HBsAg: hepatitis B surface antigen, HCV: hepatitis C virus, HIV: human immunodeficiency virus, AST: aspartate aminotransferase, ALT: alanine aminotransferase, TB: tuberculosis, ALKP: alkaline phosphatase, CCBs: calcium channel blockers, ACEi: angiotensin-converting enzyme inhibitors, ARBs: angiotensin receptor blockers, CNI: calcineurin inhibitor, MMF: mycophenolate mofetil, AKI: acute kidney injury.

Financial support and sponsorship

The project I-TANGIBLE is funded by ICMR, sanction number 5/4/7-1/Nephro/2021-NCD-II.

Conflicts of interest

Dr. Vivekanand Jha has received grant funding from GSK, Baxter, Astra Zeneca, Boerhringer Ingelheim, NephroPlus, and Zydus Cadilla, under the policy of all honoraria being paid to the organization. All the other authors do not have any conflict of interest to declare.