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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 4  |  Page : 325-331

Low glomerular filtration rate in apparently healthy young individuals is an important factor preventing kidney transplantation from living kidney donors – A single-center observational study from India


1 Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Nuclear Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
3 Department of Urology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
4 Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, USA

Date of Submission07-Oct-2020
Date of Decision19-Dec-2020
Date of Acceptance14-Jan-2021
Date of Web Publication30-Dec-2021

Correspondence Address:
Dr. Sreejith Parameswaran
Department of Nephrology, Super Speciality Block, Jawaharlal Institute of Postgraduate Medical Education and Research Campus, Dhanvantari Nagar, Puducherry - 605 006
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_127_20

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  Abstract 

Background: India performed 7936 kidney transplantation operations in 2018 with living donor as the source in 85%. Identifying a living kidney donor (LKD) is difficult due to medical, social, and regulatory barriers. In addition, only a proportion of patients who volunteer may be able to donate eventually. Despite living donors being the predominant source, there are very few studies addressing the factors influencing living donor kidney donation in India. Methods: We analyzed data from our prospective LKD registry between July 1, 2011 and June 31, 2018. Demographic details, medical history, serum creatinine, and measured glomerular filtration rate (mGFR), blood pressure and the eventual outcome of LKD evaluation, including reason for noneligibility were collected. In a prospective cohort of 12 LKDs, renal functional reserve was studied using protein loading and dietary protein intake was measured from urine urea nitrogen excretion. Results: Over a period of 81 months, 316 LKDs were enrolled in our program. On 101 instances factors related to recipients prevented transplantation and on 92 occasions donor related factors precluded donation. Among 182 medically eligible LKDs with no evidence of CKD, only 33% had mGFR >90 ml/min/1.73 m2. Based on our institutional criteria, 22% of LKDs with mGFR <70 ml/min/1.73 m2 were ineligible solely based this criterion. Eventually, only 32% of enrolled LKDs were accepted for donation. Dietary protein intake was low in all 12 LKDs studied, only one had mGFR >90 ml/min/1.73 m2. Eight LKDs with mGFR <90 ml/min/1.73 m2 showed renal functional reserve of more than 20% with protein loading. Conclusion: Only one-third of voluntary kidney donors enrolled for evaluation were eventually able to donate their kidney. Low mGFR in otherwise apparently healthy LKDs was an important reason precluding kidney donation. Only 33% of individual found medically fit for donation had a mGFR ≥90 ml/min/m2 at our center. Low dietary protein intake may be a factor contributing to low mGFR in healthy LKDs.

Keywords: India, kidney transplantation, living donors, spouses, tissue and organ procurement


How to cite this article:
Parameswaran S, Kulothungan SA, Ponnusamy M, Reddi S, Haridasan S, Manikandan R, Pillai Puthenpurackal PS, Vazhayil A, Lalgudi DN, Sreenivasan SK, Radhakrishnan J. Low glomerular filtration rate in apparently healthy young individuals is an important factor preventing kidney transplantation from living kidney donors – A single-center observational study from India. Indian J Transplant 2021;15:325-31

How to cite this URL:
Parameswaran S, Kulothungan SA, Ponnusamy M, Reddi S, Haridasan S, Manikandan R, Pillai Puthenpurackal PS, Vazhayil A, Lalgudi DN, Sreenivasan SK, Radhakrishnan J. Low glomerular filtration rate in apparently healthy young individuals is an important factor preventing kidney transplantation from living kidney donors – A single-center observational study from India. Indian J Transplant [serial online] 2021 [cited 2022 Aug 10];15:325-31. Available from: https://www.ijtonline.in/text.asp?2021/15/4/325/334419




  Introduction Top


India performed the largest number of kidney transplants after USA in 2018, With 7936 kidney transplantation operations.[1] It is estimated that approximately 200000 people develop end stage kidney disease (ESKD) every year in India[2] and there is a large mismatch between the demand and availability of kidney donors. With the deceased donor program in its nascent stages, 85% of the kidneys were from living donors in India.[1] While there are ongoing efforts to promote deceased donor organ procurement, living donors are expected to continue to contribute a significant proportion of kidneys in the foreseeable future in India. Reports show that only a proportion of individuals who volunteer for living kidney donation eventually donate their kidney.[3],[4],[5] Donor being medically unfit, withdrawal of consent by donor, recipient becoming medically unfit for transplantation or declining donation and immunological incompatibility were found to be the major reasons precluding living kidney donation in the United Kingdom.[3] The only study of its kind from India, which analyzed medical and nonmedical determinants of living donor transplantation in patients with ESKD at a single center, reported lack of blood group compatibility, being found medically unfit and coercion by spouse as major factors precluding living donor kidney transplantation in India.[5] Despite living donors being the predominant source, there are very few studies addressing the factors influencing living donor kidney donation in India. We studied the factors which prevent living kidney donors (LKDs) from donating at our center.




  Materials and Methods Top


A prospectively maintained living donor registry database was established at our center in the year 2011. Inclusion criteria- We analyzed the database to identify factors which prevent transplantation from living donors at our center. All individuals who volunteered to donate and were enrolled in the registry after screening evaluation was included in the study. Exclusion criteria- All those unwilling to provide informed consent were excluded.

LKD evaluation was performed in three stages. As per provisions of the Transplantation of Human Organs Act (1994) and its amendments enacted by Indian parliament, only “near relatives,” defined as first degree relatives, spouse, grandparents, and grandchildren of the ESKD patient and who were above 18 years of age, were accepted as LKD in our program. Our center did not perform kidney transplantation across blood group barrier. Individuals, from among “near relatives” of an ESKD patient, who express willingness to donate their kidney and had a matching blood group, undergo a screening evaluation [Figure 1]. Only those individuals who were found to have no absolute contraindication to donate on screening evaluation were enrolled in the LKD registry database and proceeded to further evaluation. Information on individuals who were ineligible as LKD after screening evaluation was not available in the registry database. Once the LKDs were registered for kidney transplant evaluation, in the second stage of transplant evaluation, they were subjected to a standard panel of clinical evaluations and laboratory testing [Figure 1] based on KDIGO guidelines.[6] This evaluation included measurement of serum creatinine, 24-h urine protein and creatinine, ultrasonographic (USG) imaging of the kidneys among other investigations. Proteinuria >150 mg/day, a kidney length <9 cm and altered echogenicity of kidney parenchyma on USG imaging were considered abnormal and the individual considered ineligible to donate. Once the LKD and the prospective recipient were found medically fit based on the standard panel of clinical evaluations and laboratory testing, glomerular filtration rate (GFR) was measured GFR (mGFR) with Tc-99 m-DTPA by multiple plasma sampling technique and human leukocyte antigen typing and Complement-dependent cytotoxicity (CDC) crossmatch were performed in the third (last) stage of evaluation [Figure 1]. This strategy of performing expensive genetic and immunological testing and assessing mGFR after other evaluations were completed, was adopted to conserve resources. A minimum mGFR of 70 ml/min/1.73 m2 was necessary for LKD to be accepted for organ donation. If the mGFR is found to be <70 ml/min/1.73 m2, the measurement is repeated after 4 weeks, after ensuring proper hydration, avoiding nonsteroidal anti-inflammatory drugs or any medicines which may influence GFR and ensuring intake of a balanced diet for that period. Any prospective LKD who was found to have GFR <70 ml/min/1.73 m2 on the repeat measurement was ineligible as kidney donor, even if there were no other abnormalities detected on LKD evaluation. All LKDs registered for kidney transplantation between July 1, 2011 and June 31, 2018, were included in the analysis and data were collected using a predefined data collection form. The information collected included demographic details, laboratory reports including serum creatinine and mGFR, presence of hypertension and the eventual outcome of LKD evaluation as recorded in the registry, including reason for rejection of the LKD and successful donor nephrectomy.
Figure 1: Stages of living kidney donor evaluation

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Subsequently, in a pilot study, 12 consecutive LKDs enrolled in 2019 were subjected to protein loading (intravenous amino acid infusion) to assess their renal functional reserve. Dietary protein intake at baseline, while the LKDs were on their normal diet, was calculated from 24 urine urea nitrogen excretion and creatinine clearance (Cr Cl) was calculated by 24-h collection of urine. Protein intake was calculated as urine nitrogen excreted in grams/day + (weight in kilograms × 0.031 g nitrogen/kg/day) multiplied by 6.25.[7] mGFR (Plasma clearance of Tc-99 m DTPA and Cr Cl (by 24 h collection) measured at baseline. The LKDs were then placed on a low protein diet (0.6 gm/kg/day) for 10 days, following which Cr Cl and mGFR were measured. 24-h urine urea nitrogen excretion was measured after 10 days of low protein diet to check compliance with the prescribed diet. Subsequently, the LKD was started on IV Amino Acid infusion (10% solution, 500 ml/6 h started at 6:00 pm and continued till GFR was measured by Tc-99 m-DTPA clearance the next day morning after a minimum infusion duration of 14 h. Cr Cl was also measured by 24 urine collection during the protein loading phase. Renal functional reserve was calculated as the percent difference between stimulated mGFR (Cr Cl) and prestimulation mGFR (Cr Cl).

Statistical analysis

Descriptive statistics were used to describe socio-demographic characteristics, continuous variables were expressed as mean with standard deviation or median with interquartile range based on the normality of the data. If data were missing, descriptive analysis was done using available data.

Patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethic clearence

The study was approved by the institute ethics committee (IEC). (Approval letter no. JIP/IEC/2019/0267 dated 07.08.2019).

All principles of declaration of Helsinki were followed.


  Results Top


During the study, 316 LKDs were enrolled in the LKD registry. The mean age of LKD was 44.11 (±10.85) years and the mean age of ESKD patients was 32.34 (±10.58) years. Among the LKDs, 253 were female (80%, n = 316) compared to 62 (20.2%) of ESKD patients (prospective recipients) who were females. Two hundred and eighty-two (89.5%) of our patients were “Below Poverty Line (BPL),” with family income less than INR 5000/-per month (Approx. $66 per month at USD to INR conversion rate of $1: INR76.25 as on June 21, 2020).

Only 101 (32%) among those volunteering as LKD and initiated on pretransplant evaluation eventually donated [Figure 2]. We found that in 101 instances factors related to the prospective recipient was responsible for precluding the transplantation operation; while in 92 instances factors related to the LKD prevented the transplantation. The factors related to the LKD which precluded transplantation in our patient population is summarized in [Table 1].
Figure 2: Outcome of pretransplant evaluation

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Table 1: Donor related factors preventing kidney donation by living kidney donor

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In 134 LKDs, mGFR was not measured because donor or recipient-related factors precluding donation were identified before they reached the third stage of evaluation, or they were still awaiting mGFR at the end of study period. Among the LKDs who underwent mGFR (n = 182), the distribution of GFR is depicted in [Table 2]. There were 182 LKDs who were medically fit to donate, in whom mGFR was determined. They were considered “medically fit” because no abnormalities of kidney structure of function could be found on evaluation as per KDIGO guidelines and they did not have any metabolic or other health conditions precluding kidney donation. Among them, 40 (22%) LKDs were found to have mGFR <70 ml/min/1.73 m2 and this prevented them from donating [Figure 2]. Only 60 (33%) had mGFR ≥90 mI/min/1.73 m2. The characteristics of LKDs who eventually donated and those who were ineligible due to low GFR are compared in [Table 3].
Table 2: Distribution of measured glomerular filtration rate among living kidney donors

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Table 3: Comparison of living kidney donors who successfully donated versus living kidney donors who were ineligible due to low glomerular filtration rate

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All the 12 LKDs in whom renal functional reserve was studied had low baseline dietary protein intake before imposing the low protein diet; only one had mGFR >90 ml/min/1.73 m2 [Table 4]. There were significant differences in estimated GFR (eGFR) (CKD-EPI), Cr Cl (24-h urine collection) and GFR measured using Tc99 m DTPA clearance in LKDs. The findings from protein loading and its effect on mGFR in 12 LKDs is depicted in [Table 5]. Five of the LKDs demonstrated a significant improvement (>25% from baseline) of mGFR with protein loading and 6 showed >25% improvement in Cr Cl.
Table 4: Comparison of estimated glomerular filtration rate, creatinine clearance, and measured glomerular filtration rate among 12 living kidney donors who underwent renal functional reserve study [Table 5]

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Table 5: Renal functional reserve study on 12 living kidney donors

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  Discussion Top


LKDs constitute the primary source of organs for patients with kidney failure in India. However, we found that only about 30% LKDs initially accepted for evaluation eventually donated. While medical conditions and blood group incompatibility are well known barriers for donation, we found that low mGFR was the sole reason for rejecting 22% of LKDs who were willing to donate and were otherwise found fit after medical evaluation.

The evaluation of GFR and deciding an acceptable level of GFR in the LKD is problematic in the Indian context due to various reasons. The KDIGO guidelines on LKD evaluation recommends that when the GFR in the LKD is between 60 and 89 ml/min/1.73 m2, the decision be individualized, based on age and clinical parameters and the risk threshold level acceptable to the center.[6] However, none of the eGFR equations or the CKD risk prediction model is validated in Indians. Hence, when the mGFR of the LKD is between 60 and 89 ml/min/1.73 m2, using the KDIGO recommendations is not feasible in the Indian context at this point of time. It may be inferred that in the absence of data, a GFR cut off >90 ml/min/1.73 m2 may be considered a safe limit. However, as we observed in our LKDs and already reported form elsewhere in India, many apparently healthy LKDs have GFR <90 ml/min.[8],[9] If mGFR ≥90 ml/min/1.73 m2 is accepted as safe, it appears that only a small proportion of otherwise healthy Indians will be eligible to donate their kidney. Among 182 LKDs in whom GFR was measured in our study, only 60 (33%) had mGFR ≥90 mI/min/1.73 m2.

There are reports of GFR being low in healthy Indian adults, compared to a western population. Among 100 healthy LKDs, Barai et al.[7] reported that the mean GFR was 82.4 ± 12.7 mL/min/1.73 m2, when GFR was measured using Tc-99 m-DTPA by plasma clearance technique. Kumar et al.[9] measured GFR in a population of 63 LKDs and 67 patients with CKD by inulin clearance and reported that the mean GFR in LKDs was 79.44 ± 20.19 (range: 41.90-134.50) ml/min/1.73 m2; this study also reported low protein intake in the study population and that the creatinine-based eGFR equations overestimated GFR in Indians. GFR estimation in a multi-ethnic Asian population of healthy volunteers showed lower GFR in people with Indian ethnicity compared to Japanese and Malay ethnicities.[10] We used a minimum mGFR of 70 ml/min/1.73 m2, based on the assumption that GFR is constitutionally low in Indians. This practice is prevalent among kidney transplantation centers in India (personal communication). However, it is a cause of concern that our LKDs are relatively young and long-term safety of this strategy is not proven. This is all the more relevant in the context of increasing recognition that living donors are at increased health risks in the long-term including CKD and ESKD, even though the absolute risk may be low.[11],[12]

One reason for the low GFR observed in Indians is thought to be low dietary protein intake. A significant number of Indians are vegetarians, and even among individuals who claim to be non-vegetarians, the intake of animal protein is infrequent. Available data showed that the BMI of individuals who could not donate because of low GFR was significantly lower that of individuals who successfully donated [Table 3]. Hence, it is possible that nutritional factors, especially low protein intake, may be contributing to the low GFR. Kumar et al. reported that 50% of their study population was strict vegetarian and among meat-eaters, the frequency of meat intake was 4.8 per month.[9] It is possible that chronic low protein intake may be one reason for low GFR observed in healthy Indian adults; but other well-known factors like low birth weight and a low nephron mass may also be playing a role. However, preserved kidney functional reserve demonstrated by a rise in GFR following protein loading was reported in LKDs in India.[13] The significance of the low GFR observed in Indians need further studies. The technique used for GFR measurement also may be important. Among the various techniques used for the measurement of GFR in clinical practice, Plasma clearance of Tc-99 mDTPA was reported to be less accurate compared to plasma clearance of 51Cr-EDTA or iothalamate.[14] However, DTPA clearance remains the most used technique to measure GFR in LKD in India. We considered the possibility that LKDs who were found to have low GFR may be having CKD, because CKD of Unknown Etiology (CKDu) is endemic in our region.[15] However, these LKDs did not have any features of CKDu or evidence of any structural or functional abnormality other than the isolated finding of low mGFR. Hence, it is very unlikely that the low mGFR was due to CKD in this population.

To assess the role of dietary protein intake and BMI on mGFR in healthy LKDs we initiated a pilot study of kidney functional reserve using protein loading. Preliminary findings [Table 4] and [Table 5] from a limited number of LKDs suggest the presence of significant kidney functional reserve in them even when mGFR at baseline was <90 ml/min/1.73 m2. The dietary protein intake was less than recommended daily allowance for all of them when protein intake was estimated on their regular diet. It appears that low protein intake may indeed be a factor contributing to low GFR observed in our LKDs, but this needs more studies for confirmation. There was significant variation between eGFR (CKD-EPI), Cr Cl (estimated and measured) and mGFR, highlighting the complexity in assessing GFR in our patient population.

Our center is a public sector hospital offering free or highly subsidized medical care to an underprivileged population belonging to some of the poorest districts in the state of Tamil Nadu[16],[17] About 90% of our patients were in the “BPL” category defined by the government of India. The socio-economic profile of patients seeking care at our center may not be comparable to that of people from more affluent background and our findings need to be considered in the socio-economic context. Our study also has limitations inherent to studies based on registry data. The data on individuals who volunteered for kidney donation but were ineligible after preliminary evaluation without registering them for further evaluation was not captured. Therefore, we could not estimate the number of individuals who volunteered to donate but where ineligible based on blood group incompatibility, diabetes, severe hypertension, kidney disease, and other common medical conditions.

Meaningful scientific advances in determining whether the “normal” GFR in Indians is lower compared to other population and defining a lower limit of GFR for LKD is not possible without having an eGFR equation validated in the Indian population. Instead of DTPA clearance, more accurate techniques like EDTA clearance may be advisable for GFR measurement in LKDs. In view of the knowledge gap in this area, developing a validated eGFR equation for Indians followed by the validation of CKD prediction model in general population as well as in LKD in India should be a priority area for research.

Limitation

Study was a single centre study.


  Conclusions Top


Only 32% of voluntary kidney donors enrolled for evaluation were eventually able to donate their kidney. Low measured GFR in otherwise apparently healthy LKDs is an important reason precluding kidney donation in India. Only 33% of individual found medically fit for donation had a mGFR ≥90 ml/min/m2 at our center. In the pilot study of renal functional reserve, all 12 LKDs had low baseline dietary protein intake and at least five showed significant renal functional reserve. There is urgent need of studies to ascertain the impact of socio-economic factors and dietary protein intake on mGFR in LKDs and the best method to assess GFR in individuals of Indian ethnicity.

Acknowledgments

The JIPMER Renal Registry was supported by the International Society of Nephrology under the Sister Renal Centre program.

Financial support and sponsorship

JIPMER Renal Registry was supported by the International Society of Nephrology under the Sister Renal Centre program.

Conflicts of interest

There are no conflicts of interest.



 
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Bailey PK, Tomson CRV, MacNeill S, Marsden A, Cook D, Cooke R, et al. A multicenter cohort study of potential living kidney donors provides predictors of living kidney donation and non-donation. Kidney Int 2017;92:1249-60.  Back to cited text no. 3
    
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Veerappan I, Neelakantan N, Tamilarasi V, John GT. Medical and non-medical factors that affect voluntary living-related kidney donation: A single-center study. Indian J Nephrol 2011;21:14-20.  Back to cited text no. 5
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Lentine KL, Kasiske BL, Levey AS, Adams PL, Alberú J, Bakr MA, et al. KDIGO Clinical practice guideline on the evaluation and care of living kidney donors. Transplantation 2017;101 Suppl 1:S1-109.  Back to cited text no. 6
    
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Barai S, Gambhir S, Prasad N, Sharma RK, Ora M, Kumar A, et al. Levels of GFR and protein-induced hyperfiltration in kidney donors: A single-center experience in India. Am J Kidney Dis 2008;51:407-14.  Back to cited text no. 13
    
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Parameswaran S, Krishnankutty RP, Kar SS, Thazhath HK, Devassiya JT, Sivan Pillai PP, et al. A newly recognized endemic region of chronic kidney disease of undetermined aetiology (CKDu) in South India-”Tondaimandalam Nephropathy.” Kidney Int Rep 2020;5:2066-73.  Back to cited text no. 15
    
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