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Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors
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Kaohsiung Journal of Medical Sciences (2016) xx, 1e6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.kjms-online.com
ORIGINAL ARTICLE
Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors Turun Song, Zhengsheng Rao, Yang Qiu, Jinpeng Liu, Zhongli Huang, Xianding Wang, Tao Lin* Department of Urology, Urology Institute and Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China Received 25 September 2015; accepted 20 November 2015
KEYWORDS Body weight; Kidney function; Kidney volume; Living donor; Proteinuria
Abstract To investigate whether the ratio of remnant kidney volume to body weight (V/W ratio) can impact renal function in donors, 45 living kidney donors were enrolled. Kidney volume was analyzed by magnetic resonance imaging. Renal function was compared between donors with a V/W ratio of < 2.0 mL/kg (n Z 23) or 2.0 mL/kg (n Z 22). Donors in both V/W groups showed similar serum creatinine levels and estimated glomerular filtration rates (eGFRs) at 7 days and 1 year, whereas donors with a V/W ratio of < 2.0 mL/kg had significantly higher 24-hour urine protein levels at 1 year (0.54 0.23 g/d vs. 0.33 0.19 g/d, p Z 0.028). Multivariate analysis revealed no correlation between the V/W ratio and eGFR at 7 days or 1 year, and a V/W ratio of < 2 mL/kg was not associated with an increased incidence of eGFR < 60 mL/min/1.73 m2 at 1 year (risk ratio 1.73, 95% confidence interval 0.10e29.47). The V/W ratio correlated inversely with 24-hour urine protein (r Z 0.377, p Z 0.021) at 1 year, and donors with a V/W ratio of < 2.0 mL/kg were more likely to show 24-hour urine protein >300 mg (risk ratio 1.70, 95% confidence interval 1.08e2.67) at 1 year. Donors with lower V/W ratios have higher 24-hour urinary protein levels at 1 year after transplantation. These findings suggest that the V/W ratio may be useful for kidney selection. Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
Conflicts of interest: All authors declare no conflicts of interest. * Corresponding author. Department of Urology, Urology Institute and Organ Transplantation Center, West China Hospital, Sichuan University, Guoxue Alley, Number 37, Chengdu, Post Code 610041, Sichuan, China. E-mail address: [email protected] (T. Lin). http://dx.doi.org/10.1016/j.kjms.2016.01.003 1607-551X/Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Song T, et al., Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.01.003
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T. Song et al.
Introduction
Assessment of kidney function
Kidney transplantation has long been considered the preferred treatment for patients with end-stage renal disease, providing substantially longer survival and better quality of life than dialysis [1,2]. Rising numbers of patients reaching end-stage renal disease intensify the demand for expansion of donor pool, and living kidney transplantation is one of the solutions. Although living kidney transplantation results in better patient and graft survival and avoids the long wait on dialysis [3], controversies over safety of donors remain. While a large cohort study has reported living donor nephrectomy to be safe [4], this is still a major procedure that carries potential risks for the donor. Additionally, there is uncertainty on the risk of increased cardiovascular mortality and progression to end-stage renal disease in the long term [4,5]. This highlights the need to optimize how living kidney donors are selected in order to ensure the best posttransplantation outcomes for them as well as for recipients. Several studies suggest that the ratio of allograft weight to recipient body weight predicts renal function in kidney transplantation recipients. One study reported that the mismatch of allograft weight to recipients’ body weight was associated with an increased risk of graft failure [6], and another study found that lower ratios of kidney weight to recipient body weight were associated with inferior kidney function at 12 months [7]. Moreover, Nicholson et al. [8] found that lower ratios of ultrasound-based allograft size to recipient weight predicted poor long-term renal allograft function. These observations led us to ask whether the analogous ratio of remnant kidney volume to body weight (V/W ratio) may predict kidney function in donors after transplantation. We are unaware of studies addressing this question. Therefore, we carried out a prospective study to investigate a possible association of the V/W ratio with renal function in living donors. We estimated kidney volume using magnetic resonance imaging (MRI)-based disc summation, which has been proved to be a reliable and reproducible method [9].
Renal scintigraphy with 99mTc-mercaptoacetyltriglycine was performed in all donors, and effective renal plasma flow was calculated using a camera-based technique. If renal function differed by > 15% between the right and left kidneys, usually the less functional kidney was removed. Serum creatinine levels were determined preoperatively and on Postoperative Day 7 in all 45 patients, and at 1 year postoperatively in 36 patients. The estimated glomerular filtration rate (eGFR) was estimated using the CockorofteGault formula [10]. Preoperative single-kidney eGFR was calculated by multiplying the preoperative total eGFR by the differential ratio of single-kidney effective renal plasma flow. In order to rule out differences in body surface area (BSA) among the donors, pre- and postoperative eGFRs were adjusted to the standard BSA (1.73 m2). BSA was calculated as described previously [11].
Methods
Both donated and remnant kidney volumes were recorded in milliliters, and preoperative body weight of each donor was recorded in kilograms. The V/W ratio was calculated for each donor as an index of nephron dose.
Patients Between July 2011 and January 2012, we prospectively enrolled a consecutive sample of living kidney donors at our clinic. Participants had to be at least 18 years old, not pregnant, and without any contraindications to MRI. In addition, all potential participants underwent a thorough preoperative evaluation to ensure that they were medically fit for donation and that their kidney was suitable for transplantation. All patients provided informed consent before undergoing MRI. This study was approved by our hospital’s Ethics Committee (West China Hospital, Sichuan University).
Estimation of kidney volume All donors were analyzed by MRI within 5 days prior to surgery. MRI was performed using a 3.0-Tesla scanner (Magnetom Trio Tim; Siemens, Munich, Germany). An eightchannel, phased-array coil was used for signal reception. A plain scan covering the entire kidney length in the craniocaudal direction was acquired using a T1-weighted gradient echo sequence. The specific acquisition parameters were as follows: TR (repetition time), 110 milliseconds; TE (echo time), 2.5 seconds; FOV (field of view), 380 380; flip angle, 70 ; slice number, 7; slice thickness, 6 mm; gap, 1.2 mm; and breath-hold duration, 15 seconds. A fat saturation pulse was used to suppress the signal from surrounding perirenal adipose tissue and to improve delineation of the renal border. Kidney volume was calculated from three dimensional volume images using the voxel-count method applied to coronal MR images, as described previously [9]. Boundaries of the renal parenchyma of each kidney slice were manually mapped, and kidney volume was calculated as follows: Kidney volume ðmLÞZ nSðiÞ ðparenchymal area slice thicknessÞi
ð1Þ
Statistical analysis All continuous data were reported as mean standard deviation and compared using the Student t test; categorical data were compared using the Chi-square test. Spearman’s correlation coefficients were calculated to evaluate the relationship between kidney function and donor characteristics. Logistical regression was used to assess the relationship between the V/W ratio and kidney function, and results were expressed as risk ratios (RRs) with 95%
Please cite this article in press as: Song T, et al., Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.01.003
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Kidney volume and renal function in donors
3 creatinine levels, eGFR, and increment of eGFR (Table 2). The two V/W groups differed significantly in levels of 24hour urinary protein at 1 year after transplantation. Donors with a V/W ratio of < 2.0 mL/kg showed significantly higher 24-hour urinary protein levels (0.54 0.23 g vs. 0.33 0.19 g, p Z 0.028). The difference between groups remained significant even after correcting for BSA: 0.34 0.21 g/m2/d for patients with a V/W ratio of < 2.0 mL/kg vs. 0.21 0.16 g/m2/d for patients with a V/W ratio of 2.0 mL/kg (p Z 0.035). We also investigated whether clinical and demographic characteristics of donors correlated with remnant kidney volume (Table 3). Univariate analysis revealed that body weight (p < 0.001) and preoperative eGFR of the remnant kidney (p Z 0.006) positively correlated with remnant kidney volume. Female donors were more likely to have a lower remnant kidney volume (p Z 0.024). In multivariate regression, only body weight correlated positively with remnant kidney volume (p Z 0.016). We performed multiple linear regression to identify factors that influence kidney function (Table 4). There was a significant correlation between gender and eGFR at 7 days (r Z 0.291, p Z 0.035) and 1 year (r Z 0.304, p Z 0.037). Preoperative eGFR of remnant kidney also positively correlated with remnant kidney function at 7 days (r Z 0.626, p < 0.001) and 1 year (r Z 0.737, p < 0.001). The V/W ratio did not correlate significantly with kidney function at 7 days (r Z 0.149, p Z 0.167) or 1 year (r Z 0.204, p Z 0.07). However, the V/W ratio correlated negatively with 24-hour urine protein (r Z 0.377, p Z 0.021) at 1 year. A V/W ratio of < 2.0 mL/kg was not associated with an increased incidence of eGFR of < 60 mL/ min/1.73 m2 at 1 year (RR Z 1.73, 95% CI 0.10e29.47), whereas donors with a V/W ratio of < 2.0 mL/kg were associated with an increased risk of 24-hour urine protein level of > 0.3 g at 1 year (RR Z 1.70, 95% CI 1.08e2.67).
confidence intervals (CIs). All tests were two sided, and p < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 18.0 (IBM, Chicago, IL, USA).
Results We enrolled a consecutive sample of 45 living donors (11 males and 34 females) in this study. The average volume of donated kidney was similar to the average volume of remnant kidney (124.45 25.53 mL vs. 118.06 23.51 mL, p Z 0.068). The same was true for preoperative kidney function (47.61 10.90 mL/min/1.73 m2 vs. 47.67 11.92 mL/min/1.73 m2, p Z 0.946). Since the mean V/W ratio in donors was 2.03 mL/kg, we divided participants into two groups: one with V/W ratios of < 2.0 mL/kg (n Z 23) and the other with V/W ratios of 2.0 mL/kg (n Z 22). Donors in both groups were well matched for age, weight, height, body mass index (BMI), BSA, 24-hour urinary protein, BSA-corrected 24-hour urinary protein, preoperative serum creatinine levels, and eGFR in both the donated and the remnant kidney. Although there were slightly more males in the group with a V/W ratio of 2.0 mL/kg, the difference did not reach significance (p Z 0.219). Donors with a V/W ratio of 2.0 mL/kg donated a significantly larger kidney volume (102.65 17.75 mL vs. 134.17 17.20 mL, p < 0.001) and were left with a significantly larger remnant kidney volume (116.93 26.00 mL vs. 132.32 23.05 mL, p Z 0.042; Table 1). After kidney removal, serum creatinine levels increased significantly from 65.34 11.41 mol/L to 105.07 22.62 mol/L at 7 days (p < 0.001), which subsequently stabilized at 97.54 19.09 mol/L at 1 year after transplantation (p < 0.001 with respect to presurgery; Table 2). In both V/W groups, eGFR of the remnant kidney increased from 48.75 8.93 mL/min/1.73 m2 before kidney removal to 61.61 13.41 mL/min/1.73 m2 at 1 week after surgery (p < 0.001), finally reaching 62.97 15.94 mL/min/ 1.73 m2 at 1 year (p < 0.001 with respect to presurgery). No difference was detected between both groups in serum Table 1
Discussion To the best of our knowledge, this is the first study analyzing whether the V/W ratio can influence remnant
Basic characteristics of included living kidney donors.
Characteristics Sex (male) Age (y) Weight (kg) Height (m) BMI (kg/m2) BSA (m2) Pre-Scr (mmol/L) Pre-24 h urine protein (g) Pre-eGFR (mL/min/1.73 m2) Pre-eGFR of donated kidney (mL/min/1.73 m2) Pre-eGFR of remaining kidney (mL/min/1.73 m2) Prevolume of donated kidney (mL) Prevolume of remaining kidney (mL)
V/W < 2.0 4 (17.4) 47.70 57.74 1.59 22.74 1.60 65.72 0.13 96.59 48.13 48.45 102.65 116.93
8.87 7.09 0.59 2.65 0.11 11.60 0.09 19.85 11.00 9.84 17.75 26.00
V/W 2.0 7 (31.8) 48.81 58.41 1.61 22.75 1.61 64.94 0.20 93.91 47.19 46.72 134.17 132.32
7.47 6.40 0.07 3.43 0.09 11.46 0.09 24.27 13.05 12.08 17.20 23.05
p 0.219 0.649 0.741 0.495 0.986 0.599 0.821 0.177 0.687 0.794 0.600 <0.001 0.042
Data are presented as n (%) or mean standard deviation. BMI Z body mass index; BSA Z body surface area; eGFR Z estimated glomerular filtration rate; Scr Z serum creatinine; V/W Z ratio of remnant kidney volume to body weight.
Please cite this article in press as: Song T, et al., Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.01.003
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Kidney function change of included living kidney donors. V/W < 2.0
Characteristics Serum creatinine at 7 d (mmol/L) Serum creatinine at 1 y (mmol/L) 24 h urine protein at 1 y (g) eGFR at 7 d (mL/min/1.73 m2) eGFR at 1 y (mL/min/1.73 m2) eGFR increment at 1 y (mL/min/1.73 m2)
104.59 101.61 0.54 60.86 62.60 13.74
20.71 22.62 0.23 12.57 12.89 71.7
V/W 2.0
p
0.885 0.520 0.028* 0.838 0.893 0.444
105.58 97.03 0.33 59.90 63.33 16.00
24.95 19.48 0.19 18.57 18.89 10.06
Data are presented as n (%) or mean standard deviation. *p < 0.05. eGFR Z estimated glomerular filtration rate; V/W Z ratio of remnant kidney volume to body weight.
kidney function in living donors. The main findings of this study are that V/W ratios of < 2.0 do not correlate with reduced renal function in donors after kidney donation, but they are associated with higher risk of 24-hour urinary protein levels that exceed the upper normal limit. Cheong et al. [9] concluded from their study that kidney volumes acquired from MRI with contrast using the disc summation methods were within 5% of true kidney volume, as determined by the reference standard water displacement methods. Other studies also found that MRI with gadolinium provides excellent tissue contrast [12,13]. However, an important limitation of gadolinium is that its use may lead to the development of nephrogenic systemic fibrosis [14]. Recently, Mignani et al. [15] proved that MRI without contrast is a reliable, objective, and reproducible method of assessing the total renal volume in autosomaldominant polycystic kidney disease. Therefore, we opted to use MRI without contrast enhancement and the discsummation method to estimate kidney volumes. Brenner et al. [16] and Brenner [17] have hypothesized that a deficient-functioning renal mass leads to progressive renal injury due to the detrimental effects of glomerular hyperfiltration, which sets in place a vicious cycle that glomerular damage leads to further reduction in renal mass, followed by ever worsening hyperfiltration. This theory has raised the proposal that a relatively small kidney
may not meet the requirements of a patient with a relatively large body mass who has a large metabolic demand for renal mass. Evidence from kidney transplantation has confirmed this concern. A multicenter study of 1189 patients in France found that a ratio of allograft weight to recipient body weight of < 2.3 g/kg was associated with a 55% higher risk of transplant failure at 2 years and a larger decrease in eGFR at 7 years (3.17 mL/min/y vs. 1.34 mL/ min/y, p < 0.001) [6]. Akoglu et al. [18] reported that recipients with ratios of graft volume to body weight of < 2.7 had significantly higher serum creatinine levels and lower eGFRs than those with higher ratios at 6 months, 12 months, and 24 months. Yakoubi et al. [19] have demonstrated that BSA-adjusted remnant kidney volume was an independent predictor of eGFR at 1 year (p Z 0.02) in living kidney donors, suggesting that the dosage of preserved kidney volume should be considered. Our results showed a borderline correlation between the V/W ratio and eGFR at 1 year after kidney removal as well. It is known that upon kidney removal, the effective renal blood flow of the remnant kidney increases immediately [20,21]; consequently, it will work at a compensatory state and the GFR will increase. Our previous study have shown that the volume of remnant kidney was
Table 4 Correlation between preoperative patient characteristics and kidney function. Table 3 Correlation between preoperative patient characteristics and volume of remaining kidney. Univariate analysis b Sex (female vs. male) Age Weight Height Pre-Scr Pre-eGFR of donated kidney Pre-eGFR of remaining kidney
p
Multivariate analysis b
p
0.337
0.024
0.138
0.385
0.01 0.568 0.03 0.108 0.069
0.946 <0.001 0.847 0.481 0.650
0.238 0.396 0.057 0.128 0.041
0.198 0.016 0.703 0.761 0.822
0.405
0.006
0.292
0.126
eGFR Z estimated glomerular filtration rate; Scr Z serum creatinine.
eGFR at 7 d
b
p
eGFR at 1 y
b
p
24 h urine protein at 1 y b
Sex (female 0.291 0.035 0.304 0.037 0.505 vs. male) Age 0.149 0.25 0.076 0.491 0.19 Weight 0.117 0.445 0.063 0.716 0.215 Height 0.104 0.385 0.101 0.39 0.29 Pre-Scr 0.2 0.118 0.061 0.565 0.308 Pre-eGFR of 0.626 <0.001 0.737 <0.001 0.078 remaining kidney V/W ratio 0.149 0.167 0.204 0.07 0.189
p 0.012 0.305 0.156 0.095 0.094 0.684
0.022
eGFR Z estimated glomerular filtration rate; Scr Z serum creatinine; V/W ratio Z ratio of remaining kidney volume to body weight.
Please cite this article in press as: Song T, et al., Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.01.003
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Kidney volume and renal function in donors negatively associated with volume increment after nephrectomy and the kidney with larger volume compensation had lower serum creatinine, indicating that small kidneys may have better function compensation [22]. In this cohort, donors with a V/W ratio of < 2 had a similar eGFR increment to those with a V/W ratio of 2. However, our results must be interpreted with caution because the BMI of included donors is relatively small (22.75 3.02 kg/m2). Whether it is applicable to those who have a much higher BMI remains to be clarified. Reports on kidney transplantation concerning the mismatch between allograft and recipients’ body weight demonstrated conflicting results regarding proteinuria. One study of 69 kidney transplantations from living donors found similar 24-hour urinary protein excretion for low, medium, and high volume/weight ratios over a 24-month follow-up period [18]. Another study similarly failed to detect a correlation between the volume/weight ratio and the incidence of proteinuria for up to 5 years after transplantation [23]. By contrast, one study involving 1189 transplantations found that recipients with a ratio of allograft weight to recipient body weight of < 2.3 g/kg were at a significantly higher risk of proteinuria > 0.5 g/d at 1 year (RR 1.35, 95% CI 1.08e1.66) [6]. Another study went so far as to conclude that the ratio of allograft size to recipient weight is the most important determinant of proteinuria risk in recipients [24]. We found that living donors with lower V/W ratios had higher 24-hour urinary protein levels and were more likely to have 24-hour urinary protein levels above the upper normal limit. This suggests that insufficient remnant kidney volume in a donor of a given body weight can lead to hyperfiltration and subsequent proteinuria. This is the first study to demonstrate that the V/W ratio does not affect eGFR in donors, and that donors with lower V/W ratios show higher 24-hour urinary protein excretion at 1 year after surgery. Nevertheless, our results should be interpreted with caution because we did not conduct longterm follow-up of renal outcomes, and the BMI in our cohort was relatively small. Whether our findings are applicable to long-term outcomes and to donors with much higher BMI remains to be clarified. In conclusion, the V/W ratio does not appear to affect eGFR, but donors with lower V/W ratios have higher 24hour urinary protein levels at 1 year after transplantation. Our study suggests that remnant kidney volume and donor body weight should be taken into consideration in kidney selection.
Acknowledgments
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[7]
[8]
[9]
[10] [11] [12]
[13]
[14]
[15]
[16] [17]
[18]
[19]
This study was supported by the National Nature Science Foundation of China (grant nos. 30872579 and 81470980). [20]
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kidney donors: a systematic review. Am J Transplant 2006;6: 2965e7. Naderi GH, Mehraban D, Kazemeyni SM, Darvishi M, Latif AH. Living or deceased donor kidney transplantation: a comparison of results and survival rates among Iranian patients. Transplant Proc 2009;41:2772e4. Muzaale AD, Massie AB, Wang MC, Montgomery RA, McBride MA, Wainright JL, et al. Risk of end-stage renal disease following live kidney donation. JAMA 2014;311:579e86. Hourmant M, Lerat L, Karam G. Donation from old living donors: how safe is it? Nephrol Dial Transplant 2013;28:2010e4. Giral M, Foucher Y, Karam G, Labrune Y, Kessler M, Hurault de Ligny B, et al. Kidney and recipient weight incompatibility reduces long-term graft survival. J Am Soc Nephrol 2010;21: 1022e9. Douverny JB, Baptista-Silva JC, Pestana JO, Sesso R. Importance of renal mass on graft function outcome after 12 months of living donor kidney transplantation. Nephrol Dial Transplant 2007;22:3646e51. Nicholson ML, Windmill DC, Horsburgh T, Harris KP. Influence of allograft size to recipient body-weight ratio on the long-term outcome of renal transplantation. Br J Surg 2000;87:314e9. Cheong B, Muthupillai R, Rubin MF, Flamm SD. Normal values for renal length and volume as measured by magnetic resonance imaging. Clin J Am Soc Nephrol 2007;2:38e45. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31e41. Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317:1098. Lee YR, Lee KB. Reliability of magnetic resonance imaging for measuring the volumetric indices in autosomal-dominant polycystic kidney disease: correlation with hypertension and renal function. Nephron Clin Pract 2006;103:c173e80. Reichardt W, Romaker D, Becker A, Buechert M, Walz G, von Elverfeldt D. Monitoring kidney and renal cyst volumes applying MR approaches on a rapamycin-treated mouse model of ADPKD. MAGMA 2009;22:143e9. Wiginton CD, Kelly B, Oto A, Jesse M, Aristimuno P, Ernst R, et al. Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue. AJR Am J Roentgenol 2008;190:1060e8. Mignani R, Corsi C, De Marco M, Caiani EG, Santucci G, Cavagna E, et al. Assessment of kidney volume in polycystic kidney disease using magnetic resonance imaging without contrast medium. Am J Nephrol 2011;33:176e84. Brenner BM, Cohen RA, Milford EL. In renal transplantation, one size may not fit all. J Am Soc Nephrol 1992;3:162e9. Brenner BM. Hemodynamically mediated glomerular injury and the progressive nature of kidney disease. Kidney Int 1983; 23:647e55. Akoglu H, Yildirim T, Eldem G, Arik G, Yilmaz R, Kutlugun AA, et al. Living donor kidney volume as a predictor of graft function: is there a role for proteinuria? Transplant Proc 2013; 45:77e81. Yakoubi R, Autorino R, Kassab A, Long JA, Haber GP, Kaouk JH. Does preserved kidney volume predict 1 year donor renal function after laparoscopic living donor nephrectomy? Int J Urol 2013;20:931e4. Ziada G, Youseif H, Khalil M. Compensatory changes in the function of the remnant kidney immediately after unilateral nephrectomy in sheep. Tohoku J Exp Med 2009;219: 165e8. Anderson RG, Bueschen AJ, Lloyd LK, Dubovsky EV, Burns JR. Short-term and long-term changes in renal function after donor nephrectomy. J Urol 1991;145:11e3. Song T, Fu L, Huang Z, He S, Zhao R, Lin T, et al. Change in renal parenchymal volume in living kidney transplant donors. Int Urol Nephrol 2014;46:743e7.
Please cite this article in press as: Song T, et al., Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.01.003
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6 [23] Alcalde G, Escallada R, Rodrigo E, Cotorruelo JG, Zubimendi JA, de Francisco AL, et al. Disproportion between kidney graft and recipient size is the main predictor of longterm proteinuria. Transplant Proc 1997;29:127e8.
T. Song et al. [24] Miles AM, Sumrani N, John S, Markell MS, Distant DA, Maursky V, et al. The effect of kidney size on cadaveric renal allograft outcome. Transplantation 1996;61:894e7.
Please cite this article in press as: Song T, et al., Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.01.003
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Kaohsiung Journal of Medical Sciences (2016) xx, 1e6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.kjms-online.com
ORIGINAL ARTICLE
Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors Turun Song, Zhengsheng Rao, Yang Qiu, Jinpeng Liu, Zhongli Huang, Xianding Wang, Tao Lin* Department of Urology, Urology Institute and Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, China Received 25 September 2015; accepted 20 November 2015
KEYWORDS Body weight; Kidney function; Kidney volume; Living donor; Proteinuria
Abstract To investigate whether the ratio of remnant kidney volume to body weight (V/W ratio) can impact renal function in donors, 45 living kidney donors were enrolled. Kidney volume was analyzed by magnetic resonance imaging. Renal function was compared between donors with a V/W ratio of < 2.0 mL/kg (n Z 23) or 2.0 mL/kg (n Z 22). Donors in both V/W groups showed similar serum creatinine levels and estimated glomerular filtration rates (eGFRs) at 7 days and 1 year, whereas donors with a V/W ratio of < 2.0 mL/kg had significantly higher 24-hour urine protein levels at 1 year (0.54 0.23 g/d vs. 0.33 0.19 g/d, p Z 0.028). Multivariate analysis revealed no correlation between the V/W ratio and eGFR at 7 days or 1 year, and a V/W ratio of < 2 mL/kg was not associated with an increased incidence of eGFR < 60 mL/min/1.73 m2 at 1 year (risk ratio 1.73, 95% confidence interval 0.10e29.47). The V/W ratio correlated inversely with 24-hour urine protein (r Z 0.377, p Z 0.021) at 1 year, and donors with a V/W ratio of < 2.0 mL/kg were more likely to show 24-hour urine protein >300 mg (risk ratio 1.70, 95% confidence interval 1.08e2.67) at 1 year. Donors with lower V/W ratios have higher 24-hour urinary protein levels at 1 year after transplantation. These findings suggest that the V/W ratio may be useful for kidney selection. Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
Conflicts of interest: All authors declare no conflicts of interest. * Corresponding author. Department of Urology, Urology Institute and Organ Transplantation Center, West China Hospital, Sichuan University, Guoxue Alley, Number 37, Chengdu, Post Code 610041, Sichuan, China. E-mail address: [email protected] (T. Lin). http://dx.doi.org/10.1016/j.kjms.2016.01.003 1607-551X/Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Song T, et al., Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.01.003
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Introduction
Assessment of kidney function
Kidney transplantation has long been considered the preferred treatment for patients with end-stage renal disease, providing substantially longer survival and better quality of life than dialysis [1,2]. Rising numbers of patients reaching end-stage renal disease intensify the demand for expansion of donor pool, and living kidney transplantation is one of the solutions. Although living kidney transplantation results in better patient and graft survival and avoids the long wait on dialysis [3], controversies over safety of donors remain. While a large cohort study has reported living donor nephrectomy to be safe [4], this is still a major procedure that carries potential risks for the donor. Additionally, there is uncertainty on the risk of increased cardiovascular mortality and progression to end-stage renal disease in the long term [4,5]. This highlights the need to optimize how living kidney donors are selected in order to ensure the best posttransplantation outcomes for them as well as for recipients. Several studies suggest that the ratio of allograft weight to recipient body weight predicts renal function in kidney transplantation recipients. One study reported that the mismatch of allograft weight to recipients’ body weight was associated with an increased risk of graft failure [6], and another study found that lower ratios of kidney weight to recipient body weight were associated with inferior kidney function at 12 months [7]. Moreover, Nicholson et al. [8] found that lower ratios of ultrasound-based allograft size to recipient weight predicted poor long-term renal allograft function. These observations led us to ask whether the analogous ratio of remnant kidney volume to body weight (V/W ratio) may predict kidney function in donors after transplantation. We are unaware of studies addressing this question. Therefore, we carried out a prospective study to investigate a possible association of the V/W ratio with renal function in living donors. We estimated kidney volume using magnetic resonance imaging (MRI)-based disc summation, which has been proved to be a reliable and reproducible method [9].
Renal scintigraphy with 99mTc-mercaptoacetyltriglycine was performed in all donors, and effective renal plasma flow was calculated using a camera-based technique. If renal function differed by > 15% between the right and left kidneys, usually the less functional kidney was removed. Serum creatinine levels were determined preoperatively and on Postoperative Day 7 in all 45 patients, and at 1 year postoperatively in 36 patients. The estimated glomerular filtration rate (eGFR) was estimated using the CockorofteGault formula [10]. Preoperative single-kidney eGFR was calculated by multiplying the preoperative total eGFR by the differential ratio of single-kidney effective renal plasma flow. In order to rule out differences in body surface area (BSA) among the donors, pre- and postoperative eGFRs were adjusted to the standard BSA (1.73 m2). BSA was calculated as described previously [11].
Methods
Both donated and remnant kidney volumes were recorded in milliliters, and preoperative body weight of each donor was recorded in kilograms. The V/W ratio was calculated for each donor as an index of nephron dose.
Patients Between July 2011 and January 2012, we prospectively enrolled a consecutive sample of living kidney donors at our clinic. Participants had to be at least 18 years old, not pregnant, and without any contraindications to MRI. In addition, all potential participants underwent a thorough preoperative evaluation to ensure that they were medically fit for donation and that their kidney was suitable for transplantation. All patients provided informed consent before undergoing MRI. This study was approved by our hospital’s Ethics Committee (West China Hospital, Sichuan University).
Estimation of kidney volume All donors were analyzed by MRI within 5 days prior to surgery. MRI was performed using a 3.0-Tesla scanner (Magnetom Trio Tim; Siemens, Munich, Germany). An eightchannel, phased-array coil was used for signal reception. A plain scan covering the entire kidney length in the craniocaudal direction was acquired using a T1-weighted gradient echo sequence. The specific acquisition parameters were as follows: TR (repetition time), 110 milliseconds; TE (echo time), 2.5 seconds; FOV (field of view), 380 380; flip angle, 70 ; slice number, 7; slice thickness, 6 mm; gap, 1.2 mm; and breath-hold duration, 15 seconds. A fat saturation pulse was used to suppress the signal from surrounding perirenal adipose tissue and to improve delineation of the renal border. Kidney volume was calculated from three dimensional volume images using the voxel-count method applied to coronal MR images, as described previously [9]. Boundaries of the renal parenchyma of each kidney slice were manually mapped, and kidney volume was calculated as follows: Kidney volume ðmLÞZ nSðiÞ ðparenchymal area slice thicknessÞi
ð1Þ
Statistical analysis All continuous data were reported as mean standard deviation and compared using the Student t test; categorical data were compared using the Chi-square test. Spearman’s correlation coefficients were calculated to evaluate the relationship between kidney function and donor characteristics. Logistical regression was used to assess the relationship between the V/W ratio and kidney function, and results were expressed as risk ratios (RRs) with 95%
Please cite this article in press as: Song T, et al., Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.01.003
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Kidney volume and renal function in donors
3 creatinine levels, eGFR, and increment of eGFR (Table 2). The two V/W groups differed significantly in levels of 24hour urinary protein at 1 year after transplantation. Donors with a V/W ratio of < 2.0 mL/kg showed significantly higher 24-hour urinary protein levels (0.54 0.23 g vs. 0.33 0.19 g, p Z 0.028). The difference between groups remained significant even after correcting for BSA: 0.34 0.21 g/m2/d for patients with a V/W ratio of < 2.0 mL/kg vs. 0.21 0.16 g/m2/d for patients with a V/W ratio of 2.0 mL/kg (p Z 0.035). We also investigated whether clinical and demographic characteristics of donors correlated with remnant kidney volume (Table 3). Univariate analysis revealed that body weight (p < 0.001) and preoperative eGFR of the remnant kidney (p Z 0.006) positively correlated with remnant kidney volume. Female donors were more likely to have a lower remnant kidney volume (p Z 0.024). In multivariate regression, only body weight correlated positively with remnant kidney volume (p Z 0.016). We performed multiple linear regression to identify factors that influence kidney function (Table 4). There was a significant correlation between gender and eGFR at 7 days (r Z 0.291, p Z 0.035) and 1 year (r Z 0.304, p Z 0.037). Preoperative eGFR of remnant kidney also positively correlated with remnant kidney function at 7 days (r Z 0.626, p < 0.001) and 1 year (r Z 0.737, p < 0.001). The V/W ratio did not correlate significantly with kidney function at 7 days (r Z 0.149, p Z 0.167) or 1 year (r Z 0.204, p Z 0.07). However, the V/W ratio correlated negatively with 24-hour urine protein (r Z 0.377, p Z 0.021) at 1 year. A V/W ratio of < 2.0 mL/kg was not associated with an increased incidence of eGFR of < 60 mL/ min/1.73 m2 at 1 year (RR Z 1.73, 95% CI 0.10e29.47), whereas donors with a V/W ratio of < 2.0 mL/kg were associated with an increased risk of 24-hour urine protein level of > 0.3 g at 1 year (RR Z 1.70, 95% CI 1.08e2.67).
confidence intervals (CIs). All tests were two sided, and p < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 18.0 (IBM, Chicago, IL, USA).
Results We enrolled a consecutive sample of 45 living donors (11 males and 34 females) in this study. The average volume of donated kidney was similar to the average volume of remnant kidney (124.45 25.53 mL vs. 118.06 23.51 mL, p Z 0.068). The same was true for preoperative kidney function (47.61 10.90 mL/min/1.73 m2 vs. 47.67 11.92 mL/min/1.73 m2, p Z 0.946). Since the mean V/W ratio in donors was 2.03 mL/kg, we divided participants into two groups: one with V/W ratios of < 2.0 mL/kg (n Z 23) and the other with V/W ratios of 2.0 mL/kg (n Z 22). Donors in both groups were well matched for age, weight, height, body mass index (BMI), BSA, 24-hour urinary protein, BSA-corrected 24-hour urinary protein, preoperative serum creatinine levels, and eGFR in both the donated and the remnant kidney. Although there were slightly more males in the group with a V/W ratio of 2.0 mL/kg, the difference did not reach significance (p Z 0.219). Donors with a V/W ratio of 2.0 mL/kg donated a significantly larger kidney volume (102.65 17.75 mL vs. 134.17 17.20 mL, p < 0.001) and were left with a significantly larger remnant kidney volume (116.93 26.00 mL vs. 132.32 23.05 mL, p Z 0.042; Table 1). After kidney removal, serum creatinine levels increased significantly from 65.34 11.41 mol/L to 105.07 22.62 mol/L at 7 days (p < 0.001), which subsequently stabilized at 97.54 19.09 mol/L at 1 year after transplantation (p < 0.001 with respect to presurgery; Table 2). In both V/W groups, eGFR of the remnant kidney increased from 48.75 8.93 mL/min/1.73 m2 before kidney removal to 61.61 13.41 mL/min/1.73 m2 at 1 week after surgery (p < 0.001), finally reaching 62.97 15.94 mL/min/ 1.73 m2 at 1 year (p < 0.001 with respect to presurgery). No difference was detected between both groups in serum Table 1
Discussion To the best of our knowledge, this is the first study analyzing whether the V/W ratio can influence remnant
Basic characteristics of included living kidney donors.
Characteristics Sex (male) Age (y) Weight (kg) Height (m) BMI (kg/m2) BSA (m2) Pre-Scr (mmol/L) Pre-24 h urine protein (g) Pre-eGFR (mL/min/1.73 m2) Pre-eGFR of donated kidney (mL/min/1.73 m2) Pre-eGFR of remaining kidney (mL/min/1.73 m2) Prevolume of donated kidney (mL) Prevolume of remaining kidney (mL)
V/W < 2.0 4 (17.4) 47.70 57.74 1.59 22.74 1.60 65.72 0.13 96.59 48.13 48.45 102.65 116.93
8.87 7.09 0.59 2.65 0.11 11.60 0.09 19.85 11.00 9.84 17.75 26.00
V/W 2.0 7 (31.8) 48.81 58.41 1.61 22.75 1.61 64.94 0.20 93.91 47.19 46.72 134.17 132.32
7.47 6.40 0.07 3.43 0.09 11.46 0.09 24.27 13.05 12.08 17.20 23.05
p 0.219 0.649 0.741 0.495 0.986 0.599 0.821 0.177 0.687 0.794 0.600 <0.001 0.042
Data are presented as n (%) or mean standard deviation. BMI Z body mass index; BSA Z body surface area; eGFR Z estimated glomerular filtration rate; Scr Z serum creatinine; V/W Z ratio of remnant kidney volume to body weight.
Please cite this article in press as: Song T, et al., Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.01.003
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T. Song et al. Table 2
Kidney function change of included living kidney donors. V/W < 2.0
Characteristics Serum creatinine at 7 d (mmol/L) Serum creatinine at 1 y (mmol/L) 24 h urine protein at 1 y (g) eGFR at 7 d (mL/min/1.73 m2) eGFR at 1 y (mL/min/1.73 m2) eGFR increment at 1 y (mL/min/1.73 m2)
104.59 101.61 0.54 60.86 62.60 13.74
20.71 22.62 0.23 12.57 12.89 71.7
V/W 2.0
p
0.885 0.520 0.028* 0.838 0.893 0.444
105.58 97.03 0.33 59.90 63.33 16.00
24.95 19.48 0.19 18.57 18.89 10.06
Data are presented as n (%) or mean standard deviation. *p < 0.05. eGFR Z estimated glomerular filtration rate; V/W Z ratio of remnant kidney volume to body weight.
kidney function in living donors. The main findings of this study are that V/W ratios of < 2.0 do not correlate with reduced renal function in donors after kidney donation, but they are associated with higher risk of 24-hour urinary protein levels that exceed the upper normal limit. Cheong et al. [9] concluded from their study that kidney volumes acquired from MRI with contrast using the disc summation methods were within 5% of true kidney volume, as determined by the reference standard water displacement methods. Other studies also found that MRI with gadolinium provides excellent tissue contrast [12,13]. However, an important limitation of gadolinium is that its use may lead to the development of nephrogenic systemic fibrosis [14]. Recently, Mignani et al. [15] proved that MRI without contrast is a reliable, objective, and reproducible method of assessing the total renal volume in autosomaldominant polycystic kidney disease. Therefore, we opted to use MRI without contrast enhancement and the discsummation method to estimate kidney volumes. Brenner et al. [16] and Brenner [17] have hypothesized that a deficient-functioning renal mass leads to progressive renal injury due to the detrimental effects of glomerular hyperfiltration, which sets in place a vicious cycle that glomerular damage leads to further reduction in renal mass, followed by ever worsening hyperfiltration. This theory has raised the proposal that a relatively small kidney
may not meet the requirements of a patient with a relatively large body mass who has a large metabolic demand for renal mass. Evidence from kidney transplantation has confirmed this concern. A multicenter study of 1189 patients in France found that a ratio of allograft weight to recipient body weight of < 2.3 g/kg was associated with a 55% higher risk of transplant failure at 2 years and a larger decrease in eGFR at 7 years (3.17 mL/min/y vs. 1.34 mL/ min/y, p < 0.001) [6]. Akoglu et al. [18] reported that recipients with ratios of graft volume to body weight of < 2.7 had significantly higher serum creatinine levels and lower eGFRs than those with higher ratios at 6 months, 12 months, and 24 months. Yakoubi et al. [19] have demonstrated that BSA-adjusted remnant kidney volume was an independent predictor of eGFR at 1 year (p Z 0.02) in living kidney donors, suggesting that the dosage of preserved kidney volume should be considered. Our results showed a borderline correlation between the V/W ratio and eGFR at 1 year after kidney removal as well. It is known that upon kidney removal, the effective renal blood flow of the remnant kidney increases immediately [20,21]; consequently, it will work at a compensatory state and the GFR will increase. Our previous study have shown that the volume of remnant kidney was
Table 4 Correlation between preoperative patient characteristics and kidney function. Table 3 Correlation between preoperative patient characteristics and volume of remaining kidney. Univariate analysis b Sex (female vs. male) Age Weight Height Pre-Scr Pre-eGFR of donated kidney Pre-eGFR of remaining kidney
p
Multivariate analysis b
p
0.337
0.024
0.138
0.385
0.01 0.568 0.03 0.108 0.069
0.946 <0.001 0.847 0.481 0.650
0.238 0.396 0.057 0.128 0.041
0.198 0.016 0.703 0.761 0.822
0.405
0.006
0.292
0.126
eGFR Z estimated glomerular filtration rate; Scr Z serum creatinine.
eGFR at 7 d
b
p
eGFR at 1 y
b
p
24 h urine protein at 1 y b
Sex (female 0.291 0.035 0.304 0.037 0.505 vs. male) Age 0.149 0.25 0.076 0.491 0.19 Weight 0.117 0.445 0.063 0.716 0.215 Height 0.104 0.385 0.101 0.39 0.29 Pre-Scr 0.2 0.118 0.061 0.565 0.308 Pre-eGFR of 0.626 <0.001 0.737 <0.001 0.078 remaining kidney V/W ratio 0.149 0.167 0.204 0.07 0.189
p 0.012 0.305 0.156 0.095 0.094 0.684
0.022
eGFR Z estimated glomerular filtration rate; Scr Z serum creatinine; V/W ratio Z ratio of remaining kidney volume to body weight.
Please cite this article in press as: Song T, et al., Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.01.003
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Kidney volume and renal function in donors negatively associated with volume increment after nephrectomy and the kidney with larger volume compensation had lower serum creatinine, indicating that small kidneys may have better function compensation [22]. In this cohort, donors with a V/W ratio of < 2 had a similar eGFR increment to those with a V/W ratio of 2. However, our results must be interpreted with caution because the BMI of included donors is relatively small (22.75 3.02 kg/m2). Whether it is applicable to those who have a much higher BMI remains to be clarified. Reports on kidney transplantation concerning the mismatch between allograft and recipients’ body weight demonstrated conflicting results regarding proteinuria. One study of 69 kidney transplantations from living donors found similar 24-hour urinary protein excretion for low, medium, and high volume/weight ratios over a 24-month follow-up period [18]. Another study similarly failed to detect a correlation between the volume/weight ratio and the incidence of proteinuria for up to 5 years after transplantation [23]. By contrast, one study involving 1189 transplantations found that recipients with a ratio of allograft weight to recipient body weight of < 2.3 g/kg were at a significantly higher risk of proteinuria > 0.5 g/d at 1 year (RR 1.35, 95% CI 1.08e1.66) [6]. Another study went so far as to conclude that the ratio of allograft size to recipient weight is the most important determinant of proteinuria risk in recipients [24]. We found that living donors with lower V/W ratios had higher 24-hour urinary protein levels and were more likely to have 24-hour urinary protein levels above the upper normal limit. This suggests that insufficient remnant kidney volume in a donor of a given body weight can lead to hyperfiltration and subsequent proteinuria. This is the first study to demonstrate that the V/W ratio does not affect eGFR in donors, and that donors with lower V/W ratios show higher 24-hour urinary protein excretion at 1 year after surgery. Nevertheless, our results should be interpreted with caution because we did not conduct longterm follow-up of renal outcomes, and the BMI in our cohort was relatively small. Whether our findings are applicable to long-term outcomes and to donors with much higher BMI remains to be clarified. In conclusion, the V/W ratio does not appear to affect eGFR, but donors with lower V/W ratios have higher 24hour urinary protein levels at 1 year after transplantation. Our study suggests that remnant kidney volume and donor body weight should be taken into consideration in kidney selection.
Acknowledgments
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[7]
[8]
[9]
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[13]
[14]
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[16] [17]
[18]
[19]
This study was supported by the National Nature Science Foundation of China (grant nos. 30872579 and 81470980). [20]
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Please cite this article in press as: Song T, et al., Impact of remaining kidney volume to body weight ratio on renal function in living kidney donors, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.01.003