Factors influencing contralateral renal hypertrophy after living donor nephrectomy

ORGAN DONATION

Factors Influencing Contralateral Renal Hypertrophy After Living Donor Nephrectomy S.-G. Chang, J.-H. Kim, S.-J. Lee, J.-M. Choi, and J.-S. Huh

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HE use of living related donors yields the most successful renal transplantations. The safety of donor nephrectomy was initially based on life insurance actuarial data and surveys, which concluded that unilateral nephrectomy did not present an increased survival risk.1 Anderson et al2 reported that 232 patients who underwent nephrectomy for various reasons showed a return of blood urea nitrogen (BUN) and serum creatinine levels to blood urea nitrogen (BUN) and serum creatinine levels to normal and a survival rate that was equal to the control population when the procedure was performed for benign disease. Compensatory renal growth occurs after unilateral nephrectomy, both in animals as well as in healthy renal donors. The removal of a normal kidney results in a prompt increase in the glomerular filtration rate (GFR) of the remaining kidney.3 Unilateral nephrectomy in the rat, rabbit, or dog is followed by prompt hypertrophy4 and hyperplasia of the remaining kidney.5 The living donors for kidney transplantation afford an opportunity to study renal size before and after nephrectomy in a large group of healthy adults. Only a few clinical studies have examined the factors that determine or the patterns of serial volume changes leading to compensatory renal growth in patients after living donor nephrectomy. The purpose of this study was to evaluate the patterns of renal growth and clinically significant factors, in order to establish a useful method to assess renal volume secondary to nephrectomy in normal adult kidney donors. MATERIALS AND METHODS From January 1990 to December 1998, a total of 180 living donor nephrectomies were performed at our hospital. A total of 56 men © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 1139 –1142 (2002)

and 43 women, with a mean age of 43.2 years, participated in the study. All kidney donors had been evaluated before donor nephrectomy to assure the absence of renal or systemic disease. Patient body status parameters, such as height, weight, body mass index (weight/surface m2), body surface area, body density (g/cm3), body volume (L), and body fat compositions (%) were measured just prior to nephrectomy. Clinical parameters such as serum BUN, creatinine, insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), creatinine clearance, 24-hour urine protein and serum creatinine were measured before and at 3 months, 6 months, and 12 months after donor nephrectomy to evaluate renal function. Thyroid function test, (serum T3, T4, TSH) and serum albumin levels were evaluated before surgery to exclude patients with abnormal thyroid function or poor nutritional status that may impact on serum IGF-1 and IGFBP3 studies. To identify the compensatory renal growth of the remaining kidney after donor nephrectomy, renal volume was measured serially before and at 3 months, 6 months, and 12 months after donor nephrectomy using Tc-99m DMSA Spect (Toshiba, GCA-90 gamma camera, Tokyo, Japan) and by ultrasonography. Using the repeated measure analysis of variance and the paired t test, we analyzed the method of renal volume measurement. We used Pearson’s correlation coefficient to examine the relationship between the change of renal volume and possible impact factors. All P values ⬍ .05 were considered significant. All subjects gave their informed consent prior to inclusion in this study.

From the Departments of Urology (S.-G.C., J.-H.K., S.-J.L.) and Preventive Medicine (J.-M.C.), School of Medicine, Kyung Hee University, Seoul, Korea, and Department of Urology (J.-S.H.), School of Medicine, Cheju National University, Cheju, Korea. Address reprint requests to Prof. Sung-Goo Chang, MD, Department of Urology, Kyung Hee University Medical Center, No. 1 Hoegidong Dongdaemun-Ku, Seoul 130-702 Korea (R.O.K.). 0041-1345/02/$–see front matter PII S0041-1345(02)02762-8 1139

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CHANG, KIM, LEE ET AL Table 1. Patient Demographics Men Mean ⫾ SD

No. of patients Patient age Height (cm) Weight (kg) Body mass index (kg/m2) Body surface (m2) Body volume (L) Body density (g/cm3) Body fat (%)

Women Range

Mean ⫾ SD

56 41.9 ⫾ 13.1 170.1 ⫾ 4.3 69.3 ⫾ 6.5 23.9 ⫾ 1.8 1.8 ⫾ 0.1 64.9 ⫾ 6.4 1.07 ⫾ 0.01 13.8 ⫾ 2.3

RESULTS Patient Characteristics

Table 1 shows the demographic features of this cohort. A total of 99 patients (56 men and 43 women) who underwent donor nephrectomy were included in this study. Their mean age, height, body weight, body mass index, body surface area, and body volume were 43.2 years, 162.5 cm, 62.2 kg, 23.25 kg/m2, 1.65 m2, and 58.95 L, respectively.

Range

43 20 –71 162.0 –182.0 52.0 – 88.0 18.6 –27.3 1.6 –2.09 48.5– 83.9 1.05–1.08 9.9 –21.9

44.6 ⫾ 13.5 155.9 ⫾ 3.7 55.1 ⫾ 7.1 22.6 ⫾ 2.0 1.5 ⫾ 0.1 53.0 ⫾ 6.9 1.04 ⫾ 0.003 25.9 ⫾ 1.4

24 –71 150.0 –164.0 47.0 –77.0 19.7–28.9 1.4 –1.8 45.1–74.6 1.03–1.05 22.9 –29.0

Spect–measured renal volume of the remaining kidney in the 99 patients was 181.2 ⫾ 23.9 mL. Three months after nephrectomy, the mean renal volume had increased by 12.3% to 203.5 ⫾ 30.0 mL. After 12 months, it had increased by 23.7% over the preoperative volume to 224.2 ⫾ 33.2 mL. The postoperative renal volume increased rapidly during the first 3 postoperative months. Impact Factors for Renal Growth

Change of Renal Volume and Volume Increment

Figure 1 shows the difference in the estimate of renal volume using ultrasonographic versus DMSA Spect measurements over 1 year posttransplant. The repeated measures analysis of variance of renal volumes showed no significant interaction between ultrasonographic and DMSA Spect measurement (P ⫽ .3063), but there were statistically significant differences over time and between subjects (P ⫽ .001). The renal volume increment significantly increased over time (P ⫽ .001), but there were no statistically significant interactions between the two types of effects (P ⫽ .170) or for the between-subject effects (P ⫽ .733). Thus, a significant difference existed between the results of DMSA Spect and ultrasound methods for measuring renal volumes. The mean preoperative DMSA

Fig 1. Postoperative renal volume changes were measured using ultrasound and DMSA Spect. There was a significant difference between DMSA Spect and ultrasound for measuring renal volume (P ⫽ .001). Error bars indicate the standard error.

When the patients were grouped according to age, donors under age 40 years displayed a higher rate of renal growth than did those older than 40 years (P ⫽ .008). Using a sex-adjusted analysis of covariance, there were significant differences in renal volume at each measurement period (Fig 2). The postoperative renal volume increased in both men and women to a similar degree using an age-adjusted analysis (P ⫽ 0.08; Fig 3). An inverse correlation existed between the preoperative body mass index and the postoperative total increment in renal volume (r ⫽ ⫺0.1977; P ⫽ .05), but no correlation existed with other factors such as height, weight, body surface, body density, and body fat. Serum IGF-1 and IGFBP-3 levels were measured in 44 patients. Serum levels of IGF-1 preoperatively, and 3, 6, and 12 months postoperatively were 217.5 ⫾ 16.86, 293.9 ⫾ 85.91, 287.7 ⫾ 74.05, and 228.7 ⫾ 72.36 ng/mL, respectively.

Fig 2. Postoperative renal growth was measured according to age group. More rapid renal growth was seen in patients younger than 40 years (P ⫽ .008).

CONTRALATERAL RENAL HYPERTROPHY

Fig 3. Comparison of renal growth between male and female patients. There was no significant difference (P ⫽ .08). Error bars indicate the standard error.

Serum IGF-1 levels showed a marked increment from the preoperative to the postoperative value at 6 months (P ⫽ .0001) and returned to the baseline levels at 12 months. The serum IGFBP-3 levels also increased significantly from the preoperative to the postoperative state during follow-up in this study (P ⫽ .0001; Fig 4). Postoperative Renal Function

The postoperative renal function as assessed by BUN, serum creatinine, 24-hour urine protein, and creatinineclearance showed that none of the patients displayed impaired renal function during this study. DISCUSSION

Loss of one kidney by either disease or surgical removal results in compensatory changes in the remaining kidney. Little is known about the factors that impact on or are related to the compensatory increases in renal function and

Fig 4. Serial changes of serum IGF-1, IGFBP3 and renal volumes are shown. The IGF-1 levels showed a marked increment at 3 months and returned to baseline levels at 12 months. The IGFBP3 levels also increased during follow-up. However, they were not correlated with renal volume increment.

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size after unilateral nephrectomy. Some investigators believe that increased renal blood flow and glomerular pressures stimulate growth by mechanical means. Hyperplasia and hypertrophy are both characteristics of the compensatory growth response. Increases in DNA and RNA synthesis appear within 12 hours and persist for weeks as the renal mass increases.6 Compensatory growth is stimulated by various factors, including a high protein diet, amino acids, ammonium chloride, several endogenous hormones, and growth factors such as IGF-1.7–9 IGF-1 is one of the regulators that mediates compensatory renal growth in animal models, but only limited clinical studies have examined the correlation between compensatory renal growth and IGF-1 or its pattern of serial changes in humans. In this study, we evaluated serum IGF-1 and IGFBP3 levels in 44 healthy adult kidney donors before and after donor nephrectomy, comparing them to measurements of renal growth in order to examine the correlation between IGF-1 and compensatory renal growth. Serum IGF-1 levels are known to be decreased in older patients compared to nutritional status. They showed a marked increase during the 3rd to 6th months compared with the preoperative levels (P ⫽ .0001), and they returned to baseline at 12 months after donor nephrectomy. Serial measurement of serum IGFBP3 levels showed increases compared with baseline studies (P ⫽ .0001); however, there was no significant correlation between renal growth and IGF-1 or IGFBP3. Serum IGF-1 levels were increased at 6 months, returning to baseline level at 12 months, despite which compensatory renal enlargement continued. Further studies with larger numbers of patients are needed to confirm that IGF-1 represents an independent predictive factor for renal growth in patients after donor nephrectomy. There are several reports that unilateral nephrectomy including donor nephrectomy does not lead to a long-term decrease in renal function.10 –13 However, some reports indicate that unilateral nephrectomy patients should undergo regular follow-up in order to effectively manage complications and to detect hypertension, proteinuria, and renal tubular injury or renal impairment at an early stage.14 –16 Postoperative renal function is an important factor for patients who have undergone unilateral nephrectomy. Many reports show that after living donor nephrectomy patients display stable postoperative renal function. However, compensatory renal growth is inevitable after unilateral nephrectomy. The glomerular filtration rate and renal blood flow increase to about 70% of prenephrectomy values within 7 days after donation.10 However, this compensatory hypertrophy may ultimately lead to renal insufficiency.17 Therefore, clinical studies of compensatory hypertrophy as well as evaluation of postoperative renal function are indicated. Increased renal blood flow stimulates postoperative renal hypertrophy. Anderson et al,10 reported that male patients had a significantly greater increase in effective renal plasma

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CHANG, KIM, LEE ET AL Table 2. Correlation Coefficients Between Impact Factors and Change of Renal Volume DMSA Spect Renal Volume

Gender Age Height (cm) Weight (kg) Body mass index (kg/m2) Body surface (m2) Body volume (L) Body density (g/cm3) Body fat (%)

Absolute Changes in Volume

Preop

Postop 3 months

Postop 6 months

Postop 12 months

Postop 3 months

Postop 6 months

Postop 12 months

Total increment

⫺0.195 ⫺0.381* 0.197 0.113 ⫺0.012 0.148 0.101 0.183 ⫺0.183

⫺0.200 ⫺0.317* 0.165 0.069 ⫺0.066 0.106 0.053 0.191 ⫺0.192

⫺0.114 ⫺0.352* 0.072 0.009 ⫺0.070 0.033 ⫺0.001 0.114 ⫺0.115

⫺0.162 ⫺0.295* 0.127 0.007 ⫺0.141 0.051 ⫺0.007 0.144 ⫺0.145

⫺0.094 ⫺0.028 0.017 ⫺0.044 ⫺0.117 ⫺0.023 ⫺0.058 0.095 ⫺0.096

⫺0.171 ⫺0.105 ⫺0.188 ⫺0.123 ⫺0.015 ⫺0.151 ⫺0.115 ⫺0.150 0.150

⫺0.016 ⫺0.071 0.114 ⫺0.002 ⫺0.145 0.039 ⫺0.011 0.070 ⫺0.070

⫺0.033 ⫺0.031 ⫺0.021 ⫺0.110 ⫺0.197* ⫺0.082 ⫺0.120 0.018 ⫺0.020

*P ⬍ .05 considered significant.

flow than did female patients and that older patients had less, albeit not statistically significant, compensatory hypertrophy. In our study, the postoperative renal volume was increased in both men and women, but, there was no significant difference in renal volume increment between men and women in an age-adjusted analysis. However, there was a significantly greater increment of the postoperative renal volume in patients under 40 years of age (P ⫽ .008). Either DMSA Spect or ultrasonography may be used to clinically evaluate compensatory renal hypertrophy. Compensatory renal hypertrophy continued over 12 months postoperatively in our study. However, a significant and rapid increase in renal volume was observed as early as 3 months postoperatively. It was interesting that there was an inverse correlation between the total increment of renal volume and body mass index. Because of the small number of cases, however, further studies with larger numbers of patients will be needed to clarify this issue. CONCLUSIONS

The results from this study clearly demonstrate that postoperative renal hypertrophy in patients with donor nephrectomy continues out to the 12th month postoperatively and that renal volume rapidly increases during the first 3 months. Compensatory hypertrophy depends on age rather than gender. Body status parameters are not predictive factors for renal hypertrophy, but serum IGF-1 may be one

of the contributing factors to compensatory renal growth. There is a significant difference between DMSA Spect and ultrasound in the evaluation of renal compensatory growth. REFERENCES 1. Santiago EA, Simmons RL, Kjellstrand CM, et al: Transplantation 14:131, 1972 2. Anderson B, Hansen JB, Jorgensen SJ: J Urol Nephrol 2:91, 1968 3. Krohn AG, Ogden DA, Holmes JH: JAMA 196:322, 1966 4. Mitchell AD, Valk WL: J Urol 88:11, 1962 5. Williams GE: Br J Exp Pathol 42:386, 1961 6. Halliburton IW, Thomson RY: Cancer Res 25:1882, 1965 7. Feld SM, Hirschberg R, Artishevsky A, et al: Kidney Int 48:45, 1995 8. Ike J, Fervenza FC, Hoffman AR, et al: Kidney Int 51:840, 1995 9. Nam UC, Lee CH, Chang S-G: Transplant Proc 31:2114, 1999 10. Anderson RG, Bueschen AJ, Lloyd LK, et al: J Urol 145:11, 1991 11. Kasiske BL, Ma JZ, Louis TA, et al: Kidney Int 48:814, 1995 12. Narkun-Burgess DM, Nolan CR, Norman JE, et al: Kidney Int 43:1110, 1993 13. Najarian JS, Chavers BM, McHugh LE, et al: Lancet 340: 807, 1992 14. D’Almeida P, Keitel E, Bittar A: Transplant Proc 28:93, 1996 15. Higashihara E, Horie S, Takeuchi T, et al: J Urol 143:239, 1990 16. Saran R, Marshall SM, Madsen R: Nephrol Dial Transplant 12:1615, 1997 17. Brenner BM, Meyer TW, Hostetter TH: N Engl J Med 11:652, 1982