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Renal Function up to 50 Years After Unilateral Nephrectomy in Childhood
Renal Function up to 50 Years After Unilateral Nephrectomy in Childhood Paul Baudoin, MD, Abraham P. Provoost, PhD, and Jan C. Molenaar, MD, PhD • Removal of one kidney during childhood differs from removal of a kidney from an adult as the child's future depends on an adequate function of the remaining kidney during a longer period of time. We assessed the long-term effect of unilateral nephrectomy in childhood on renal function, protein excretion, and blood pressure. Data were obtained from 111 subjects undergoing uninephrectomy for unilateral renal disease before the age of 16 years who had no evidence of renal abnormalities in the contralateral kidney at the time of surgery. At investigation the patients were 18 to 56 years of age with an interval of up to 52 years after uninephrectomy. On average, renal function was well maintained at approximately 75% of the reported normal tWO-kidney value. Blood pressure in men was higher than in women. Stratification for age showed no statistically significant differences between those undergoing uninephrectomy before or after the age of 4.5 years. Stratification for post-uninephrectomy interval revealed renal function to be lower and blood pressure, urinary albumin excretion, and protein excretion to be higher in those with an interval of more than 25 years. In men over 30 years of age, linear regression analysis indicated a decrease in glomerular filtration rate, effective renal plasma flow, and creatinine clearance, and an increase in blood pressure and albumin excretion with time. Controlled longitudinal studies are needed to detect true changes and to ascertain whether such changes are different from the age-related changes seen in individuals with two kidneys. It is concluded that, in general, renal function is well maintained for up to 50 years after unilateral nephrectomy in childhood. © 1993 by the National Kidney Foundation, Inc. INDEX WORDS: Unilateral nephrectomy; pediatric; renal function; glomerular filtration rate; effective renal plasma flow; blood pressure; proteinuria; albuminuria; long-term follow-up.
S
INCE THE FIRST elective removal of one kidney in the I 860s, the long-term outcome of unilateral nephrectomy in humans has been a subject of concern and debate. l -4 In the 1980s, Brenner and colleagues 5- 7 proposed a hypothesis defining the inevitable loss of renal function after nephron loss. Based on findings in rats after subtotal nephrectomy, these investigators surmised that the hemodynamic adaptations of the remaining glomeruli after nephron loss may lead to the development of renal damage and a decline in renal function over time. This hypothesis renewed interest and stimulated new research into the outcome of unilateral nephrectomy in humans. 8- IO In humans, there are several specific groups of subjects that depend on the adequate function of a single kidney. One kidney can be absent at birth due to unilateral renal agenesis, or it may have been surgically removed for acquired unilateral renal disease in childhood or in adult life, or for kidney transplant donation. In addition, there are the pediatric and adult recipients of a transplanted kidney. As the reason for having only one kidney and the age at which loss of one kidney occurred differ among the groups, the longterm outcome of one specific group does not necessarily apply for the others. Consequently, the outcome of each group has to be investigated separately.
Unilateral nephrectomy in children differs from that in adults since children have their entire life ahead. They or their parents ask the surgeon whether the remaining kidney will be able to function adequately during a complete life span and what the life expectancy of the child will be. Specific studies limited to the effect of unilateral nephrectomy in childhood covering the major part of a normal lifetime therefore are needed. Our experimental work in rats indicates that after unilateral nephrectomy at a young age the compensatory increased glomerular filtration rate (GFR) eventually declines. I I This decrease is preceded by progressive proteinuria. I I However, From lhe Departmenl oj Pediatric Surgery. Erasmlls Universily. ROllerdam. Th e Netherlands. Received December 15. 1992; accepted in revisedform February 2, 1993. Supporled by Grall! No. C88. 788 Jrom the Dulch Kidney Foundalion (Nier Slichting Nederland) . Presented in part at the 43rd Sciemijic Meeting oJthe Dutch S ociety oj Nephrology, Utrecht, The Netherlands, October 26, 1991; at lhe 241h Annual Meeting oJthe American SocielyoJ Nephrology. Ballimore, MD, November 17-20, 1991; and al the 91h Congress oj the 1mernational Pediatric Nephrology Association, Jerusalem, 1srael, August 30 to September 4. 1992. Address reprim requests to Abraham P. Provoost, PhD, Department oj Pediatric SlIrgery, LaboralOry Jar Surgery. Erasmus University. PO Box 1738, 3000 DR ROllerdam, The Netherlands. © 1993 by the Nat ional Kidney Foundation, Inc. 0272-6386/ 93/ 2106-0003$3.00/ 0
American Journal of Kidney Diseases, Vol 21. No 6 (June), 1993: pp 603-611
603
BAUDOIN, PROVOOST, AND MOLENAAR
604
it may take a substantial part of the normal lifetime before a decrease in GFR becomes apparent, and this interval is influenced by various factors. 12 Studies performed in humans after unilateral nephrectomy in childhood include only a limited number of cases with a follow-up time extending over 25 years, the longest being 40 yearsY·14 Our aim was to investigate the current renal function, blood pressure, and proteinuria in individuals with a single kidney remaining after unilateral nephrectomy in childhood. The nephrectomies were all performed at a single pediatric hospital. MATERIALS AND METHODS The study group was selected from patients who had undergone unilateral nephrectomy at the Sophia Children's Hospital in Rotterdam, The Netherlands. Surgical notebooks dating back to 1936 enabled us to create a file of224 patients who had undergone unilateral nephrectomy in childhood « 16 year of age) and who were now at least 18 years of age. Sixtytwo of these patients were excluded because the patient file at the time of surgery reported structural damage to the remaining kidney (eg, urologic abnormalities, infection, etc). Thus, the present study includes only those cases (n = 162) without reported damage to the remaining kidney. An overview of the selection of the study population is presented in Table 1. Eighteen patients had died; these were mainly oncology patients whose cause of death was unrelated to renal disease. Four of the 144 potential study subjects were unable to participate due to physical or mental handicaps. Nineteen patients, mostly young adults who did not want to be reminded of their medical situation, refused to participate. Ultimately, data were obtained from 121 subjects. Ten were excluded from analysis because some data were either incomplete or
unreliable. The general characteristics of the 111 study subjects are given in Table 1. The diagnoses leading to nephrectomy included obstructive uropathy in 41 patients, reflux in 34, Wilms' tumor in 14, renal calculi in 11, a perirenal abscess in four, hypertension in three, renal dysplasia in three, and renal trauma in one. Throughout a period of approximately I year all 144 potential participants randomly received a letter of introduction, after which an appointment was made by the principal investigator (P.B.). During a home visit the protocol was fully explained. After written consent had been obtained, the first blood sample was taken. Participants were asked to collect two subsequent 24-hour urinary outputs. They were invited to visit a health center in Rotterdam, where all the investigations took place. The study protocol and a questionnaire were given to the participants during the home visit. The questionnaire asked for additional information about the patient's well-being, medical history, and use of medication. The subjects were asked to arrive at the health center at 8 AM with an empty stomach. However, fluid intake was allowed, but excluded tea, coffee, and alcohol. The urine containers and the questionnaires were collected at the health center. After measuring height and weight, the subjects were asked to lie down on a bench in a quiet room for the duration of the test, which lasted approximately 3 hours. The GFR and effective renal plasma flow (ERPF) were assessed as the constant infusion renal and plasma clearances of polyfructosan (inutest, Laevosan-Gesellschaft, Linz, Austria) and sodium para-aminohippurate (MSD, West Point, PA), respectively. Two indwelling cannulas were inserted into an antecubital vein of each arm , one for blood sampling, the other for the continuous in fusion of polyfructosan and paraaminohippurate. Urine was collected following spontaneous micturition. To ensure optimal diuresis, an oral water intake of 15 mL/kg body weight/hr was maintained. After a loading dose, the infusion of poly fructosan (200 mgJL) and para-aminohippurate (20 mgJL) was started. The measurements were made after an equilibration time of approximately 90 minutes.
Table 1. Selection Survey and General Characteristics of Investigated Subjects Currently Aged More Than 18 Years Who Had a Unilateral Nephrectomy in Childhood Total no. of subjects No. of subjects with damaged kidney remaining after surgery No. of subjects with no damage reported No. of subjects who had died Potential no. of study subjects No. of subjects who refused or were unable to participate No. of subjects from whom data were obtained No. of subjects with incomplete and/or unreliable data No. of subjects with complete set of data General characteristics (n = 111)* Age at time of surgery (yr) Age at time of follow-up (yr) No. of years postsurgeryt
224 62 162 18 144 23 121 10 111 5.3 ± 3.5 (0.1-15.5) 31 .3 ± 10.7 (18.6-56.6) 26.0 ± 11.4 (7.1-51.9)
• Data are given as mean values ± SO; ranges are given in parentheses. t Breakdown of postsurgery interval: <10 years, five patients; 10 to 15 years, 12 patients; 15 to 20 years, 29 patients; 20 to 25 years, 16 patients; 25 to 30 years, 11 patients; 30 to 35 years, seven patients; 35 to 40 years, 16 patients; and ~40 years, 15 patients.
605
RENAL FUNCTION AFTER UNILATERAL NEPHRECTOMY Table 2. Renal Function and Blood Pressure in Subjects With a Unilateral Nephrectomy in Childhood Grouped According to Gender, Age at the Time of Surgery, and the Interval Since Surgery
All patients (n ~ 111) Female (n ~ 56) MaIe(n ~ 55) Age at the time of nephrectomy < 4.5 yr (n ~ 53) ",4.5 yr (n ~ 58) Interval postnephrectomy < 25 yr (n ~ 62) ,,25 yr (n ~ 49)
GFR (mLjminj 1.73m')
ERPF (mL/minj 1.73m')
CCRCG (mgjdL)
PCR (mg/dL)
SBP (mmHg)
DBP (mmHg)
MBP (mmHg)
U..V (mgjdj 1.73m'l
Upm
86 ± 17 86 ± 17 86 ± 18
441 ± 104 429 ± 104 452 ± 104
109 ± 23 108 ± 24 111 ± 23
0.87 ± 0.20 0.78 ± 0.15 0 .96 ± 0.23'
135 ± 17 131 ± 17 140 ± 16'
8O± 14 76± 11 83 ± 15"
101 ± 14 97 ± 12 106 ± 15"
69 ± 230 35 ± 94 104 ± 277
168 ± 471 83 ± 133 256 ± 646
86 ± 15 86 ± 19
430 ± 93 450±114
113 ± 23 106 ± 23
0.85 ± 0.23 0.88 ± 0.19
132 ± 13 138 ± 20
77 ± 12 82 ± 15
l00 ± 11 103 ± 16
57 ± 177 80 ± 270
185 ± 523 153 ± 421
90 ± 14 82 ± 19t
478 ± 97 393 ± 93t
119 ± 21 96 ± 20t
0.84 ± 0 .17 0.92 ± 0.25t
131 ± 10 141 ± 22t
75 ± 9 85 ± 17t
96 ± 9 108 ± 17t
25 ± 43 124 ± 336t
60 ± 82 309 ± 681t
NOTE. All data are mean values ± SO. Abbreviations: PCR • plasma creatinine; SBP. systolic blood pressure; DBP. diastolic blood pressure; MBP. mean blood pressure; U..,V. urinary albumin excretion; U....V. urinary protein excretion. " P < 0.05. men compared with women. t P < 0.05. ",25 years compared with < 25 years (Student's t·test).
There were three collection periods lasting 30 minutes each. Before and at the end of each clearance period a venous blood sample was obtained to determine the levels of poly fructosan and para-aminohippurate. The GFR and ERPF were calculated as the renal and plasma clearances of polyfructosan and para-aminohippurate, respectively, using standard formulae, and corrected to 1.73 m 2 body surface area (BSA). Although the mean values of the three 3D-minute clearance periods were not significantly different between the renal and plasma clearances, the plasma clearance showed much less variation. Therefore, the mean plasma clearances of each individual were used in the analyses. Renal function also was evaluated by the determination of the plasma creatinine level and the calculated creatinine clearance (CCRCG) according to Cockcroft and Gault. '5 The blood sample obtained during the home visit was used for this purpose. Standardized blood pressure measurements were taken four times in the supine position during the last 90 minutes of the clearance test. To minimize intraobserver variation, a semiautomated blood pressure measurement device (Criticon Oinamap vital signs monitor 8100; Portanje BV, Soest, The Netherlands) was used. This device measures mean blood pressure and extrapolates systolic and diastolic blood pressure values. The average of the four pressure readings was used in the analysis. A mean blood pressure of 107 mm Hg, corresponding with a systolic/diastolic pressure of 140/90 mm Hg, was considered to be the upper limit of normal blood pressure. 16 Samples obtained from the collected urine were used to determine the levels of albumin and total protein. Samples were stored initially in liquid nitrogen, and all were analyzed at the same time. The 24-hour excretion was then calculated from the urinary concentrations and the total volume. An albumin excretion higher than 30 mg/d was considered to be elevated. ' 7 The concentrations of poly fructosan in blood, urine, and infusion fluid were determined using a commercially available enzymatic assay (catalog no. 139106; Boehringer GmbH,
Mannheim, Germany). The concentrations of para-aminohippurate in blood and urine were determined with the method of Bratton and Marshall'S as modified by Smith et al. 19 Plasma creatinine was assessed using a commercially available enzymatic method (catalog no. 836885 ; Boehringer GmbH). Urinary albumin was determined by turbidimetric measurement on an Array Immunoanalyzer (Beckman, Mijdrecht, The Netherlands) according to the manufacturer's instructions. Urinary protein concentration was determined colorimetrically with a p yrogallol red-molybdate complex.20 The results were analyzed with a statistical software package (SPSS/PC+; SPSS Inc, Chicago, IL). The entire study population was analyzed after subgrouping according to gender, age at the time of unilateral nephrectomy, and interval since surgery. Mean values were compared by Student's I-test. Excluding the five subjects receiving antihypertensive therapy, multiple linear regression analysis was performed to determine the relative importance of current age, age at the time of nephrectomy, or interval since surgery on the variation in the current renal function, blood pressure, and protein excretion. Linear regression analysis was performed in subjects under or over 30 years of age to determine age-related changes in the various parameters. In subjects over 30 years of age, separate analyses were made for men and women. Finally, correlation coefficients were calculated between the dependent variables of renal function, blood pressure, urinary protein excretion, and albumin excretion. In all analyses, P < 0.05 was considered statistically significant. Results are given as mean ± SO. RESULTS
Mean values for GFR, ERPF, plasma creatinine, CCRCG, blood pressure, and 24-hour urinary albumin and protein excretion for the II I subjects are presented in Table 2, which also gives the results after stratification for gender, age at
606
BAUDOIN, PROVOOST, AND MOLENAAR Table 3. Individual Data on Parameters of Renal Function and Blood Pressure in Subjects With a Unilateral Nephrectomy in Childhood Who Were Receiving Antihypertensive Therapy at the Time of the Investigation
Subject
Sex
A B
M
C D
M
E
F
F F
Present Age (yr)
Age at Time of Surgery (yr)
No. of Years Postnephrectomy
GFR (mL/min/ 1.73 m')
ERPF (mL/min/ 1.73m')
CCRCG (mL/min/ 1.73 m')
U...V
Upro
PCR (mg/dL)
SBP (mm Hg)
DBP (mm Hg)
MBP (mm Hg)
(mg/d/ 1.73 m')
(mg/d/ 1.73 m')
56.6 47.9 35.1 34.7 24.7
4.7 2.0 7.0 8.1 0.8
51.9 45.9 28.0 26.6 23.9
40 77 112 87 100
225 345 485 383 465
61 84 120 101 146
1.24 1.13 0.72 0.88 0.59
158 128 164 188 141
94 83 91 130 88
118 100 114 149 103
39 1183 8 99 12
61 1832 36 208 46
Abbreviations: PeR, plasma creatinine; SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure; UalbV, urinary albumin excretion; U",otV, urinary protein excretion.
the time of unilateral nephrectomy, and time elapsed since surgery. The mean values for the total group indicated that GFR and ERPF were well maintained at a level of approximately 75% to 80% of that of the normal two-kidney value?' Blood pressure was on average in the high normal range, while mean levels of albuminuria and proteinuria showed a slightly enhanced excretion rate. Separation according to gender showed no differences in renal function parameters, except for a higher mean plasma creatinine level in men. Blood pressure in men, however, was significantly higher (approximately 10% on average) than in women. Segregation according to age at unilateral nephrectomy (ie, before or after 4.5 years of age) indicated no significant differences for any of the investigated parameters. Division of the total group according to the interval after surgery (ie, more or less than 25 years) showed statistically significant differences for all parameters. In subjects with a postsurgery interval longer than 25 years, GFR, ERPF, and creatinine clearance were reduced, while blood pressure, plasma creatinine level, and urinary albumin and protein excretion were increased compared with patients with a postsurgery interval less than 25 years. Individual data of the five cases receiving antihypertensive medication are presented in Table 3. The blood pressure of these patients was not well controlled. An elevated mean blood pressure was present in three patients, with microalbuminuria present in two. The GFR of subject A was only 40 mL/min/1.73 m 2 BSA (ie, in the upper chronic renal failure range). One of the two normotensive subjects (subject B) had marked albuminuria and proteinuria.
To facilitate a comparison with published data, individual data on the GFR (Fig 1), mean blood pressure (Fig 2), and urinary albumin excretion (Fig 3) are presented graphically in relation to the age at the time of the investigations. Compared with published data on GFR in healthy subjects,2' a substantial part (50%) of the subjects were above the lower 5% limit of the normal two-kidney range. Only three patients had a GFR below 60 mL/min/1.73 m 2 BSA (ie, 50% of the value for healthy normals). The lowest value of 35 mL/ min/1.73 m 2 BSA was found in a 40-year-old man; the other two patients were more than 50 years of age. An elevated mean blood pressure (> 107 mm Hg) was present in 19 men and six women. Thirteen of the 22 men over 30 years of age (59%) had an elevated mean blood pressure. Including the five subjects receiving antihypertensive therapy, an elevated mean blood pressure was present in 27% of the total study group. An elevated urinary albumin excretion (> 30mg/d/ 1. 73 m 2 BSA) was present in 13 men and 10 women. Including the three subjects with albuminuria receiving antihypertensive therapy, 23% of the study population had an elevated albumin excretion. Four men and two women presented with overt albuminuria (>250 mg/d/1.73 m 2 BSA). Mean blood pressure and albumin excretion were both elevated in nine men and five women (13% of the study population). Multiple linear regression analysis was performed to uncover the relative importance of age at the time of investigation, the interval since unilateral nephrectomy, and age at the time of nephrectomy on current renal function, blood pressure, and albumin and protein excretion.
607
RENAL FUNCTION AFTER UNILATERAL NEPHRECTOMY
Analysis of the entire group indicated that the present age was the most important factor explaining the observed variation in most of the dependent variables (data not shown). Only with regard to mean blood pressure was the interval after nephrectomy more important than current age. For all variables there was multicollinearity between current age and the interval after unilateral nephrectomy. No variable showed a statistically significant correlation with age at the time of unilateral nephrectomy. Figure 1 shows that the GFR remains stable up to the age of approximately 30 years and then slowly declines with age. As it is known that renal function declines with age in persons with two normal kidneys, linear regression analysis was performed after dividing the subjects into two age groups. A comparison of the results of the subjects under 30 years with those over 30 years of age (Table 4) indicated that the older patients had a significantly lower GFR, ERPF, and CCRCG. Blood pressure and urinary albumin and protein excretion were all significantly higher in patients over 30 years of age. The results of the linear regression analyses are presented in Tables 4 and 5. No statistically significant linear regression with age was observed in the subjects under 30 years of age (P> 0.05). Subjects over 30 years of age showed a statistically significant negative regression between age and ERPF and CCRCG, as well as a positive regression
160 MAP (mmHg)
.,
140 120 100 80
60L-----~------~------~------~----~
10
20
40
30
50
60
Age (yrs)
Fig 2. Mean blood pressure of subjects with a unilateral nephrectomy in childhood plotted against age at the time of the investigation. Open triangles indicate women; closed triangles indicate men; circles indicate patients receiving antihypertensive therapy. The line indicates a level of 107 mm Hg, corresponding with a systolic/diastolic pressure of 140/90 mm Hg (the upper limit of normal arterial pressure). (Data from the World Health Organization. '8 )
between age and blood pressure and albumin excretion. Breakdown of the group of subjects over 30 years of age indicated that the statistically significant findings were restricted to men. The data in Table 5 indicate that in men over 30 years of age there are statistically significant decreases in GFR, ERPF, and CCRCG at rates of 1.55,8.91, and 1.48 mL/min/1.73 m 2 BSA/yr, respectively. Blood pressure increased at a rate between 1.5 and 2 mm Hg/yr, while albuminuria increased at a rate of 34 mg/d/yr. No significant correlation 10000 Albumin excretion (mg/24h)
150 GFR/1.73m2 (ml/min) 1000 120
9 100
90
." t
J
10
60
, ci". ~6'" I:.
,,* a
I
I:.
1
&A';'...
~6~
. "-
, , ,
B
.,. .,.. . . .. ,
,
'
6
6lJ.
6..
'III"
,
ltc,
6. A lJ.
9
U
'';'
30 0.1 10
20
30
40
50
60
Age (yrs)
Fig 1. The GFR of subjects with a unilateral nephrectomy in childhood plotted against age at the time of the investigation. Open triangles indicate women; closed triangles indicate men; circles indicate patients receiving antihypertensive therapy. The thick line indicates the mean value of healthy normals; the thin line indicates the 5% lower Iimit.21
10
20
30
40
50
60
Age (yrs)
Fig 3. Urinary albumin excretion of subjects with a unilateral nephrectomy in childhood plotted against age at the time of the investigation. Open triangles indicate women; closed triangles indicate men; circles indicate patients receiving antihypertensive therapy. The line indicates a level of 30 mg/day (the upper limit of normal albuminuria).'7
608
BAUDOIN, PROVOOST, AND MOLENAAR Table 4. Characteristics, Mean Results of Renal Function, and Blood Pressure and Linear Regression With Current Age (Y = a + /3 X Age) in Subjects With a Unilateral Nephrectomy in Childhood Who Are Not Receiving Antihypertensive Therapy and Who Are Currently Aged Less Than or More Than 30 Years Age < 30 yr (n = 60)"
Male to female Age at time of investigation (yr) Age at time of surgery (yr) Interval since surgery (yr)
Age
~ 30
31 :29 22.7 ± 2.9 5.6 ± 3.6 17.1 ± 4.4
22:24 41 .7 ± 6.1t 5.0 ± 3.4 36.7 ± 7.0t
(18.6-29.1 ) (0.1-15.5) (7.1-28.5)
Regression Coefficients Mean ± GFR (mL/min/1.73 m2) ERPF (mL/min/1.73 m2 ) CCRCG (mL/min/1. 73 m2 ) SBP(mm Hg) DBP(mm Hg) MBP(mm Hg) UBlbV (mg/d/1.73 m2 ) Up'otV (mg/d/1.73 m2 )
90 476 120 131 75 96 24 56
± ± ± ± ± ± ±
+0.022 +0.007 - 0.158 -0.228 +0.018 +0.050 +0.134 +0.017
(30.1 -54.9) (0.2-12.9) (22.8-51.7)
Regression Coefficients Mean ±
P
SO
14 97 21 10 9 9 42 ± 79
yr (n = 46)"
0.867 0.955 0.227 0.080 0.889 0.707 0.308 0.898
82 401 96 139 84 106 106 286
± ± ± ± ± ± ± ±
SO
"
~
18t 97t 18t 21t 16t 17t 308t 663t
118 631 133 93 56 66 - 556 -697
-0.85 -5.51 -0.88 + 1.09 +0.66 +0.95 +15.8 + 23.6
p
- 0.287 -0.347 -0.297 +0.315 + 0.258 +0.349 +0.316 +0.247
0.053 0.018 0.045 0.033 0.083 0.017 0.032 0.147
Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure; Ua1bV, urinary albumin excretion; UprotV, urinary protein excretion . • Data are given as mean values ± SD; ranges are given in parentheses. t p < 0.05 compared with patients <30 years of age (Student's t-test).
was present between age and total protein excretion. In women over 30 years of age no statistically significant correlations with age were found . Calculation of the correlation coefficients (r) between the dependent variables revealed the ex-
pected significant positive correlations between the renal function parameters GFR, ERPF, and CCRCG, with r values ranging from 0.41 to 0.69. Similarly, positive correlations were found between systolic, diastolic, and mean blood pres-
Table 5. Linear Regression of Renal Function and Blood Pressure With Current Age (Y = a + /3 X Age) of Men and Women Over 30 Years of Age With a Unilateral Nephrectomy in Childhood Who Are Not Receiving Antihypertensive Therapy Women (n = 24) Regression Coefficients Mean ± GFR (mL/min/1.73 m2 ) ERPF (mL/min/1.73 m2 ) CCRCG (mL/min/1.73 m2 ) SBP (mm Hg) DBP (mm Hg) MBP (mm Hg) UalbV (mg/d/1 .73 m~ Up'otV (mg/d/1 .73 m~
82 ± 395 ± 95 ± 133 ± 77± 100 ± 50 ± 112 ±
P
SO
13 58 18 21 14 14 139 177
Men (n = 22) Regression Coefficients
-0.035 -0.163 -0.057 +0.027 +0.096 +0.010 -0.133 -0.000
0.872 0.447 0.793 0.902 0.657 0.962 0.534 0.999
Mean ± 82 408 97 145 91 113 167 477
± ± ± ± ± ± ± ±
SO
"
~
23 129 18 20t 15t 16t 417 914
146 729 159 59 27 35 -1235 -1497
- 1.55 -8.91 -1.48 +2.08 + 1.56 +1.90 +33.9 +47.7
p
-0.439 - 0.451 - 0.532 +0.693 +0.671 +0.750 +0.528 +0.340
0.041 0.035 0.011 <0.001 <0.001 <0.001 0.012 0.122
Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure; UalbV, urinary albumin excretion; Up'otV, urinary protein excretion. t p < 0.05 compared with women (Student's t-test).
RENAL FUNCTION AFTER UNILATERAL NEPHRECTOMY
sures (r = 0.81 to 0.93) and between urinary albumin and protein excretion (r = 0.66). The correlation coefficients between GFR, mean blood pressure, and protein excretion were calculated for the total group and separately for men and women. In the total group, there was a statistically significant negative correlation between GFR and proteinuria (r = -0.46) and a positive correlation between mean blood pressure and proteinuria (r = 0.38). Separation according to gender showed that these correlations were limited to men (r = -0.61 and 0.43, respectively). In men only there was a significant negative correlation between GFR and mean blood pressure (r = -0.34). DISCUSSION
The currently held view that the long-term consequences of unilateral nephrectomy are rather mild is based mainly on the outcome of donor nephrectomy and uninephrectomy for acquired disease in adults. Although the interpretation of many of these studies is hampered by methodologic flaws, the common opinion is that a compensatory increased renal function is well maintained during several decades. 8- 1O As the effect of unilateral nephrectomy at young age on compensatory renal growth differs from that of adults,22-25 the long-term outcome also may differ. The results from the present study indicate that good renal function also can be maintained during an extended period after unilateral nephrectomy in childhood. Within the pediatric age group, age at the time of surgery (ranging from oto 16 years) does not affect the outcome of renal function up to 50 years of age. However, our study does not exclude the fact that age at the time of nephrectomy may be important when the outcome of unilateral nephrectomy in childhood is compared with that in adults. Our study group consisted of subjects with no reported structural damage or disease of the remaining kidney. However, this does not necessarily mean that all kidneys were normal at the time of surgery. It did include patients (n = 13) undergoing a unilateral nephrectomy to remove a renal tumor in whom the remaining kidney had been subjected to irradiation and/or chemotherapy. All but one of these patients was younger than 30 years of age at the time of the study. Separate analysis of this group indicated
609
no significant differences with the nononcologic patients under 30 years of age. Our findings, from studying a larger group with a longer follow-up than any previously published study related to unilateral nephrectomy in childhood, substantially enlarge the current knowledge about the outcome of unilateral nephrectomy in childhoody,14 They confirm the findings of Robitaille et al,13 which indicate that neither gender nor age at the time of nephrectomy resulted in a statistically significant difference in renal function. This is in contrast with findings in rats, in whom male gender and young age at the time of nephrectomy are considered to increase the risk for an early development of renal damage and function loss after unilateral nephrectomy.12 Although mean levels. of GFR, ERPF, and creatinine clearance were the same in men and women, men still may be more at risk of an earlier and more rapid loss of renal function than women. First, blood pressure was significantly higher in men, especially in those over 30 years of age. Second, in contrast to women, linear regression analyses with age in men indicated a decrease in renal function and an increase in blood pressure and urinary albumin and protein excretion with time. These findings are the main differences between men and women found in this study. Our data diverge from those of Robitaille et alY and support those ofWikstad et al 14 regarding the renal function more than 25 years after unilateral nephrectomy. Group mean values showed a lower level of renal function and a higher level of blood pressure and albumin and protein excretion in patients with the longest follow-up period. Comparing the intervals from 7 to 15, 16 to 25, and 26 to 40 years, Wikstad et al 14 found a decrease in the GFR and ERPF with follow-up time. Albumin excretion increased with longer follow-up time, and significant albuminuria (2.50 mg/d/ 1.73 m 2 BSA) was present in 47% of patients. Men who have had a single kidney since childhood appear, after the age of 30 years, to have a faster decrease in renal function and a faster increase in blood pressure and albumin and protein excretion when compared with the age-related changes in renal function and blood pressure reported in healthy persons 21 ,26-29 and in patients with essential hypertension 30 ,31 who have two
610
kidneys. It should be emphasized, however, that due to the cross-sectional design of our study, a true change in any of the parameters has not been established. Longitudinal studies with sequential measurements over a prolonged period are needed to uncover true changes in renal function, blood pressure, and urinary albumin and protein excretion over time. A rate of decline of approximately 1.5 mL/min/yr after the age of 30 years is not alarmingly fast, and renal function may, on average, be maintained for another 50 years. In diabetic nephropathy the GFR may decrease at a rate of up to 10 to 15 mL/min/yr,32,33 while for nondiabetic renal disease with a moderate to severe renal insufficiency a decrease of 6 mL/ min/yr has been reported. 34 In another setting of single kidneys (ie, chronic renal transplant rejection) the CCRCG decreased at a rate of approximately 5 mL/min/yr. 35 A slow progressive decline in renal function does not immediately require dietary or pharmacologic intervention. It may, however, require a more frequent and careful long-term follow-up of adults with a unilateral nephrectomy in childhood. After 30 years of age, such a follow-up should include an annual examination of the blood pressure, urinary albumin and protein excretion, and plasma creatinine to calculate creatinine clearance. A full assessment of renal function, including GFR, once every 5 years seems appropriate. Finally, it should be stressed once more that the present findings after unilateral nephrectomy in children with unilateral renal disease do not necessarily apply to unilateral nephrectomy for kidney donation in adults. As both the age at the time of kidney loss and the cause for uninephrectomy are different, the final outcome also may differ. The long-term effect of uninephrectomy for kidney donation can only be established by specific studies of these donors. Currently, the published follow-up studies cover only the first two decades after kidney donation in sufficient numbers. 8- IO Additional longer, and preferably longitudinal, follow-up studies are needed to determine the future of the remaining kidney of the kidney donor beyond that period. In conclusion, the results of this and previously reported studies indicate that the outcome of unilateral nephrectomy in childhood appears largely uneventful. When an intact kidney re-
BAUDOIN, PROVOOST, AND MOLENAAR
mains, a compensatory increased GFR is well maintained up to 50 years after unilateral nephrectomy. In men over 30 years of age, there is a negative correlation between age and renal function , and a positive correlation between age and blood pressure, albumin excretion, and protein excretion. Whether these correlations reflect true changes with time needs to be confirmed by sequential studies over a prolonged period. ACKNOWLEDGMENT The authors are indebted to all the study subjects, without whose participation this study would not have been possible. The authors thank Dr. D.E. Grobbee (Department of Epidemiology) and Dr E.D. Wolff(Department of Pediatric Nephrology) for their valuable help during the study, and M. de Haes-Kistemaker and J.1. Ambagtsheer for their tec.hnical assistance.
REFERENCES I. Ellis LB, Weiss S: Renal function in persons with one kidney. Am J Med Sci 186:242-248, 1933 2. Deming CL: The future of the unilaterally nephrectomized patient. J Urol 40:74-82, 1938 3. Kretschmer HL: Life after nephrectomy. JAMA 121 : 474-478, 1943 4. Goldstein AE: Longevity following nephrectomy. J Urol 76:31-41 , 1956 5. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM: Hyperfiltration in remnant nephrons: A potentially adverse response to renal ablation. Am J Physiol 241 :F85-F93, 1981 6. Brenner BM, Meyer TW, Hostetter TH: Dietary protein intake and the progressive nature of kidney disease: The role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. New Engl J Med 307: 652-659, 1982 7. Brenner BM: Hemodynamically mediated glomerular injury and the progressive nature of kidney disease. Kidney Int 23:647-655, 1983 8. Fotino S: The solitary kidney: A model of chronic hyperfiltration in humans. Am J Kidney Dis 13:88-98, 1989 9. Steckler RE, Riehle RA, Jr, Vaughan ED, Jr: Hyperfiltration-induced renal injury in normal man: Myth or reality. J UroI144:1323-1327, 1990 10. Oldrizzi L, Rugiu C, De Biase V, Maschio G: The solitary kidney: A risky situation for progressive renal damage? Am J Kidney Dis 17:57-61 , 1991 (Suppl I) II . Provoost AP, De Keijzer MH, Molenaar JC: Effect of protein intake on lifelong changes in renal function of rats unilaterally nephrectomized at young age. J Lab Clin Med 114: 19-26, 1989 12. Provoost AP, Baudoin P, De Keijzer MH, Van Aken M, Molenaar JC: The role of nephron loss in the progression of renal failure: Experimental evidence. Am J Kidney Dis 17: 27-32, 1991 (Suppl I)
RENAL FUNCTION AFTER UNILATERAL NEPHRECTOMY
13. Robitaille P, Lortie L, Mongeau J-G, Sinnasammy P: Long-term follow-up of patients who underwent unilateral nephrectomy in childhood. Lancet 1:1297-1299, 1985 14. Wikstad I, Celsi G, Larsson L, Herin P, Aperia A: Kidney function in adults born with unilateral renal agenesis or nephrectomized in childhood. Pediatr Nephrol 2: 177-182, 1988 15. Cockcroft OW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976 16. WHO Expert Committee: Arterial hypertension. World Health Organ Tech Rep Ser 628:1-58,1978 17. Mogensen CE, Chachati A, Christensen CK, Close CF, Deckert T, Hommetl E, Kastrup J, Lefebvre P, Mathiesen ER, Feldt-Rasmussen B, Schmitz A, Viberti GC: Microalbuminuria: An early marker of renal involvement in diabetes. Uremia Invest 9:85-95, 1985-86 18. Bratton AC, Marshall EK: A new coupling component for sulfanilamide determination. J Bioi Chern 128:537-550, 1938 19. Smith HW, Finkelstein N, Aliminosa L, Crawford B, Graber M: The renal clearance of substituted hippuric acid derivatives and other aromatic acids in dog and man. J Clin Invest 24:388-404, 1945 20. Watanabe N, Kamei S, Ohkubo A, Yamanaka M, Ohsawa S, Makino K, Tokuda K: Urinary protein as measured with pyrogallol red-molybdate complex, manually and in a Hitachi 726 automated analyzer. C1in Chern 32:1551-1554, 1986 21. Slack TK, Wilson OM: Normal renal function. C1N and CPAH in healthy donors before and after nephrectomy. Mayo Clin Proc 51 :296-300, 1976 22. Aperia A, Broberger 0, Wilton P: Renal functional adaptation in the remnant kidney in patients with renal agenesis and in patients nephrectomized in childhood. Acta Paediatr Scand 67:611-615, 1978 23. Simon J, Zamora I, Mendizabal S, Castel V, Lurbe A: Glomerulotubular balance and functional compensation in nephrectomized children. Nephron 31 :203-208, 1982
611 24. Larsson L, Aperia A, Wilton P: Effect of normal development on compensatory renal growth. Kidney Int 18:2935, 1980 25. Celsi G, Jakobsson B, Aperia A: Influence of age on compensatory renal growth in rats. Pediatr Res 20:347-350, 1986 26. Davies OF, Shock NW: Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest 29:496-507, 1950 27. Wesson LG: Renal hemodynamics in physiological states, in Physiology of the Human Kidney. New York, NY, Grune & Stratton, 1969, pp 96- 108 28. Lindeman RD, Tobin J, Shock NW: Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 33:278-285, 1985 29. Lindeman RD, Goldman R: Anatomic and physiologic age changes in the kidney. Exp GerontoI21:379-406, 1986 30. De Leeuw PW, Kho TL, Falke HE, Birkenhager WH, Wester A: Haemodynamic and endocrinological profile of essential hypertension. Acta Med Scand SuppI622:1-86, 1978 31. Bauer JH, Reams GP, Wu Z: The agin~hypertensive kidney: Pathophysiology and therapeutic options. Am J Med 90:2IS-27S, 1991 (SuppI4B) 32. Viberti GC, Bilous RW, Mackintosh 0, Keen H: Monitoring glomerular function in diabetic nephropathy. A prospective study. Am J Med 74:356-364, 1983 33. Parving H-H, Hommel E, Smidt UM: Protection of kidney function and decrease in albuminuria by captopril in insulin dependent diabetics with nephropathy. Br Med J 297: 1086-1091,1988 34. Ihle BU, Becker GJ, Whitworth JA, Charlwood RA, Kincaid-Smith P: The effect of protein restriction on the progression of renal insufficiency. New Engl J Med 321: 17731777, 1989 35. Modena F, Hostetter TH, Salahudeen AK, Najarian JS, Matas AJ, Rosenberg ME: Progression of kidney disease in chronic renal transplant rejection. Transplantation 52:239244,1991
S
INCE THE FIRST elective removal of one kidney in the I 860s, the long-term outcome of unilateral nephrectomy in humans has been a subject of concern and debate. l -4 In the 1980s, Brenner and colleagues 5- 7 proposed a hypothesis defining the inevitable loss of renal function after nephron loss. Based on findings in rats after subtotal nephrectomy, these investigators surmised that the hemodynamic adaptations of the remaining glomeruli after nephron loss may lead to the development of renal damage and a decline in renal function over time. This hypothesis renewed interest and stimulated new research into the outcome of unilateral nephrectomy in humans. 8- IO In humans, there are several specific groups of subjects that depend on the adequate function of a single kidney. One kidney can be absent at birth due to unilateral renal agenesis, or it may have been surgically removed for acquired unilateral renal disease in childhood or in adult life, or for kidney transplant donation. In addition, there are the pediatric and adult recipients of a transplanted kidney. As the reason for having only one kidney and the age at which loss of one kidney occurred differ among the groups, the longterm outcome of one specific group does not necessarily apply for the others. Consequently, the outcome of each group has to be investigated separately.
Unilateral nephrectomy in children differs from that in adults since children have their entire life ahead. They or their parents ask the surgeon whether the remaining kidney will be able to function adequately during a complete life span and what the life expectancy of the child will be. Specific studies limited to the effect of unilateral nephrectomy in childhood covering the major part of a normal lifetime therefore are needed. Our experimental work in rats indicates that after unilateral nephrectomy at a young age the compensatory increased glomerular filtration rate (GFR) eventually declines. I I This decrease is preceded by progressive proteinuria. I I However, From lhe Departmenl oj Pediatric Surgery. Erasmlls Universily. ROllerdam. Th e Netherlands. Received December 15. 1992; accepted in revisedform February 2, 1993. Supporled by Grall! No. C88. 788 Jrom the Dulch Kidney Foundalion (Nier Slichting Nederland) . Presented in part at the 43rd Sciemijic Meeting oJthe Dutch S ociety oj Nephrology, Utrecht, The Netherlands, October 26, 1991; at lhe 241h Annual Meeting oJthe American SocielyoJ Nephrology. Ballimore, MD, November 17-20, 1991; and al the 91h Congress oj the 1mernational Pediatric Nephrology Association, Jerusalem, 1srael, August 30 to September 4. 1992. Address reprim requests to Abraham P. Provoost, PhD, Department oj Pediatric SlIrgery, LaboralOry Jar Surgery. Erasmus University. PO Box 1738, 3000 DR ROllerdam, The Netherlands. © 1993 by the Nat ional Kidney Foundation, Inc. 0272-6386/ 93/ 2106-0003$3.00/ 0
American Journal of Kidney Diseases, Vol 21. No 6 (June), 1993: pp 603-611
603
BAUDOIN, PROVOOST, AND MOLENAAR
604
it may take a substantial part of the normal lifetime before a decrease in GFR becomes apparent, and this interval is influenced by various factors. 12 Studies performed in humans after unilateral nephrectomy in childhood include only a limited number of cases with a follow-up time extending over 25 years, the longest being 40 yearsY·14 Our aim was to investigate the current renal function, blood pressure, and proteinuria in individuals with a single kidney remaining after unilateral nephrectomy in childhood. The nephrectomies were all performed at a single pediatric hospital. MATERIALS AND METHODS The study group was selected from patients who had undergone unilateral nephrectomy at the Sophia Children's Hospital in Rotterdam, The Netherlands. Surgical notebooks dating back to 1936 enabled us to create a file of224 patients who had undergone unilateral nephrectomy in childhood « 16 year of age) and who were now at least 18 years of age. Sixtytwo of these patients were excluded because the patient file at the time of surgery reported structural damage to the remaining kidney (eg, urologic abnormalities, infection, etc). Thus, the present study includes only those cases (n = 162) without reported damage to the remaining kidney. An overview of the selection of the study population is presented in Table 1. Eighteen patients had died; these were mainly oncology patients whose cause of death was unrelated to renal disease. Four of the 144 potential study subjects were unable to participate due to physical or mental handicaps. Nineteen patients, mostly young adults who did not want to be reminded of their medical situation, refused to participate. Ultimately, data were obtained from 121 subjects. Ten were excluded from analysis because some data were either incomplete or
unreliable. The general characteristics of the 111 study subjects are given in Table 1. The diagnoses leading to nephrectomy included obstructive uropathy in 41 patients, reflux in 34, Wilms' tumor in 14, renal calculi in 11, a perirenal abscess in four, hypertension in three, renal dysplasia in three, and renal trauma in one. Throughout a period of approximately I year all 144 potential participants randomly received a letter of introduction, after which an appointment was made by the principal investigator (P.B.). During a home visit the protocol was fully explained. After written consent had been obtained, the first blood sample was taken. Participants were asked to collect two subsequent 24-hour urinary outputs. They were invited to visit a health center in Rotterdam, where all the investigations took place. The study protocol and a questionnaire were given to the participants during the home visit. The questionnaire asked for additional information about the patient's well-being, medical history, and use of medication. The subjects were asked to arrive at the health center at 8 AM with an empty stomach. However, fluid intake was allowed, but excluded tea, coffee, and alcohol. The urine containers and the questionnaires were collected at the health center. After measuring height and weight, the subjects were asked to lie down on a bench in a quiet room for the duration of the test, which lasted approximately 3 hours. The GFR and effective renal plasma flow (ERPF) were assessed as the constant infusion renal and plasma clearances of polyfructosan (inutest, Laevosan-Gesellschaft, Linz, Austria) and sodium para-aminohippurate (MSD, West Point, PA), respectively. Two indwelling cannulas were inserted into an antecubital vein of each arm , one for blood sampling, the other for the continuous in fusion of polyfructosan and paraaminohippurate. Urine was collected following spontaneous micturition. To ensure optimal diuresis, an oral water intake of 15 mL/kg body weight/hr was maintained. After a loading dose, the infusion of poly fructosan (200 mgJL) and para-aminohippurate (20 mgJL) was started. The measurements were made after an equilibration time of approximately 90 minutes.
Table 1. Selection Survey and General Characteristics of Investigated Subjects Currently Aged More Than 18 Years Who Had a Unilateral Nephrectomy in Childhood Total no. of subjects No. of subjects with damaged kidney remaining after surgery No. of subjects with no damage reported No. of subjects who had died Potential no. of study subjects No. of subjects who refused or were unable to participate No. of subjects from whom data were obtained No. of subjects with incomplete and/or unreliable data No. of subjects with complete set of data General characteristics (n = 111)* Age at time of surgery (yr) Age at time of follow-up (yr) No. of years postsurgeryt
224 62 162 18 144 23 121 10 111 5.3 ± 3.5 (0.1-15.5) 31 .3 ± 10.7 (18.6-56.6) 26.0 ± 11.4 (7.1-51.9)
• Data are given as mean values ± SO; ranges are given in parentheses. t Breakdown of postsurgery interval: <10 years, five patients; 10 to 15 years, 12 patients; 15 to 20 years, 29 patients; 20 to 25 years, 16 patients; 25 to 30 years, 11 patients; 30 to 35 years, seven patients; 35 to 40 years, 16 patients; and ~40 years, 15 patients.
605
RENAL FUNCTION AFTER UNILATERAL NEPHRECTOMY Table 2. Renal Function and Blood Pressure in Subjects With a Unilateral Nephrectomy in Childhood Grouped According to Gender, Age at the Time of Surgery, and the Interval Since Surgery
All patients (n ~ 111) Female (n ~ 56) MaIe(n ~ 55) Age at the time of nephrectomy < 4.5 yr (n ~ 53) ",4.5 yr (n ~ 58) Interval postnephrectomy < 25 yr (n ~ 62) ,,25 yr (n ~ 49)
GFR (mLjminj 1.73m')
ERPF (mL/minj 1.73m')
CCRCG (mgjdL)
PCR (mg/dL)
SBP (mmHg)
DBP (mmHg)
MBP (mmHg)
U..V (mgjdj 1.73m'l
Upm
86 ± 17 86 ± 17 86 ± 18
441 ± 104 429 ± 104 452 ± 104
109 ± 23 108 ± 24 111 ± 23
0.87 ± 0.20 0.78 ± 0.15 0 .96 ± 0.23'
135 ± 17 131 ± 17 140 ± 16'
8O± 14 76± 11 83 ± 15"
101 ± 14 97 ± 12 106 ± 15"
69 ± 230 35 ± 94 104 ± 277
168 ± 471 83 ± 133 256 ± 646
86 ± 15 86 ± 19
430 ± 93 450±114
113 ± 23 106 ± 23
0.85 ± 0.23 0.88 ± 0.19
132 ± 13 138 ± 20
77 ± 12 82 ± 15
l00 ± 11 103 ± 16
57 ± 177 80 ± 270
185 ± 523 153 ± 421
90 ± 14 82 ± 19t
478 ± 97 393 ± 93t
119 ± 21 96 ± 20t
0.84 ± 0 .17 0.92 ± 0.25t
131 ± 10 141 ± 22t
75 ± 9 85 ± 17t
96 ± 9 108 ± 17t
25 ± 43 124 ± 336t
60 ± 82 309 ± 681t
NOTE. All data are mean values ± SO. Abbreviations: PCR • plasma creatinine; SBP. systolic blood pressure; DBP. diastolic blood pressure; MBP. mean blood pressure; U..,V. urinary albumin excretion; U....V. urinary protein excretion. " P < 0.05. men compared with women. t P < 0.05. ",25 years compared with < 25 years (Student's t·test).
There were three collection periods lasting 30 minutes each. Before and at the end of each clearance period a venous blood sample was obtained to determine the levels of poly fructosan and para-aminohippurate. The GFR and ERPF were calculated as the renal and plasma clearances of polyfructosan and para-aminohippurate, respectively, using standard formulae, and corrected to 1.73 m 2 body surface area (BSA). Although the mean values of the three 3D-minute clearance periods were not significantly different between the renal and plasma clearances, the plasma clearance showed much less variation. Therefore, the mean plasma clearances of each individual were used in the analyses. Renal function also was evaluated by the determination of the plasma creatinine level and the calculated creatinine clearance (CCRCG) according to Cockcroft and Gault. '5 The blood sample obtained during the home visit was used for this purpose. Standardized blood pressure measurements were taken four times in the supine position during the last 90 minutes of the clearance test. To minimize intraobserver variation, a semiautomated blood pressure measurement device (Criticon Oinamap vital signs monitor 8100; Portanje BV, Soest, The Netherlands) was used. This device measures mean blood pressure and extrapolates systolic and diastolic blood pressure values. The average of the four pressure readings was used in the analysis. A mean blood pressure of 107 mm Hg, corresponding with a systolic/diastolic pressure of 140/90 mm Hg, was considered to be the upper limit of normal blood pressure. 16 Samples obtained from the collected urine were used to determine the levels of albumin and total protein. Samples were stored initially in liquid nitrogen, and all were analyzed at the same time. The 24-hour excretion was then calculated from the urinary concentrations and the total volume. An albumin excretion higher than 30 mg/d was considered to be elevated. ' 7 The concentrations of poly fructosan in blood, urine, and infusion fluid were determined using a commercially available enzymatic assay (catalog no. 139106; Boehringer GmbH,
Mannheim, Germany). The concentrations of para-aminohippurate in blood and urine were determined with the method of Bratton and Marshall'S as modified by Smith et al. 19 Plasma creatinine was assessed using a commercially available enzymatic method (catalog no. 836885 ; Boehringer GmbH). Urinary albumin was determined by turbidimetric measurement on an Array Immunoanalyzer (Beckman, Mijdrecht, The Netherlands) according to the manufacturer's instructions. Urinary protein concentration was determined colorimetrically with a p yrogallol red-molybdate complex.20 The results were analyzed with a statistical software package (SPSS/PC+; SPSS Inc, Chicago, IL). The entire study population was analyzed after subgrouping according to gender, age at the time of unilateral nephrectomy, and interval since surgery. Mean values were compared by Student's I-test. Excluding the five subjects receiving antihypertensive therapy, multiple linear regression analysis was performed to determine the relative importance of current age, age at the time of nephrectomy, or interval since surgery on the variation in the current renal function, blood pressure, and protein excretion. Linear regression analysis was performed in subjects under or over 30 years of age to determine age-related changes in the various parameters. In subjects over 30 years of age, separate analyses were made for men and women. Finally, correlation coefficients were calculated between the dependent variables of renal function, blood pressure, urinary protein excretion, and albumin excretion. In all analyses, P < 0.05 was considered statistically significant. Results are given as mean ± SO. RESULTS
Mean values for GFR, ERPF, plasma creatinine, CCRCG, blood pressure, and 24-hour urinary albumin and protein excretion for the II I subjects are presented in Table 2, which also gives the results after stratification for gender, age at
606
BAUDOIN, PROVOOST, AND MOLENAAR Table 3. Individual Data on Parameters of Renal Function and Blood Pressure in Subjects With a Unilateral Nephrectomy in Childhood Who Were Receiving Antihypertensive Therapy at the Time of the Investigation
Subject
Sex
A B
M
C D
M
E
F
F F
Present Age (yr)
Age at Time of Surgery (yr)
No. of Years Postnephrectomy
GFR (mL/min/ 1.73 m')
ERPF (mL/min/ 1.73m')
CCRCG (mL/min/ 1.73 m')
U...V
Upro
PCR (mg/dL)
SBP (mm Hg)
DBP (mm Hg)
MBP (mm Hg)
(mg/d/ 1.73 m')
(mg/d/ 1.73 m')
56.6 47.9 35.1 34.7 24.7
4.7 2.0 7.0 8.1 0.8
51.9 45.9 28.0 26.6 23.9
40 77 112 87 100
225 345 485 383 465
61 84 120 101 146
1.24 1.13 0.72 0.88 0.59
158 128 164 188 141
94 83 91 130 88
118 100 114 149 103
39 1183 8 99 12
61 1832 36 208 46
Abbreviations: PeR, plasma creatinine; SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure; UalbV, urinary albumin excretion; U",otV, urinary protein excretion.
the time of unilateral nephrectomy, and time elapsed since surgery. The mean values for the total group indicated that GFR and ERPF were well maintained at a level of approximately 75% to 80% of that of the normal two-kidney value?' Blood pressure was on average in the high normal range, while mean levels of albuminuria and proteinuria showed a slightly enhanced excretion rate. Separation according to gender showed no differences in renal function parameters, except for a higher mean plasma creatinine level in men. Blood pressure in men, however, was significantly higher (approximately 10% on average) than in women. Segregation according to age at unilateral nephrectomy (ie, before or after 4.5 years of age) indicated no significant differences for any of the investigated parameters. Division of the total group according to the interval after surgery (ie, more or less than 25 years) showed statistically significant differences for all parameters. In subjects with a postsurgery interval longer than 25 years, GFR, ERPF, and creatinine clearance were reduced, while blood pressure, plasma creatinine level, and urinary albumin and protein excretion were increased compared with patients with a postsurgery interval less than 25 years. Individual data of the five cases receiving antihypertensive medication are presented in Table 3. The blood pressure of these patients was not well controlled. An elevated mean blood pressure was present in three patients, with microalbuminuria present in two. The GFR of subject A was only 40 mL/min/1.73 m 2 BSA (ie, in the upper chronic renal failure range). One of the two normotensive subjects (subject B) had marked albuminuria and proteinuria.
To facilitate a comparison with published data, individual data on the GFR (Fig 1), mean blood pressure (Fig 2), and urinary albumin excretion (Fig 3) are presented graphically in relation to the age at the time of the investigations. Compared with published data on GFR in healthy subjects,2' a substantial part (50%) of the subjects were above the lower 5% limit of the normal two-kidney range. Only three patients had a GFR below 60 mL/min/1.73 m 2 BSA (ie, 50% of the value for healthy normals). The lowest value of 35 mL/ min/1.73 m 2 BSA was found in a 40-year-old man; the other two patients were more than 50 years of age. An elevated mean blood pressure (> 107 mm Hg) was present in 19 men and six women. Thirteen of the 22 men over 30 years of age (59%) had an elevated mean blood pressure. Including the five subjects receiving antihypertensive therapy, an elevated mean blood pressure was present in 27% of the total study group. An elevated urinary albumin excretion (> 30mg/d/ 1. 73 m 2 BSA) was present in 13 men and 10 women. Including the three subjects with albuminuria receiving antihypertensive therapy, 23% of the study population had an elevated albumin excretion. Four men and two women presented with overt albuminuria (>250 mg/d/1.73 m 2 BSA). Mean blood pressure and albumin excretion were both elevated in nine men and five women (13% of the study population). Multiple linear regression analysis was performed to uncover the relative importance of age at the time of investigation, the interval since unilateral nephrectomy, and age at the time of nephrectomy on current renal function, blood pressure, and albumin and protein excretion.
607
RENAL FUNCTION AFTER UNILATERAL NEPHRECTOMY
Analysis of the entire group indicated that the present age was the most important factor explaining the observed variation in most of the dependent variables (data not shown). Only with regard to mean blood pressure was the interval after nephrectomy more important than current age. For all variables there was multicollinearity between current age and the interval after unilateral nephrectomy. No variable showed a statistically significant correlation with age at the time of unilateral nephrectomy. Figure 1 shows that the GFR remains stable up to the age of approximately 30 years and then slowly declines with age. As it is known that renal function declines with age in persons with two normal kidneys, linear regression analysis was performed after dividing the subjects into two age groups. A comparison of the results of the subjects under 30 years with those over 30 years of age (Table 4) indicated that the older patients had a significantly lower GFR, ERPF, and CCRCG. Blood pressure and urinary albumin and protein excretion were all significantly higher in patients over 30 years of age. The results of the linear regression analyses are presented in Tables 4 and 5. No statistically significant linear regression with age was observed in the subjects under 30 years of age (P> 0.05). Subjects over 30 years of age showed a statistically significant negative regression between age and ERPF and CCRCG, as well as a positive regression
160 MAP (mmHg)
.,
140 120 100 80
60L-----~------~------~------~----~
10
20
40
30
50
60
Age (yrs)
Fig 2. Mean blood pressure of subjects with a unilateral nephrectomy in childhood plotted against age at the time of the investigation. Open triangles indicate women; closed triangles indicate men; circles indicate patients receiving antihypertensive therapy. The line indicates a level of 107 mm Hg, corresponding with a systolic/diastolic pressure of 140/90 mm Hg (the upper limit of normal arterial pressure). (Data from the World Health Organization. '8 )
between age and blood pressure and albumin excretion. Breakdown of the group of subjects over 30 years of age indicated that the statistically significant findings were restricted to men. The data in Table 5 indicate that in men over 30 years of age there are statistically significant decreases in GFR, ERPF, and CCRCG at rates of 1.55,8.91, and 1.48 mL/min/1.73 m 2 BSA/yr, respectively. Blood pressure increased at a rate between 1.5 and 2 mm Hg/yr, while albuminuria increased at a rate of 34 mg/d/yr. No significant correlation 10000 Albumin excretion (mg/24h)
150 GFR/1.73m2 (ml/min) 1000 120
9 100
90
." t
J
10
60
, ci". ~6'" I:.
,,* a
I
I:.
1
&A';'...
~6~
. "-
, , ,
B
.,. .,.. . . .. ,
,
'
6
6lJ.
6..
'III"
,
ltc,
6. A lJ.
9
U
'';'
30 0.1 10
20
30
40
50
60
Age (yrs)
Fig 1. The GFR of subjects with a unilateral nephrectomy in childhood plotted against age at the time of the investigation. Open triangles indicate women; closed triangles indicate men; circles indicate patients receiving antihypertensive therapy. The thick line indicates the mean value of healthy normals; the thin line indicates the 5% lower Iimit.21
10
20
30
40
50
60
Age (yrs)
Fig 3. Urinary albumin excretion of subjects with a unilateral nephrectomy in childhood plotted against age at the time of the investigation. Open triangles indicate women; closed triangles indicate men; circles indicate patients receiving antihypertensive therapy. The line indicates a level of 30 mg/day (the upper limit of normal albuminuria).'7
608
BAUDOIN, PROVOOST, AND MOLENAAR Table 4. Characteristics, Mean Results of Renal Function, and Blood Pressure and Linear Regression With Current Age (Y = a + /3 X Age) in Subjects With a Unilateral Nephrectomy in Childhood Who Are Not Receiving Antihypertensive Therapy and Who Are Currently Aged Less Than or More Than 30 Years Age < 30 yr (n = 60)"
Male to female Age at time of investigation (yr) Age at time of surgery (yr) Interval since surgery (yr)
Age
~ 30
31 :29 22.7 ± 2.9 5.6 ± 3.6 17.1 ± 4.4
22:24 41 .7 ± 6.1t 5.0 ± 3.4 36.7 ± 7.0t
(18.6-29.1 ) (0.1-15.5) (7.1-28.5)
Regression Coefficients Mean ± GFR (mL/min/1.73 m2) ERPF (mL/min/1.73 m2 ) CCRCG (mL/min/1. 73 m2 ) SBP(mm Hg) DBP(mm Hg) MBP(mm Hg) UBlbV (mg/d/1.73 m2 ) Up'otV (mg/d/1.73 m2 )
90 476 120 131 75 96 24 56
± ± ± ± ± ± ±
+0.022 +0.007 - 0.158 -0.228 +0.018 +0.050 +0.134 +0.017
(30.1 -54.9) (0.2-12.9) (22.8-51.7)
Regression Coefficients Mean ±
P
SO
14 97 21 10 9 9 42 ± 79
yr (n = 46)"
0.867 0.955 0.227 0.080 0.889 0.707 0.308 0.898
82 401 96 139 84 106 106 286
± ± ± ± ± ± ± ±
SO
"
~
18t 97t 18t 21t 16t 17t 308t 663t
118 631 133 93 56 66 - 556 -697
-0.85 -5.51 -0.88 + 1.09 +0.66 +0.95 +15.8 + 23.6
p
- 0.287 -0.347 -0.297 +0.315 + 0.258 +0.349 +0.316 +0.247
0.053 0.018 0.045 0.033 0.083 0.017 0.032 0.147
Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure; Ua1bV, urinary albumin excretion; UprotV, urinary protein excretion . • Data are given as mean values ± SD; ranges are given in parentheses. t p < 0.05 compared with patients <30 years of age (Student's t-test).
was present between age and total protein excretion. In women over 30 years of age no statistically significant correlations with age were found . Calculation of the correlation coefficients (r) between the dependent variables revealed the ex-
pected significant positive correlations between the renal function parameters GFR, ERPF, and CCRCG, with r values ranging from 0.41 to 0.69. Similarly, positive correlations were found between systolic, diastolic, and mean blood pres-
Table 5. Linear Regression of Renal Function and Blood Pressure With Current Age (Y = a + /3 X Age) of Men and Women Over 30 Years of Age With a Unilateral Nephrectomy in Childhood Who Are Not Receiving Antihypertensive Therapy Women (n = 24) Regression Coefficients Mean ± GFR (mL/min/1.73 m2 ) ERPF (mL/min/1.73 m2 ) CCRCG (mL/min/1.73 m2 ) SBP (mm Hg) DBP (mm Hg) MBP (mm Hg) UalbV (mg/d/1 .73 m~ Up'otV (mg/d/1 .73 m~
82 ± 395 ± 95 ± 133 ± 77± 100 ± 50 ± 112 ±
P
SO
13 58 18 21 14 14 139 177
Men (n = 22) Regression Coefficients
-0.035 -0.163 -0.057 +0.027 +0.096 +0.010 -0.133 -0.000
0.872 0.447 0.793 0.902 0.657 0.962 0.534 0.999
Mean ± 82 408 97 145 91 113 167 477
± ± ± ± ± ± ± ±
SO
"
~
23 129 18 20t 15t 16t 417 914
146 729 159 59 27 35 -1235 -1497
- 1.55 -8.91 -1.48 +2.08 + 1.56 +1.90 +33.9 +47.7
p
-0.439 - 0.451 - 0.532 +0.693 +0.671 +0.750 +0.528 +0.340
0.041 0.035 0.011 <0.001 <0.001 <0.001 0.012 0.122
Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure; UalbV, urinary albumin excretion; Up'otV, urinary protein excretion. t p < 0.05 compared with women (Student's t-test).
RENAL FUNCTION AFTER UNILATERAL NEPHRECTOMY
sures (r = 0.81 to 0.93) and between urinary albumin and protein excretion (r = 0.66). The correlation coefficients between GFR, mean blood pressure, and protein excretion were calculated for the total group and separately for men and women. In the total group, there was a statistically significant negative correlation between GFR and proteinuria (r = -0.46) and a positive correlation between mean blood pressure and proteinuria (r = 0.38). Separation according to gender showed that these correlations were limited to men (r = -0.61 and 0.43, respectively). In men only there was a significant negative correlation between GFR and mean blood pressure (r = -0.34). DISCUSSION
The currently held view that the long-term consequences of unilateral nephrectomy are rather mild is based mainly on the outcome of donor nephrectomy and uninephrectomy for acquired disease in adults. Although the interpretation of many of these studies is hampered by methodologic flaws, the common opinion is that a compensatory increased renal function is well maintained during several decades. 8- 1O As the effect of unilateral nephrectomy at young age on compensatory renal growth differs from that of adults,22-25 the long-term outcome also may differ. The results from the present study indicate that good renal function also can be maintained during an extended period after unilateral nephrectomy in childhood. Within the pediatric age group, age at the time of surgery (ranging from oto 16 years) does not affect the outcome of renal function up to 50 years of age. However, our study does not exclude the fact that age at the time of nephrectomy may be important when the outcome of unilateral nephrectomy in childhood is compared with that in adults. Our study group consisted of subjects with no reported structural damage or disease of the remaining kidney. However, this does not necessarily mean that all kidneys were normal at the time of surgery. It did include patients (n = 13) undergoing a unilateral nephrectomy to remove a renal tumor in whom the remaining kidney had been subjected to irradiation and/or chemotherapy. All but one of these patients was younger than 30 years of age at the time of the study. Separate analysis of this group indicated
609
no significant differences with the nononcologic patients under 30 years of age. Our findings, from studying a larger group with a longer follow-up than any previously published study related to unilateral nephrectomy in childhood, substantially enlarge the current knowledge about the outcome of unilateral nephrectomy in childhoody,14 They confirm the findings of Robitaille et al,13 which indicate that neither gender nor age at the time of nephrectomy resulted in a statistically significant difference in renal function. This is in contrast with findings in rats, in whom male gender and young age at the time of nephrectomy are considered to increase the risk for an early development of renal damage and function loss after unilateral nephrectomy.12 Although mean levels. of GFR, ERPF, and creatinine clearance were the same in men and women, men still may be more at risk of an earlier and more rapid loss of renal function than women. First, blood pressure was significantly higher in men, especially in those over 30 years of age. Second, in contrast to women, linear regression analyses with age in men indicated a decrease in renal function and an increase in blood pressure and urinary albumin and protein excretion with time. These findings are the main differences between men and women found in this study. Our data diverge from those of Robitaille et alY and support those ofWikstad et al 14 regarding the renal function more than 25 years after unilateral nephrectomy. Group mean values showed a lower level of renal function and a higher level of blood pressure and albumin and protein excretion in patients with the longest follow-up period. Comparing the intervals from 7 to 15, 16 to 25, and 26 to 40 years, Wikstad et al 14 found a decrease in the GFR and ERPF with follow-up time. Albumin excretion increased with longer follow-up time, and significant albuminuria (2.50 mg/d/ 1.73 m 2 BSA) was present in 47% of patients. Men who have had a single kidney since childhood appear, after the age of 30 years, to have a faster decrease in renal function and a faster increase in blood pressure and albumin and protein excretion when compared with the age-related changes in renal function and blood pressure reported in healthy persons 21 ,26-29 and in patients with essential hypertension 30 ,31 who have two
610
kidneys. It should be emphasized, however, that due to the cross-sectional design of our study, a true change in any of the parameters has not been established. Longitudinal studies with sequential measurements over a prolonged period are needed to uncover true changes in renal function, blood pressure, and urinary albumin and protein excretion over time. A rate of decline of approximately 1.5 mL/min/yr after the age of 30 years is not alarmingly fast, and renal function may, on average, be maintained for another 50 years. In diabetic nephropathy the GFR may decrease at a rate of up to 10 to 15 mL/min/yr,32,33 while for nondiabetic renal disease with a moderate to severe renal insufficiency a decrease of 6 mL/ min/yr has been reported. 34 In another setting of single kidneys (ie, chronic renal transplant rejection) the CCRCG decreased at a rate of approximately 5 mL/min/yr. 35 A slow progressive decline in renal function does not immediately require dietary or pharmacologic intervention. It may, however, require a more frequent and careful long-term follow-up of adults with a unilateral nephrectomy in childhood. After 30 years of age, such a follow-up should include an annual examination of the blood pressure, urinary albumin and protein excretion, and plasma creatinine to calculate creatinine clearance. A full assessment of renal function, including GFR, once every 5 years seems appropriate. Finally, it should be stressed once more that the present findings after unilateral nephrectomy in children with unilateral renal disease do not necessarily apply to unilateral nephrectomy for kidney donation in adults. As both the age at the time of kidney loss and the cause for uninephrectomy are different, the final outcome also may differ. The long-term effect of uninephrectomy for kidney donation can only be established by specific studies of these donors. Currently, the published follow-up studies cover only the first two decades after kidney donation in sufficient numbers. 8- IO Additional longer, and preferably longitudinal, follow-up studies are needed to determine the future of the remaining kidney of the kidney donor beyond that period. In conclusion, the results of this and previously reported studies indicate that the outcome of unilateral nephrectomy in childhood appears largely uneventful. When an intact kidney re-
BAUDOIN, PROVOOST, AND MOLENAAR
mains, a compensatory increased GFR is well maintained up to 50 years after unilateral nephrectomy. In men over 30 years of age, there is a negative correlation between age and renal function , and a positive correlation between age and blood pressure, albumin excretion, and protein excretion. Whether these correlations reflect true changes with time needs to be confirmed by sequential studies over a prolonged period. ACKNOWLEDGMENT The authors are indebted to all the study subjects, without whose participation this study would not have been possible. The authors thank Dr. D.E. Grobbee (Department of Epidemiology) and Dr E.D. Wolff(Department of Pediatric Nephrology) for their valuable help during the study, and M. de Haes-Kistemaker and J.1. Ambagtsheer for their tec.hnical assistance.
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RENAL FUNCTION AFTER UNILATERAL NEPHRECTOMY
13. Robitaille P, Lortie L, Mongeau J-G, Sinnasammy P: Long-term follow-up of patients who underwent unilateral nephrectomy in childhood. Lancet 1:1297-1299, 1985 14. Wikstad I, Celsi G, Larsson L, Herin P, Aperia A: Kidney function in adults born with unilateral renal agenesis or nephrectomized in childhood. Pediatr Nephrol 2: 177-182, 1988 15. Cockcroft OW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976 16. WHO Expert Committee: Arterial hypertension. World Health Organ Tech Rep Ser 628:1-58,1978 17. Mogensen CE, Chachati A, Christensen CK, Close CF, Deckert T, Hommetl E, Kastrup J, Lefebvre P, Mathiesen ER, Feldt-Rasmussen B, Schmitz A, Viberti GC: Microalbuminuria: An early marker of renal involvement in diabetes. Uremia Invest 9:85-95, 1985-86 18. Bratton AC, Marshall EK: A new coupling component for sulfanilamide determination. J Bioi Chern 128:537-550, 1938 19. Smith HW, Finkelstein N, Aliminosa L, Crawford B, Graber M: The renal clearance of substituted hippuric acid derivatives and other aromatic acids in dog and man. J Clin Invest 24:388-404, 1945 20. Watanabe N, Kamei S, Ohkubo A, Yamanaka M, Ohsawa S, Makino K, Tokuda K: Urinary protein as measured with pyrogallol red-molybdate complex, manually and in a Hitachi 726 automated analyzer. C1in Chern 32:1551-1554, 1986 21. Slack TK, Wilson OM: Normal renal function. C1N and CPAH in healthy donors before and after nephrectomy. Mayo Clin Proc 51 :296-300, 1976 22. Aperia A, Broberger 0, Wilton P: Renal functional adaptation in the remnant kidney in patients with renal agenesis and in patients nephrectomized in childhood. Acta Paediatr Scand 67:611-615, 1978 23. Simon J, Zamora I, Mendizabal S, Castel V, Lurbe A: Glomerulotubular balance and functional compensation in nephrectomized children. Nephron 31 :203-208, 1982
611 24. Larsson L, Aperia A, Wilton P: Effect of normal development on compensatory renal growth. Kidney Int 18:2935, 1980 25. Celsi G, Jakobsson B, Aperia A: Influence of age on compensatory renal growth in rats. Pediatr Res 20:347-350, 1986 26. Davies OF, Shock NW: Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest 29:496-507, 1950 27. Wesson LG: Renal hemodynamics in physiological states, in Physiology of the Human Kidney. New York, NY, Grune & Stratton, 1969, pp 96- 108 28. Lindeman RD, Tobin J, Shock NW: Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 33:278-285, 1985 29. Lindeman RD, Goldman R: Anatomic and physiologic age changes in the kidney. Exp GerontoI21:379-406, 1986 30. De Leeuw PW, Kho TL, Falke HE, Birkenhager WH, Wester A: Haemodynamic and endocrinological profile of essential hypertension. Acta Med Scand SuppI622:1-86, 1978 31. Bauer JH, Reams GP, Wu Z: The agin~hypertensive kidney: Pathophysiology and therapeutic options. Am J Med 90:2IS-27S, 1991 (SuppI4B) 32. Viberti GC, Bilous RW, Mackintosh 0, Keen H: Monitoring glomerular function in diabetic nephropathy. A prospective study. Am J Med 74:356-364, 1983 33. Parving H-H, Hommel E, Smidt UM: Protection of kidney function and decrease in albuminuria by captopril in insulin dependent diabetics with nephropathy. Br Med J 297: 1086-1091,1988 34. Ihle BU, Becker GJ, Whitworth JA, Charlwood RA, Kincaid-Smith P: The effect of protein restriction on the progression of renal insufficiency. New Engl J Med 321: 17731777, 1989 35. Modena F, Hostetter TH, Salahudeen AK, Najarian JS, Matas AJ, Rosenberg ME: Progression of kidney disease in chronic renal transplant rejection. Transplantation 52:239244,1991