Renal growth in response to unilateral ureteral obstruction

Transcription

1 Kidney International, Vol. 23 (1983), pp Renal growth in response to unilateral ureteral obstruction STEVEN J. ZELMAN, TERRY V. ZENSER, and BERNARD B. DAVIS Veterans Administration Medical Center, St. Louis, Missouri Unilateral renal disease or a unilateral nephrectomy results in a stimulus to growth of the contralateral kidney that returns the total kidney mass and the glomerular filtration rate to a value near normal [ Unilateral ureteral obstruction also initiates growth of both the obstructed and the contralateral untouched kidney [6, Since the growth characteristics of the two kidneys differ, we would like to examine the literature on kidney growth in the hydronephrotic kidney model and direct attention to the differences between the hydronephrotic and the contralateral intact kidney. Renal growth after ipsilateral ureteral obstruction Ligation of the ureter causes an initial increase in ipsilateral renal mass followed by a progressive decline until only a thin rim of fibrotic and atrophic parenchyma surrounds a dilated collecting system [19, 21]. Sixteen of 46 human adult kidneys (35%) which demonstrated the radiographic features of obstructive uropathy were actually larger than their supposedly normal mates [22]. In these kidneys contralateral hypertrophy was not detected. Enlargement of the kidneys by up to I to 1.5 cm in length was noted primarily during acute obstruction. Within a few days kidney size decreased. In many of these kidneys a thinning of the renal parenchyma was noted. This suggests that either the renal substance was stretched around the dilated renal pelvis or was becoming atrophic. In another study utilizing high dose intravenous pyelography, 39 of 73 grossly hydronephrotic kidneys (53%) were enlarged, and five showed marked enlargement [23]. However, it is not clear to what extent the enlargement represented distortion of the renal parenchyma by the distended collecting system. Among the morphological changes in the renal parenchyma of the unilaterally obstructed rabbit kidney that contribute to increased renal size are dilatation of the tubules, widening of the interstitial spaces, proliferation or enlargement of fibroblasts and mononuclear cells in the renal interstitium, and congestion of the peritubular capillaries with extravasation of red cells and protein into the interstitium [21, 24]. At the ultrastructural level, the fibroblasts appear metabolically active with prominent nucleoli, increased rough-surfaced endoplasmic reticulum with dilated cisternae, and prominent Golgi apparati. The mononuclear cells also contain abundant rosettes of ribosomes [241. Received for publication October 11, by the International Society of Nephrology In early studies of compensatory hypertrophy following unilateral ureteral obstruction, hydronephrotic rat kidneys were noted to be enlarged, but this was ascribed to the collection of urine within them [25]. In 40-day-old mice, the renal weight increased by as much as 39% 24 hr after ureteral ligation and then declined to about 45% of the original weight 35 days later [261. However, even after the urine was carefully drained from the kidney, obstructed rat kidneys were heavier than either contralateral or control kidneys as early as 2 days following ureteral ligation and until at least 10 days following obstruction [27]. It is doubtful that all the excess urine can be drained from the dilated tubules. In fact, the water content of the rat kidney after ureteral ligation may be increased by as much as 69% compared to controls even after decapsulation and transection [281. Even in tissue slices, the water content of the hydronephrotic rat kidney is increased from 76.0 to 81.7% in the cortex and 80.6 to 84.1% in the medulla [14]. Thus, it is difficult to use kidney weight as the sole measure of the degree of hypertrophy in the hydronephrotic kidney. However, counts of mitotic figures and autoradiographic images after tritiated thymidine labeling clearly demonstrate increased cell turnover as early as 24 hr after ureteral ligation in both the rat [25, 29] and the rabbit [24]. Initially the mitotic activity in the obstructed kidney exceeds that in the untouched kidney [25, 27]. The rate of DNA synthesis peaks in the cortex of the obstructed rat kidney by 2 to 3 days and in the medulla by 3 to 5 days [27, 29]. There is no increase in mitotic counts in the glomeruli. The DNA content in the cortex of the adult rat rises from igiml dry tissue to a peak of 23, pg/mg 4 days following ureteral obstruction, and then falls progressively to pg/mg by day 14 [14]. A similar increase in DNA from pg/mg to tg/mg on day 4 was found in the medulla. This hyperplastic response was accompanied by a hypertrophic response as evidenced by a rise in the RNA/DNA ratio from 1.25 to 1.51 in the cortex and 0.90 to 1.22 in the medulla, peaking in both segments at 48 hr [14]. In 40-day-old mice, the increases in DNA and RNA in the hydronephrotic kidney and the change in the RNA/DNA ratio are significantly different from those in nonoperated or sham-operated controls [15]. Furthermore, renal protein increases by 12.5% in the obstructed mouse kidney 24 hr after ureteral ligation, and then begins to decline [30]. In sham-operated and nonoperated controls, no change in renal protein was detected during this interval. Nagle, Johnson, and Jervis [24] prepared autoradiomicrographs of cortical and interstitial tissues after tritiated thymidine labeling of obstructed rabbit kidneys. By this means the labeling of parenchymal cells could be distinguished from that of fibroblasts and monocytes. A marked proliferative response 594

2 was noted in the interstitial cells of the cortex and outer medulla at 24, 48, and 72 hr, and in the inner medulla at 72 hr compared to sham-operated controls. The proliferative response in the cortex peaked at 72 hr at 21.9 times the sham mean value and in the medulla at 18.3 times the sham mean value. The labeling of interstitial cells from the obstructed kidney was significantly greater than that in the contralateral untouched kidney at 24, 48, and 72 hr in the cortex and outer medulla, and at 48 and 72 hr in the inner medulla [24]. Most of the labeled cells in the cortex and outer medulla appeared to be stimulated fibroblasts and were frequently in close proximity to unlabeled monocytic cells [24]. In the inner medulla, the labeled cells were predominately endothelial cells. Thus, certainly a significant portion of the growth of the obstructed kidney is due to a proliferation of interstitial fibroblasts in the cortex and outer medulla. Our laboratory has recently cultured two types of cells from the cortex of unilaterally obstructed rabbit kidneys. These cells were identified as macrophages and fibroblasts. Cells obtained from the hydronephrotic kidney grew faster in culture than those from either the contralateral or a normal kidney. The doubling times for macrophages derived from the hydronephrotic and the contralateral kidneys were 1.8 and 3.1 days, respectively. Fibroblasts demonstrated doubling times of 2.4, 5.1, and 6.9 days when cultured from the obstructed, contralateral, or normal kidneys. The growth rate of macrophages or fibroblasts derived from a hydronephrotic kidney was significantly greater (P < 0.01) than for the same cell type from a nonoperated or normal kidney [31]. This suggests that the hyperplasia in the hydronephrotic kidney is different from that in the unobstructed kidney in that significant proliferation of macrophages and fibroblasts only occurs in the injured kidney. Thus a significant proportion of the growth in the obstructed kidney is probably mesenchymal rather than parenchymal. In the rat, ureteral obstruction initially increases the rate of oxygen uptake measured in slices of ipsilateral renal cortex [14]. However, this peaks at 24 hr and diminishes rapidly. A similar pattern is seen in medullary slices. Cortical oxygen consumption per cell remains stable for the first 24 hr, and then falls progressively to half its original value by 2 weeks. Anaerobic glycolysis, on the other hand, increases markedly in both the cortex and the medulla, peaking 7 days after ipsilateral ureteral obstruction [14]. Mean renal blood flow in dogs [18, 32, 33] and rabbits [13] initially increases after unilateral ureteral ligation and then falls progressively to half its original value by 7 hr of complete obstruction. Seven days later, ipsilateral renal blood flow averages only one fourth to one sixth of its control value. At this time cortical blood flow is reduced to a greater degree than is outer medullary blood flow in the rat [34]. Renal growth after contralateral ureteral obstruction In children with unilateral hydronephrosis due to ureteropelvic obstruction, hypertrophy of the contralateral kidney has been noted by intravenous pyelography despite an insignificant reduction in function of the obstructed kidney [20]. In one third of the kidneys, the renal size was more than 2 SD greater than the normal mean. On the other hand, following unilateral ureteral obstruction in adults, compensatory hypertrophy only occurred in four of 51 patients [23]. Hodson and Craven [22] observed contralateral enlargement Renal growth with ureteral obstruction 595 in adults only when the obstructed kidney had decreased in size. In his series of 27 patients with a small obstructed kidney, 17 (63%) contralateral kidneys were longer than 14 cm and 7 (26%) were longer than 15 cm. Thus the minimal data available for man suggests that in children, obstruction alone is sufficient for compensatory hypertrophy to occur. In adults, loss of renal mass must be present before hypertrophy begins. Albarran [35] was one of the first researchers to demonstrate renal hypertrophy following obstructive atrophy of the contralateral kidney. Hinman [36] showed that in the rat compensatory hypertrophy was essentially complete within 20 to 30 days of ureteral ligation and that the degree of hypertrophy was comparable to that following unilateral nephrectomy. A similar 20% increase in renal size was also seen in rabbits, cats, dogs, and pigs after contralateral ureteral ligation [36]. Other studies soon followed and confirmed this early work [14, 28, 37, 38]. In the young rat, the enlargement of the contralateral kidney may equal the weight loss of the obstructed kidney so that the total weight of both kidneys is not different from nonoperated controls [191. The increased renal mass may be due to an increase in the number of nephrons, the number of cells per nephron (hyperplasia), the size of cells (hypertrophy), or to a migration of another cell type into the enlarging kidney. The increase in renal mass is not the result of an increased proportion of water or an infiltrative process [14, 15]. Goss and Rankin [25] demonstrated the hyperplastic response by noting an increase in the number of mitotic figures in both the obstructed and the contralateral rat kidney 48 hr following ureteral ligation. After tritiated thymidine labeling of DNA, autoradiographic counts of labeled nuclei failed to confirm renal hyperplasia 24, 48, and 72 hr after contralateral ureteral ligation [29]. This discrepancy could not be explained by the age of the rats [29]. Further studies with Sprague-Dawley rats suggested that it took 7 days before either a significant increase in weight or number of cortical mitoses could be demonstrated in a kidney contralateral to a hydronephrotic kidney [27]. Increased medullary mitoses were demonstrated within 5 days. This is in contrast to the hydronephrotic kidney, in which an increase in cortical mitotic figures is present within 3 days and an increase in medullary mitotic figures is present by 2 days. Thus the hyperplasia develops earlier in the obstructed kidney than in the contralateral untouched kidney. In studies with 200 to 250 g body weight rats, the DNA content in the cortex of the kidney contralateral to a ureteral obstruction decreases while the ratio of RNA to DNA content increases [19]. This would be consistent with an increase in cell size without any increase in the number of renal cells, since the DNA content per cell is relatively constant [39]. No significant changes in DNA or RNA content occur in the medulla [14]. Forty-day-old mice respond to unilateral ureteral ligation with an increase in the wet weight, total protein content, RNA, and DNA of the unobstructed kidney [15, 26, 30]. During a 35- day study, these kidneys increased in weight by 64% compared to a 26% increase in nonoperated controls. A similar increase in total protein content was recorded, but the increase in DNA content was only 39%. In control kidneys, the increase in DNA was only 23%. RNA content increased by 52% in the kidney contralateral to the obstruction, but paralleled the increase in DNA in the controls. In older mice, these changes are less

3 596 Zelrnan Cl at dramatic [151. The discrepancy between these studies and previous studies in rats may be due to the age and species of animal studied. Nevertheless, it seems clear that hyperplasia does occur in the kidney contralateral to ureteral ligation, particularly in the younger animal. With aging, hyperplasia may be less prominent. Renal hypertrophy as evidenced by increased tissue weight, renal protein, and the RNA/DNA content ratio supplements this hyperplastic response. As renal growth occurs contralateral to an obstructed kidney, the amount of heavy, rapidly-sedimenting polyribosomes increases over a 20-day period [15]. This change is similar to that seen following unilateral nephrectomy [40]. Orotic acid-2-c'4 labeling of polyribosomes increases progressively during the period of compensatory growth [15]. The specific activity of the 28S and l8s ribosomal subunits also increases. Since the halflife of ribosomal RNA is unchanged following uninephrectomy, these observations in combination with the increase in total RNA content implies that the rate of RNA synthesis increases during the growth phase after contralateral ureteral ligation [15]. Oxygen consumption by the cortex of the unobstructed kidney is increased within 24 hr of ureteral ligation and remains elevated up to 7 days. By 2 weeks, oxygen consumption has returned to control levels [14]. This is similar to the response of the solitary kidney remaining after unilateral nephrectomy [41]. When oxygen consumption is corrected for the change in DNA content, oxygen uptake per cell increases from a control value of 0.94 ml/mg DNA to 1.39 ml/mg DNA 4 days following ureteral ligation [14]. There are no changes in the rate of anaerobic glycolysis [14]. Mean renal blood flow appears to increase after contralateral ureteral ligation [13, 33, 34, 42, 431, although this remains controversial [18, 32]. The distribution of intrarenal blood flow measured by xenon-133 washout does not appear to be altered [18]. However earlier studies suggested a relative decrease in medullary blood flow [34]. In the rat, inulin clearance and urine flow increase markedly within 24 hr of contralateral ureteral ligation, peak at 48 hr. and then stabilize by 7 days [14, 43]. At this time the glomerular filtration rate is about 60 to 70% above its pre-operative level [14]. Deep nephrons appear to increase their GFR more than do superficial nephrons [34]. Fractional sodium excretion is not changed by contralateral ureteral ligation [14]. In the rabbit, however, no increase in GFR measured by iodothalamate clearance was detected up to 32 days following contralateral ureterovesical junction ligation [211. In the dog, both inulin and PAH clearance are increased to about 165% of control 1 hr after release of a contralateral ureteral obstruction of I-week duration [42]. The induction of pyelonephritis in the contralateral kidney several weeks prior to ureteral ligation does not prevent the compensatory increase in GFR [44]. Nevertheless, an increase in GFR and compensatory renal growth are not invariably linked [451. Regulation of renal mass Persistent ureteral obstruction eventually results in hydronephrotic atrophy [361. However, if the complete obstruction is relieved alter Ito 4 weeks, a contralateral nephrectomy induces a greater degree of recovery in the hydronephrotic kidney than would otherwise occur [22, 46]. Thus, the obstructed kidney preserves its compensatory ability. Furthermore, even while a kidney remains partially obstructed, in the absence of a contralateral kidney, a stimulus to renal growth must exist. Obstruction of rat ureters by encircling cellophane strips causes hydronephrosis, tubular atrophy, and interstitial fibrosis. However, when a contralateral nephrectomy is performed simultaneously, minimal atrophy and fibrosis develop [47]. The dry weight of these obstructed kidneys is also greater than that from animals with an intact kidney [48]. Nevertheless, despite the preservation of mass, renal function is poor. Thus, increased tubular pressures need not cause a loss of renal substance. Furthermore, 4 months to 2 years after release of I to 4 weeks of unilateral ureteral occlusion, when the GFR and renal plasma flow are stable, a contralateral nephrectomy induces a further increase in these parameters [42, 46]. However, 48 hr of ureteral obstruction do not augment renal growth in response to a contralateral nephrectomy performed at the time of ureteral deligation [16]. These observations are consistent with Hinman's concept of "renal counterregulation" [36]. If both kidneys are equally responsive, they will hypertrophy symmetrically when either renal mass or function is inadequate. However, if one kidney is at a disadvantage because of obstruction or injury, that kidney will demonstrate reduced growth. As the healthy kidney undergoes hypertrophy, renal mass and function improve and the stimulus to growth will be reduced. The diseased kidney will then be subjected to a reduced growth stimulus and will progressively atrophy, or at least not return to normal. Removal of the enlarged kidney releases this inhibition, and the diseased kidney will then enlarge and increase its function. In the nephrectomy model of compensatory renal hypertrophy, it is not possible to distinguish the relative importance of loss of renal parenchyma, loss of function, or increased physiologic work as the stimulus to hypertrophy in the untouched kidney. Ureteral obstruction initially preserves renal mass but reduces the function of that kidney and increases the work of the contralateral kidney. Furthermore, this is a unique model in that two types of renal growth are demonstrated. Enlargement of the obstructed kidney is probably in large part due to the proliferation of interstitial fibroblasts and macrophages and may be a local response to injury. The contralateral kidney however enlarges as a result of hyperplasia and hypertrophy of renal parenchyma. Because this compensatory response is delayed in comparison with that after a uninephrectomy, the contralateral hypertrophy may very well he in response to obstructive atrophy and not solely loss of function [15, 491. Thus, the contributions to our understanding of compensatory renal growth derived from this model add to those derived from the uninephrectomy and urine reinfusion models [50 52] and determine our current understanding of this phenomenon. Summary. Unilateral ureteral ligation results in growth of both the obstructed as well as the contralateral untouched kidney. The factors that contribute to the growth of the obstructed kidney include an increase in renal water content, proliferation of interstitial fibroblasts and macrophages in both the cortex and outer medulla, and proliferation of endothelial cells in the inner medulla. The doubling times of fibroblasts and macrophages are significantly shorter when the cells are cultured from the cortex of the unilateral hydronephrotic kidney than when they are cultured from the untouched kidney.

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