Renovascular Adaptive Changes in Chronic Hypoxic Polycythemia

Kidney International, Vol. 54 (1998), pp. 2014–2020

ION CHANNELS - MEMBRANE TRANSPORT - INTEGRATIVE PHYSIOLOGY

Renovascular adaptive changes in chronic hypoxic polycythemia

C. DENNIS THRON,JIAN CHEN,JAMES C. LEITER, and LO CHANG OU

Departments of Physiology and Medicine, Dartmouth Medical School, Lebanon, New Hampshire, USA

Renovascular adaptive changes in chronic hypoxic polycythemia. tends to reduce renal blood flow (RBF), and the reduced Background. Chronic hypoxia in rats produces polycythemia, plasma fraction reduces renal plasma flow (RPF) relative to and the plasma fraction falls, reducing renal plasma flow (RPF) relative to renal blood flow (RBF). Polycythemia also causes RBF. On the other hand, renal regulation of the rate of increased blood viscosity, which tends to reduce RBF and renal synthesis and release of erythropoietin (EPO) responds to oxygen delivery. We studied how renal regulation of electrolyte changes in renal tissue PO2 [1, 2]. The response to renal balance and renal tissue oxygenation (which is crucial for eryth- hypoxia, with increased cellularity and viscosity of the ropoietin regulation) are maintained in rats during hypoxic expo- blood, may cause a reduction in RBF that cannot be fully sure. Methods. Rats of two strains with differing polycythemic re- compensated by the higher oxygen-carrying capacity of the sponses, with surgically implanted catheters in the urinary blad- blood, so that renal oxygen delivery is reduced, exacerbat- der, femoral artery, and left renal and right external jugular veins, ing renal hypoxia and producing a vicious cycle of increas- were exposed to a simulated high altitude (0.5 atm) for 0, 1, 3, 14, ing polycythemia and increasing renal hypoxia. and 30 days, after which RPF (para-aminohippurate clearance), Erslev, Caro and Besarab have suggested that this vicious glomerular filtration rate (GFR, polyfructosan clearance), hematocrit and blood gases were measured, and RBF, renal vascular cycle is prevented because decreased RBF reduces the resistance and hindrance (resistance/viscosity), renal oxygen de- filtered load of sodium for reabsorption and thereby re- livery, and renal oxygen consumption were calculated. duces renal oxygen consumption, mitigating renal hypoxia Results. During chronic hypoxia RBF increased, but RPF [3]. However, RBF is not reduced, but is rather substan- decreased because of the polycythemia. GFR remained normal because the filtration fraction (FF) increased. Renal vascular tially increased in rats with hypoxia-induced polycythemia, resistance decreased, and renal vascular hindrance decreased and the glomerular filtration rate (GFR) is maintained more markedly. Renal oxygen delivery and consumption both within the normal range [4]. Therefore, in these animals the increased. mechanism suggested by Erslev et al [3] does not appear to Conclusions. During chronic hypoxia GFR homeostasis appar- operate. ently took precedence over RBF autoregulation. The large decrease in renal vascular hindrance suggested that renal vascular The increase in RBF therefore appears to be important remodeling contributes to GFR regulation. The reduced hin- for homeostatic control of both electrolyte balance and red drance also prevented a vicious cycle of increasing polycythemia blood cell mass in chronic hypoxia. Arterial blood pressure and blood viscosity, decreasing RBF, and increasing renal hypoxia does not increase appreciably during chronic hypoxic expo- and erythropoietin release. sure [4, 5], and therefore the increase in RBF implies that renal vascular resistance decreases sufficiently to account for the increased blood flow despite the increased blood The kidney, as the organ of homeostatic control of viscosity. Renal vascular adaptive changes are therefore electrolyte balance and red blood cell mass, faces two important in sustaining normal homeostatic function of the serious functional challenges during chronic hypoxic expo- kidney in the presence of chronic hypoxia and polycythe- sure. Control of electrolyte balance depends upon mainte- mia. nance of the glomerular filtration rate (GFR), which could The present investigation extends our previous study [4]. be compromised by the polycythemia of chronic hypoxia in We have studied two Sprague-Dawley rat strains with two ways: the increased viscosity of polycythemic blood differing polycythemic responses to hypoxia: Hilltop rats develop excessive polycythemia whereas Madison rats develop only moderate polycythemia [2, 4, 6, 7]. These strain Key words: hypoxia renal function, vascular remodeling, blood viscosity, differences in the polycythemic responses to chronic hyp- renal blood flow, erythropoietin. oxia allowed us to evaluate the effect of polycythemia on

Received for publication April 21, 1998 the renal circulation and renal function with respect to and in revised form June 30, 1998 electrolyte regulation and EPO regulation. Here we report Accepted for publication July 1, 1998 the effects of hypoxia and polycythemia on RBF, RPF, © 1998 by the International Society of Nephrology ﬁltration fraction (FF), GFR, renal oxygen delivery and

2014 Thron et al: Renovascular adaptations to polycythemia 2015 renal oxygen consumption. The effects of hypoxia and underneath the restraining cage. Urine volume was mea- polycythemia on EPO gene expression, EPO protein pro- sured by weight. After a 30 to 60 minute period of duction, renal venous PO2, sodium excretion and sodium equilibration to the restraining cage, at least two duplicate reabsorption are described in a separate paper [2]. samples of urine and arterial and renal venous blood were obtained from each animal under appropriate oxygen ten- METHODS sion conditions. To avoid possible adverse effects of re- Animals peated blood sampling, which might change the hematocrit, each rat was studied only once. Each animal was killed, and Male Sprague-Dawley rats weighing 270 to 320 g from the location of the renal venous catheter was determined. Hilltop (Scottsdale, PA, USA; altitude susceptible strain) Data were accepted only when the renal venous catheter and Madison (Madison, WI, USA) breeding laboratories was midway between the inferior vena cava and the left were used. Five groups of at least five rats from each strain kidney. were exposed to simulated high altitude (0.5 atm) for 0, 1, 3, 14, and 30 days. At the end of each of these exposure Analytical techniques periods, RBF, RPF, GFR, hematocrit and blood gases were The following determinations were made in all plasma measured or calculated. A total of 32 Hilltop rats and 33 and urine samples: polyfructosan by the anthrone method Madison rats were used for RBF and RPF determinations, [9], and PAH by the method of Bratton and Marshall as and 11 Hilltop and 9 Madison rats were used for GFR and modified by Smith et al [10]. Hematocrit was determined by FF levels. a micromethod. Urine flow and clearance rates are ex- Surgical preparations pressed per 100 g body wt. Arterial and venous blood gas samples were obtained anaerobically by withdrawing 300 ␮l Five to seven days prior to measurement, each animal from the rat; only the last 160 ␮l were used for analysis. The was anesthetized with a combination of ketamine (60 mg/kg residue was returned to the rat. pH, PO2, and PCO2 were body wt, i.m.) and pentobarbital (20 mg/kg body wt, i.p.) measured with microelectrodes at 37°C (Model BMS 3 and catheters were implanted in the urinary bladder, MK2; Radiometer America, Cleveland, OH, USA). The femoral artery and left renal and right external jugular oxygen content in arterial and venous blood was estimated veins as previously described [4, 8]. After surgery, the rats from a published rat oxy-hemoglobin dissociation curve were treated with penicillin (100,000 U daily, i.m.) for five [11]. Renal oxygen delivery and consumption were calcu- days and were allowed free access to water and laboratory lated by multiplying renal blood flow by the arterial oxygen rat chow. For the next two days, the animals were accli- content or renal arteriovenous oxygen content difference, mated to a plastic restraining cage employed for renal respectively. function measurements. The animals recovered from surgery uneventfully, and the majority had gained weight by Statistical analysis the time of measurements. Least squares linear regression and analysis of covariance were done according to Snedecor and Cochran [12]. Experimental procedures P Ͻ 0.05 was considered significant. During measurements, each rat was housed in a restraining cage. A Plexiglas hood fit over the front of the RESULTS restraining cage so that the desired gas mixture could be The hematocrit increased with time of hypoxic exposure flushed through the hood. Measurements were made under from the sea level control value of 42.6 Ϯ 1.4 to a peak Ϯ Ϯ hypoxic conditions (10.5% O2) for the hypoxic rats and value of 73.0 0.9 in Hilltop rats and from 41.2 3.0 to Ϯ under normoxic conditions (20.9% O2) for the sea level 61.0 1.0 in Madison rats after 30 days of hypoxia. control rats. Figure 1 shows the changes in RBF (Fig. 1A), FF (Fig. The GFR was measured by the clearance of polyfruc- 1B), RPF (Fig. 1C) and GFR (Fig. 1D) as functions of the tosan (Inutest; Laevasan, Linz-Donau, Austria), and RPF hematocrit. All four variables were approximately linear was determined from the extraction of para-aminohippu- functions of hematocrit. Analysis of covariance showed no rate (PAH; Merck Sharp & Dohme, West Point, PA, significant differences between the regression lines for USA). The jugular venous catheter was connected to a Madison and Hilltop rats. RBF increased linearly as the variable-speed infusion pump (Sage Instruments; Orion hematocrit rose [slope ϭ 91.2 Ϯ 8.8 ␮l/min/100 g body Research Inc., Cambridge, MA, USA), and following a wt/% hematocrit (Hct)], P Ͻ 0.001) and exceeded the sea priming injection (0.25 ml/100 g body wt), an infusion of level control values by approximately 50% at the highest 10% polyfructosan and 1% PAH in sterile saline was hematocrit. Similarly, the FF increased by about 30% from started at a rate of 10 ␮l/min/100 g body wt. The exposed a control value of 0.360 Ϯ 0.003 to a value of 0.470 Ϯ 0.007 end of the bladder catheter was extended with a short at a hematocrit of 70% (slope ϭ 0.0036 to 0.0010, P Ͻ length of polyethylene tubing to allow collection of urine 0.002). In contrast, RPF fell slightly, but significantly 2016 Thron et al: Renovascular adaptations to polycythemia

Fig. 1. Renal blood flow (A), renal plasma flow (B), filtration fraction (C) and glomerular filtration rate (D) have been plotted as functions of the hematocrit (Hct). Analysis of covariance showed no significant differences between the Madison (E) and Hilltop (F) rats, and the regression lines shown are for pooled data from both strains. Slopes and significance values are: renal blood flow, 91.2 Ϯ 8.8 ␮l/min/100 g body wt/% Hct, P Ͻ 0.001; renal plasma flow, Ϫ17.2 Ϯ 4.3 ␮l/min/100 g body wt/% Hct, P Ͻ 0.001; filtration fraction, 0.0036 Ϯ 0.0010% filtration/% Hct, P Ͻ 0.002; glomerular filtration rate, Ϫ3.2 Ϯ 2.2 ␮l/min/100 g body wt/% Hct, P ϭ 0.17.

(slope ϭϪ17.2 Ϯ 4.3 ␮l/min/100 g body wt/% Hct, P Ͻ lower shear rates, and the changes in hindrance necessary 0.001) as the hematocrit rose. The GFR remained constant to maintain constant RBF would be even larger than those over the entire range of hematocrits (slope ϭϪ3.3 Ϯ 2.2 shown in Figure 2B at lower shear rates. These Figures ␮l/min/100 g body wt/% Hct, P ϭ 0.17). show a marked fall in renal vascular resistance and a Hypoxic exposure had no consistent effect on systemic somewhat greater fall in renal vascular hindrance. blood pressure, and we never observed any differences in Renal oxygen delivery is not comparable under normoxic systemic blood pressure between rat strains. We did not and hypoxic conditions, and we considered normoxic and record systemic blood pressure in this study, but reviewing hypoxic values separately. Under normoxic conditions, studies of 42 rats of each strain in other studies at sea level renal oxygen delivery was 39.7 Ϯ 1.3 ml/min/100 g body wt and high altitude revealed a mean arterial blood pressure in Hilltop rats and 36.3 Ϯ 1.5 ml/min/100 g body wt in of approximately 120 mm Hg. Assuming a mean arterial Madison rats (triangular points, Fig. 3A). This difference pressure of 120 mm Hg and a venous pressure of zero, we was not statistically significant. Once hypoxia was estab- estimated the relationship between hematocrit and renal lished, renal oxygen delivery increased linearly as the vascular resistance (120 mm Hg/RBF) in the rats in this hematocrit rose (Fig. 3A). The increase in renal oxygen study (Fig. 2A). We also calculated renal vascular hin- delivery as a function of hematocrit was significantly (P ϭ drance (resistance/viscosity) [13, 14] as a function of he- 0.04) less steep in Hilltop rats compared to Madison rats matocrit (Fig. 2B). We estimated viscosity from the hema- because Hilltop rats had lower arterial O2 saturation at any tocrit-viscosity relationship measured by Jan and Chien given hematocrit under hypoxic conditions (slope, Hilltop, assuming a shear rate of 200/sec [15]. No single shear rate 1.17 Ϯ 0.08 ml/min/100 g body wt/% Hct, P Ͻ 0.001; can be applied to blood flow in vivo, but the relationships Madison, 1.59 Ϯ 0.20 ml/min/100 g body wt/% Hct, P Ͻ shown in Figure 2 are applicable for the particular shear 0.001). rate chosen. The apparent viscosity rises more steeply at There is no a priori reason to expect renal oxygen Thron et al: Renovascular adaptations to polycythemia 2017

Fig. 2. Calculated renal vascular resistance (A) and renal vascular Fig. 3. Renal oxygen delivery (A) and renal oxygen consumption (B) have hindrance (B) have been plotted as functions of the hematocrit. The renal been plotted as functions of the hematocrit. The triangles represent sea vascular hindrance was calculated by dividing renal vascular resistance by level, normoxic values, and the circles represent hypoxic values. (A) viscosity in centipoises. Viscosity was estimated from the hematocrit- Regarding renal oxygen delivery, the regression slopes for hypoxic condi- viscosity curve [15], assuming a shear rate of 200/sec. Comparisons tions (normoxic points excluded) differ significantly for the two strains between strains have not been calculated since renal vascular resistance (P Ͻ 0.05, analysis of covariance). Slopes and P values are: Madison, and renal vascular hindrance are linearly dependent on arterial blood 1.59 Ϯ 0.20 ml/min/100 g body wt/% Hct, P Ͻ 0.001; Hilltop, 1.17 Ϯ 0.08 pressure and RBF, which did not differ between strains. The renal ml/min/100 g body wt/% Hct, P Ͻ 0.001. For renal oxygen consumption vascular hindrance data were fitted to a second order polynomial since the (B), the regression slopes did not differ significantly between rat strains goodness of fit was superior to linear regression. Equations for the plotted (Hilltop, slope ϭ 0.077 Ϯ 0.028 mol/min/100 g body wt/% Hct, P Ͻ 0.02; curves: renal vascular resistance ϭ 42.74-0.38 ϫ Hct; renal vascular Madison, slope ϭ 0.071 Ϯ 0.038 mol/min/100 g body wt/% Hct, P ϭ 0.07). hindrance ϭ 28.85-0.71 ϫ Hct ϩ 0.00465 ϫ Hct2. Symbols are (E) However, renal oxygen consumption was higher in Hilltop rats across all Madison and (F) Hilltop rats. hematocrits compared to Madison rats (P ϭ 0.01 for adjusted means, analysis of covariance). consumption to differ either between strains or across hematocrits, so normoxic and hypoxic values were consid- DISCUSSION ered together. Renal oxygen consumption increased as the The several measures of kidney function changed as hematocrit rose, but the rate of change in oxygen consump- uniform functions of the hematocrit, regardless of the tion was not different between strains (Hilltop, slope ϭ particular rat strain and despite the marked disparity in the 0.077 Ϯ 0.028 mol/min/100 g body wt/% Hct, P Ͻ 0.02; severity of the polycythemic responses in the two rat strains. Madison, slope ϭ 0.071 Ϯ 0.038 mol/min/100 g body wt/% This suggests that the changes were in response to the Hct, P Ͻ 0.07). Renal oxygen consumption was significantly polycythemia rather than the hypoxia. The present study higher across all hematocrits in Hilltop rats compared to confirms the previous finding [4] that the GFR is main- Madison (the adjusted means in the covariance analysis tained in the face of the reduced plasma fraction and RPF were significantly different, P Ͻ 0.01). Chronic hypoxia associated with the polycythemic response to chronic hyp- ϩ caused only minor changes in filtered Na load, fractional oxia. As the hematocrit (Hct) increases, other things being ϩ ϩ Na reabsorption, and Na excretion [2], and the reason equal, maintenance of a normal RPF would require that for increased renal oxygen consumption is not known. RBF increase hyperbolically [that is, in a proportion of 2018 Thron et al: Renovascular adaptations to polycythemia

1/(100 Ϫ Hct)]. However, this was not seen. RBF increased of resistance vessels in the kidney is equal to the number of linearly by 50%, which was not enough to produce a normal nephrons, and the number of nephrons probably does not RPF, but the FF increased by 30%, and the combined increase appreciably in mature animals. Moreover, there is effect of the increases in RBF and FF maintained a normal little increase in the amount of renal tissue during hypoxic GFR. RBF, RPF, FF, and GFR were approximately linear exposure: Sylvette observed a 10 to 20% increase in renal functions of hematocrit, and there were no significant weight in hypoxia [28], but Kuwahira et al found no differences between the regression lines for Madison and increase [16]. Appreciable shunting of arterial blood past Hilltop rats. the glomeruli seems unlikely, as there do not appear to be Total peripheral resistance is unchanged in chronic any pre-existing shunts that might be enlarged. Further- hypoxia [16, 17], but polycythemia increases blood viscosity. more, if shunting were appreciable, that would mean that It follows that there must be some decrease in vascular the true single-nephron filtration fraction was somewhat hindrance, that is, some increase in the number or diameter higher than the observed filtration fraction, and the effer- of resistance vessels. However, although there appears to ent arteriolar hematocrit might be increased by filtration to be a general decrease in vascular hindrance in chronic a level associated with a prohibitively high blood viscosity. hypoxia [18], there is no appreciable increase in blood flow At the observed FF of 0.47, an afferent arteriolar hemato- to any major organ other than the kidney [16, 19]. The crit of 70 to 73% is already increased to a hematocrit of 80 increase in RBF is therefore due to a regulatory mechanism to 85% in the efferent arteriole, corresponding to a blood peculiar to the kidney. This is probably largely a response viscosity at least four times normal. to the polycythemia, rather than the hypoxia, since RBF It seems likely, therefore, that the decreased renal vas- increases similarly in chronic polycythemia caused by EPO cular resistance is due almost entirely to an increase in the without hypoxia [20] and in primary polycythemia [21]. diameter of the afferent and efferent arterioles. These Acutely, autoregulation of renal vascular resistance has vessels account for most of the renal vascular resistance. at least two components [22, 23]: a myogenic mechanism Kindred has reported that the kidneys of chronically hy- and tubuloglomerular feedback (TGF). The constancy of poxic rats characteristically show hyperemia [29]: the glo- GFR during chronic hypoxia suggests that TGF plays an merular capillaries are distended, the efferent arterioles important role. As already noted, the increased hematocrit are dilated, and the intertubular capillaries are enlarged. of chronic hypoxia tends to reduce GFR, and this probably Afferent arterioles must also be dilated because otherwise leads to reduced NaCl concentration at the macula densa, glomerular capillary pressure and filtration fraction would which by TGF mechanisms, decreases resistance of the decrease. afferent arteriole. The myogenic response probably plays a Wilcox et al found that normal rats had a large compo- smaller part. Increased blood viscosity would presumably nent of nitric oxide-induced renal vasodilation that was increase the pressure drop in the renal arterial tree, and enhanced in chronic EPO-induced polycythemia [20]. Re- reduced arterial pressure should elicit a vasodilatory, myo- nal vascular resistance after treatment with a nitric oxide genic response. Renal vascular hindrance does decrease synthase inhibitor was approximately the same in normal when the hematocrit increases acutely from 10% to 60% and polycythemic rats. However, the latter finding, taking under isovolemic conditions [13], though it increases mark- into consideration the increased blood viscosity in polycy- edly at higher hematocrit levels, presumably because of themia, indicates a decreased renal vascular hindrance in vasoconstriction. The mechanism of this acute vasocon- polycythemia that is not due to nitric oxide-induced vaso- striction is not known, nor is it known whether it persists dilation. The 65 to 80% reduction in vascular hindrance chronically. estimated here is considerably larger than the 25 to 45% Since systemic blood pressure in chronically hypoxic rats decrease in resistance that can be produced acutely by is not increased [4, 24], the rise in RBF implies a corre- vasodilators [30, 31]. This suggests that the vascular en- sponding chronic decrease in the renal vascular resistance largement is at least in part a chronic change due to (Fig. 2A). Furthermore, the increased blood viscosity im- vascular remodeling [32] in response to chronically in- plies that renal vascular hindrance decreases proportion- creased RBF induced by transforming growth factor ately more than RBF increases (Fig. 2B). During hypoxic (TGF). Similar, but usually somewhat smaller, increases in exposure, the hematocrit increased from a control value of afferent and efferent arteriolar conductance and glomeru- 42% to 73%. Acute hematocrit increases of this magnitude lar blood flow occur in compensatory renal hypertrophy increase the apparent resistance of vascular beds perfused one to four weeks after partial renal ablation [33–35]. at a constant rate by a factor of 2 to 3 [25–27]. Applying this Increased blood flow, which causes acute vasodilation [36, to the 1.5-fold increase in RBF observed here would 37], also causes blood vessels to enlarge in diameter by indicate a decrease in renal vascular hindrance by a factor growth [38]. The growth stimulus, like the cause of acute of 1/3 to 1/4.5, that is, a 65 to 80% decrease in renal vasodilation, is probably increased wall shear stress, and in vascular hindrance. This change is probably not due to an polycythemia the wall shear effect may be enhanced by the increase in the number of blood vessels, since the number high viscosity [39]. Thron et al: Renovascular adaptations to polycythemia 2019

Studies of O2 delivery have shown an inverted-U rela- TGF and myogenic mechanisms that sustain the GFR by tionship between hematocrit [13, 40] and O2 delivery under modifying renal vascular resistance and RBF [22, 23]. Our isovolemic, normoxic, sea level conditions when the hemat- observations suggest that the GFR is the primary variable ocrit changes have been made acutely. The maximal O2 controlled chronically, and autoregulation of RBF, though delivery occurs at a hematocrit of 40%. At a low hemato- it may arise in considerable part from acute myogenic crit, O2 delivery declines because the O2-carrying capacity regulation of arterial wall tension, is keyed to regulation of of the blood is decreased. At a high hematocrit, O2 delivery the GFR over the long term, possibly by vascular remod- decreases because of decreased blood flow caused by high eling. Presumably, there is readjustment of the set point of blood viscosity. The present experiments were not acute the myogenic mechanism when RBF must rise to maintain but chronic, and an inverted-U relationship was not seen. GFR, as in chronic hypoxia associated with polycythemia, RBF did not decrease as the hematocrit increased (possibly in primary polycythemia, and following partial renal abla- because of vascular remodeling) and renal O2 delivery tion. increased approximately linearly with hematocrit (Fig. 3). Despite the steady increase in renal oxygen delivery ACKNOWLEDGMENT (after an initial fall on the first day of hypoxia) to a level This study was supported by National Heart, Lung and Blood Institute 30% greater than the sea level value after 30 days of Grant HL21159 (L. C. Ou). hypoxia, renal tissue oxygenation was not maintained at Reprint requests to Lo Chang Ou, Ph.D., Dartmouth Medical School, normal levels. Renal venous PO2 remains below the sea Department of Physiology, Borwell Building, 1 Medical Center Drive, Leba- level control values, and is lower in Hilltop than in Madison non, New Hampshire 03756-0001, USA. rats [2, 7]. Renal oxygen delivery is among the variables E-mail: [email protected] controlling EPO regulation, but it is not an accurate REFERENCES predictor of renal PO2, and hence of EPO responses, when arterial oxygenation changes. If arterial P falls, renal 1. KURTZ A, ECKARDT KU: Renal function and oxygen sensing, in O2 Erythropoietin: Molecular, Cellular, and Clinical Biology, edited by oxygen delivery must increase above normal to maintain ERSLEV AJ, ADAMSON JW, ESCHBACH JW, WINEARL CG, Baltimore, normal tissue oxygenation, because as arterial PO2 falls Johns Hopkins University Press, 1991, pp 79–98 2. 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