absence of compensatory renal hypertrophy in baboons

J. Physiol. (1972), 223, pp. 365-373 365

Printed in Great Britain

ABSENCE OF COMPENSATORY RENAL HYPERTROPHYIN BABOONS

By S. E. DICKER* AND CHRISTINE A. MORRIStFrom the Department of Physiology, Medical School,

University of the Witwatersrand, Johannesburgh, South Africa

(Received 7 December 1971)

SUMMARY

1. The weights of kidneys of fifteen adolescent and forty-six adult malebaboons were estimated. In contrast with what has been described in othermammals, in the majority of baboons (thirty-nine out of fifty-seven) theleft kidney was heavier than the right.

2. The medulla/cortex ratio was of the order of 1-8. The maximumurinary concentration, after 36 hr of food and water deprivation, averaged1050 + 80 m-osmole/kg H20.

3. Unilateral nephrectomy was performed in twelve baboons with bodyweight ranging from 5 to 14 kg. In six animals, the left kidney was removedand the right kidney in the others.

4. In two baboons, the left kidney was transplanted to the left iliacartery and vein, the ureters being left intact. After a few weeks, the rightkidney was taken out, and the animals were kept under observation, onefor a further 3 months and the other for a further 4 months.

5. In none of the animals, whether after simple unilateral nephrectomyor after unilateral nephrectomy following transplant of one kidney, didthe renoprival kidney show any significant enlargement.

6. After unilateral nephrectomy, the health of the animals remainedexcellent, all the baboons increasing in body weight. The ability to con-centrate urine by the renoprival kidney was not impaired.

7. In contrast with what has been described in mice and rats, inunilaterally nephrectomized baboons no significant changes in the con-centration of either RNA or DNA in renal cortex and medulla of the con-tralateral kidney were observed.

8. After unilateral nephrectomy in baboons, there was a marked in-crease of oxygen uptake in slices from the cortex, but not from the medulla.In contrast with what had been observed in rats where the enhanced rateof oxygen uptake returned to pre-operative values, in baboons no decrease

* Present address: Department of Chemistry, University College London.t Present address: Department of Pharmacology, University College London.

S. E. DICKER AND CHRISTINE A. MORRIS

was observed, the rate of oxygen uptake remaining high during the wholeperiod of observation.

9. In the limit of time of observation (maximum 4 months) there was noevidence that unilateral nephrectomy resulted in compensatory hyper-trophy of the contralateral kidney.

INTRODUCTION

After unilateral nephrectomy compensatory renal hypertrophy occursin the remaining kidney in mice, rats, rabbits and dogs, though accordingto Janicki (1969) not in cats. Compensatory renal growth is usually accom-panied by enhanced renal function.

In man, opinions are divided as to whether the removal of one kidneyresults in compensatory growth of the other. It is of some interest thatSimon (1871) who was the first to perform unilateral nephrectomy in mansuccessfully, did not mention renal hypertrophy.

Reliable studies of renal function in men who underwent unilateralnephrectomy are of recent date only (Friedman, Setzer, Kreutzmann &Sampson, 1942; Bricker, Guild, Reardan & Merrill, 1956; Fida & Cerruti,1960; Krohn, Ogden & Holmes, 1966). Ogden (1967) studied the renalfunction of twenty-eight donors 2-4 years after kidney transplantationand compared it with that found before the operation: after removal of onekidney, inulin and p-aminohippuric acid clearances increased in the reno-prival kidney of young people, whereas in donors over 35 years very littlechange was observed. A critical appraisal of recent work leads one toconclude that, though the renal function of the renoprival kidney in manmay be increased, its size is not.

It has been increasingly recognized that laboratory animals (mice, rats,rabbits, dogs) which are far removed taxonomically and phylogeneticallyfrom man may be less suitable for some research than members of man'sown order, the primates; it was therefore thought of interest to see howthe kidneys ofbaboons would behave after unilateral nephrectomy. Thoughthe baboon belongs to the family of Cercopithecidae (Hill, 1969) and istherefore different from the hominidae (Kratochvil, 1969) it has manyfeatures, both chemical and structural, that resemble those of man(Gresham & Howard, 1969), which has led to experiments of renalheterotransplantation from baboon to man (Starzl, 1964a, b; Reemtsma,1969). Since baboons were freely available it was hoped that an investi-gation using a primate instead of small laboratory animals would yieldresults which might throw some light on the problem of the mechanism ofcompensatory renal hypertrophy.

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COMPENSATORY RENAL HYPERTROPHY IN BABOONS 367

METHODS

The animals used were all male South African baboons, Papio ursinus, known aschacma. They were kept in a farm and brought to the laboratory for investigation orsurgery. While in captivity their diet consisted of a mixture of mealie meal (500 g);sweet potato (500 g), cabbage (350 g), liver (500 g), skimmed milk (500 g), salt(25 g) and one orange. Of this, they ate approximately 1 kg a day which representedan intake of some 2200 cal. The amount of protein in the diet was ofthe order of 10%.No information as to the age of the animals was available. Their body weight

ranged from 5 to 17 kg, thus presumably representing young and more matureanimals.

Before operation, animals were tranquilized with an injection of a mixture ofphenylcyclidine hydrochloride and phemeridine (Sermylan, Parke Davis) followedby an injection of a solution of sodium pentobarbitone (Sagatal, May and Baker).Anaesthesia was by inhalation of halothane.

Unilateral nephrectomy was performed through a lumbar incision. When renalhomotransplantation was performed, the renal vessels and nerves having been cutthe kidneys were perfused with saline solution and then the renal artery and veinwere anastomosed by suture on the iliac artery and vein, the ureter remainingintact. Duration of operation: 20-30 min.Removed kidneys were weighed and their size was measured. They were cut trans-

versally and the cortex and medulla were measured.Urine was collected by catheterization of the bladder, under anaesthesia, usually

before the operation. Urine osmolality was estimated using an 'Advance' osmo-meter, model 64-31 (Advanced Instruments, Inc.).

Estimation of oxygen uptake. The rate of oxygen uptake was measured on weighedslices from the cortex and medulla, using an Oxygen Monitor Y 51 Model 53 (YellowSprings Instruments, Inc.) and values were corrected for altitude (6000 ft). Two slicesfrom the cortex and two from the medulla were used usually.

Estimations ofRNA and DNA were made as described by Dicker & Shirley (1971 b)on the whole kidneys. No distinction was made between cortex and medulla. Resultsfor Q02, RNA and DNA were expressed per mg wet tissue.

All data are given as means and their standard errors.

RESULTS

Forty-six out of sixty-one baboons considered to be adult animals hada mean body weight of 12-9 + 0-82 kg, while the mean body weight of theremaining fifteen baboons was 7-6 + 0 75 kg. The range of weight of allbaboons used was 5-16-8 kg.

In contrast with what has been observed in most mammals, where theright kidney is usually heavier than the left, in the majority of the baboons(thirty-nine out of fifty-seven) the left kidney was the heavier. When theweights of the kidneys were correlated with body weight and hence pre-sumably with age, it was found that in twenty-seven out of thirty-fouradult animals (body weight: 11-16 8 kg) the left kidney was heavier thanthe right, while in less adult animals (body weight 5-11 kg) the leftkidney was heavier in only twelve out of twenty-three baboons.


While in 4 lightest, presumably young baboons (mean body weight5-2 + 0.01 kg with a range from 5 0 to 5-5 kg) the weight of both kidneyswas 31 1 + 0t19 g, or 5- 6 + 0 21 g/kg body wt., in 4 heaviest, and presumablyoldest baboons (mean body weight 16-5 + 0-02 kg, range from 16*4 to16-8 kg) the weight of both kidneys was 69-3 + 1-61 g or 4-2 + 0-15 g/kgbody wt. These figures agree very well with those found in young and adultman (Smith, 1951), but are appreciably smaller than those in rats (Arataki,1926; Smith, 1951). Thus by comparing the four lightest with the fourheaviest baboons, for approximately a threefold increase in body weightthere was only about a twofold increase in the weights of the kidneys.The length of the kidneys did not appear to be related either to kidney

or body weights. Measured on a sagittal section of kidneys of adultbaboons (range of body weight 11-15 kg) the mean thickness of the cortexwas 11 0 + 0-51 mm (22) and that of the medulla 20'0 + 1-2 mm (22), witha medulla/cortex ratio of 1x8 irrespective of whether they were left or rightkidneys. Such a ratio would suggest a relative paucity of long loops ofHenle which would agree with the observation that after 36 hr of food andwater deprivation, the urine osmolality did not exceed 1200 m-osmole/kgH20 (mean 1050 + 80 (9) m-osmole/kg H20). No microscopy of the kidneyswas made for lack of histological facilities.

Effect of unilateral nephrectomy on weight of the contralateral kidney.Unilateral nephrectomy was performed on twelve baboons. In six animals(range of body weight 5-4-12-3 kg) the left kidney was removed and theright kidney in six others (range of body weight 5-0-14-0 kg). The meanweights of the left and the right kidneys which had been removed was3-08 + 0-12 and 2-70 + 0-20 g/kg, respectively.

After periods of observation varying from 35 to 120 days during whichthe animals remained in good health and increased in weight, the baboonswere killed and the contralateral kidney was removed and weighed. Afterright nephrectomy, the mean weight of the left kidney was 3-14 + 0-09(6) g/kg body wt.; and after left nephrectomy the mean weight of theright kidneys was 2-70 + 0-29 (6) g/kg body wt. These values were notsignificantly different from those recorded at the operation. No correlationbetween weights of either left or right contralateral kidneys with lengthof survival was observed.

In an attempt to see whether the severance of renal nerves would affectthe size of the renoprival kidney, the left kidney of two baboons (bodyweight 8-2 and 12-3 kg) was transplanted in the iliac region, the renalartery and vein being anastomosed to the iliac artery and vein, respec-tively. The ureter was left intact. Six weeks later, the right kidneys wereremoved; their weights were 20-6 and 28-0 g or 2-57 and 2-27 g/kg body wt.The animals were kept under observation, one for another 3 months and

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the other for 4 months, after which they were killed; during that time theirbody weight had increased from 8-2 to 9'9 kg and from 12-3 to 13-6 kgrespectively. The weights of the transplanted left kidneys, when removed,were 26*9 and 33-5 g or 2-72 and 2*47 g/kg body wt., which is of the sameorder as that of left kidneys of control baboons.

Effect of unilateral nephrectomy on Q0, of renal cortex and medulla. Therate of oxygen uptake was estimated in slices of cortex and medulla ofkidney removed from six control animals. The mean value for Qo2in thecortex was 1*31 + 0 017 (6) and in the medulla 0-63 + 0 026 (5)1d. 02/hr.mgwet wt. (Table 1), which is lower than in rats or guinea-pigs (Dicker &Shirley, 1971 a) or in rabbits (Whittam, 1961). After unilateral nephrectomythere was an increased rate of oxygen uptake in the cortex of the con-tralateral kidney, while in the medulla values for QO remained unchanged.

TABLE 1. Rates of oxygen uptake in renal cortex and medulla in baboons

Qo2 in 4csl./hr.mg wet wt.

Unilaterally nephrectomized

Controls After 2 months After 3 months After 4 months

Cortex Medulla Cortex Medulla Cortex Medulla Cortex Medulla1'33 0*54 1*45 0*70 1*80 0*57 1*86 0-811*26 0.64 1*40 0*60 2*18 0'57 1.76 0.551*25 0*72 1-38 0'56 1.65 0*61 2*20 0*611*35 0.65 1*50 0.61 1-70 0*58 1.90* 0.60*1*31 0*61 - - 1*80 0-671.36 - 2.05* 0.63*1*31 0*63 1.43 0.59 1.86 0-60 1-93 0.64

+ 0.017 + 0*026 + 0*020 + 0-026 + 0*077 + 0-014 + 0-082 + 0 049Values marked with * are those of two baboons whose left kidney had been trans-

planted before the right kidney was removed (see text).

In contrast with what had been observed in rats, where after an initialincrease of Q02 values in the cortex of the contralateral kidney, the rate ofoxygen uptake returned to pre-operative levels in about 6 weeks (Dicker& Shirley, 1971 b), in the baboons values for Q02 remained high: 4 monthsafter operation, the rate of oxygen uptake in cortical slices was some 47%higher than in control kidneys (Table 1).

Effect ofnephrectomy on RNA andDNA concentrations in the contralateralkidney. The ratio of RNA/DNA estimated in six control kidneys removedfor unilateral nephrectomy averaged 1- 17. In renoprival kidneys examined2, 3 and 4 months after the operation, the ratio RNA/DNA varied between5% above and 4% below the control value, with no significant changes inRNA or DNA content. This is in contrast with what has been reported in


mice (Malt, 1969) and rats (Dicker & Shirley, 1971 b) where unilateralnephrectomy resulted in an increase of RNA/DNA ratio commensuratewith an increase of kidney weights.

Urinary concentration after unilateral nephrectomy. In animals whichhad been operated for at least 3 months, urine collected after 24-36 hr offood and water deprivation had an osmolal concentration (1020 + 100 (6)m-osmole/kg H20) indistinguishable from that of control chacmas.

DISCUSSION

From the present investigation it is not possible to say that com-pensatory renal hypertrophy does not occur in the baboon; however in thelimit of time of the observations no signs of renal enlargement wereobserved. This is in sharp contrast with what has been observed in othermammals, such as mice, rats, rabbits and dogs. Though comparisonbetween the pre- and post-operative weights of the kidneys was compli-cated by the fact that in the majority of animals, but by no means in all,the left kidney was heavier than the right one, it may be argued that therate of hypertrophy of the renoprival kidney in chacmas is too slow to beobserved by the method used; on the other hand it is equally possiblethat the baboon, which has many features resembling those of man(Gresham & Howard, 1969; Wiener & Moor-Jankowski, 1969) behavesas the latter.

It is only since renal homotransplantation has been achieved using livingdonors that there has been an opportunity to study renal size and functionbefore and after nephrectomy in reasonably large groups of healthy adultmen. Bricker et al. (1956) reported that after removal of one kidney in amale twin-donor, age 24 yr, there was a twofold increase of effective renalplasma flow, as measured by p-aminohippuric acid clearance, withoutappreciable changes in glomerular filtration rate and that the kidneytransplanted in the twin-recipient behaved in a similar way. Ogden (1967)studied renal function in twenty-eight donors of an average age of 37*4 yr(range 21-56 yr) before and up to 34 months after unilateral nephrectomy.He showed that 24 hr after the removal of one kidney there was in thecontralateral kidney an increase of renal blood flow and of glomerularfiltration and that both reached their greatest increase 7 days after theoperation, after which they slowly decreased. Ogden stressed the point thatthe increases in effective renal blood flow and filtration rate were completeafter 7 days. But neither Bricker et al. (1956) nor Ogden (1967) investi-gated whether there had been any compensatory renal growth. This wasdone by Heideman & Rosenbaum (1970) who followed a series of fifteenhealthy donors (age range 30-60 years) who responded to a request for

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follow-up intravenous urography. The length of the renal axis parallel tothe psoas muscle shadow was measured before and after the operation.The average length of the kidneys before transplantation was 13 6 + 0 04cm. The length of the renoprival kidneys 26 months after the operationwas 13-7 + 0 03 cm. Thus more than 2 years after nephrectomy the sizeof the remaining kidney was the same as before the operation. Similarobservations had been made previously by Fida & Cerruti (1960) who didnot see any compensatory renal hypertrophy in adult man but reportedthat in young patients there was some increase in renal size observablewithin one month of the operation.

Indications that renal functions of the contralateral kidney of baboonsdid increase may be deduced from the finding that in all cases there was anincrease of oxygen uptake by renal cortical slices (Table 1), as has beenobserved after unilateral nephrectomy in rats (Dicker & Shirley, 1971 b).In these rodents the rate of oxygen uptake rose immediately after uni-lateral nephrectomy, but returned to preoperative levels in about 6 weeks.But since, during that period, there had been a marked cellular hyper-plasia, it is clear that in rats there was an over-all increase ofoxygen uptakeby the hypertrophied renoprival kidney. In the baboon, however, no signsof hyperplasia were observed, the ratio of RNA/DNA as well as theamount of DNA remaining unchanged.

Immediately after unilateral nephrectomy in dogs, rats, man (and pre-sumably baboon), thus in animals which do and do not present compen-satory renal hypertrophy, there is an initial increase of effective renalplasma flow. Krohn, Peng, Antell, Stein & Waterhouse (1970) suggestedthat the remaining kidney accepts an amount of blood which, previouslyto the operation, was destined to the opposite kidney. This would appearto agree with results of acute experiments on dogs by Sellwood & Verney(1955). An increase of renal blood flow is normally accompanied by anincrease of glomerular filtration rate, which in turn will increase theamount of reabsorptive work by the tubules. An increase in the reabsorp-tive work will demand a greater expenditure of energy, which will bereflected by an enhanced rate of oxygen uptake, especially in the cortex.Such an increase has been found in acute experiments in rats, after oraladministration of a 0-6 % NaCl solution (S. E. Dicker & D. G. Shirley,unpublished)-. Similarly, there is an increased rate of oxygen uptake in therenal cortex of rats, after unilateral nephrectomy, before any increase inmitotic activity (Dicker & Shirley, 1971 b). But whereas in rats, the over-all oxygen consumption needed to meet the excess reabsorptive work isultimately produced by hyperplasia and the hypertrophy of renal tubules.(Oliver, 1944), in the baboon the increase of.oxygen uptake occurs withoutnoticeable hyperplasia or renal hypertrophy. Such a situation would exist

S. E. DICKER AND CHRISTINE A. MORRISif in the baboon, and presumably in adult man, the tubular cells have a'reserve' of energy on which they can draw when work increases, the cellsbehaving in a manner similar to what is known to occur in muscles,whereas in species without such a reserve hyperplasia is required. Whetheror not this interpretation is correct, the fact is that in adult man and pre-sumably in the baboon normal health is apparently preserved afterremoval of one kidney without any apparent enlargement of the remainingkidney; and if this is so it is difficult to see how the theory (Burch, 1968)according to which the mass of organs (in this case of kidneys) is con-trolled centrally through a feed-back mechanism can obtain.The authors wish to thank Mr I. Lissoos (Department of Urology, General

Hospital, Johannesburg) for performing the kidney transplantations.

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absence of compensatory renal hypertrophy in baboons

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