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African Journal of Biomedical Research
Ibadan Biomedical Communications Group
ISSN: 1119-5096
Vol. 6, Num. 1, 2003, pp. 1-7
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African Journal of Biomedical Research, Vol. 6, No. 1, Jan, 2003,
pp. 1-7
A METHOD FOR INDUCTION OF CHRONIC RENAL FAILURE IN RATS
PIUS I ODIGIE 1 AND MARCOS MARIN-GREZ
Institute of Physiology , University of Munich ,
Pettenkoferstrasse 12, 80336 Munich , Germany
1 Correspondence (Current Address): Department of Physiology,
University of Lagos . Lagos , Nigeria
Received: September 2001
Accepted: May 2002
Code Number: md03001
ABSTRACT
Chronic Renal Disease (CRD) is a major health burden, which has recieved
increased attention in recent times and has thus become one major focus of
intensive research. All is agreed that the complex interplay of major pathophysiological
factors that are characteristic of CRD and end stage renal failure (ESRF)
is of multifactorial aetiology. However, commonly used animal models for
CRD are bedeviled by methodologically induced complexities, which make the
procedures not only laborious but also make interpretation of results less
explicit. More often than not, some of these procedures present in addition,
pathological parameters that may not universally reflect the settings of
clinical forms of CRD. We have therefore characterized a simple and reproducible
method for inducing chronic renal failure (CRF) in rats; in which the pathological
parameters better reflect the usual findings in clinical situations. This
approach has methodological and experimental advantages with respect to commonly
used procedures for inducing CRF in rats, which may involve extensive renal
surgery in which the renin-angiotensin system is often markedly stimulated.
This later complication is at variance with clinical CRD in which low to
normal renin activity is more often the rule rather than the exception. The
simplicity and reproducibility of this model, coupled with a better correlation
with the known features of CRF makes it a useful rat model not only for research
purposes but also for testing of therapeutic maneuvers commonly used in the
clinical setting.
Key words: chronic renal failure-hypertension-acid-base balance-kallikrein
INTRODUCTION
Chronic renal disease (CRD) has become a major burden to mankind in recent
times (United States Renal Data System, 1990 Annual data report). A majority
of patients with CRD suffer from hypertension, irrespective of the cause of
their renal disease. In these groups of patients, uncontrolled hypertension,
as a result of increased cardiovascular risk factors, contributes to the high
morbidity and mortality associated with the disease. Although fluid overload
plays a significant role in the sustenance of hypertension in CRD, euvolaemic
patients are also known to have significantly higher blood pressures compared
to controls, thereby suggesting the operation of a persistent hypertensive
stimulus other than volume overload (Schmidt & Baylis, 2000).
Most commonly used models of hypertension require nephron reduction to the
level of nephrectomy to effect significant features of end-stage renal disease
(ESRD). Thus the classical "DOCA salt model of hypertension" requires
considerable nephron reduction to achieve significant hypertensive renal disease
(Selye et al ., 1943). More over, the remnant kidney model of progressive
renal disease, is associated with arterial hypertension in which, nephrectomy
is combined with partial infarction (Ibrahim & Hostetter, 2000). The effects
of renal infarction presents on its own, a unique spectrum of pathological
manifestations which may add on to the effects of hypertension on renal function;
thereby making data interpretation less explicit. For instance, the known suppressive
effect of potassium loading on plasma renin activity (PRA) is inhibited by
the scar-derived renin secretion in the remnant kidney model (Linas, 1981).
Other commonly used models of CRD besides ablation of renal mass and ureteral
obstruction (Reyes et al ., 1994), includes cyclosporine induced renal
damage (Andoh et al ., 1997) and chronic Nitric Oxide Synthase (NOS)
inhibition (Zatz & Baylis, 1998) which for obvious reasons also have predictable
short-comings. Generally, CRF is often associated with low to normal plasma
renin activity (Ibrahim et al ., 1997). This observation is in direct
conflict with the fact that most commonly employed models of chronic renal
disease are of the high renin variety (Ibrahim & Hostetter , 2000).
We have therefore characterized a method for inducing hypertensive renal
disease where renin angiotensin activation is not marked and where extracellular
volume expansion plays a significant role in the established stage of hypertension,
a setting similar to what obtains in CRD; in order to provide a rat model,
not only for research purposes but also for testing of therapeutic maneuvers
that are relevant to real clinical situations.
MATERIALS AND METHODS
Animal preparation:
Male Sprague-Dawley rats weighing 230.4±2.3 g were used for the experiment.
The rats were allowed free access to normal rat chaw containing 0.4% sodium
(Na + ), 1.4% potassium (K + ) and 0.5% chloride (Cl - ) and tap water ad
libitum up to the day of operation and throughout the observation period.
The operation for the induction of hypertensive renal disease was performed
in two stages under ether anaesthesia: During the first operation, a 0.2mm "U" shaped
silver clip (internal diameter) was placed on the left renal artery via a left-flank
incision. The control rats were sham-operated. After recovery from the first
operation, usually 36 to 48 hours, the experimental and control rats were subjected
to a right nephrectomy under ether anaesthesia. The rats were kept under observation
for one day in the laboratory. They were thereafter returned to the animal-care
house which had a room temperature of 28 ° C, dark / light cycle of 12 hours
and relative humidity of 60%, all regulated by electronic devices. The rats
received no antibiotics and infection was not observed in any of them.
Blood pressure was measured in conscious rats twice weekly using rat-tail
plethysmography. Based on previous pilot studies, the rats were used for standard
clearance experiments 4 weeks after operation. Only rats whose blood pressures
were clearly above 140 mmHg were used for clearance experiment.
Clearance experiment:
On the day of experiment, the rats were anaesthesized with inactin R (sodium
salt of 5-ethyl-5-(1'-methyl-propyl)-2-thiobarbituric acid; Byk Gulden, Konstanz
Germany ) at a dose of about 75-80 mg/Kg body weight. This dose of inactin
is about 75% to 80% of the usual dose of inactin, in order to eliminate anaesthesia
induced alterations in acid-base balance studies as previously reported (Odigie & Marin-Grez,
2000). A tracheostomy was performed to guarantee spontaneous breathing. The
rectal temperature was maintained at 37.0 ± 0.5 °C using a heated rat-operating
table coupled to a rectal thermometer. A PP50 polyethylene catheter was placed
in the carotid artery for blood pressure measurement (strain gauge transducer,
Tekman Electronic GmbH, Germany ) and for blood samples. A PP50 femoral catheter
was inserted for continuous infusion of physiological saline solution (PSS)
containing 150 mmol sodium chloride and 6% polyfructosan (inutest R Laevosan
GmbH, Linz ) at the rate of 1ml /hr i.v. A PP100 polyethylene catheter filled
with PSS containing 50 U/ml heparin was placed in the lower abdominal aorta
for venous pressure measurement. The ureter was canulated via a mid-abdominal
incision and the ureter catheter was fixed with a ligature. After 120 min equilibration
period, urine flow was controlled by collecting 30 min samples of ureter urine.
It was assumed that the rat was stable when constant urine samples were obtained.
Urine samples were then collected in pre-weighed vials (eppendorf) for two
30 min periods. Blood samples were collected anaerobically in heparinized capillary
tubes and were immediately subjected to complete acid-base-balance analysis
on an Automatic Blood-Gas Analyzer (AVL 990, AVL Biochemical Instruments, Graz,
Austria) as previously reported (Odigie & Marin-Grez, 2000). Blood was
also collected in heparinized capillary tubes for haematocrit determination.
Blood plasma was obtained by centrifugation of blood samples at 3000 r.p.m.
for 10 min ( Eppendorf Centrifuge , Hamburg ). Aliquots of plasma samples were
stored in a deep freezer at -30 °C until the day of measurement. Plasma from
first blood sample was used for aldosterone measurement. Plasma creatinine
and plasma electrolytes were measured within 24 hours. At the end of the experiment,
the kidney was decapsulated in-vivo and together with the heart were removed
and weighed (Sartorious Digital Balance). The hearts were examined optically
and the kidneys were sliced using a series of blades mounted on a holder. A
piece of renal cortex was immediately shock-frozen in liquid nitrogen and stored
at -30 °C and later used for renal kallikrein measurement.
Analytical Methods:
Urine was determined gravimetrically without correcting for specific gravity.
Kallikrein excretion in urine and renal tissue kallikrein was measured using
a chromogenic substrate as previously described (Klein et al ., 1989).
Plasma aldosterone concentration was determined using a computer assisted specific
Aldosterone radioimmunoassay. Creatinine was measured using the Jaffe's reaction.
Glomerular filtration rate (GFR) was calculated using the clearance of polyfructosan
(Fuhr et al ., 1955). Plasma and urinary electrolyte concentration was
measured using a flame photometer (Instrumentation Laboratory IL943, IL Fisher
Science, U.S.A). Chloride concentration was determined with an automatic chloridometer
(Buchler-Cotlove Automatic Chloride Titrator; Buchler Instruments Inc. Fort
Lee N. J. USA). Urinary bicarbonate concentration was calculated from the measured
values of urinary PCO2 and pH after taking the ionic strength of the urine
into consideration as previously reported (Odigie & Marin-Grez, 2000).
Haemoglobin concentration was measured using the method of Van Kampten and
Zilstra, which involves the conversion of haemoblobin to haemoglobin cyanide.
Crystallized rat haemoglobin was used as standard (Sigma Chemie GmbH, Diesenhofen
, Germany ). The determination of renal blood flow using p-amino-hippuric acid
(PAH) was avoided because this substance interferes with acid base balance
determination (Silbernagl , 1986).
All animal handling and experimentation were in accordance with the guidelines
laid down by the American Physiological Society for animal care and experimentation.
Statistical analysis:
Values are expressed as means ± SEM (Standard Error of Mean).
Unpaired "t" test was used for hypothesis testing between hypertensive
rats and controls. A difference was considered statistically significant when
P < 0.05
RESULTS
Application of a 0.2mm clip on the renal arteries of rats with body weight
of 230.4 ± 2.3 g led to a rapid progression of hypertension, resulting
in CRF. A significant reduction in blood PCO2 , BE, BEecf, Blood HCO3- and
standard HCO3- was found in Rats with CRF (all P<0.001). The clipped rats
developed a metabolic acidosis (Table 1). Rats with CRF had a significantly
reduced body weight (P<0.001) and an increased respiratory rate (P<0.05).
A significant elevation in arterial blood pressure (P<0.001) and venous
pressure (P<0.05) was observed. There was no significant difference in the
weight of the kidneys of controls compared to the clipped rats (Table 2).
Table 1: Acid-base balance parameters of rats with chronic renal failure (CRF) compared
to controls. H + = proton concentration; PCO2 = partial pressure of carbon
dioxide in arterial blood; BE=base excess; BEecf=Base excess of extracellular
fluid; BB= Buffer base; O2 .Sat.=arterial oxygen saturation; St.HCO3- =
standard bicarbonate.
|
C ontrol
(n = 8) |
CRF
(n = 5) |
P-VALUES |
[H + ] (nmol/L) |
40.2
± 0.7 |
38.1
± 2.0 |
NS |
PCO2 (mmHg) |
45.7
± 1.2 |
30.7
± 2.6 |
P< 0.001 |
BE (mmol/L) |
2.7
± 0.5 |
- 3.5
± 1.1 |
P< 0.001 |
BE ecf (mmol/L) |
3.2
± 0.5 |
- 4.4
± 1.2 |
P< 0.001 |
BB (mmol/L) |
46.9
± 3.8 |
43.5
± 1.0 |
NS |
[HCO3- ] (mmol/L) |
27.7
± 0.5 |
19.2
± 1.2 |
P< 0.001 |
(PO2 ) (mmHg) |
76.3
± 2.4 |
87.8
± 5.7 |
NS |
O2 .Sat (%) |
94.9
± 0.4 |
96.4
± 0.7 |
NS |
[St.HCO3- ] (mmol/L) |
26.1
± 0.4 |
21.0
± 0.8 |
P< 0.001 |
Table 2: Arterial blood pressure (BP) and venous blood pressure (VP),
Body weight (BW), Kidney weight (Kid.Wt), Heart weight (Hrt.Wt) and Respiratory
rate (RR) in rats with CRF and Controls.
|
C ontrol
(n = 8) |
CRF
(n = 5) |
P-VALUES |
BP (mmHg) |
125.0
± 3.8 |
154.0
± 2.4 |
P < 0.01 |
V.P. (mmH2O) |
5.6
± 0.13 |
6.9
± 0.42 |
P < 0.05 |
B. W. (g) |
390.4
± 8.4 |
345.2
± 3.30 |
P <0.001 |
Kid. Wt (g) |
2.17
± 0.12 |
1.89
± 0.10 |
NS |
Hrt. Wt (g) |
0.74
± 0.01 |
0.99
± 0.05 |
P < 0.05 |
Resp. rate (Rate/min) |
88.0
± 0.8 |
109.4
± 3.4 |
P < 0.05 |
Plasma potassium concentration (P<0.005) and plasma chloride concentration
(P<0.005) were significantly elevated. The Anion-Gap was comparable in the
two groups. Plasma creatinine on the other hand was significantly elevated
P<0.001) in rats with CRF. The haematocrit values were significantly lower
than controls (P<0.001, Table 3).
There was a marked reduction in urine flow rate (P<0.005) compared to
controls and GFR was significantly reduced (P<0.001). A marked reduction
in the ability of the clipped kidney to excrete electrolytes was noted. Thus
the sodium (P<0.05), potassium (P<0.001), chloride (P<0.001) and bicarbonate
(P<0.05) excretion rates were all reduced (Table 4).
Table 3: Serum electrolytes, serum creatinine and haematocrit values of rats with CRF
compared to controls. Na + p=plasma sodium concentration; K + p=plasma potassium
concentration; Cl - p=plasma chloride concentration; AN-GP=anion-gap; creat.p=serum
creatinine concentration; Hct=haematocrit of arterial blood.
|
C ontrol
(n = 8) |
CRF
(n = 5) |
P-VALUES |
[ Na + ] p (mmol/L) |
148.5
± 0.8 |
146.7
± 0.5 |
NS |
[K + ] p (mmol/L) |
5.10
± 0.90 |
6.20
± 0.30 |
P< 0.005 |
[Cl - ] p (mmol/L) |
102.7
± 1.2 |
107.8
± 0.3 |
P< 0.005 |
An- Gp (mmol/L) |
18.1
± 1.5 |
19.7
± 1.4 |
NS |
(Creat.) p(mg/100ml) |
1.02
± 0.03 |
1.82
± 0.08 |
P< 0.001 |
Hct. (%) |
49.6
± 0.5 |
40.0
± 3.2 |
P< 0.001 |
Table 4: Urine flow rate (V), Glomerular filtration rate (GFR), and
electrolyte excretion in rats with CRF compared to controls. [Na + ]u.V=sodium
excretion rate; [K + ]u.V=potassium excretion rate; [Cl - ]u.V=chloride excretion
rate; [HCO3- ]u.V=bicarbonate excretion rate
|
Controls
(N = 8) |
Crf
(N = 5) |
P-Values |
V (µl/min.) |
7.9 ± 0.5 |
3.9 ± 0.8 |
P< 0.005 |
GFR (ml/min) |
1.68± 0.11 |
0.36± 0.08 |
P< 0.001 |
[Na + ] .V(µmol/min |
0.30± 0.06 |
0.09± 0.05 |
P < 0.05 |
[K + ] u .V(µmol/min |
2.52± 0.21 |
0.28 ± 0.11 |
P< 0.001 |
[Cl - ] u .V(µmol/min |
1.16± 0.19 |
0.13 ± 0.06 |
P< 0.001 |
[HCO3- ] u .V(µmol/min |
17.7 ± 6.9 |
1.30 ± 0.40 |
P < 0.05 |
Rats with CRF had reduced fractional excretion of sodium (P<0.05), potassium
(P<0.001), and bicarbonate (P<0.001). The fractional excretion of chloride
was not significantly different from controls. Rats with CRF had a significant
reduction in urinary kallikrein excretion (P<0.001, Table 5)
Renal tissue kallikrein content was significantly reduced in the clipped
rats (112.5 ± 6.3 vs 87.5 ± 4.2 mU/g kidney, n=12, P<0.001).
The haemoglogin concentration in rats with CRF and controls showed no significant
difference (16.7 ± 0.4 g/dl vs 17.3 ± 0.3 g/dl). Plasma aldosterone
concentration was markedly elevated in rats with CRF (3.14 ± 0.41 vs
0.63 ± 0.16nmol/L, n=13, P<0.001)
Table 5: Urinary kallikrein excretion and fractional electrolyte excretion
in rats with CRF compared to controls. Ukalli=urinary kallikrein excretion
rate; FE-Na + =fractional excretion of sodium; FE-K + =fractional excretion
of potassium; FE-Cl-=fractional excretion of chloride; FE-HCO3- =fractional
excretion of bicarbonate
|
C ontrol
(n = 8) |
CRF
(n = 5) |
P-VALUES |
Ukalli(mU/min. |
1.59 ± 0.12 |
0.46 ± 0.03 |
P < 0.001 |
FE-Na + (%) |
0.12 ± 0.02 |
0.07 ± 0.03 |
P < 0.05 |
FE-K + (%) |
29.5 ± 1.50 |
11.9 ± 3.50 |
P < 0.001 |
FE-Cl - (%) |
0.65 ± 0.11 |
0.45 ± 0.30 |
NS |
FE-HCO3- (%) |
0.08 ± 0.04 |
0.02 ± 0.01 |
P < 0.001 |
DISCUSSION
The pathogenesis of elevated blood pressure in patients with chronic renal
failure is being debated on many platforms. Among the factors currently implicated
for elevated blood pressure is Nitric Oxide (NO). This physiologically important
endogenous vasodilator has been reported to be deficient in CRD (Schmidt & Baylis,
2000; Ketteler & Ritz, 2000; Blum et al , 1998) and in ESRF (Vallence et
al ., 1992; Reyes et al ., 1994). The reasons advanced for reduction
of NO production includes NO substrate deficiency as a result of reduced renal
mass (Morris Jr., 1992); accumulation of NO inhibitors in progressive renal
disease (Vaziri et al ., 1998) and endothelial dysfunction due to increased
inactivation of endothelial NO as a result of oxidative stress (Vaziri et
al ., 1998). In renovascular hypertension, at least in the 2K-1C model,
increased free radicals generation leading to impaired vascular response to
endogenous and exogenous nitrovasodilators has been reported (Heitzer et
al ., 1999). Besides, NO influences blood flow distribution in renovascular
hypertension (Sigmon & Beierwaltes, 1994) so that its deficiency readily
sets the pace for the abnormal renal haemodynamics that characterize CRD. The
strength of this assertion is exemplified by the fact that chronic arginine
supplementation in the diet protects against progressive deterioration of renal
function in a wide range of CRD models (Andoh et al ., 1997; Reyes et
al ., 1994). However, this is not always the case as shown by the fact
that a randomized double-blind, placebo-controlled study of supplementation
of L-argininie in patients with moderate CRF did not improve renal function
(Denicola et al ., 1999); an observation that calls for further studies.
The role of NO in CRD remains controversial as some workers have reported increased
exhaled NO in CRF rather than a reduction (Matsumoto et al ., 1999).
Since exhaled NO in mainly generated in the lungs, it may not necessarily reflect
systemic or renal events. The role played by other vasoactive substances in
CRD remains to be completely elucidated.
In the rat model of CRF characterized above, widespread electrolyte and acid-base
balance disturbances were observed. The markedly elevated serum aldosterone
levels and reduced fractional excretion of electrolytes as well as reduced
urinary excretion speak for the possibility of fluid overload in the pathogenesis
of hypertension in this model of CRD. Renal Kallikrein excretion and renal
tissue content of the enzyme were markedly reduced as expected. Significantly
reduced haematocrit levels reveal evidence of anaemia. Serum creatinine was
significantly elevated and the reduced body weight of rats with CRF reveals
a negative nitrogen balance, as is characteristic of the disease.
In the setting of CRD and hypertension, the kidney could be the victim or
the culprit or both. Hypertension is a major risk factor that determines not
only the rate of progression of renal disease but also generally aggravates
the development of glomerular sclerosis. One way it could do this is as a result
of increase in glomerular capillary pressure and the resulting pressure damage
("barotrauma") then leads to glomerular sclerosis (Brenner, 1985).
These effects are generally more severe in the face of glomerular hypertrophy
(Miller et al ., 1991) as obtains in progressive glomerular loss of
CRD. On the other hand, the intrinsic vascular damage of chronic hypertension
by causing reduction in arterial lumen may lead to glomerular hypoperfusion
and chronic ischaemic renal damage (Greco & Breyer, 1997). The role played
by angiotensin II in this regard is significant since angiotensin converting
enzyme inhibitors attenuates glomerular sclerosis independent of glomerular
capillary pressure (Fogo et al ., 1988). It follows therefore, that
glomerular hyperperfusion and hypertension are not essential for the development
of glomerular sclerosis. However, a significant difference between human and
rat kidney is the increased glomerular sclerosis with normal aging present
in the rat (Bolton & Sturgil, 1980). These factors should be taken into
consideration in the interpretation of rodent results, as these results cannot
necessarily be substituted for clinical observations.
Non-haemodynamic factors mediating glomerular damage and interstitial fibrosis
include angiotensin II as well as various growth factors and cytokines (Chung & Chevalier,
1996). The effects of angiotensin II on glomerular damage, in particular, are
known to be independent of hypertension (Yoo et al ., 1998). The pathophysiological
effects of these additional factors can only be exhaustively investigated in
a suitable animal model of CRD.
In summary, it is clear to see that although isolated breakthroughs have
been made in the management of CRD, we certainly need more information on the
pathophysiology involved before meaningful interventions can be made and the
model, presented here serves as a simple, reproducible and uncomplicated model
for such interventions.
ACKNOWLEDGEMENTS
This work was supported by the German research foundation grant to M.
Marin-Grez. I.P. Odigie was a recipient of the International Society of Nephrology
(ISN) international training fellowship award. The technical assistance of
Marion Neff is gratefully acknowledged. We express profound gratitude to
Prof. Dr.med.Dr.h.c. Klaus Thurau for his support and interest.
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