Aggravated Cardiac Remodeling post Aortocaval Fistula in Unilateral Nephrectomized Rats
Aggravated Cardiac Remodeling post Aortocaval Fistula in Unilateral Nephrectomized Rats
Jie Wu☯ 0 1
Zhong Cheng☯ 0 1
Ye Gu 0 1
Wusong Zou 0 1
Mingjing Zhang 0 1
Pengfei Zhu 0 1
Shao Hu 0 1
0 Heart Center at Puai Hospital, Wuhan Puai Hospital, Huazhong University of Science and Technology , Wuhan, Hubei , China
1 Editor: Jaap A. Joles, University Medical Center Utrecht , NETHERLANDS
Aortocaval fistula (AV) in rat is a unique model of volume-overload congestive heart failure and cardiac hypertrophy. Living donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Impact of AV on animals with mild renal dysfunction is not fully understood. In this study, we explored the effects of AV in unilateral nephrectomized (UNX) rats.
Competing Interests: The authors have declared
that no competing interests exist.
Adult male Sprague-Dawley (SD) rats were divided into Sham (n = 10), UNX (right kidney
remove, n = 10), AV (AV established between the levels of renal arteries and iliac
bifurcation, n = 18) and UNX+AV (AV at one week after UNX, n = 22), respectively. Renal outcome
was measured by glomerular filtration rate, effective renal plasma flow, fractional excretion
of sodium, albuminuria, plasma creatinine, and cystatin C. Focal glomerulosclerosis (FGS)
incidence was evaluated by renal histology. Cardiac function was measured by
echocardiography and hemodynamic measurements.
UNX alone induced compensatory left kidney enlargement, increased plasma creatinine
and cystatin C levels, and slightly reduced glomerular filtration rate and increased FGS. AV
induced significant cardiac enlargement and hypertrophy and reduced cardiac function and
increased FGS, these changes were aggravated in UNX+AV rats.
Although UNX only induces minor renal dysfunction, additional chronic volume overload
placement during the adaptation phase of the remaining kidney is associated with
aggravated cardiac dysfunction and remodeling in UNX rats, suggesting special medical care is
required for UNX or congenital monokidney subjects in case of chronic volume overload as
in the case of pregnancy and hyperthyroidism to prevent further adverse cardiorenal events
in these individuals.
Clinical and experimental studies evaluating the cardiac-renal interaction are of importance in
health care research. Renal dysfunction is common in patients with heart failure and often
associated with high morbidity and mortality, moreover, cardiac and renal dysfunction may
worsen each other[1, 2].Clinically, heart failure may also occur in patients with nearly normal
or mildly impaired renal dysfunction, as in the case of living donor kidney transplantation.
Although living donor kidney transplantation is regarded as beneficial to allograft recipients
and not particularly detrimental to the donors and mortality of kidney donors is very low
(<0.1%)[4, 5], unilateral nephrectomy might cause an early abrupt decrease in plasma arginine
and simultaneous reduction in glomerular filtration rate in living kidney donors. Up to
twothirds of donors after nephrectomy fulfil the criteria for chronic kidney disease stage 3 (eGFR,
30–59 mL/min per 1.73 m2) depending on baseline age and renal function. Previous study
showed that there was a graded inverse relationship between cardiovascular risk and eGFR,
deleterious cardiovascular effects were clearly evident once eGFR falls to <60 mL/min per
1.73 m2. Thus, kidney donors might face increased risk in case of additional cardiac insults.
The renal and cardiac consequences and heart-kidney interaction with ischemic cardiac insult
in unilateral nephrectomized rats were reported previously[8, 9], while the impact of chronic
volume-overload in unilateral nephrectomized rats remained largely unknown. In this study,
we observed the heart-kidney interaction in a rat aortocaval fistula (AV) model established at
one week post right kidney remove (UNX).
Materials and Methods
Experimental Animals and Study Groups
Experiments were approved by the Tongji Medical College Council on the Animal Care
Committee of Huazhong University of Science and Technology (Wuhan, China). Animals were
maintained in accordance with the Guide for the Care and Use of Laboratory Animals
published by the US National Institute of Health (NIH Publication No.85-23, revised 1996). All
surgery was performed under sodium pentobarbital anesthesia, and all efforts were made to
minimize suffering. Male Sprague-Dawley (SD) rats (weighing 200 to 250 g) were housed
under standard conditions with free access to food and drinking water. Rats received a normal
salt diet (0.3% NaCl) throughout the study. Rats were randomly divided into Sham (n = 10),
UNX (n = 10), AV (AV established between the levels of renal arteries and iliac bifurcation,
n = 18) and UNX+AV (AV established at one week after UNX, n = 22), respectively. The
following steps were taken to minimize the suffering of the rats. First, the rats were handled gently
to reduce their discomfort and distress. Second, anesthesia was administered prior to blood
sample collection, echocardiography, invasive hemodynamic measurements (40 mg/kg sodium
pentobarbital intraperitoneally) and before animal sacrifice(70 mg/kg sodium pentobarbital
intraperitoneally). Additionally, anesthesia, examinations and animal sacrifice were
undertaken in separate rooms to avoid instilling fear in other rats. The rats were monitored three
times a day during the eight-week study period. Moribund animals were euthanized under
deep anesthesia. The signs and symptoms of moribund were as follows: (a) impaired
ambulation (unable to reach either food or water easily); (b) any obvious severe illness, including signs
and symptoms such as lethargy (drowsiness, aversion to activity, a lack of physical or mental
alertness), anorexia (loss of appetite, particularly prolonged behavior), bleeding, difficulty
breathing, or chronic diarrhea; (c) an inability to remain upright; (d) either rapid weight loss or
a net weight loss of more than 20% of body weight; and (e) unconsciousness or
unresponsiveness to external stimuli. After eight weeks, survived rats were placed in individual metabolic
cages. After 5 days of adaptation, two consecutive 24-hour urine was collected from each rat.
Echocardiography was performed two days after the metabolic cage studies. After
echocardiography examination, rats received invasive hemodynamic and renal function measurements.
Blood sample was obtained from the vena cava post above measurements. Finally, all rats were
killed under deep anesthesia (70 mg/kg sodium pentobarbital intraperitoneally), and organs
were removed, weighed, and processed for histological quantification.
Laparotomy was performed under anesthesia with 1% pentobarbital sodium salt (40mg/kg,
intraperitoneal injection). The right kidney was carefully separated from the adrenal gland and
the surrounding tissue. The right renal artery and vein, as well as the urethra, were ligated with
a 4.0 silk suture, followed by removal of the right kidney. These rats were allowed to recover
from surgery in a warmed cage for 1 to 2 hours. One week after nephrectomy, rats assigned to
UNX+AV group were re-anesthetized with 1% pentobarbital sodium salt (40mg/kg,
intraperitoneal injection) and the aortocaval fistula was produced according to the method described by
Garcia and Diebold  with some modifications. Briefly, ventral abdominal laparotomy was
performed in anesthetized rats, the intestines were displaced laterally and wrapped with normal
saline-soaked sterilized gauze to retain moisture. The aorta and vena cava between the levels of
renal arteries and iliac bifurcation were then exposed by blunt dissection of the overlaying
adventitia. Both vessels were temporarily occluded proximal and distal to the intended
puncture site, and a 18-gauge needle held on a plastic syringe was inserted into the exposed
abdominal aorta and advanced through the medial wall into the vena cava to create the shunt. The
needle was inserted and withdrawn across the medial wall several times through the same hole,
to ensure the size and presence of the fistula, before it was finally withdrawn from the aorta.
The ventral aortic puncture site was immediately sealed with a drop of cyanoacrylate (Medical
Adhesive Glue; Baiyun Medical Adhesive Co., China) after withdrawal of the needle. Creation
of a successful fistula was confirmed by visualizing the pulsatile flow of oxygenated blood into
the vena cava from the abdominal aorta. The intestines were repositioned, and the abdominal
musculature and skin incisions were closed by standard techniques with absorbable suture and
autoclips. Sham rats underwent similar surgical procedures as rats in UNX+AV group without
right kidney removal and AV creation.
Echocardiography examination was performed by an investigator blinded to the study
protocol. Left parasternal and left apical echocardiographic images of light anesthetized (1%
pentobarbital sodium salt, 40mg/kg, intraperitoneal injection) rats lying in a supine position were
obtained with an echocardiographic system (GE Vivid 7) equipped with a 11.4 MHz
transducer. A two-dimensional short-axis view of the left ventricle was obtained at the level of the
papillary muscles. Left ventricular M-mode tracings were used to define the internal systolic
and diastolic diameters. Fractional shortening (FS) is defined as [(LVEDd-LVEDs)/LVEDd]
100%, in which LVEDd is the left ventricular end-diastolic diameter and LVEDs is the
corresponding left ventricular end-systolic diameter. Left ventricular ejection fraction (LVEF) is
defined as [(LVEDV-LVESV)/LVEDV] 100%, in which LVEDV is the left ventricular
enddiastolic volume and LVESV is the left ventricular end-systolic volume. Measurements
represent the mean of at least three consecutive cardiac cycles.
Forty-eight hours after echocardiography examination, the rats underwent left and right heart
catheterization under pentobarbital sodium salt anesthesia (40mg/kg, intraperitoneal
injection). The right carotid artery and right jugular vein were exposed, cannulated, saline-filled
PE50 tubings (0.58 mm ID, 0.96 mm OD) connected to a pressure transducer (BL-420F biological
function experimental system, Chengdu Technology & Market Co. Ltd., Chengdu, China) were
inserted into the right carotid artery and right jugular vein, respectively. The jugular vein
catheter was advanced into the right ventricle and the right atrium for the recording of right
ventricular systolic pressure (RVSP), right ventricular end-diastolic pressure (RVEDP), and right
atrium pressure (RAP), and the maximum rate of rise (dP/dtmax) and decrease (dP/dtmin) of
RV systolic pressure. The carotid catheter was advanced into the left ventricle for the recording
of left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), the
maximum rate of rise (dP/dtmax) and decrease (dP/dtmin) of LV systolic pressure and then
was withdrawn into the aortic root to measure the heart rate (HR), systolic aortic pressure
(SAP) and diastolic aortic pressure (DAP), and the mean arterial pressure (MAP) was
calculated as: [(2 DAP)+SAP]/3.
Renal function measurements
The jugular vein catheter was connected to a syringe and each rat was given an i.v. bolus
(2ml/kg) of the inulin/ para-aminohippurate(PAH) solution, followed by an i.v. infusion
(25μl/min) of the inulin/PAH solution via an infusion pump. The inulin/PAH solution
contained 3% inulin and 2% PAH in saline. An additional infusion of 25μl/min of saline into the
jugular vein catheter was also performed and was continued for the duration of the experiment.
Following the l hour equilibration period, hemodynamics and renal function were determined
for 90 min (three 30 min clearance periods). Urine was collected in pretared vials at 30 min
intervals through the bladder catheter. Arterial blood samples (500μl) were drawn through the
carotid artery catheter at the midpoint of each urine collection period into prechilled
heparinized tubes. A small blood sample was taken into microhematocrit tubes for measurement of
hematocrit. The urine samples were measured gravimetrically for urine volume. Urine samples
were then refrigerated until they were assayed. Plasma samples were separated by
centrifugation and kept at -80℃ freezer until analysis.
After blood sampling from vena cava, the rats were sacrificed under additional deep anesthesia
(70 mg/kg sodium pentobarbital intraperitoneally). Rats were weighed, hearts from five rats of
each group underwent gross morphology study. The hearts were taken out, washed, and fixed
in formalin buffer for 1 week. The hearts were then blotted dry and sagitally cut to show the
size of the cavity and thickness of the LV and RV walls as well as that of the septum. Hearts
from the other rats were removed and immediately placed in ice-cold saline to wash out the
blood. Total heart, right ventricular, left ventricular weight including the septum were
measured. Then all tissues were embedded in paraffin, and cut into 4 μm slices, which were stained
with HE and Masson and then images were captured with a Leica microscope. Cardiomyocyte
size was determined by measuring the narrowest diameter of 75 cardiomyocytes from left and
right ventricle. Kidney, liver and lung were also removed from all animals and immediately
placed in ice-cold saline to wash out the blood, wet weights were measured.
Kidneys were weighed and then fixed by immersion for 48 hours in 4% neutral
formaldehyde after longitudinal bisection. Subsequently, they were processed for paraffin embedding
according to standard procedures. Sections of 3 μm were stained with periodic acid–Schiff
(PAS) and microscopically evaluated by determining the incidence of focal glomerulosclerosis
(FGS) as previously descried. For each animal, 100 glomeruli were examined in the inner
and outer cortical region and the number of sclerotic glomeruli was counted. Criteria on which
glomeruli were designated as sclerotic consisted of adhesion of the glomerulus to Bowman’s
capsule, thickening of Bowman’s capsule, the presence of increased amounts of PAS-positive
material in the mesangial region, and/or folding of the glomerular basement membrane with
entrapment of amorphous material. Glomerulosclerosis was scored by quadrants, on a scale of
zero to four, where zero means no quadrant affected and four means that the whole glomerulus
was affected. Gross glomerulosclerosis score was calculated as a summation of (n glomeruli)
(score)/100. An examiner blinded for the groups evaluated all sections.
24-hour urine albumin was measured by using a sensitive enzyme-linked immunosorbent
assay (ELISA) kit (Abcam, America). Plasma creatinine was measured with the Jaffé method
with deproteinization. Plasma rBNP-45 concentrations were measured by using a sensitive
enzyme-linked immunosorbent assay (ELISA) kit (Assaypro, America). Plasma cystatin C
concentrations were measured by using a sensitive enzyme-linked immunosorbent assay (ELISA)
kit (R&D Systems, America). An enzymatic method was used for the determination of inulin,
and a calorimetric method was used for determination of PAH in the plasma and urine
samples. GFR was estimated as the clearance of inulin (urine volume urine inulin/plasma inulin).
Effective renal plasma flow (ERPF) was estimated as the clearance of PAH (urine volume urine
PAH/plasma PAH). Renal blood flow was calculated as ERPF/(1-hematocrit). Renal vascular
resistance was calculated as mean arterial pressure divided by the renal blood flow. Fractional
excretion of sodium was calculated as the clearance of sodium divided by the GFR.
All data are presented as mean±SD. Differences between groups in mean values with normal
distribution were compared by 2-way ANOVA followed by Tukey test, otherwise a
kruskalwallis test followed by Mann-Whitney U test with Bonferroni correction was used. P<0.05 was
considered statistically significant.
One moribund rat was euthanized under deep anesthesia(70 mg/kg sodium pentobarbital
intraperitoneally) on the first post-operation day in UNX+AV group due to difficulty breathing
and drowsiness, post mortem examination revealed massive bleeding around the puncture site,
and the symptoms might be associated with failure of sealing the puncture site by
cyanoacrylate. Another rat in AV group was found dead on the morning of the 18th day post operation
day and post mortem examination revealed hypertrophied heart, congested liver and lung,
presence of ascites and pleural effusion, as well as edema of the limbs, suggesting that overt
congestive heart failure might be the cause of death in this rat. Seven rats (4 in AV group and 3
in UNX+AV group) were excluded from the final analysis because the lack of mixing of venous
and arterial blood in the vena cava visualized before sacrifice. Finally, data from 10 rats in
SHAM(n = 5)
UNX(n = 5)
AV(n = 7)
UNX +AV(n = 13)
Sham and UNX group, 13 rats in AV group and 19 rats in UNX+AV group were analyzed.
Ascites and pleural effusion were not evidenced on the rats survived to study end.
Body weight and organ weights, morphological changes
Body weight (BW) and organ weights are shown in Table 1. Eight weeks post various
procedures, body weight was similar among groups, heart weight and heart/BW ratio, LVW(mg),
LVW/BW(mg/g), RVW(mg) and RVW/BW(mg/g) were similar between UNX and Sham
groups, while significantly increased in AV and UNX+AV groups compared both Sham and
UNX groups. These values (except RVW/BW) also tended to be higher in UNX+AV group
compared to AV group. Wet lung weight was significantly higher in UNX+AV groups
compared to Sham and UNX groups, while wet lung/BW ratio significantly increased in AV and
UNX+AV groups compared to Sham and UNX groups. Liver wet weight and liver wet weight/
BW ratio were similar among groups. Left kidney weight was significantly higher in UNX and
UNX+AV groups compared to Sham and AV groups.
The gross morphological changes of the hearts from various groups are shown in Fig 1. As
expected, heart enlargement and LV and RV cavity dilation as well as and hypertrophied wall
thickness were observed in the vertically cut hearts of the AV group and these changes were
more apparent in UNX+AV group while there were no obvious changes in the heart of UNX
and Sham groups.
As shown in Fig 2 and Table 2, LVEDD and LVESD were significantly higher while LVEF and
LVFS values were significantly lower in the AV and UNX+AV groups than in Sham and UNX
groups. There is a trend of severer LV remodeling and dysfunction in UNX+AV group
compared to AV group.
Fig 1. Gross heart morphology showing ventricular enlargement and cardiac hypertrophy (of rat hearts) in the AV group, especially (of rat hearts)
in the UNX+AV group.
Hemodynamic measurements results are shown in Figs 3 and 4. As shown in Fig 3, RAP, RVSP
and RVEDP were significantly higher while RV dP/dtmax and RV dP/dtmin were lower in AV
and UNX+AV groups compared to Sham and UNX groups, these changes tended to be more
apparent in UNX+AV group compared to AV group, but did not reach statistical significance.
Fig 4 shows that LVSP and MAP tended to be lower, LVEDP to be higher in AV and UNX+AV
groups compared to Sham and UNX groups. LV dp/dtmax and dP/dtmin were significantly lower
in UNX+AV group compared to Sham and UNX groups. Heart rate was similar among groups.
Biochemistry and renal function parameters
Rat brain natriuretic peptide-45 tended to be slightly higher post UNX and AV operations
compared to Sham group. Plasma creatinine and cystatin C levels were significantly increased
in UNX and UNX+AV groups compared to Sham and AV groups and there was a trend for
more apparent changes in UNX+AV group than in UNX group, but these changes did not
reach statistical significance (Table 3). GFR tended to be lower in UNX rats and was
significantly reduced in UNX+AV rats compared to Sham rats; ERPF and RBF tended to be lower in
UNX and UNX+AV groups and tended to be higher in AV group compared to Sham group;
RVR was significantly increased in UNX and UNX+AV groups compared to Sham group;
FENa was significantly increased in AV and UNX+AV group compared to Sham group; UV
Fig 2. Transthoracic echocardiography. Representative B- and M-mode images of the rats from SHAM, UNX, AV and UNX+AV groups.
SHAM (n = 8)
UNX (n = 9)
AV (n = 12)
UNX +AV (n = 16)
tended to be lower in UNX group and higher in AV group compared to Sham group; 24 hours
albuminuria tended to be higher in UNX+AV group compared to Sham group (Table 3). Renal
function was similar one day before AV placement in UNX+AV group and at 9 weeks post
operation in UNX group (data not shown).
Renal and cardiac histology
Fig 5A showed that the glomerular capillary loops were thin and delicate, endothelial and
mesangial cells were normal in Sham group and AV group. In UNX group, there were signs of
compensatory glomerular enlargement and the mild mesangial region hyperplasia. In UNX
Fig 3. Right heart hemodynamic analysis. [A, Sham (n = 10); B, UNX (n = 10); C, AV (n = 9); D, UNX+AV (n = 15)]. Values are mean±SD. RA, right atrium;
RV, right ventricle; RAP, right atrial pressure; RVSP, right ventricular systolic pressure; RVEDP, right ventricular diastolic pressure; dP/dtmax, first derivative
of pressure rise; dP/dtmin, first derivative of pressure decrease. *p<0.05 vs. Sham; †p<0.05 vs. UNX; ‡ p<0.05 vs. AV.
Fig 4. Left heart hemodynamic analysis. [A, Sham (n = 10); B, UNX (n = 10); C, AV(n = 9); D, UNX+AV (n = 15)]. Values are mean±SD. LV, left ventricle;
Aorta, Aorta artery; LVSP, left ventricular systolic pressure; LVEDP, left ventricular diastolic pressure; MAP, mean arterial pressure; dP/dtmax, first derivative
of pressure rise; dP/dtmin, first derivative of pressure decrease; HR, heart rate. *p<0.05 vs. Sham; †p<0.05 vs. UNX; ‡ p<0.05 vs. AV.
+AV group, there was an area of collagenous sclerosis running across the middle of this
glomerulus implying a focal segmental glomerulosclerosis. Focal segmental glomerulosclerosis
quantification showed FGS was significantly increased in both UNX and AV groups and
strikingly increased in UNX+AV group (Fig 5B).
Fig 6A presented HE-stained myocardial sections showing cardiomyocyte hypertrophy in
the AV group and UNX+AV group, Fig 6B presented Masson-stained myocardial section and
collagen content was similar among groups. Fig 6C showed that cardiomyocyte width from left
ventricle and Fig 6D showed that from right ventricle were significantly increased in AV and
UNX+AV groups compared to Sham and UNX groups.
The major finding of present study is that chronic volume overload induced cardiac
remodeling is significantly aggravated, which is joined by a trend of more apparent renal and cardiac
dysfunction, in the presence of minor renal dysfunction post unilateral nephrectomy.
Most patients with heart failure have mild or moderate renal dysfunction.Both mild
and severe renal dysfunctions are closely related to poor outcome in heart failure patients
SHAM (n = 10)
UNX (n = 10)
AV (n = 9)
UNX +AV (n = 15)
and cardiac and renal dysfunction may worsen each other. Previous studies mostly focused
the pathogenesis and interactive associations between renal and cardiac dysfunction on disease
outcome and therapy goal. Experimental studies already verified the interaction between
mild renal dysfunction and ischemic cardiac insult in UNX rats[8, 9], while the impact of
chronic volume overload on preexisting mild renal dysfunction remains largely unknown.
Results from present study show that UNX alone is only linked with very mild renal
dysfunction, as shown by light focal glomerulosclerosis, compensatory enlargement of the
remaining left kidney and slightly but significantly increased plasma creatinine and cystatin C level,
Fig 5. Histological features of renal tissue. [Sham (n = 10); UNX (n = 10); AV (n = 12); UNX+AV (n = 18)]. A. Periodic Acid-Schiff staining (x400) of rat with
the highest proteinuria from every experimental group. B. FGS quantification. *p<0.05 vs. Sham;†p<0.05 vs. UNX;‡p<0.05 vs. AV.
Fig 6. Histological features of cardiac tissue. [Sham (n = 10); UNX (n = 10); AV (n = 13); UNX+AV (n = 19)].A. Hematoxylin and eosin (HE) staining, x200.
B. Masson’s trichrome staining, x400. C. Bar graphs of left ventricular cardiomyocyte width. D. Bar graphs of right ventricular cardiomyocyte width. *p<0.05
vs. Sham;†p<0.05 vs. UNX;‡p<0.05 vs. AV.
and mildly reduced GFR and UV as well as significantly increased RVR. However, chronic
volume overload-induced cardiac and renal remodeling tended to be more significant on the basis
of mild renal dysfunction post UNX. Thus, mild renal dysfunction is a key determinant for
future aggravated cardiac and renal remodeling and function worsening in case of volume
overload induced cardiac insult. In a landmark study, Metra and colleagues demonstrated that
worsening renal function, characterized by an increase in serum creatinine levels 0.3 mg/dL,
alone is not an independent determinant of outcomes in patients with heart failure, but it has
an additive prognostic value when it occurs in patients with persistent signs of congestion.
It is to note that although we evidenced more significant morphological cardiac remodeling in
UNX+AV rats than in AV rats, there were mostly just a trend of aggravation on the measured
cardiac and renal remodeling and dysfunction parameters in the UNX+AV rats compared to
AV rats, the underlying reason might partly explained by the relative short observation period
and the limited interval between UNX and AV placement (1 week interval). Future studies
with longer observation period and longer interval between UNX and AV placement are
warranted to verify if there would be significant differences between UNX+AV and AV groups
in rats with only mild renal dysfunction. Taken together, our study provoked a potential
detrimental role of slightly increase serum creatinine in case of chronic volume overload in this
UNX+AV rat model.
Results from present study are obtained from the rat model of aortocaval fistula, which is a
unique model of volume-overload congestive heart failure and cardiac hypertrophy. Creation
of aortocaval fistula results in an immediate and sustained decrease in mean arterial pressure
together with a substantial increase in venous blood flow to the right heart. These
hemodynamic changes could result in compensatory activation of several neuro-hormonal systems as
well as adaptive structural alterations in myocardium and vascular system, as shown previously
by other investigators[17–19]. Our results showed that UNX resulted in a very mild state of
chronic, mild renal function loss. Despite the very mild renal dysfunction observed in this
UNX model, additional chronic volume load resulted in greater cardiac and renal remodeling
and dysfunction in this model. These results are joined by increased preload of both right and
left ventricles as evidenced by higher RVEDP and LVEDP in UNX+AV rats, reduced LV and
RV function as shown by reduced EF, FS and LV and RV dP/dtmax and dP/dtmin. Increased
RAP also indicated increased right-side volume overload in both AV and UNX+AV rats. Thus,
healthy living donors might thus face increased cardiac and renal dysfunction risk in case of
future cardiac insult, as in terms of chronic volume load shown in the present study.
Living donor kidney transplantation is regarded as beneficial to allograft recipients and not
particularly detrimental to the donors. In 2014, 17105 kidney transplants took place in the U.S.
Of these, 11,570 came from deceased donors and 5,535 came from living donors.According
to our results, healthy living donors might face increased cardiac and renal dysfunction risk in
case of future chronic volume overload cardiac insult, as in the case of pregnancy and other
high output heart failure situations as in the case of hyperthyroidismand patients with
arteriovenous fistula. Ibrahim and colleagues determined the fetal and maternal outcomes in a
large cohort of kidney donors and found that post-donation pregnancies (vs. pre-donation)
were associated with a lower likelihood of full-term deliveries and a higher likelihood of fetal
loss, with a higher risk of gestational diabetes, gestational hypertension, proteinuria and
preeclampsia.Thus, special medical care and education should be afforded to this population
to actively treat and avoid volume overload conditions and related negative renal and cardiac
This study has several limitations that should be acknowledged. First, although the AV is
produced by 18-gauge needle in all animals, we are unable to confirm that the flow over the
AVfistula was comparable between AV and UNX+AV groups and between individual animals,
future studies with different size of needles are warranted to explore the impact of various
fistula flow in this model. Second, the water intake was not measured in this study, so the
potential impact of hypovolemic on echocardiographic and hemodynamic measurements remain
unknown. Third, one week recovery after UNX might not be enough to reach a new stable
phase of renal function. It is possible that increased renal hypoxia and damage during the
adaptation-phase might lead to neurohormonal activation and subsequently lead to increased
volume retention and observed negative impact on AV-induced renal and cardiac performance.
Our finding is thus limited to the AV placement during adaptation of the remaining kidney
phase, and future studies with longer UNX and AV placement interval and longer observation
period are needed to explore the exact time-frame of events.
In conclusion, although UNX only induces minor renal dysfunction, additional chronic
volume overload placement during the adaptation phase of the remaining kidney is associated
with aggravated cardiac remodeling and cardiac and renal dysfunction in UNX rats. Special
medical care and education should be afforded to living kidney donors and people with
congenital monokidney, especially in pregnancy and other high-output situations like in patients
with hyperthyroidism and arteriovenous fistula to avoid/correct volume overload conditions
and to attenuate the negative consequences of volume overload in this special population.
Conceived and designed the experiments: ZC YG SH. Performed the experiments: JW WZ
MZ. Analyzed the data: JW PZ. Contributed reagents/materials/analysis tools: MZ PZ. Wrote
the paper: JW SH.
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