Received: 17 March 2019 Revised: 11 May 2019 Accepted: 28 May 2019

DOI: 10.1002/cnm.3224

RESEARCH ARTICLE ‐ APPLICATION

Estimation of the kidney metabolic heat generation rate

Helcio R.B. Orlande1 | Nelson Afonso Lutaif2 | José Antonio Rocha Gontijo2

1
Department of Mechanical Engineering,
Politécnica/COPPE, Federal University of
Abstract
Rio de Janeiro, Rio de Janeiro, Brazil Thermogenesis results from the cellular metabolism and has a fundamental
2
Department of Medical Clinic, School of role for body thermoregulation in endothermic species. The motivation for this
Medical Sciences, State University of work is the analysis of the kidneys' contribution for thermoregulation. An
Campinas—UNICAMP, Campinas, Brazil
inverse problem is solved for the estimation of the heat generation rate that
Correspondence results from the metabolic activities in the kidney, by using transient tempera-
Helcio R. B. Orlande, Department of
ture measurements of the urine. The Markov chain Monte Carlo (MCMC)
Mechanical Engineering,
Politécnica/COPPE, Federal University of method is applied for the solution of the inverse problem, which presents
Rio de Janeiro, UFRJ, Cid. Universitaria, inherent difficulties associated with low sensitivity of the parameters of main
Cx. Postal 68503, Rio de Janeiro
21941‐972, Brazil.
interest that represent the transient heat source term and strong correlation
Email: helcio@mecanica.coppe.ufrj.br of the remaining model parameters. Such difficulties are dealt with in this
work by using a version of the Metropolis‐Hastings algorithm that samples
Funding information
Conselho Nacional de Desenvolvimento the parameters in blocks. Simulated temperature measurements are used for
Científico e Tecnológico, Grant/Award the inverse problem solution, and the convergence of the Markov chains is ver-
Number: Universal; Coordenação de
ified with two different techniques.
Aperfeiçoamento de Pessoal de Nível
Superior, Grant/Award Number: Finance
KEYWORDS
code 001; Fundação Carlos Chagas Filho
de Amparo à Pesquisa do Estado do Rio de inverse problem, Markov chain Monte Carlo method, metabolic heat generation, Metropolis‐Hastings
Janeiro, Grant/Award Number: Cientista algorithm, thermoregulation
do Nosso Estado

1 | INTRODUCTION

The uniform body temperature in endothermic species is maintained by thermogenesis, which is directly related to the
cellular metabolism.1-3 Experimental studies revealed that the kidney has a great contribution in thermoregulation.4-8 In

Nomenclature: A, surface area; c, specific heat; D, matrix for the Gaussian Markov random field prior; F , flow rate; h, specific enthalpy; I, number of
transient measurements; m, mass; m′, mass flow rate; n, number of states in the Markov chain; N, number of parameters; P, parameter; P, vector of
parameters; P1, [α, β, γ, ϕ, ψ, Ta, Ts ]T, see Equation (9a); P2, [Qm0, Qm1, … , QmI]T, see Equation (9b); Ql, heat transfer rate lost by the kidney to the
surroundings; Qm, metabolic heat generation rate in the kidney; q(P*| P(t)) , proposal distribution; T, temperature; t, time; Tk,0, initial kidney
temperature; U, global heat transfer coefficient; V, covariance matrix for the Gaussian prior; V, volume; W, covariance matrix for the
measurements; Y, vector of measurements
Greeks: α, parameter defined by Equation (5a); β, parameter defined by Equation (5b); γ, parameter defined by Equation (5c); ϕ, parameter defined by
Equation (5d); μ, vector with the means for the Gaussian prior; π, 4 tan−1(1); π(.), probability density function; π(P), a priori probability density
function; π(P|Y), a posteriori probability density function; π(Y|P), likelihood function; ψ, parameter defined by Equation (5e)
Superscripts: (r), state of the Markov chain without the burn in period; (t), state of the Markov chain; *, candidate for the Markov chain; _, mean value
Subscripts: a, arterial blood; j, parameter j; k, kidney; s, organs and tissues surrounding the kidney; u, urine; v, venous blood

Int J Numer Meth Biomed Engng. 2019;35:e3224. wileyonlinelibrary.com/journal/cnm © 2019 John Wiley & Sons, Ltd. 1 of 19
https://doi.org/10.1002/cnm.3224
2 of 19 ORLANDE ET AL.

fact, for more than 50 years, it has been recognized that only a small portion of the energy consumed by the kidneys is
used for the ionic and molecular osmotic transfer.9
Lutaif et al5 revealed the important role of kidneys in the body thermoregulation. Their experiments were conducted
with Sprague‐Dawley rats, which were subjected to surgeries to simulate renal insufficiency, like the bilateral renal
denervation and the partial nephrectomy (renal mass reduction by ablation). Two groups of rats were used as controls:
one without any kind of surgical intervention and another in which the rats were subjected to the same surgical proce-
dure as the denervated group but with the preservation of nerves and renal anatomy. Afterwards, the animals had their
brown adipose tissue (BAT) of the cervical region surgically removed. The groups with the smallest BAT masses were
the ones subjected to denervation and nephrectomy. The lowest rectal temperature was of the nephrectomized group,
while the temperatures of the other groups were practically the same. These results suggested that the hypothermia
observed in the nephrectomized animals has been caused by the small metabolic heat generation due to the partial
removal of the kidneys, which is compensated by the activation of the facultative thermogenesis that consumes the
BAT. It has also been demonstrated that the main mechanism that activates the facultative thermogenesis is due to
the kidney efferent nervous system, since the denervated animals had small masses of BAT even with the kidneys fully
preserved. Therefore, there are strong experimental evidences that the kidneys and the renal neural pathways have an
important role in the body thermoregulation, beyond the classically known kidneys' functions that include10 excretion
of products and chemical substances undesirable to the organism; regulation of water and electrolytes in the body; reg-
ulation of osmolality of the body liquids; regulation of the acid‐base equilibrium; secretion, metabolism, and excretion
of hormones; and gluconeogenesis.
The objective of this work is to solve an inverse problem dealing with the estimation of the kidney metabolic heat gen-
eration rate, by using transient temperatures of the urine. Although the main envisioned application is related to a more
accurate quantification of the kidney's role in the thermoregulation process, the techniques advanced here might also be
applied to monitor the renal functions in clinical practice. For example, patients in intensive care units often need a cath-
eter to maintain the flow of urine. Therefore, a sensor introduced via this catheter to measure the temperature of the urine
would not cause additional discomfort to the patient and would avoid the use of other intrusive sensors for the temperature
measurements. Fallis11 has compared temperatures measured in the bladder and in the pulmonary artery, indicating that
both can be used to identify thermal instabilities caused by infections or inflammations.
The inverse problem of interest here is solved within the Bayesian framework of statistics by using the Markov chain
Monte Carlo (MCMC) method, for inference on the posterior probability distribution function.12-20 The
Metropolis‐Hastings algorithm21,22 of the MCMC method is applied in this work by sampling the parameters in
blocks.18,19,23 Such approach is needed because the kidney heat generation rate, which is the quantity of interest for
the inverse problem solution, exhibits sensitivity coefficients with magnitudes much smaller than those for the other
parameters. Moreover, the model parameters are strongly correlated. A noninformative prior, in the form of a Gaussian
Markov Random field,12 is used for the parameters that represent the transient variation of the kidney metabolic heat
generation rate. Prior distributions for the other model parameters are proposed based on a Monte Carlo uncertainty
quantification analysis. Simulated transient temperature measurements are used in the inverse analysis.

2 | M A T H EM A TI C A L F O R M U LA T I O N OF TH E D I R E C T P R O B L E M

The main simplifications for the mathematical model used in this work are to consider the kidney as a homogeneous
medium with a uniform temperature. Although the kidney is an organ with a complex morphology (see, for example,
Guyton and Hall10), there is great uncertainty and lack of information about the physical properties of its internal
structure.
Mass and energy balances are written for a control volume surrounding the kidney. The model includes mass trans-
fer processes to/from this control volume, which involve the flow of arterial blood, venous blood, and urine. Blood and
urine are considered as homogeneous fluids. Blood is composed of cells and plasma. Plasma, which normally constitutes
55% of the blood volume, is formed by water (92% vol) and contains proteins, glucose, hormones, etc. Water constitutes
around 93% of the urine volume, which also contains inorganic and organic compounds depending on the substances
excreted by the kidney.10 Figure 1 illustrates the kidney model used in this work, where m′ and h denote mass flow rate
and specific enthalpy, respectively. The subscripts a, v, and u represent the arterial blood, the venous blood, and urine,
respectively, while Qm is the metabolic heat generation rate in the kidney, and Ql is the heat transfer rate lost from the
kidney to the surroundings.
ORLANDE ET AL. 3 of 19

FIGURE 1 Sketch of the kidney model

We further assume that the kidney volume is constant, as well as that variations in kinetic and potential energies
inside the kidney are negligible. The kidney mass and the blood and urine mass flow rates are also considered constant
in this work. Therefore, the mass balance is given by

m′a − m′v − m′u ¼ 0 (1)

With the above hypotheses and considering the blood and urine as incompressible fluids with constant specific heats,
the energy balance can be written as

d T k ðt Þ
mk c k ¼ m′a cb T a ðt Þ − m′v cb T v ðt Þ − m′u cu T u ðtÞ þ Qm ðt Þ − Ql ðt Þ in V k for t > 0; (2a)
dt

with initial condition given by a uniform temperature inside the kidney:

T k ¼ T k;0 in V k at t ¼ 0; (2b)

where c is the specific heat, T is the temperature, and the subscript k refers to the kidney.
Heat transfer from the kidney to the surrounding organs and tissues is modeled in terms of a global heat transfer
coefficient, U, that is,

Ql ðt Þ ¼ UAk ½T k ðt Þ − T s ; (3)

where Ak is the surface area of the kidney and Ts is the temperature of the surroundings, which is assumed as constant.
Additional hypotheses are made regarding the temperatures of the venous blood and urine, in order to reduce the num-
ber of dependent variables of the model. Two limit conditions exist regarding heat transfer between the kidney and the
blood inside the kidney: null heat transfer and complete heat transfer. Null heat transfer corresponds to a situation where
the blood circulating inside the kidney is thermally insulated from the kidney tissues, which is conspicuously unfeasible.
In fact, the renal artery is gradually divided into arterioles, which then converge to the venous system that progressively
form the renal vein.10 Thus, blood vessels of small caliper, distributed throughout the kidney, favor the limit condition
of complete heat transfer, that is, the temperature of the venous blood is the same as the kidney temperature. The urine
is formed by three processes: filtration, reabsorption, and secretion, which involve intense mass transfer distributed inside
the kidney.10 Therefore, we assume in our model that Tv(t) = Tu(t) = Tk(t), so that we can rewrite Equations (2) as

dT k ðtÞ
þ ðα þ γ þ ψÞT k ðt Þ ¼ βT a ðt Þ þ ψT s þ ϕQm ðt Þ in V k for t > 0; (4a)
dt
4 of 19 ORLANDE ET AL.

T k ¼ T k;0 in V k at t ¼ 0; (4b)

where

′ 
m′u cu m′a cb ma − m′u cb
α¼ ;β¼ ;γ¼ ; (5ac)
mk c k mk c k mk c k

1 UAk
ϕ¼ ; ψ¼ : (5de)
mk c k mk ck

We note that the parameter γ was written by using Equation (1), that is, m′v ¼ m′a − m′u :
The mathematical formulation given in Equations (4a) and (4b) is a direct problem when the parameters (α, β, γ, ϕ,
ψ,Ts), the initial condition (Tk,0), and the functions Ta(t) and Qm(t) are known.

3 | INVERSE PROBLEM A ND METHOD OF SOLUTION

This work aims at the solution of the inverse problem of estimating the kidney metabolic heat generation rate, Qm(t),
with measurements of the urine temperature. As discussed above, the urine is considered in thermal equilibrium
with the kidney, that is, Tu(t) = Tk(t). Moreover, the urine temperature is assumed to be measured sufficiently
close to the kidney, so that heat transfer between the urine and the surroundings is not taken into account in the
model.
The MCMC is used for the solution of the inverse problem, within the Bayesian framework of statistics.12-20 In this
framework, the solution of the inverse problem is obtained from statistical inference of the posterior distribution π(P|Y),
where P is the vector of model parameters and Y is the vector of measurements, by assuming that all quantities
appearing in the mathematical formulation of the direct problem are random. From Bayes theorem, we have

π ðY j P Þ π ðP Þ
π ðPjYÞ ¼ ; (6)
π ðY Þ

where π(P) is the prior density, π(Y|P) is the likelihood function, and π(Y) is a normalizing constant for π(P|Y). The
prior density represents the information about the model parameters before the measurements are available, which is
coded in terms of a statistical distribution. The likelihood function is the statistical model for the measurement errors,
which are assumed here as additive, Gaussian, with zero mean, and covariance matrix W. Thus,
 
1
π ðYjPÞ ¼ ð2πÞ−I=2 jWj−1=2 exp − ½Y−TðPÞT W−1 ½Y − TðPÞ ; (7)
2

where I is the number of transient measurements and T(P) is the solution of the direct problem given in Equations (4a)
and (4b) with the parameters P.12-20
The parameters of our mathematical model are given by

PT ¼ ½α; β; γ; ϕ; ψ; T a ; T s ; Qm0 ; Qm1 ; …; QmI ; (8)

where the arterial blood temperature, Ta, was assumed constant. The transient metabolic heat generation rate was
Δt Δt
parameterized with piecewise constant basis functions so that Qmj ≡ Qm(tj) in t j − ≤ t ≤ t j þ , j = 0, …,I, where
2 2
Δt is the time interval between consecutive measurements.
The vector P given in Equation (8) includes a group of the constant parameters in Equation (4a) and a group of
parameters that represent the transient variation of Qm(t), given, respectively, by

PT1 ¼ ½α; β; γ; ϕ; ψ; T a ; T s ; (9a)

PT2 ¼ ½Qm0 ; Qm1 ; …; QmI ; (9b)

ORLANDE ET AL. 5 of 19

so that we can write

 
PT ¼ PT1 ; PT2 : (10)

Therefore, the present inverse problem provides a natural selection of two blocks of model parameters. Moreover, as
it will be apparent below, several parameters in P1 are linearly dependent and with sensitivity coefficients much larger
than those for the parameters of major interest in this work, which are given by P2. Linearly dependent parameters gen-
erally result in correlated and periodic Markov chains, with small statistical efficiencies.
A modified version of the Metropolis‐Hastings algorithm has been proposed for cases that involve groups of linearly
dependent parameters.18,23 In this modified version, the sampling procedure and the acceptance/rejection test are per-
formed separately for each block of parameters, within one iteration of the Metropolis‐Hastings algorithm.18,23 For the
case under analysis in this work, the Metropolis‐Hastings algorithm with sampling by block of parameters can be sum-
marized by the following steps:

P(1).
1. Let t = 1 and start the Markov chains with the sample 
ðt Þ ðt Þ
2. Sample candidates P1 from the proposal distribution q1 P*1 jP1 for the vector P1 and make P*2 ¼ P2 :
*

3. Compute the Metropolis‐Hastings ratio

2
  ðt Þ 3
 π P* jY q1 P1 jP*1
α1 P* jPðtÞ ¼ min41;
  5: (11a)
ðt Þ
π PðtÞ jY q1 P*1 jP1

4. Generate a random number with a uniform distribution in (0,1), U1~U(0,1).

ðtþ1Þ ðtþ1Þ ðt Þ
5. If U1 ≤ α1(P*| P(t)), make P1 = P*1 : Otherwise, make P1 = P1 :
* ðt Þ ðtþ1Þ
6. Sample candidates P2 from the proposal distribution q2 P2 jP2 for the vector P2 and make P*1 ¼ P1 :
*

7. Compute the Metropolis‐Hastings ratio

2
  ðt Þ 3
 π P* jY q2 P2 jP*2
α2 P* jPðtÞ ¼ min41;
  5: (11b)
ðt Þ
π PðtÞ jY q2 P*2 jP2

8. Generate a random number with a uniform distribution in (0,1), U2~U(0,1).

ðtþ1Þ ðtþ1Þ ðt Þ
9. If U2 ≤ α2(P*| P(t)), make P2 = P*2 : Otherwise, make P2 = P2 :
10. Let t = t+1 and return to step 2 in order to generate the sequence {P(1), P(2), … , P(n)}.

For the approximate computation of the statistics of the posterior distribution with the sequence {P(1), P(2), … , P(n)},
the samples of the initial states need to be discarded while the Markov chains have not reached equilibrium (burn in
period). Let the duration of the burn in period be of z states. Thus, the statistics are computed with {P(z+1), P(z
+2)
, … , P(n)}. By changing the index from t = z+1, … ,n to r = 1, … ,s, where s = n − z is the number of samples used
for inference, this sequence is given by {P(1), P(2), … , P(s)}.
The integrated autocorrelation time (IACT) represents the number of correlated samples between linearly indepen-
dent samples in a Markov chain. For a sequence obtained from the Markov chain for a parameter Pj, that is,
n o
Pjð1Þ ; Pjð2Þ ; …; PjðsÞ ; the IACT is given by17,18,24

∞
τ j ¼ 1 þ 2 ∑ ρj ðkÞ; (12a)
k¼1

where

C j ðk Þ
ρj ðkÞ ¼ (12b)
C j ð0Þ
6 of 19 ORLANDE ET AL.

is the normalized autocovariance function at lag k and

h i
ðr Þ ðrþkÞ
Cj ðk Þ ¼ cov Pj ; Pj (12c)

ðr Þ ðrþk Þ
is the covariance between Pj and Pj .
The statistical efficiency of the sampling algorithm can be assessed by examining τj for each parameter Pj, j = 1,...,N.
Algorithms that result in small values of τj promote better sampling. For cases involving many parameters, such as in
the present work, the statistical efficiency can be examined with the IACT of the posterior distribution π(P(r)| Y),
r = 1, … ,s.23
Quantitative techniques are available for the analysis of the convergence of a Markov chain to an equilibrium distri-
bution. Geweke's technique25 compares the means calculated with the samples from different ranges of states of the
Markov chain. Let

a 1 sa ðr Þ b 1 s ðr Þ
Pj ¼ ∑ Pj ; Pj ¼ ∑ Pj (13ab)
sa r¼1 sb r¼s*

be the means calculated with sa and sb states, respectively. Geweke25 recommends

s* ¼ s − sb þ 1 ; sa ¼ 0:1s ; sb ¼ 0:5s: (13ce)

For the convergence analysis, it is also recommended to repeat the sampling procedure by starting the Markov chains
from different initial values. Gelman and Rubin26 developed a method for inference on multiple chains, based on two
steps: (a) An estimate is obtained for the posterior distribution with an initial Markov chain, which is then used to start
new independent chains. The initial states for these new multiple chains must have a dispersion larger than that of the
initial chain; (b) the new multiple chains are then used for inference with analyses inter chains and within each chain.
The posterior distribution simulated with the multiple chains exhibit a variability larger than that of the initial chain.
The multiple chains also allow a convergence analysis to an equilibrium distribution that represents the sought pos-
terior. We consider the case of a parameter Pj, j = 1,...,N. The variance of the means of m chains, each one with n states,
is given by26

Bj 1 m  2
k
¼ ∑ Pj −Pj ; (14)
n ðm − 1Þ k¼1

k
where Pj is the mean of the chain k, k = 1,...,m, and Pj is the mean of these means.
The mean of the m variances of the chains k = 1,...,m, is given by26

1 m n  k 2
ðsÞ;k
Wj ¼ ∑ ∑ Pj −Pj ; (15)
mðn − 1Þ k¼1 s¼1

ðsÞ;k
where Pj is the sample for Pj at the state s, s = 1, …,n, of chain k, k = 1,...,m.
The variance of the posterior distribution simulated with the multiple chains for Pj is thus obtained as26


1 Bj
b
σ 2j ¼ 1− Wj þ (16)
n n

This variance of the mn samples of the multiple chains, σ b2j , overestimate the variance of the actual posterior, while
the equilibrium distribution has not been reached. On the other hand, Wj underestimates the variance of the actual pos-
terior if each chain has not reached equilibrium. Gelman and Rubin26 thus proposed a parameter to indicate conver-
gence based on σ b2j and Wj, called scale reduction coefficient, which was lately simplified by Gamerman and Lopes18 as

sffiffiffiffiffiffi
2
b
σj
bj ¼
R : (17)
Wj
ORLANDE ET AL. 7 of 19

b j > 1, but R
Note that R b j →1 when n → ∞. Gelman and Shirley27 have suggested the empirical test R
b j < 1:1 for con-
18
vergence of the multiple chains, but larger threshold values have also been proposed.

4 | R E S U L T S AN D D I S C U S S I O N S

The analysis of the sensitivity coefficients with respect to the different parameters, the definitions of the prior and pro-
posal distributions for the solution of the inverse problem, as well as the results obtained for the estimation of the met-
abolic heat generation rate vector, PT2 ¼ ½Qm0 ; Qm1 ; …; QmI , are presented in this section.
Simulated temperature measurements were used in the inverse analysis. The measurement errors were modeled as
additive and uncorrelated Gaussian variables, with zero mean and a constant standard deviation of 0.001°C. This standard
deviation is typical of thermistors used in catheters for the measurement of the blood temperature inside vessels.4 In order
to avoid an inverse crime,12 the measurements were generated with a finite difference solution of the direct problem, while
an analytical solution was applied for the inverse problem. The measurements were assumed available with a frequency of
1 Hz, during 150 seconds. The objective was then to estimate fast variations of the metabolic heat generation rate.
The sensitivity coefficients were analyzed, and the simulated measurements were generated with reference values for
the kidney, blood, and urine parameters, which can be found in the literature. Tables 1 and 2 present the values for spe-
cific heat and density, respectively, which were obtained from the website of the It Is Foundation.28 These tables show
mean, minimum, maximum, and standard deviation values. The number of measurements available is also presented by
these tables. Such number is in general quite low, thus characterizing large uncertainties for the values presented.
Values for the kidney metabolic heat generation rate per unit mass were also obtained from this source, as presented
in Table 3. The kidney of an adult human10 has approximately 150 g. Therefore, the minimum and maximum values for
the heat generation rate obtained with the values shown in Table 3 are 1.86 and 3.98 W, respectively. Brundin and
Wahren4 presented a study regarding the effects of the intravenous infusion of amino acids on the renal thermogenesis
and renal oxygen consumption. The study was conducted with eight adult men. These authors concluded that the infu-
sion of amino acids significantly increased their consumption by the kidneys. On the other hand, there were no signif-
icant changes in the renal oxygen consumption, metabolic heat generation, and blood flow. The metabolic heat
generation rate remained between 8 and 10 W during infusion.4 Therefore, there are large discrepancies between the
values of the metabolic heat generation rate reported by Brundin and Wahren4 and those obtained from Table 3.
A typical arterial blood flow rate to both kidneys in an adult human is of 1000 mL min−1, while the flow rate of urine10
is 1 mL min−1. Therefore, for each kidney, these flow rates are F a = 8.33 × 10−6 m3 s−1 and F u = 8.33 × 10−9 m3 s−1,
respectively. The global heat transfer coefficient from the kidney to the surrounding tissues/organs was estimated based

TABLE 1 Specific heat28

c, J kg−1 K−1 Mean Minimum Maximum Standard Deviation Number of Measurements

Kidney 3763 3653 3891 120 3

Blood 3617 3300 3900 301 3
Urine 4178 4178 4178 0 1

TABLE 2 Density28

ρ, kg m−3 Mean Minimum Maximum Standard Deviation Number of Measurements

Kidney 1066 1019 1147 56 4

Blood 1050 1025 1060 17 4
Urine 1024 1012 1035 16 2

TABLE 3 Metabolic heat generation rate per unit mass28

HGR, W kg−1 Mean Minimum Maximum Standard Deviation Number of Measurements

Kidney 18.05 12.40 26.50 2.59 88

8 of 19 ORLANDE ET AL.

on the heat conduction thermal resistance for a slab of fat. The thickness of the fat surrounding the kidney was estimated
as 5 mm, while the kidney surface area was estimated as 0.02 m2, based on typical dimensions of this organ.10 The ther-
mal conductivity of fat was taken28 as 0.21 W m−1 K−1. Hence, the global heat transfer coefficient was estimated as
U = 40 W m−2 K−1.

4.1 | Analysis of the sensitivity coefficients

A local analysis of the reduced sensitivity coefficients is performed here. These coefficients are defined as15,16,29-31

∂ T k ðt Þ
X j ðt Þ ¼ P j j ¼ 1; …; N: (18)
∂ Pj

The reduced sensitivity coefficients were computed by forward finite differences, for the reference parameter values
presented in Table 4, where the metabolic heat generation rate was considered constant. Such reference values are typ-
ical of adult humans, as discussed above. Note in Table 4 that, for the analysis of the sensitivity coefficients, the kidney
was assumed in thermal equilibrium with blood and with the surrounding tissues/organs at time t = 0. In such case, the
temperature of the urine increased by approximately 0.65 K, and the steady state was reached in about 100 seconds.
The reduced sensitivity coefficients with respect to the different model parameters are presented in Figure 2A to H.
These figures show that the sensitivity coefficients with respect to β and Ta are identical, as expected from the analysis of
Equation (4a). The sensitivity coefficients with respect to β, Ta, and γ are perfectly correlated. The sensitivity coefficients
with respect to β and Ta are positive, since an increase in the temperature or in the mass flow rate of the arterial blood
increases the kidney and urine temperatures. On the other hand, the sensitivity coefficient with respect to γ is negative,
because an increase of the venous blood flow rate decreases the temperatures of the kidney and of the urine. The mag-
nitudes of the sensitivity coefficients with respect to β, Ta, and γ are much larger than those with respect to the other
parameters. Figure 2 also shows a strong linear dependence among all parameters, except ϕ, which is the parameter
related to the thermal storage in the kidney. The magnitude of the sensitivity coefficient with respect to ϕ is of the same
order of the urine temperature variation, such as for α, which is the parameter related to the urine mass flow rate, and
for Qm, which is the parameter of main interest in this work. The parameter with the smallest magnitude of the sensi-
tivity coefficients is ψ, which is related to heat transfer from the kidney to the surroundings. The maximum value of the
sensitivity coefficient with respect to ψ is one order smaller than the urine temperature variation. The magnitude of the
sensitivity coefficient with respect to the surrounding temperature, Ts, is larger than the urine temperature variation but
much smaller than the sensitivity coefficients for the parameters β, Ta, and γ.

TABLE 4 Reference values used for the local analysis of the sensitivity coefficients

Kidney Mass mk = 0.150 kg

Kidney specific heat ck = 3763 J kg−1 K−1
Blood specific heat cb = 3617 J kg−1 K−1
Urine specific heat cu = 4178 J kg−1 K−1
Arterial blood temperature Ta = 309.4 K
Temperature of the surrounding tissues and organs Ts = 309.4 K
Kidney initial temperature Tk,0 = 309.4 K
Arterial blood flow rate F a = 8.33 × 10−6 m3 s−1
Urine flow rate F u = 8.33 × 10−9 m3 s−1
Kidney density ρk = 1066 kg m3
Blood density ρb = 1050 kg m3
Urine density ρu = 1024 kg m3
Global heat transfer coefficient U = 40 W m−2 K−1
Kidney surface area Ak = 0.02 m2
Kidney metabolic heat generation rate Qm = 10 W
ORLANDE ET AL. 9 of 19

FIGURE 2 Reduced sensitivity coefficients with respect to: A, α; B, β; C, γ; D, ϕ; E, ψ; F, Ta; G, Ts; H, Qm

The analysis of Figure 2A to H reveals that there are parameters with sensitivity coefficients of the same order of
magnitude of the urine temperature variation (α, ϕ, Qm, and ψ), but there are parameters with sensitivity coefficients
of much larger magnitudes (β, γ, Ta, and Ts). The parameter of interest for this work, Qm, is not among those with
the largest magnitudes of the sensitivity coefficients. Moreover, most of the parameters are correlated. These difficulties
can be overcome by prescribing priors with small variances for the correlated parameters, which could be obtained, for
example, by performing other experiments. Unfortunately, such is not the case here, because the model parameters can
vary from one patient to another and also depend on the physiological state of the patient. In addition, a Monte Carlo
analysis used for uncertainty quantification shows large relative variances of the model parameters, as described next.
Therefore, the Metropolis‐Hastings algorithm with sampling by block of parameters was used in this work.

4.2 | A priori distributions for the model parameters

The parameters α,β,γ,ϕ,and ψ are composed of other input parameters (see Equations 5a‐e). Therefore, the priors for
α,β,γ,ϕ,and ψ are based on the priors for [mk, ck, ρu, F u, ρa, F a, cu, cb, U, Ak], where m′u ¼ ρu F u and m′a ¼ ρa F a . The priors
for the input parameters were prescribed by using the reference values available in the literature, which were presented
above. Most of the parameters were assumed Gaussian, with means given by the values presented in Table 4 and with
standard deviations of 1% of these means (see Table 5). However, the kidney specific heat and the urine density were
assumed with uniform distributions, with their minimum and maximum values given in Tables 1 and 2, respectively.
The kidney specific heat was assumed with a uniform prior distribution because this organ is considered as a homoge-
neous medium, despite its nonhomogeneous internal structure. The urine density was also assumed with a uniform
prior distribution, since the values presented in Table 2 were obtained from only two measurements. Furthermore,
the urine density may vary depending on the blood composition and on the kidney function. By using a Monte Carlo
10 of 19 ORLANDE ET AL.

TABLE 5 Gaussian prior distributions for some input parameters

Parameter Mean Standard Deviation

mk, kg 0.150 0.0015

−1 −1
cb, J kg K 3617 36.17
cu, J kg−1 K−1 4178 41.78
−1 −6
F a, m s 3
8.33 × 10 8.33 × 10−8
F u, m3 s−1 8.33 × 10−9 8.33 × 10−11
ρb, kg m3 1050 10.5
−2 −1
U, W m K 40 0.4
2
Ak, m 0.02 0.0002

simulation with 105 samples from the priors for [mk, ck, ρu, F u, ρa, F a, cu, cb, U, Ak], the histograms and the statistics of
the distributions for α,β,γ,ϕ,and ψ were obtained. The histograms are not presented here for the sake of brevity, but each
resembled a Gaussian distribution. Therefore, the priors for α,β,γ,ϕ,and ψ were assumed as Gaussian, with means and
standard deviations obtained from the Monte Carlo simulation. These priors, which were truncated at the 2.5% and
97.5% quantiles, are presented in Table 6. The arterial blood temperature, as well as the temperature of the
organs/tissues surrounding the kidney, was assumed as truncated Gaussian, with mean of 309.4 K, standard deviation
of 0.05 K and limited to the interval between 307 and 313 K.
A noninformative prior was used for the parameters that represent the metabolic heat generation rate,
P2 ¼ ½Qm0 ; Qm1 ; …; QmI ; in the form of a Gaussian Markov Random field.12 The hyperparameter (φ) of this prior was
T

modeled by a Rayleigh distribution, so that the posterior distribution can be written as


1
π ðP1 ; P2 ; φjYÞ ∝ φðIþ3Þ=2 exp − ½Y−TðPÞT W−1 ½Y − TðPÞ −
2

) (19)
1 T −1 1 2 1 φ 2
− ½P1 −μ 1  V1 ½P1 − μ 1  − φkDP2 k − ;
2 2 2 φ0

where, as described above, the likelihood was assumed Gaussian (see Equation 7). Similarly, the prior for
PT1 ¼ ½α; β; γ; ϕ; ψ; T a ; T s  was prescribed as truncated Gaussian with mean μ1 and covariance matrix V1, as discussed
in this section. In Equation (19), the matrix D is given by
2 3
−1 1
6 7
6 −1 7
6 1 7
D¼6 7 with size I x ðI þ 1Þ: (20)
6 : : 7
4 5
−1
1

4.3 | Inverse problem solution

The following proposal distributions were applied for the estimation of PT1 ¼ ½α; β; γ; ϕ; ψ; T a ; T s  and
PT2 ¼ ½Qm0 ; Qm1 ; …; QmI , respectively, by using the Metropolis‐Hastings algorithm with sampling by block of parameters:
 


 1 * T −1  * 
q1 P*1 jP1ðtÞ ¼ π prior P*1 ∝ exp − P1 −μ 1 V1 P1 − μ 1 ; (21a)
2

2 

 0:1
q2 P*2 jP2ðtÞ ¼ N P2ðtÞ I ; (21b)
2N

where N(a|B) is a Gaussian distribution with mean a and covariance matrix B.

ORLANDE ET AL. 11 of 19

TABLE 6 Truncated Gaussian priors for α,β,γ,ϕ,and ψ

Parameter Mean Standard Deviation Minimum Maximum

α , s−1 6.2986 × 10−5 1.6343 × 10−6 0.5991 × 10−4 0.6618 × 10−4

β, s−1 0.0559 0.0015 0.0531 0.0589
γ , s−1 0.0559 0.0015 0.0530 0.0588
−1 −5
ϕ,KJ 0.001768 3.6783 × 10 0.0017 0.0018
−1 −5
ψ, s 0.0014 3.5635 × 10 0.0013 0.0015

The candidates P*1 were generated from the prior for P1 due to the strong linear dependence of the parameters in this
vector. It was also taken into account in P*1 that the urine flow rate is approximately 1% of the arterial blood flow rate.10
Hence, the candidate γ* was obtained as a function of the candidate β* as

γ * ¼ 0:999β* ð1 þ wÞ; (22)

where w is a random number with Gaussian distribution, zero mean, and standard deviation of 10−5. The reader is
referred to Cui23 regarding the proposal for P2.
For all cases examined here, the initial kidney temperature was taken as the steady state temperature with the met-
abolic heat generation rate at t = 0. Eight different functions were used to generate the simulated measurements, includ-
ing those with discontinuities, discontinuities in the first derivative and smooth continuous, with variations between 2
and 10 W, for Qm(t). These functions are summarized in Table 7, where t f = 150 seconds.
Table 8 summarizes the cases examined in this work, which involve the different functions presented in Table 7 and
different numbers of states in the Markov chains. For all cases, 10 multiple chains were used for Gelman and Rubin's
analysis.26 The number of states in each multiple chain was taken as the number of states in the initial chain, divided by
10. Based on visual inspections of the posterior distributions, the number of burn in states of the initial chains was set to
105. By following Gelman and Rubin,26 the burn in period of the multiple chains was taken as half of their number of
states. For PT2 ¼ ½Qm0 ; Qm1 ; …; QmI , the initial Markov chains were started at 6 W, while the multiple chains were started
at samples taken from the initial chains. The vector PT1 ¼ ½α; β; γ; ϕ; ψ; T a ; T s  was sampled from its prior distribution, as
given in Equation (21a). For convergence analyses, the numbers of states in the chains were varied in cases 1 to 3 for
function 1, as well as in cases 4 and 5 for function 2. Based on such convergence analyses, the number of states was fixed
as 7 × 105 in the initial chains, and 7 × 104 in each multiple chain, for the other cases examined in this work. Case 9 is a

TABLE 7 Exact functions for Qm(t)

Function 1 Function 2
( 8
10 ; t ≤ t f =2 < 10 ; t ≤ tf =4
>
Qm ðt Þ ¼
2 ; t > tf =2 Qm ðtÞ ¼ 2 ; tf =4 < t ≤ tf =2
>
:
10 ; t > tf =2
Function 3 Function 4
8 8
< 10 ;
t ≤ tf =4
> > 10 ; t ≤ tf =4
 < "
#
Qm ðt Þ ¼ t − t f =4 ; t > tf =4 Q m ðt Þ ¼ t − tf =4
>
: 10 − 8
 >
: 10 − 8 sin π
 ; t > tf =4
3tf =4 3tf =4

Function 5 Function 6
8 (
>
< 2 ; t ≤ tf =4 2 ; t ≤ tf =4
Q m ðt Þ ¼
Qm ðt Þ ¼ 10 ; t f =4 < t ≤ tf =2 10 ; t > t f =4
>
:
2 ; t > tf =2
Function 7 Function 8

 8
t > 2 ; t ≤ t f =4
Qm ðt Þ ¼ 6 − 4 sin 2π < "
#
tf Q m ðt Þ ¼ t − tf =4
>
: 2 þ 8 sin π
 ; t > t f =4
3t f =4
12 of 19 ORLANDE ET AL.

TABLE 8 Cases examined

Initial Chain Multiple Chains

Case Function Number of States IACT CPU Time, s Number of States CPU Time, s

1 1 5 × 105 2545 7.3 × 103 5 × 104 7.4 × 103

2 1 7 × 105 2625 1 × 104 7 × 104 9 × 103
3 1 106 2780 1.5 × 104 105 1.5 × 104
5 3 4
4 2 5 × 10 2614 7.7 × 10 5 × 10 5 × 103
5 2 7 × 105 2711 1 × 104 7 × 104 6.8 × 103
6 3 7 × 105 1797 1 × 104 7 × 104 1.1 × 104
7 4 7 × 105 1978 1.1 × 104 7 × 104 9.8 × 103
8 5 7 × 105 1977 1.1 × 104 7 × 104 1.1 × 104
9 5 7 × 105 2063 1.1 × 104 7 × 104 1.1 × 104
10 6 7 × 105 2720 1 × 104 7 × 104 4.8 × 103
11 7 7 × 105 1927 1.1 × 104 7 × 104 1.1 × 104
5 4 4
12 8 7 × 10 2075 1.1 × 10 7 × 10 9.8 × 103

Abbreviation: IACT, integrated autocorrelation time.

repetition of case 8, but with the simulated measurements generated from the same analytic solution that was used in
the inverse problem. Hence, an inverse crime12 was committed in case 9.
Computational times presented in Table 8 refer to a Matlab code, running on a computer with an Intel(R) Core (TM)
i7‐5500U—2.4 GHz processor, with 8 GB of RAM memory and Windows 10 Pro—64 bits. In general, the computational
times of the initial chains are the same as those of the multiple chains, since the total numbers of states are the same for
both techniques. However, there are cases where the computational times of the multiple chains are smaller than those
of the initial chains, because some multiple chains exhibited very few accepted states in the Metropolis‐Hastings algo-
rithm used in this work. Computational times of the initial chains with 5 × 105, 7 × 105, and 106 states were around 2,
2.8, and 4.2 hours, respectively.
The IACTs (see Equation 12a), calculated for the posterior distributions, are also presented in Table 8. These tables
show that the numbers of correlated samples between independent samples ranged from 1800 to 2800, which represents
low statistical efficiency, caused by the strong linear dependence among the parameters PT1 ¼ ½α; β; γ; ϕ; ψ; T a ; T s .
The convergence of the Markov chains to equilibrium posterior distributions for PT2 ¼ ½Qm0 ; Qm1 ; …; QmI  was
assessed for function 1 (cases 1 to 3) and for function 2 (cases 4 and 5) by using the techniques proposed by Geweke25
a b
and by Gelman and Rubin.26 A comparison of the means at the begin and at the end of the initial chains, Pj and Pj ,
given in Equations (13ab), is presented in Figure 3A to C, for cases 1, 2, and 3, respectively. Figures 4A to C and 5A
to C present the multiple chains for Qm(t) at t = 60 seconds and the scale reduction coefficient given in Equation (17),
respectively, for these same cases. Figure 3A to C shows that, for cases 1 to 3, the step variation of function 1 was cor-
rectly identified. These figures also show that there is an excellent agreement between the mean values calculated with
samples in different ranges of the Markov chains, corresponding to the first 10% and last 50% of states (see Equa-
tions 13ce). The convergence of the multiple chains for Qm(t) at t = 60 seconds can be verified by the analysis of
Figure 4A to C. Multiple chains for other times behave similarly to those presented by these figures and are not pre-
sented here. The convergence of the multiple chains results in scale reduction coefficients close to 1, except for the
region with small values of Qm(t), particularly, near the final time (see Figure 5A‐C). As can be noticed in Figures 3A
to C and 5A to C, the convergence of the initial chain and of the multiple chains is better for large values of Qm(t),
because the correspondent sensitivity coefficients are larger. Lack of convergence near the final time is attributed to
the physics of the problem, since the effects of heat generation rates in this region affect the temperatures at later times,
when measurements are not available for the inverse analysis. On the other hand, even at the final time, the scale
reduction coefficient is smaller for larger number of states in the Markov chains, decreasing from around 4.4 in case
1 to less than 1.7 in case 3, with 50 000 and 100 000 states in each multiple chain, respectively. However, such as for
the convergence analysis of the initial chain (see Figure 3A‐C), a comparison of Figure 5B and 5C reveals that the
ORLANDE ET AL. 13 of 19

FIGURE 3 Comparison of the means in the initial Markov chains: A, case 1; B, case 2; C, case 3

FIGURE 4 Multiple chains for Qm(t) at t = 60 s: A, case 1; B, case 2; C, case 3

behavior of the scale reduction coefficient is not very different for case 2 (70 000 states in each multiple chain) and case
3 (100 000 states in each multiple chain). We note that the same behavior was observed with the convergence analyses
of cases 4 and 5 for function 2, which are not presented here for the sake of brevity. Therefore, for the results presented
below, 7 × 105 states were used for the initial chains, while 7 × 104 states were used for each of the 10 multiple chains.
The results obtained with the initial chain for case 2 (function 1) are presented in Figure 6. This figure compares the
exact function with the means and the 0.5% and 99.5% quantiles of the samples of the Markov chains. The estimated
heat generation rate is stable and very accurately recuperates the function discontinuity, thus demonstrating that the
noninformative Gaussian Markov Random Field prior, with the Rayleigh hyperprior for the parameter φ, is appropriate
for the inverse problem under analysis in this work. The estimated means are larger than the exact function values.
However, the estimated 99% credibility intervals enclose the exact function values. Such facts can also be observed with
the Markov chains and the histograms of the samples (with the burn in period discarded) of the solution at times
t = 60 seconds and t = 90 seconds, which are presented in Figures 7A,B and 8A,B, respectively. As expected, the Markov
chain for the solution at t = 90 seconds is more correlated than that for t = 60 seconds, due to the smaller sensitivity
coefficients for smaller values of the heat generation rate (see Figure 7A,B). The histograms of the marginal posterior
distributions for the estimated heat source terms resemble Gaussian distributions.
The states of the initial Markov chains of PT1 ¼ ½α; β; γ; ϕ; ψ; T a ; T s  for case 2 are shown in Figure 9A to G, respec-
tively. These figures reveal a very small number of accepted states for these parameters, as a result of their strong linear
dependence. Besides that, as discussed above, some parameters exhibit sensitivity coefficients of very large magnitude,
14 of 19 ORLANDE ET AL.

FIGURE 5 Scale reduction coefficient given in Equation (17): A, case 1; B, case 2; C, case 3

FIGURE 6 Estimation of the metabolic heat generation rate: Case 2, function 1

FIGURE 7 Markov chains for the metabolic heat generation rate, case 2: A, t = 60 s; B, t = 90 s

FIGURE 8 Histograms of the converged states of the Markov chains for the metabolic heat generation rate, case 2: A, t = 60 s; B, t = 90 s

which required that candidates for P1 be sampled from their priors. Hence, uncertainties in P1 were fully accounted for
in the estimation of PT2 ¼ ½Qm0 ; Qm1 ; …; QmI  that represent the transient metabolic heat generation rate, which is the
quantity of interest in this work. In special, a high correlation between the estimated artery blood temperature, Ta,
and P2 was observed. Whenever the chain for Ta tended to a value smaller than that used to generate the simulated
measurements, a heat generation rate larger than the exact one was estimated, in order to maintain the measured urine
ORLANDE ET AL. 15 of 19

FIGURE 9 Markov chains for [α, β, γ, ϕ, ψ, Ta, Ts ] in case 2

FIGURE 10 Number of accepted states in case 2

FIGURE 11 Variation of the posterior distribution in case 2

16 of 19 ORLANDE ET AL.

FIGURE 12 Estimated, exact, and measured urine temperatures in case 2

FIGURE 13 Means and 99% confidence intervals obtained with the multiple chains in case 2

FIGURE 14 Estimation of the metabolic heat generation rate with the initial chain for A, case 5; B, case 6; C, case 7; D, case 8; E, case 9; F,
case 10; G, case 11; H, case 12
ORLANDE ET AL. 17 of 19

temperature. The reverse trend was observed when the estimated Ta was larger than its exact value. Despite these
behaviors, the acceptance ratio of the Metropolis‐Hastings algorithm used in this work was around 30% and practically
constant throughout the initial Markov chain, as presented in Figure 10 for case 2.
The variation of the posterior distribution in the initial Markov chain, given by − ln [π(P1, P2, φ| Y)], is presented in
Figure 11 for case 2. Such quantity was reduced as the number of states advanced and tended to a small constant value.
In fact, the agreement between the estimated and exact urine temperatures was excellent, as demonstrated in Figure 12.
This figure shows the means and 99% credibility intervals of the urine temperature obtained with each sample of the
converged Markov chains, which demonstrated small variances and an excellent agreement with the exact temperatures
and the simulated measurements. Figure 11 also shows that the number of burn in states (105) selected was appropriate
to represent the posterior (see also Figure 7A,B).
The results presented in Figures 6–12 for case 2 were obtained with the initial Markov chain. The means of all mul-
tiple chains, as well as the 99% confidence interval calculated with the variance given in Equation (16), are shown in
Figure 13 for case 2. Similar to the results obtained with the initial chain, the means of the multiple chains
overestimated the exact function due to the underestimation of the artery blood temperature, Ta. However, the exact
function was within the estimated 99% confidence interval.
The results obtained with the initial chains and with the multiple chains, analogous to those shown in Figures 6 and
13 for case 2, are summarized in Figures 14 and 15, respectively, for the remaining cases examined in this work (see also
Tables 7 and 8). Such as for case 2, Figures 14 and 15 show that accurate estimates can be obtained for metabolic heat
generation rates that follow continuous or discontinuous functions, either increasing or decreasing. These figures also
show that the results obtained with the initial and with the multiple chains were consistent, and that the exact

FIGURE 15 Estimation of the metabolic heat generation rate with the multiple chains for A, case 5; B, case 6; C, case 7; D, case 8; E, case
9; F, case 10; G, case 11; H, case 12
18 of 19 ORLANDE ET AL.

functional forms were very well recovered. Except for cases 8 and 9, the exact functions were within the 99% confidence
level intervals. This behavior for cases 8 and 9 is probably due to the large period where the function attains small values
and correspond to the small sensitivities. Such as for case 2, estimated means are either larger or smaller than the exact
values, depending on the estimated artery blood temperature. Convergence analyses and acceptance ratios, based on
both the initial and the multiple chains, were similar to those presented above for case 2.

5 | CONCLUSIONS

The objective of this work was the estimation of the metabolic heat generation rate in the kidney by using temper-
ature measurements of the outflow urine. A mathematical model was proposed, with the hypotheses that the kidney
is a homogeneous medium and that urine and venous blood are in thermal equilibrium with the kidney. The inverse
problem was solved with the MCMC method, implemented with a modified version of the Metropolis‐Hastings algo-
rithm that samples the parameters by blocks. The use of this algorithm was required due to the strong linear depen-
dence of the model parameters and because the sensitivity coefficients of some parameters were much larger than
those relative to the metabolic heat generation rate. A Monte Carlo simulation was applied to prescribe the priors
for the constant model parameters. On the other hand, the prior for the metabolic heat generation rate was taken
in the form of a noninformative Gaussian Markov Random Field, with a hyperparameter modeled by a Rayleigh dis-
tribution. The convergence of the Markov chains was analyzed with the comparison of the means calculated with
different ranges of states, as well as with multiple chains. The solution of the inverse problem was examined with
simulated measurements for 12 cases, obtained with eight different functional forms for the metabolic heat genera-
tion rate.
The Metropolis‐Hastings algorithm with sampling by blocks of parameters resulted in accurate and stable solutions
for the kidney metabolic heat generation rate. Values of the exact function could be found within the 99% confidence
intervals of the initial or of the multiple chains, except for a functional form that involved a sudden increase of the heat
generation rate. Even for this case, the functional form that was recovered with the inverse analysis followed the exact
function closely, even though the variance of the prior for the metabolic heat generation rate was unbound. We hope
that the procedure advanced in this work can be used in the future for a more accurate quantification of the kidney's
role in the body thermoregulation. Moreover, this procedure might be applicable for monitoring renal functions of
patients in intensive care units.

ACK NO WLE DGE MEN TS

The authors are thankful for the support provided by CNPq, CAPES (Finance Code 001), and FAPERJ, Brazilian agen-
cies for the fostering of science.

CONFLICT OF INTEREST
There are no relationships of all authors with any people or organizations that could inappropriately influence (bias)
this work.

ORCID
Helcio R.B. Orlande https://orcid.org/0000-0002-3511-322X
Nelson Afonso Lutaif https://orcid.org/0000-0002-1784-0087
José Antonio Rocha Gontijo https://orcid.org/0000-0002-4658-385X

R EF E RE N C E S
1. Ricquier D. Fundamental mechanisms of thermogenesis. C R Biol. 2006;329(8):578‐586.

2. Bicego KC, Barros RC, Branco LG. Physiology of temperature regulation: comparative aspects. Comp Biochem Physiol A Mol Integr Phys-
iol. 2007;147(3):616‐639.

3. Clapham JC. Central control of thermogenesis. Neuropharmacology. 2012;63:11‐123.

ORLANDE ET AL. 19 of 19

4. Brundin T, Wahren J. Renal oxygen consumption, thermogenesis, and amino acid utilization during iv infusion of amino acids in man.
Am J Physiol Endocrinol Metab. 1994;267(5):E648‐E655.
5. Lutaif N, Rocha EM, Veloso LA, Bento LM, Gontijo JAR. Renal contribution to thermolability in rats: the role of renal nerves. Nephrol
Dial Transplant. 2008;23(12):3798‐3805.
6. Jani A, Martin S, Jain S, Keys D, Edelstein C. Renal adaptation during hibernation. Am J Physiol Renal Physiol. 2013;305(11):F1521‐F1532.
7. Dugbartey G, Hardenberg M, Kok W, et al. Renal mitochondrial response to low temperature in non‐hibernating and hibernating species.
Antioxid Redox Signal. 2017;27(9):599‐617.
8. Lee W, Kim W, Lim Y, Hong Y. High temperatures and kidney disease morbidity: a systematic review and meta‐analysis. J Prev Med Pub-
lic Health. 2019;52(1):1‐13.
9. Johnson HA, Knudsen KD. Renal efficiency and information theory. Nature. 1965;206(4987):930‐931.
10. Guyton AC, Hall JE. Textbook of medical physiology. Philadelphia. PA: WB Saunders Company; 2006.
11. Fallis WM. Monitoring urinary bladder temperature in the intensive care unit: state of the science. Am J Crit Care. 2002;11(1):38‐47.
12. Kaipio J, Somersalo E. Statistical and Computational Inverse Problems. Applied Mathematical Sciences. 160 Springer‐Verlag; 2004.
13. Kaipio J, Fox C. The Bayesian framework for inverse problems in heat transfer. Heat Transfer Eng. 2011;32(9):718‐753.
14. Calvetti D, Somersalo E. Introduction to Bayesian Scientific Computing. New York: Springer; 2007.
15. Orlande H, Fudym F, Maillet D, Cotta R. Thermal Measurements and Inverse Techniques. Boca Raton: CRC Press; 2011.
16. Orlande HRB. Inverse problems in heat transfer: new trends on solution methodologies and applications. J Heat Transfer.
2012;134(3):031011.
17. Tan S, Fox C, Nicholls G. Inverse Problems, Course Notes for Physics 707, University of Auckland; 2006.
18. Gamerman D, Lopes HFM. Chain Monte Carlo: Stochastic Simulation for Bayesian Inference. 2nd ed. Boca Raton: Chapman & Hall/CRC;
2006.
19. Brooks S, Gelman A, Jones G, Meng X. Handbook of Markov Chain Monte Carlo. Boca Raton: CRC Press; 2011.
20. Gobet E. Monte‐Carlo Methods and Stochastic Processes. Boca Raton: CRC Press; 2016.
21. Metropolis N, Rosenbluth A, Rosenbluth M, Teller A, Teller E. Equation of state calculation by fast computing machines. J Chem Phys.
1953;21(6):1087‐1092.
22. Hastings WK. Monte Carlo sampling methods using Markov chains and their applications. Biometrika. 1970;57(1):97‐109.
23. Cui T. Bayesian calibration of geothermal reservoir models via Markov chain Monte Carlo, Ph.D. Thesis, The University of Auckland;
2010.
24. Geyer C. In: Brooks S, Gelman A, Jones G, Meng X, eds. Introduction to Markov Chain Monte Carlo, Chapter 1 in. Boca Raton: Handbook
of Markov Chain Monte Carlo, CRC Press; 2011.
25. Geweke J. Evaluating the Accuracy of Sampling‐Based Approaches to the Calculation of Posterior Moments. Minneapolis, MN: Federal
Reserve Bank of Minneapolis, Research Department; 1991 Apr 15.
26. Gelman A, Rubin D. Inference from iterative simulation using multiple sequences. Stat Sci. 1992;7(4):457‐472.
27. Gelman A, Shirley K. In: Brooks S, Gelman A, Jones G, Meng X, eds. Inference from Simulations and Monitoring Convergence, Chapter 6
in. Boca Raton: Handbook of Markov Chain Monte Carlo, CRC Press; 2011.
28. https://www.itis.ethz.ch/virtual‐population/tissue‐properties/database/
29. Beck JV, Arnold KJ. Parameter Estimation in Engineering and Science. New York: Wiley Interscience; 1977.
30. Ozisik MN, Orlande HRB. Inverse Heat Transfer: Fundamentals and Applications. New York: Taylor and Francis; 2000.
31. Woodbury K. Inverse Engineering Handbook. Boca Raton: CRC Press; 2002.

How to cite this article: Orlande HRB, Lutaif NA, Gontijo JAR. Estimation of the kidney metabolic heat
generation rate. Int J Numer Meth Biomed Engng. 2019;35:e3224. https://doi.org/10.1002/cnm.3224