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FULL REVIEW
Nephrol Dial Transplant (2016) 31: 730–736
doi: 10.1093/ndt/gfv098
Advance Access publication 2 May 2015
Metabolic acidosis in renal transplantation: neglected
but of potential clinical relevance
Pier Giorgio Messa, Carlo Alfieri and Simone Vettoretti
Unit of Nephrology-Dialysis, Urology and Renal Transplantation, IRCCS Fondazione Ca’ Granda-Ospedale Maggiore-Policlinico, Milano, Italy
Correspondence and offprint requests to: Pier Giorgio Messa; E-mail: piergiorgio.messa@policlinico.mi.it
A B S T R AC T
Chronic metabolic acidosis (CMA) is a common complication
of the more advanced stages of chronic kidney diseases (CKD),
and is associated with morbidity and mortality of CKD patients
and possibly with the progression of renal disease. Nevertheless,
there is limited evidence or information on the prevalence, the
potential causal factors, the clinical impact and the effects of
© The Author 2015. Published by Oxford University Press
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inflammation. Nat Med 2012; 18: 1182–1183
40. Stefan N, Häring HU. Circulating fetuin-A and free fatty acids interact to
predict insulin resistance in humans. Nat Med 2013; 19: 394–395
41. Schafer C, Heiss A, Schwarz A et al. The serum protein alpha
2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibi-
tor of ectopic calcification. J Clin Invest 2003; 112: 357–366
42. Li M, Xu M, Bi Y et al. Association between higher serum fetuin-A concen-
trations and abnormal albuminuria in middle-aged and elderly Chinese
with normal glucose tolerance. Diabetes Care 2010; 33: 2462–2464
43. Siegel-Axel DI, Ullrich S, Stefan N et al. Fetuin-A influences vascular cell
growth and production of proinflammatory and angiogenic proteins by
human perivascular fat cells. Diabetologia. Epub ahead of print 4 February
2014
44. Yudkin JS, Eringa E, Stehouwer CD. ‘Vasocrine’ signalling from perivascu-
lar fat: a mechanism linking insulin resistance to vascular disease. Lancet
2005; 365: 1817–1820
45. Rittig K, Staib K, Machann J et al. Perivascular fatty tissue at the brachial
artery is linked to insulin resistance but not to local endothelial dysfunction.
Diabetologia 2008; 51: 2093–2099
46. Wagner R, Machann J, Lehmann R et al. Exercise-induced albuminuria is
associated with perivascular renal sinus fat in individuals at increased risk of
type 2 diabetes. Diabetologia 2012; 55: 2054–2058
47. Foster MC, Hwang SJ, Porter SA et al. Fatty kidney, hypertension, and
chronic kidney disease: the Framingham Heart Study. Hypertension
2011; 58: 784–790
48. Rittig K, Dolderer JH, Balletshofer B et al. The secretion pattern of perivas-
cular fat cells is different from that of subcutaneous and visceral fat cells.
Diabetologia 2012; 55: 1514–1525
Received for publication: 3.12.2013; Accepted in revised form: 13.3.2014
correction of CMA in kidney transplant recipients. In this re-
view, we briefly look at the more relevant, though scanty, studies
which have, over time, addressed the above-mentioned points,
with the hope that in the future the interest of transplant ne-
phrologists and surgeons will grow towards this unreasonably
neglected issue.
Keywords: allograft dysfunction, metabolic acidosis, renal
transplantation
730
 INTRODUCTION
Chronic metabolic acidosis (CMA), defined as low serum bi-
carbonate and pH levels, in association with a proportional
decrease in serum partial pressure of carbonic dioxide
(PaCO2), is usually observed in the more advanced stages of
chronic kidney disease (CKD). In fact, excluding the rare
forms of genetic CMA, CMA only occasionally occurs in
CKD patients up until when glomerular filtration rate
(GFR) falls under 30 mL/min, whereupon its prevalence in-
creases approaching 20%, 10-fold higher when compared
with patients with normal GFR [1, 2]. Experimental and clin-
ical studies suggest that CMA could contribute to increased
morbidity and mortality of CKD patients and to progression
of renal disease [3, 4].
Although the first report on CMA in kidney transplant
(KTx) patients dates from the very beginning of renal trans-
plantation history [5] and notwithstanding widespread aware-
ness of the importance of checking for CMA in CKD patients,
the routine assessment for this metabolic complication is also
not diffuse in renal transplant recipients. This is indirectly in-
ferred by the absence of any major reference to this issue in the
last version of the Kidney Disease: Improving Global Outcomes
guidelines for the care of KTx recipients [6]. There is no ration-
ale for neglecting this basic metabolic disorder, but for medical
attention being more focused on the immunologic, cardiovas-
P R E VA L E N C E A N D C H A R AC T E R I S T I C S
OF CMA IN KTx RECIPIENTS
It is not easy to define the real prevalence of CMA in KTx
patients, because only a few papers have clearly reported on
this figure, and when it occurs, it often refers to relatively
small groups of patients. Table 1 summarizes the results of
the main studies reporting on the prevalence of CMA in KTx
cohorts [7–17]. Overall, the reported prevalence ranges from
11 up to over 50%.
The considerable variability in the prevalence of CMA
among the quoted studies can be ascribed to the variability
in the transplant eras; the difference in serum bicarbonate
threshold for diagnosing metabolic acidosis; the differing
times from transplantation when it was assessed; difference in
the graft function, etc. However, considering that most of these
studies included KTx patients with GFR values over 40 mL/
min, this figure is consistently higher than that reported for
other non-KTx CKD cohorts with comparable degrees of
renal function. To add some personal information, Figure 1
shows the prevalence of CMA at the first and the 12th month
after KTx in a group of patients who received a renal graft in our
centre in the past 3 years. We observed a fall in the CMA preva-
lence from 27 to 16%, though the percentage of patients treated
with bicarbonate supplementation remained substantially
unchanged (15 versus 16%). However, given that less than

cular, infectious and other relevant clinical complications in the
transplant set. However, given the potential consequences of
CMA on both patient and graft outcome and knowing that
checking for and correcting it are easy and cheap tasks, it
would be worth remembering some simple concepts on this
issue.
FULL REVIEW
10% of these patients had GFR values under 30 mL/min, both
figures clearly remain well above what is usually found in
non-KTx CKD patients. In agreement with published results,
also in our patients, those with CMA had lower GFR levels
than those without at both the first (55.9 ± 18.9 versus 46.4 ±
20.8 mL/min, P = 0.03) and the 12th month (58.7 ± 21.9 versus

Table 1. Prevalence of CMA in KTx cohorts

Authors N CD % Recipient age Transplant age Graft function (eGFR) CMA diagnosis Prevalence of CMA %
Wilson et al. [7] 32 100 R R M ± SD s-Bic <22 mmol/L 25
17–49 years 3 months–3 years 59.7 ± 17.3 mL/min
Heaf et al. [8] 125 nr M (R) M (R) M ± SD s-Bic <21 mmol/L 12
48.9 (15–75) years 5.7 (2.3–10.3) years 50.7 ± 22.9 mL/min
Dagan et al. [9] 46 74 M ± SD nr M ± SD s-Bic <22 mmol/L 41
15.7 ± 4.6 years 61.0 ± 22.6 mL/min
Schwarz et al. [10] 576 90 M 54.1 years M 8.4 years >40 mL/min s-Bic <22 mmol/L 13.1
SD nr SD nr
Keven et al. [11] 109 19 M ± SD M ± SD >40 mL/min s-Bic <22 mmol/L 33
38 ± 11 years 6.2 ± 4.8 years
Yakupoglu et al. [12] 823 nr M ± SD M ± SD M ± SD s-Bic <24 mmol/L 58.1
43.7 ± 13 years 7.5 ± 6 years 52.7 ± 16 mL/min
Sinha et al. [13] 129 52 M (R) M (R) M (R) s-Bic <22 mmol/L 30
13.9 (2.7–20) years 3.8 (1–14.7) years 51 (18–95) mL/min
Kocyigit et al. [14] 66 38 M ± SD M (R) M ± SD s-Bic <22 mmol/L 21.2
37 ± 10.4 years 1.9 (0.1–23) years 66 ± 28 mL/min
Abdulraof Menesi et al. [15] 83 nr M ± SD M (R) M ± SD s-Bic <23 mmol/L 45
51 ± 12 years 5 (0.5–24) years 55 ± 21 mL/min
Malik et al. [16] 100 0 M ± SD M ± SD >40 mL/min s-Bic <22 mmol/L 40
34.6 ± 9.0 years 5.1 ± 4.0 years
Van den Berg et al. [17] 707 nr M 53.3 years M (R) M 52.7 mL/min SD nr s-Bic <24 mmol/L 31
SD nr 5.9 (1.3–15.2) years
KTx, kidney transplant; CD, cadaveric donor; CMA, chronic metabolic acidosis; s-Bic, serum bicarbonate; M ± SD, mean ± standard deviation; R, range; M (R), mean (range); nr, not
reported.

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 F I G U R E 1 : Frequency distribution of bicarbonate levels in 138 KTx patients, evaluated 1 month (A) and 12 months (B) after transplantation.
Acidosis was defined as serum bicarbonate levels lower than 22 mmol/L (dashed line). The percentage of acidotic patients decreased from 27 to
16% from the first to the second assessment (data on file of IRCCS-Fondazione Ca’ Granda-Ospedale Maggiore Policlinico Milano-Italy).
47.1 ± 15.1 mL/min, P = 0.03), and CMA was three times
more frequent in CDR than in LDR (15.7 versus 4.8%;
P < 0.003).
CKD-associated CMA is generally characterized by normal
or reduced levels of serum chloride (s-Cl) and a normal or in-
creased serum anion gap (s-AG). At variance, the form usual-
ly found in KTx patients resembles the typical renal tubular
FULL REVIEW
acidosis (RTA), with normal s-AG and normal or high s-Cl
levels. So, from this point on, we indifferently use the term
of RTA or CMA to indicate the form of KTx metabolic
acidosis.
Although the first reported patient with post-KTx CMA was
characterized by a complex tubular dysfunction (mixed prox-
imal and distal RTA, associated with Fanconi syndrome) [5],
later reports defined that distal RTA is by far the most repre-
sented form, with the exclusion of the very early post-KTx per-
iod (6 months) when the proximal form of RTA can also be
observed [7, 10, 14, 18–22]. From the data of the most wide
and precisely carried-available study [10], 76 of the 576 KTx
recipients had CMA. All these patients had a distal RTA, with
all the different forms being represented (classical dRTA Type
Ia: 18; hyperkalemic dRTA type Ib: 11; rate-limited dRTA: 16;
dRTA type IV: 21). Table 2 describes the different types of renal
metabolic acidosis, according to a simplified diagnostic proto-
col [modified from 10, 23].
Dealing with the degree of acidosis in KTx patients, the
available data are again very scanty. From the only two studies
where the data were available [7, 12], it can be seen that a more
severe form of metabolic acidosis (sodium bicarbonate <20
mmol/L) was present in 12.5 and 28% of patients. From our
data, such a degree of acidosis was found in 7.5 and 3% of
patients at the first and 12th month, respectively.
In summary, the occurrence of RTA in KTx patients is a
common event particularly in younger recipients, with the
prevalence being consistently higher than that expected by
the degree of graft function. This form of RTA has the
main characteristics of the distal form, of mild-to-moderate
degree.
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M A I N C A U S A L F AC T O R S A N D P AT H O G E N I C
M E C H A N I S M S O F R TA I N K T x P AT I E N T S
The findings related to the RTA prevalence suggest that, in add-
ition to the common pathogenic factors acting in any form of pro-
gressive CKD when the renal function falls under 30 mL/min,
other mechanisms may be triggered in the renal transplant set.
It is beyond the aim of this paper to address the cellular path-
ways involved in the control of acid–base balance by the kidney,
so we would limit ourselves to briefly comment on the main
mechanisms by which the most relevant causal factors act.
Generally speaking, the pathogenic mechanisms can be
divided into those common to any other CKD form and
those more specific of or at least most commonly occurring
in KTx patients.
Although most of these mechanisms share many aspects, we
will deal with these topics separately.
CMA pathogenic mechanisms common
to the CKD condition
It has long been acknowledged that CMA of CKD is second-
ary to the reduction in the capacity of the diseased kidneys to
eliminate the hydrogen ion load derived by both dietary and en-
dogenous sources and to generate bases [24–26]. Recent experi-
mental observations suggest that the metabolic pathways
involved in the pathogenesis of CMA of CKD consist of a
reduced activity of both enzymes and carrier proteins respon-
sible for glutamine reabsorption, synthesis and secretion of
ammonia, and bicarbonate transport [27]. On the other
hand, relevant acid–base changes are observed only when
GFR falls less than 20% of the normal values, owing to the com-
pensatory mechanisms put in act by the residual functioning
nephrons which can increase up to over 3-fold their capacity
of producing ammonia and eliminating net acidity [28].
As previously discussed, in KTx patients, CMA is observed
when the graft function is well over the above-mentioned GFR
threshold. To explain this discrepancy, it has been suggested
P.G. Messa et al.
 Table 2. Diagnostic criteria for the diagnosis of the different types of renal metabolic acidosis more frequently occurring in KTx patients [ modified from
10, 23]
Normal sAG/hyperchloremic acidosis
pRTA dRTA
type 2 Classical Rate-limited Voltage-dependent
type 1a type 1b
s-K =/↓ =/↓ =/↑ ↑ =/↓
u-pH <5.5 >5.5 <5.5 >5.5
u-AG neg pos pos pos
FE-Bic % >10 <5 <5 <5
sAG, serum anion gap = (Na + Cl − HCO3); pRTA, proximal renal tubular acidosis; dRTA, distal renal tubular acidosis; s-K, serum potassium; u-pH, urinary pH; u-AG, urinary anion
gap = (Na + K − Cl); Fe-Bic, fractional excretion of bicarbonate.
that, at variance with the other CKD forms, the condition of a
single kidney, as is the case of the renal graft, could be respon-
sible for a higher blood flow rate in the single organ, and this
could impair the transtubular chemical and electrical gradients
and in turn renal acid excretion [29]. In support of the above-
mentioned hypothesis, four decades ago, Chan et al. [30]
demonstrated that kidney donors had a reduced renal net
acid excretion after an acute acid load compared with controls.
Taking into account that these data were produced a long time
ago and in a small group of subjects, it could be worth reasses-
sing this issue, possibly in a wider population of mono-
nephrectomized current subjects and patients.
The reasons for the discrepancy between the GFR threshold
at which CMA is observed in KTx patients and in the other
CKD patients could be more complex, also depending on
other potential causal factors specific to the KTx context.
CMA pathogenic mechanisms specific to KTx patients
As already mentioned, CMA of KTx patients has the char-
acteristics of the distal RTA. However, at variance with the her-
editary forms of RTA, characterized by a dysfunction of specific
transporter proteins or enzymes, owing to well-defined gene
mutations [31], transplant-associated RTA seems to result
from a mixture of different deficiencies, because no specific
enzymatic defect has been found [32]. This can be explained
by the multiplicity of the additional putative causal factors
which can often act in combination.
Characteristics of the donor. Although one could expect that
factors related to the quality of the donor [living donor (LD) versus
cadaveric donor (CD), standard versus expanded criteria donor,
etc.] and to the events involving the graft immediately before sur-
gery (inflammatory and ischaemic events, etc.) can play a role in
determining the occurrence of CMA after KTx, there is no defini-
tive proof of it, given the shortage of data on these issues.
Of the four papers mentioning the different occurrence of
RTA in LD versus CD recipients [9–11, 14], only one [11] re-
ported that in the group of patients with RTA the percentage of
CD recipients was significantly higher than in the group with-
out it. As previously reported, in our experience, the occurrence
of CMA was significantly higher in CD recipients.
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High sAG /normochloremic
acidosis
RTA associated with –lactic acidosis
hypoaldosteronism –ketoacidosis
–toxic acidosis
Mixed type 4
type 3
↑ =/↓/↑
>5.5 <5.5 <5.5
pos pos neg
5-15 <10 <5
In spite of what earlier papers suggested [7, 18, 19], we have
as yet no reliable information on the impact of the donor age,
donor renal function and cold ischaemia duration on the occur-
rence of post-KTx CMA.
However, the common finding that the incidence of CMA is
consistently higher in the period immediately following the
KTx indirectly suggests that, among other early acting factors,
also those associated with donor and/or peri-transplant opera-
tive conditions might play some role.
FULL REVIEW
Immunological factors. RTA can complicate several
immune-mediated diseases, such as lupus erythematosus, Sjög-
ren disease, hypergammaglobulinemic disorders and others
[33–36]. The pathogenesis has been traced back to either cell-
and/or antibody-mediated insults to the renal tubular and
interstitial structures, with a consequent impairment of enzym-
atic and transporter activities involved in the renal control of
acid–base balance. Consequently, it is not surprising if the
same immune-mediated mechanisms have been summoned
for the RTA occurring in the renal graft.
In fact, two old studies reported that early-occurring hyper-
chloremic metabolic acidosis is often associated with acute
rejection (AR), sometimes antedating it by 1–2 weeks, and
the late-occurring CMA is often associated with histological
findings of chronic allograft rejection [19, 21]. A more recent
paper reported on a patient who presented with a severe form
of RTA concurrently with the occurrence of a third AR episode,
which completely resolved after the AR was successfully treated
with steroids [37]. Interestingly, in this study, the search for the
expression of H+-ATPase pump and of Cl−/HCO− 3 anion
exchanger 1 (AE1) in the distal tubule was completely null, in
comparison with a control biopsy. This finding would indirectly
suggest that an immune-mediated process could have been
directed towards these two key factors for controlling acid
and base regulation at the renal tubular level. At variance
with these findings, a subsequent study showed that, although
the expression of H+-ATPase was significantly lower in post-
transplant than in pre-transplant renal biopsies, no difference
in the expression of this cellular pump was observed between
patients with or without RTA [32]. The information provided
by these studies is limited due to the fact that they are anecdotal
733
 reports or have been carried out in small cohorts of patients.
Two other studies, including a more consistent number of
patients, were not able to confirm a significant association
between AR and RTA occurrence [10, 11].
So, the issue of the plausible role of the immune-mediated
factors in the pathogenesis of RTA of KTx recipients needs
still to be fully demonstrated.
Immunosuppressive drugs. Calcineurin inhibitors (CNIs)
have been charged to be the most likely contributors to RTA oc-
currence in KTx recipients among all the immunosuppressive
drugs (ISDs), because no relevant study has reported on the in-
volvement of the other ISDs in causing RTA, except for some
cases of metabolic acidosis owing to diarrhoea-associated intes-
tinal bicarbonate loss secondary to mycophenolate toxicity.
Because CNIs have renal tubular toxic effects, it is obvious
that RTA could be the consequence of their nephrotoxic activ-
ity. However, it has been suggested that CNIs might induce
functional tubular damage (in the absence of evident histo-
logical changes) which are responsible for the occurrence of dis-
turbances of the electrolyte tubular transport, including RTA
[14, 38, 39]. This type of functional tubular toxicity is charac-
terized by different mechanisms for the two main CNIs in clin-
ical use, cyclosporin A (CSA) and tacrolimus (TAC). Watanabe
et al. [38] demonstrated that CSA induces RTA by blocking the
peptidyl prolyl cis–trans isomerase (PPIase) activity, through a
specific cyclophilin-dependent mechanism, but not involving
FULL REVIEW
calcineurin inhibition. Mohebbi et al. [39] demonstrated that
TAC can affect several major transport proteins involved in
the renal control of acid–base balance, such as H+-ATPase
transport protein and AE1.
Whichever the causal mechanisms are, most data indicate
that the RTA-inducing effects of CNI are dependent on the
drug dose, because a reduction of the dosage has been reported
to be often associated with a recovery of the RTA [14, 40]. Fur-
thermore, there is some evidence that RTA is more frequent in
patients on TAC than on CSA treatment [10, 11, 41].
It is also worth remembering that RTA associated with CNI
is often characterized by high potassium levels (type 1b or rate-
limited RTA). This can be useful to take into account not only
for a correct diagnosis, but also for a proper correction of this
metabolic disturbance.
Diet and other factors. In addition to the endogenous meta-
bolic production of acidity and to the renal handling of acids
and bases, dietary supply of acids and/or bases or of their pre-
cursors is a further critical component contributing to the glo-
bal acid–balance. Recent data show that an increased dietary
acid load is associated with metabolic acidosis in KTx recipients
[17]. Although the CMA owing to increased acid dietary supply
does not have the appearance of RTA, because the renal excre-
tion of acidity and ammonia is even increased, it is worth
underlining that, in the presence of a subclinical tubular defect
(incomplete RTA), as is often the case in KTx recipients, an
increased load of acids could make this metabolic disturbance
overt.
Many additional factors have been claimed to play some role
in the pathogenesis of CMA of KTx patients, such as insulin
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resistance, diabetes mellitus, drugs and others [29]. To stay
within a practical background, we will limit ourselves to men-
tion only the role of some drugs which are frequently used in
KTx patients, dealing with those which can induce an RTA-like
condition and those which are associated with a high anion gap
acidosis separately.
The first group belongs to furosemide which has been re-
ported to cause nephrocalcinosis and/or tubule–interstitial
nephritis associated with a condition of distal RTA with in-
creased calcium excretion, hypocitraturia in the KTx set [42].
A very similar picture has also been reported in a KTx recipient
treated with high doses of vitamin D [43]. A distal RTA type 1b
(voltage-dependent) has been described in a KTx patient trea-
ted with trimethoprim–sulfamethoxazole [44]. This drug has
been demonstrated to block the renal tubular sodium channels,
reducing hydrogen ions and potassium excretion. An RTA-like
condition of the mixed type ( proximal plus distal) has also
been reported in patients treated with anticonvulsant therapy
containing topiramate, a drug that mimics the activity of acet-
azolamide inhibiting the activity of tubular carbonic anhydrase
type II [45]. It is also worth mentioning that both ace-
inhibitors and angiotensin II-receptor blockers can induce an
RTA of type 4, owing to their intrinsic aldosterone inhibiting
effect [16].
In the second group of drugs inducing a high AG metabolic
acidosis, it is worth mentioning paracetamol and some antiviral
drugs. The former, by inhibiting glutathione synthesis, induces
an increased production of pyroglutamic acid which can accu-
mulate, particularly in the presence of reduced renal function,
provoking a severe form of metabolic acidosis [46]. Other
potential life-threatening forms of high AG metabolic acidosis
have been described in KTx patients treated with antiviral
drugs, such as nucleoside/tide reverse transcriptase inhibitors
(RTIs) for HIV or HBV and ganciclovir or vanganciclovir for
CMV for HBV infections [47, 48]. All these drugs, with differ-
ent mechanisms, can induce a form of lactic acidosis by inhibit-
ing mitochondrial enzymes involved in the aerobic production
of ATP.
Although most of this evidence is based on single case re-
ports, it is worth bearing in mind the possibility of the occur-
rence of these events for a more appropriate diagnostic and
therapeutic approach.
CLINICAL CONSEQUENCES AND
T H E R A P E U T I C A P P R O AC H T O C M A I N K T X
Given that KTx recipients are usually burdened by many peri-
odic assessments and often take a great number of medications,
a transplant nephrologist could be motivated to look for and
treat a metabolic disorder in these patients only if strongly con-
vinced of the clinical utility of curing this condition.
There are a considerable number of experimental and clin-
ical studies which suggest that CMA might impair muscle and
bone health, induce metabolic and electrolyte dysfunctions,
possibly also contributing to the worsening of the renal func-
tion (Table 3). However, most of these studies have been
performed in CKD patients at different stages, but not in KTx
P.G. Messa et al.
 Table 3. Main potential clinical effects of metabolic acidosis
Metabolic disorders Increased albumin catabolism
Reduced insulin sensitivity
Reduced oxygen delivery at tissue level- Increased
β2-globulin production
Muscle and skeletal Muscle mass wasting
disorders Reduced bone mineral content (reduced bone
formation, increased bone resorption)
Growth retardation in children
Kidney function Increased protenuria, interstitial and glomerular
fibrosis (ammonium-dependent complement
activation, ET1 and aldosterone effects)
CKD progression
recipients [3, 4, 29, 49, 50]. To the best of our knowledge, only
two papers have provided evidence for a potential negative
effect of CMA on bone demineralization in adult KTx patients
[8] and of worse height growth in transplanted children [51].
Along the same lines, the evidence supporting the beneficial
effects of acidosis correction has been produced in all CKD
stages except in KTx recipients [52–54].
With this disheartening shortage of information, one could
be tempted to not be concerned about correcting acidosis in
KTx patients. However, waiting for more information to be
gained, and considering that both the assessment and correc-
tion of CMA is a low-cost issue, we should realize that it is
worth correcting.
In the clinical practice, we usually correct CMA in KTx when
serum bicarbonate levels are lower than 22 mmol/L, using the
following simple flowchart which is mainly opinion-based:
(i) CMA with high serum AG
(a) look for general clinical conditions and drugs ( para-
cetamol, metformin, NRTI, ganciclovir/valganciclo-
vir) and withdraw them or adjust their dosage
(ii) CMA with normal AG, hyperchloremic acidosis
(a) If the potassium is >5.2 mmol/L, check for drugs
(ace-inhibitor or angiotensin receptor blockers)
and consider adjusting their dosage and/or add
oral sodium bicarbonate (1–3 g/day)
(b) If potassium is normal or low
(1) Look for gastrointestinal causes (urinary
AG, if checked, usually negative)
(2) Look for drugs
• furosemide or vitamin D: check for hyper-
calciuria and/or nephrocalcinosis. Consider
withdrawal or reduction of their dosage
and add oral potassium/magnesium citrate
(20–40 mEq/day of citrate)
• trimethoprim–sulfamethoxazole or topira-
mate: consider withdrawal or reduction of
their dosage and add oral sodium bicarbon-
ate (1–3 g/day)
(3) If none of the above drugs, check for the
levels of CNI
• If high, reduce the doses of CNI, consider
shift TAC → CSA, add oral sodium
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bicarbonate (1–3 g/day) or potassium/mag-
nesium citrate (20–40 mEq/day of citrate)
• If normal or low, consider acute or chronic
rejection (graft biopsy?), add oral sodium bi-
carbonate (1–3 g/day) or potassium/magne-
sium citrate (20–40 mEq/day of citrate)
When possible, we also suggest to our KTx patients with CMA
to shift their diet towards a higher content of fruits and vegeta-
bles, because there is consolidated awareness that this can con-
sistently improve the degree of acidosis [55].
Final comments
Although metabolic acidosis is a common complication in
KTx and could have potential negative effects, the available in-
formation is very limited. There are still too many obscurities
on this issue. First, we do not as yet know what is the current
prevalence of CMA in the KTx set and how it changes over
time. The weight of the suggested potential causal factors is
far from being defined. It is even more unknown whether
there is any clinical advantage in the correction of KTx CMA,
to what degree CMA should be corrected, what should be the
desired correction target and what is the best tool for correcting
it, etc.
We strongly hope that a more overall assessment of the
metabolic parameters needed for a precise diagnosis of this
metabolic condition could help the transplant community in
FULL REVIEW
gaining further insights into this field. It could also be desirable
that some controlled trials assessing the effects of CMA correc-
tion could be started, given the potential cost effectiveness of
such an intervention.
AC K N O W L E D G E M E N T
P.M. received lecture fees or board participation from ABBVIE,
AMGEN, FRESENIUS. C.A. and S.V. do not declare any con-
flict of interest.
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Received for publication: 13.2.2015; Accepted in revised form: 10.3.2015
P.G. Messa et al.