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1279–1285 Received for publication: 3.12.2013; Accepted in revised form: 13.3.2014
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

correction of CMA in kidney transplant recipients. In this re-


A B S T R AC T view, we briefly look at the more relevant, though scanty, studies
which have, over time, addressed the above-mentioned points,
Chronic metabolic acidosis (CMA) is a common complication with the hope that in the future the interest of transplant ne-
of the more advanced stages of chronic kidney diseases (CKD), phrologists and surgeons will grow towards this unreasonably
and is associated with morbidity and mortality of CKD patients neglected issue.
and possibly with the progression of renal disease. Nevertheless,
there is limited evidence or information on the prevalence, the Keywords: allograft dysfunction, metabolic acidosis, renal
potential causal factors, the clinical impact and the effects of transplantation

© The Author 2015. Published by Oxford University Press 730


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INTRODUCTION 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
Chronic metabolic acidosis (CMA), defined as low serum bi-
carbonate and pH levels, in association with a proportional It is not easy to define the real prevalence of CMA in KTx
decrease in serum partial pressure of carbonic dioxide patients, because only a few papers have clearly reported on
(PaCO2), is usually observed in the more advanced stages of this figure, and when it occurs, it often refers to relatively
chronic kidney disease (CKD). In fact, excluding the rare small groups of patients. Table 1 summarizes the results of
forms of genetic CMA, CMA only occasionally occurs in the main studies reporting on the prevalence of CMA in KTx
CKD patients up until when glomerular filtration rate cohorts [7–17]. Overall, the reported prevalence ranges from
(GFR) falls under 30 mL/min, whereupon its prevalence in- 11 up to over 50%.
creases approaching 20%, 10-fold higher when compared The considerable variability in the prevalence of CMA
with patients with normal GFR [1, 2]. Experimental and clin- among the quoted studies can be ascribed to the variability
ical studies suggest that CMA could contribute to increased in the transplant eras; the difference in serum bicarbonate
morbidity and mortality of CKD patients and to progression threshold for diagnosing metabolic acidosis; the differing
of renal disease [3, 4]. times from transplantation when it was assessed; difference in
Although the first report on CMA in kidney transplant the graft function, etc. However, considering that most of these
(KTx) patients dates from the very beginning of renal trans- studies included KTx patients with GFR values over 40 mL/
plantation history [5] and notwithstanding widespread aware- min, this figure is consistently higher than that reported for
ness of the importance of checking for CMA in CKD patients, other non-KTx CKD cohorts with comparable degrees of
the routine assessment for this metabolic complication is also renal function. To add some personal information, Figure 1
not diffuse in renal transplant recipients. This is indirectly in- shows the prevalence of CMA at the first and the 12th month
ferred by the absence of any major reference to this issue in the after KTx in a group of patients who received a renal graft in our
last version of the Kidney Disease: Improving Global Outcomes centre in the past 3 years. We observed a fall in the CMA preva-
guidelines for the care of KTx recipients [6]. There is no ration- lence from 27 to 16%, though the percentage of patients treated
ale for neglecting this basic metabolic disorder, but for medical with bicarbonate supplementation remained substantially
attention being more focused on the immunologic, cardiovas- unchanged (15 versus 16%). However, given that less than

FULL REVIEW
cular, infectious and other relevant clinical complications in the 10% of these patients had GFR values under 30 mL/min, both
transplant set. However, given the potential consequences of figures clearly remain well above what is usually found in
CMA on both patient and graft outcome and knowing that non-KTx CKD patients. In agreement with published results,
checking for and correcting it are easy and cheap tasks, it also in our patients, those with CMA had lower GFR levels
would be worth remembering some simple concepts on this than those without at both the first (55.9 ± 18.9 versus 46.4 ±
issue. 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%; 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
P < 0.003). 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
CKD-associated CMA is generally characterized by normal
The findings related to the RTA prevalence suggest that, in add-
or reduced levels of serum chloride (s-Cl) and a normal or in-
ition to the common pathogenic factors acting in any form of pro-
creased serum anion gap (s-AG). At variance, the form usual-
gressive CKD when the renal function falls under 30 mL/min,
ly found in KTx patients resembles the typical renal tubular
FULL REVIEW

other mechanisms may be triggered in the renal transplant set.


acidosis (RTA), with normal s-AG and normal or high s-Cl
It is beyond the aim of this paper to address the cellular path-
levels. So, from this point on, we indifferently use the term
ways involved in the control of acid–base balance by the kidney,
of RTA or CMA to indicate the form of KTx metabolic
so we would limit ourselves to briefly comment on the main
acidosis.
mechanisms by which the most relevant causal factors act.
Although the first reported patient with post-KTx CMA was
Generally speaking, the pathogenic mechanisms can be
characterized by a complex tubular dysfunction (mixed prox-
divided into those common to any other CKD form and
imal and distal RTA, associated with Fanconi syndrome) [5],
those more specific of or at least most commonly occurring
later reports defined that distal RTA is by far the most repre-
in KTx patients.
sented form, with the exclusion of the very early post-KTx per-
Although most of these mechanisms share many aspects, we
iod (6 months) when the proximal form of RTA can also be
will deal with these topics separately.
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 CMA pathogenic mechanisms common
all the different forms being represented (classical dRTA Type to the CKD condition
Ia: 18; hyperkalemic dRTA type Ib: 11; rate-limited dRTA: 16; It has long been acknowledged that CMA of CKD is second-
dRTA type IV: 21). Table 2 describes the different types of renal ary to the reduction in the capacity of the diseased kidneys to
metabolic acidosis, according to a simplified diagnostic proto- eliminate the hydrogen ion load derived by both dietary and en-
col [modified from 10, 23]. dogenous sources and to generate bases [24–26]. Recent experi-
Dealing with the degree of acidosis in KTx patients, the mental observations suggest that the metabolic pathways
available data are again very scanty. From the only two studies involved in the pathogenesis of CMA of CKD consist of a
where the data were available [7, 12], it can be seen that a more reduced activity of both enzymes and carrier proteins respon-
severe form of metabolic acidosis (sodium bicarbonate <20 sible for glutamine reabsorption, synthesis and secretion of
mmol/L) was present in 12.5 and 28% of patients. From our ammonia, and bicarbonate transport [27]. On the other
data, such a degree of acidosis was found in 7.5 and 3% of hand, relevant acid–base changes are observed only when
patients at the first and 12th month, respectively. GFR falls less than 20% of the normal values, owing to the com-
In summary, the occurrence of RTA in KTx patients is a pensatory mechanisms put in act by the residual functioning
common event particularly in younger recipients, with the nephrons which can increase up to over 3-fold their capacity
prevalence being consistently higher than that expected by of producing ammonia and eliminating net acidity [28].
the degree of graft function. This form of RTA has the As previously discussed, in KTx patients, CMA is observed
main characteristics of the distal form, of mild-to-moderate when the graft function is well over the above-mentioned GFR
degree. threshold. To explain this discrepancy, it has been suggested

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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 High sAG /normochloremic
acidosis

pRTA dRTA RTA associated with –lactic acidosis


hypoaldosteronism –ketoacidosis
–toxic acidosis
type 2 Classical Rate-limited Voltage-dependent Mixed type 4
type 1a type 1b type 3
s-K =/↓ =/↓ =/↑ ↑ =/↓ ↑ =/↓/↑
u-pH <5.5 >5.5 <5.5 >5.5 >5.5 <5.5 <5.5
u-AG neg pos pos pos pos pos neg
FE-Bic % >10 <5 <5 <5 5-15 <10 <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 In spite of what earlier papers suggested [7, 18, 19], we have
single kidney, as is the case of the renal graft, could be respon- as yet no reliable information on the impact of the donor age,
sible for a higher blood flow rate in the single organ, and this donor renal function and cold ischaemia duration on the occur-
could impair the transtubular chemical and electrical gradients rence of post-KTx CMA.
and in turn renal acid excretion [29]. In support of the above- However, the common finding that the incidence of CMA is
mentioned hypothesis, four decades ago, Chan et al. [30] consistently higher in the period immediately following the
demonstrated that kidney donors had a reduced renal net KTx indirectly suggests that, among other early acting factors,
acid excretion after an acute acid load compared with controls. also those associated with donor and/or peri-transplant opera-
Taking into account that these data were produced a long time tive conditions might play some role.
ago and in a small group of subjects, it could be worth reasses-

FULL REVIEW
sing this issue, possibly in a wider population of mono- Immunological factors. RTA can complicate several
nephrectomized current subjects and patients. immune-mediated diseases, such as lupus erythematosus, Sjög-
The reasons for the discrepancy between the GFR threshold ren disease, hypergammaglobulinemic disorders and others
at which CMA is observed in KTx patients and in the other [33–36]. The pathogenesis has been traced back to either cell-
CKD patients could be more complex, also depending on and/or antibody-mediated insults to the renal tubular and
other potential causal factors specific to the KTx context. interstitial structures, with a consequent impairment of enzym-
atic and transporter activities involved in the renal control of
CMA pathogenic mechanisms specific to KTx patients acid–base balance. Consequently, it is not surprising if the
As already mentioned, CMA of KTx patients has the char- same immune-mediated mechanisms have been summoned
acteristics of the distal RTA. However, at variance with the her- for the RTA occurring in the renal graft.
editary forms of RTA, characterized by a dysfunction of specific In fact, two old studies reported that early-occurring hyper-
transporter proteins or enzymes, owing to well-defined gene chloremic metabolic acidosis is often associated with acute
mutations [31], transplant-associated RTA seems to result rejection (AR), sometimes antedating it by 1–2 weeks, and
from a mixture of different deficiencies, because no specific the late-occurring CMA is often associated with histological
enzymatic defect has been found [32]. This can be explained findings of chronic allograft rejection [19, 21]. A more recent
by the multiplicity of the additional putative causal factors paper reported on a patient who presented with a severe form
which can often act in combination. of RTA concurrently with the occurrence of a third AR episode,
which completely resolved after the AR was successfully treated
Characteristics of the donor. Although one could expect that with steroids [37]. Interestingly, in this study, the search for the
factors related to the quality of the donor [living donor (LD) versus expression of H+-ATPase pump and of Cl−/HCO− 3 anion
cadaveric donor (CD), standard versus expanded criteria donor, exchanger 1 (AE1) in the distal tubule was completely null, in
etc.] and to the events involving the graft immediately before sur- comparison with a control biopsy. This finding would indirectly
gery (inflammatory and ischaemic events, etc.) can play a role in suggest that an immune-mediated process could have been
determining the occurrence of CMA after KTx, there is no defini- directed towards these two key factors for controlling acid
tive proof of it, given the shortage of data on these issues. and base regulation at the renal tubular level. At variance
Of the four papers mentioning the different occurrence of with these findings, a subsequent study showed that, although
RTA in LD versus CD recipients [9–11, 14], only one [11] re- the expression of H+-ATPase was significantly lower in post-
ported that in the group of patients with RTA the percentage of transplant than in pre-transplant renal biopsies, no difference
CD recipients was significantly higher than in the group with- in the expression of this cellular pump was observed between
out it. As previously reported, in our experience, the occurrence patients with or without RTA [32]. The information provided
of CMA was significantly higher in CD recipients. by these studies is limited due to the fact that they are anecdotal

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reports or have been carried out in small cohorts of patients. resistance, diabetes mellitus, drugs and others [29]. To stay
Two other studies, including a more consistent number of within a practical background, we will limit ourselves to men-
patients, were not able to confirm a significant association tion only the role of some drugs which are frequently used in
between AR and RTA occurrence [10, 11]. KTx patients, dealing with those which can induce an RTA-like
So, the issue of the plausible role of the immune-mediated condition and those which are associated with a high anion gap
factors in the pathogenesis of RTA of KTx recipients needs acidosis separately.
still to be fully demonstrated. The first group belongs to furosemide which has been re-
ported to cause nephrocalcinosis and/or tubule–interstitial
Immunosuppressive drugs. Calcineurin inhibitors (CNIs) nephritis associated with a condition of distal RTA with in-
have been charged to be the most likely contributors to RTA oc- creased calcium excretion, hypocitraturia in the KTx set [42].
currence in KTx recipients among all the immunosuppressive A very similar picture has also been reported in a KTx recipient
drugs (ISDs), because no relevant study has reported on the in- treated with high doses of vitamin D [43]. A distal RTA type 1b
volvement of the other ISDs in causing RTA, except for some (voltage-dependent) has been described in a KTx patient trea-
cases of metabolic acidosis owing to diarrhoea-associated intes- ted with trimethoprim–sulfamethoxazole [44]. This drug has
tinal bicarbonate loss secondary to mycophenolate toxicity. been demonstrated to block the renal tubular sodium channels,
Because CNIs have renal tubular toxic effects, it is obvious reducing hydrogen ions and potassium excretion. An RTA-like
that RTA could be the consequence of their nephrotoxic activ- condition of the mixed type ( proximal plus distal) has also
ity. However, it has been suggested that CNIs might induce been reported in patients treated with anticonvulsant therapy
functional tubular damage (in the absence of evident histo- containing topiramate, a drug that mimics the activity of acet-
logical changes) which are responsible for the occurrence of dis- azolamide inhibiting the activity of tubular carbonic anhydrase
turbances of the electrolyte tubular transport, including RTA type II [45]. It is also worth mentioning that both ace-
[14, 38, 39]. This type of functional tubular toxicity is charac- inhibitors and angiotensin II-receptor blockers can induce an
terized by different mechanisms for the two main CNIs in clin- RTA of type 4, owing to their intrinsic aldosterone inhibiting
ical use, cyclosporin A (CSA) and tacrolimus (TAC). Watanabe effect [16].
et al. [38] demonstrated that CSA induces RTA by blocking the In the second group of drugs inducing a high AG metabolic
peptidyl prolyl cis–trans isomerase (PPIase) activity, through a acidosis, it is worth mentioning paracetamol and some antiviral
specific cyclophilin-dependent mechanism, but not involving drugs. The former, by inhibiting glutathione synthesis, induces
FULL REVIEW

calcineurin inhibition. Mohebbi et al. [39] demonstrated that an increased production of pyroglutamic acid which can accu-
TAC can affect several major transport proteins involved in mulate, particularly in the presence of reduced renal function,
the renal control of acid–base balance, such as H+-ATPase provoking a severe form of metabolic acidosis [46]. Other
transport protein and AE1. potential life-threatening forms of high AG metabolic acidosis
Whichever the causal mechanisms are, most data indicate have been described in KTx patients treated with antiviral
that the RTA-inducing effects of CNI are dependent on the drugs, such as nucleoside/tide reverse transcriptase inhibitors
drug dose, because a reduction of the dosage has been reported (RTIs) for HIV or HBV and ganciclovir or vanganciclovir for
to be often associated with a recovery of the RTA [14, 40]. Fur- CMV for HBV infections [47, 48]. All these drugs, with differ-
thermore, there is some evidence that RTA is more frequent in ent mechanisms, can induce a form of lactic acidosis by inhibit-
patients on TAC than on CSA treatment [10, 11, 41]. ing mitochondrial enzymes involved in the aerobic production
It is also worth remembering that RTA associated with CNI of ATP.
is often characterized by high potassium levels (type 1b or rate- Although most of this evidence is based on single case re-
limited RTA). This can be useful to take into account not only ports, it is worth bearing in mind the possibility of the occur-
for a correct diagnosis, but also for a proper correction of this rence of these events for a more appropriate diagnostic and
metabolic disturbance. therapeutic approach.

Diet and other factors. In addition to the endogenous meta-


bolic production of acidity and to the renal handling of acids CLINICAL CONSEQUENCES AND
and bases, dietary supply of acids and/or bases or of their pre- 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
cursors is a further critical component contributing to the glo-
bal acid–balance. Recent data show that an increased dietary Given that KTx recipients are usually burdened by many peri-
acid load is associated with metabolic acidosis in KTx recipients odic assessments and often take a great number of medications,
[17]. Although the CMA owing to increased acid dietary supply a transplant nephrologist could be motivated to look for and
does not have the appearance of RTA, because the renal excre- treat a metabolic disorder in these patients only if strongly con-
tion of acidity and ammonia is even increased, it is worth vinced of the clinical utility of curing this condition.
underlining that, in the presence of a subclinical tubular defect There are a considerable number of experimental and clin-
(incomplete RTA), as is often the case in KTx recipients, an ical studies which suggest that CMA might impair muscle and
increased load of acids could make this metabolic disturbance bone health, induce metabolic and electrolyte dysfunctions,
overt. possibly also contributing to the worsening of the renal func-
Many additional factors have been claimed to play some role tion (Table 3). However, most of these studies have been
in the pathogenesis of CMA of KTx patients, such as insulin performed in CKD patients at different stages, but not in KTx

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Table 3. Main potential clinical effects of metabolic acidosis bicarbonate (1–3 g/day) or potassium/mag-
Metabolic disorders Increased albumin catabolism nesium citrate (20–40 mEq/day of citrate)
Reduced insulin sensitivity
• If normal or low, consider acute or chronic
Reduced oxygen delivery at tissue level- Increased
β2-globulin production rejection (graft biopsy?), add oral sodium bi-
Muscle and skeletal Muscle mass wasting carbonate (1–3 g/day) or potassium/magne-
disorders Reduced bone mineral content (reduced bone sium citrate (20–40 mEq/day of citrate)
formation, increased bone resorption)
Growth retardation in children When possible, we also suggest to our KTx patients with CMA
Kidney function Increased protenuria, interstitial and glomerular to shift their diet towards a higher content of fruits and vegeta-
fibrosis (ammonium-dependent complement
bles, because there is consolidated awareness that this can con-
activation, ET1 and aldosterone effects)
CKD progression sistently improve the degree of acidosis [55].

Final comments
Although metabolic acidosis is a common complication in
recipients [3, 4, 29, 49, 50]. To the best of our knowledge, only
KTx and could have potential negative effects, the available in-
two papers have provided evidence for a potential negative
formation is very limited. There are still too many obscurities
effect of CMA on bone demineralization in adult KTx patients
on this issue. First, we do not as yet know what is the current
[8] and of worse height growth in transplanted children [51].
prevalence of CMA in the KTx set and how it changes over
Along the same lines, the evidence supporting the beneficial
time. The weight of the suggested potential causal factors is
effects of acidosis correction has been produced in all CKD
far from being defined. It is even more unknown whether
stages except in KTx recipients [52–54].
there is any clinical advantage in the correction of KTx CMA,
With this disheartening shortage of information, one could
to what degree CMA should be corrected, what should be the
be tempted to not be concerned about correcting acidosis in
desired correction target and what is the best tool for correcting
KTx patients. However, waiting for more information to be
it, etc.
gained, and considering that both the assessment and correc-
We strongly hope that a more overall assessment of the
tion of CMA is a low-cost issue, we should realize that it is
metabolic parameters needed for a precise diagnosis of this
worth correcting.
metabolic condition could help the transplant community in

FULL REVIEW
In the clinical practice, we usually correct CMA in KTx when
gaining further insights into this field. It could also be desirable
serum bicarbonate levels are lower than 22 mmol/L, using the
that some controlled trials assessing the effects of CMA correc-
following simple flowchart which is mainly opinion-based:
tion could be started, given the potential cost effectiveness of
such an intervention.
(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 AC K N O W L E D G E M E N T
(ii) CMA with normal AG, hyperchloremic acidosis P.M. received lecture fees or board participation from ABBVIE,
(a) If the potassium is >5.2 mmol/L, check for drugs AMGEN, FRESENIUS. C.A. and S.V. do not declare any con-
(ace-inhibitor or angiotensin receptor blockers) flict of interest.
and consider adjusting their dosage and/or add
oral sodium bicarbonate (1–3 g/day)
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