Nephrol Dial Transplant (2018) 1–13

doi: 10.1093/ndt/gfy151

Metabolic risk profile in kidney transplant candidates

and recipients

REVIEW
Giovanni Piotti, Ilaria Gandolfini, Alessandra Palmisano and Umberto Maggiore
Department of Nephrology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

Correspondence and offprint requests to: Umberto Maggiore; E-mail: umberto_maggiore@hotmail.com

ABSTRACT abnormalities are not fully reversed despite successful kidney

Metabolic risk factors of cardiovascular disease such as abnormal transplantation and contribute to exacerbating cardiovascular
glucose regulation, obesity and metabolic syndrome, dyslipidae- risk in kidney transplant recipients, together with the toxicity of
mia, metabolic bone disease, hyperuricaemia and other less tra- anti-rejection therapy. However, metabolic risk factors pose dif-
ditional abnormalities are common in both kidney transplant ferent challenges in transplant candidates and transplant recipi-
candidates and recipients. In kidney transplant candidates, the ents. In kidney transplant candidates, prolonged exposure to
presence of these risk factors may impede patient access to trans- metabolic risk factors may jeopardize their suitability for kidney
plantation by increasing the risk of developing comorbidities transplantation or increase the risk of severe perioperative com-
while on the waiting list, prolonging the time to wait-listing and, plications. In kidney transplant recipients, metabolic risk factors
in some patients, eventually jeopardizing their suitability for kid- may increase mortality with a functioning graft and reduce
ney transplantation or increasing the risk of severe perioperative long-term renal graft survival. Finally, treatments to correct
complications. In transplant recipients, metabolic risk factors metabolic risk factors may differ between the two categories of
may be associated with increased mortality with a functioning patients. Unlike transplant candidates, most transplant recipi-
graft and with reduced long-term renal graft survival. Although ents have no contraindication to the use of drugs that undergo
most transplant recipients have no contraindication to the use of renal excretion, but they may be at risk of drug-to-drug phar-
drugs that undergo renal excretion, they may be at risk of drug- macokinetic interactions with anti-rejection treatments.
to-drug pharmacokinetic interactions with anti-rejection medi- In this review, we have highlighted: (i) the main objectives of
cines. In this review, we have highlighted the main objectives of evaluating metabolic abnormalities in transplant candidates
evaluating the metabolic abnormalities in transplant candidates and recipients, (ii) how this evaluation should be carried out in
and recipients, how this evaluation should be carried out in prac- practice and (iii) what the most valuable treatment strategies
tice and what currently the most valuable treatment strategies are for modifying the associated risks.
are for modifying the associated risks. We conclude that, for ev-
ery potential transplant candidate, every effort should be made DIABETES MELLITUS, OBESITY AND
to control metabolic abnormalities causing arterial calcification, METABOLIC SYNDROME
which may impede access to transplantation and impair trans-
plant outcome. In transplant recipients, metabolic abnormalities Diabetes adversely affects transplant candidate survival and ac-
that result from adverse effects of anti-rejection therapy may be cess to the waiting list [1]. Nevertheless, diabetic candidates are
effectively controlled by lifestyle changes and judicious use of the category of dialysis patients who benefit the most from de-
drugs for the treatment of abnormal glucose metabolism and ceased donor kidney transplantation in terms of proportional
dyslipidaemia. increase in life expectancy [2, 3], even when the graft is pro-
cured from extended criteria donors [4]. The beneficial effect of
Keywords: diabetes, dyslipidaemia, kidney transplantation,
kidney transplantation on life expectancy is maximized when
metabolic syndrome, vascular calcification
diabetic patients undergo pre-emptive living donor kidney
transplantation [5]. Therefore, the survival benefit of transplan-
tation over haemodialysis and peritoneal dialysis is consider-
INTRODUCTION able, despite the use of anti-rejection diabetogenic drugs post-
Metabolic risk factors of cardiovascular disease (CVD) are com- transplantation. On the other hand, transplant candidates with-
mon in kidney transplant candidates and recipients. In kidney out known diabetes who develop diabetes post-transplantation
transplant candidates, their presence is associated with ad- have their renal graft survival reduced because of diabetes [6].
vanced chronic kidney disease (CKD). Some of these metabolic The reasons are unclear, although they may be related to
C The
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 physicians’ efforts to decrease diabetogenic immunosuppressive FBG 100 mg/dL, body mass index (BMI) 30 kg/m2, trigly-
treatment, which, in turn, increases the risk of rejection contrib- cerides 200 mg/dL, prescription for gout medicine, being
uting to the increase T-cell alloreactivity observed in diabetic assigned to maintenance steroids post-transplantation and fam-
patients [7], an increased incidence of infections and major car- ily history of type 2 diabetes [17]. According to this prediction
diovascular events [8] and the development of diabetic compli- model, the risk of PTDM would be 10, 30 and 50% in trans-
cations, including diabetic allograft nephropathy. Therefore, it plant candidates with 0–1, 2–3 and 4 risk factors, respectively
is important to identify transplant candidates at risk of develop- [17]. Therefore, apart from the rather obvious baseline risk fac-
ing diabetes post-transplantation, to correct their modifiable tors such as older age and pre-diabetes, three factors, namely
risk factors before and after transplantation and to adopt strate- obesity, metabolic syndrome and genetic background,
gies aimed at diagnosing and correcting hyperglycaemia after accounted for most of the risk of PTDM.
transplantation. Obesity in transplant candidates is a major risk factor for
Diabetes mellitus is a condition that is often unrecognized in both early (3 months) and late PTDM [18]. Since transplant
transplant candidates. In a Norwegian study, systematic screen- candidates on dialysis must limit their intake of fresh fruits and
ing using the oral glucose tolerance test (OGTT) revealed un- vegetables to prevent hyperkalaemia, and their protein intake to
known diabetes in 8% of candidates [9]. Indeed, despite the fact prevent hyperphosphataemia, it is hard for obese candidates to
that renal function decline in CKD causes impaired insulin sen- lose weight with dietary measures alone. Freeman et al. [19]
sitivity [10], end-stage kidney disease (ESKD) leads to improve- showed that in morbidly obese transplant candidates, laparo-
ment in glucose tolerance because of the drop in renal insulin scopic sleeve gastrectomy achieved in 6 months 38% of excess
clearance and an improved uraemic milieu upon dialysis initia- weight loss, as opposed to 4% of excess weight loss obtained us-
tion. In fact, up to one-third of diabetic dialysis patients may ex- ing specialized medical treatment in the 6 months before sur-
perience spontaneous resolution of hyperglycaemia, with gery. Moreover, compared with conservative treatment, pre-
haemoglobin A1c (HbA1c) levels of <6% [11]. Since several transplant sleeve gastrectomy has been associated with 15%
cases of post-transplant diabetes are represented by patients lower rates of delayed graft function and renal dysfunction-
with unknown pre-transplant diabetes, a recent position paper related readmissions post-transplantation [20]. In non-mor-
suggested that the old definition of new-onset diabetes after bidly obese patients, there may be medical alternatives to sleeve
transplantation (NODAT) should be replaced by post-trans- gastrectomy, based on drugs such as liraglutide, a glucagon-like
plant diabetes mellitus (PTDM) [12]. The diagnosis of PTDM peptide-1 receptor agonist with an anti-hyperglycaemic effect
may be even more challenging in transplant recipients, com- that carries a low risk of hypoglycaemia (Table 1). Despite its
pared with transplant candidates, due to the use of steroids. In gastrointestinal side effects, liraglutide represents a promising
the presence of moderate-dose steroids, peak plasma glucose agent, since it has been proven to be efficacious in the treatment
occurs 7–8 h after administration; therefore, the sensitivity of of obesity and might be used at reduced dosage in patients with
fasting blood glucose (FBG) for diabetes diagnosis is poor [13]. ESKD [30]. That said, strategies aimed at achieving drastic
Although FBG sensitivity can be increased by measuring weight loss in transplant candidates might be associated with an
plasma glucose at 4 p.m. [14], this procedure is currently not increased risk of malnutrition. In a US cohort of 15 000 trans-
recommended for routine clinical practice because normal val- plant candidates on haemodialysis who were active on the wait-
ues are not sufficiently standardized. Therefore, the diagnosis of ing list, a weight loss of 5 kg over >6 months was associated
PTDM is usually based on the OGTT or HbA1c [with a cut-off with a 20% increase in mortality after adjusting for all comor-
point of 6.2% (44 mmol/mol) in place of the traditional 6.5% bidities and malnutrition inflammation indexes [31]. Though
(48 mmol/mol)] [15], starting from 3 months following this study could not differentiate between intentional and unin-
transplantation. tentional weight loss, we recommend that interventions aimed
In the first 3 months after transplantation, hyperglycaemia at losing weight in obese transplant candidates should be car-
may be transient, and HbA1c may be unreliable [15]. Post- ried out under close surveillance to prevent malnutrition and
surgery, hyperglycaemia occurs in 80% of transplant recipients, loss of muscle mass. Moreover, weight loss achieved in trans-
regardless of their diabetic status, and often improves over the plant candidates may be transient, as most transplant recipients,
first 3 months post-transplantation [13]. However, albeit tran- especially those with large pre-transplant weight decline, often
sient, perioperative hyperglycaemia is associated with a subse- experience significant weight gain following surgery with a
quent risk of PTDM [16]. functional allograft [32]. Finally, despite an increased rate of
A relatively limited number of characteristics define the risk post-transplant surgical complications, all obese patients im-
profile of transplant candidates for developing PTDM after prove their life expectancy with kidney transplantation, as op-
transplantation. A recently developed predictive score, which posed to remaining on dialysis, irrespective of their BMI [33].
was subsequently validated in a predominantly white popula- Besides obesity, the other major risk factor for PTDM is met-
tion in the United States (US) and therefore would require fur- abolic syndrome, which carries an increased risk of graft loss and
ther validation before it can be universally used in routine death from CVD per se [34]. Among the constellation of abnor-
clinical practice, provides some useful evidence of how each of malities that can be detected, based on the clinical criteria for
the traditional determinants of PTDM may affect the risk, indi- metabolic syndrome, the two simplest are the simultaneous pres-
vidually as well as in combination with each other. The score ence of an increased waist girth (i.e. waist-to-hip ratio, an indi-
was based on the following items: older age (50 years), rect measure of visceral fat) and fasting triglyceride levels, a

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 Table 1. Drugs for the treatment of diabetes, obesity and dyslipidaemia in transplant candidates and recipients

Drug Main metabolism/ Maximum Expected Dose adjustment Dose with cyclospor- Exposure increase
substrate daily dose reduction in advanced ine [25] with cyclosporine
for transporters [25] (mg) in HbA1c (%) CKD [22] [25]
Anti-diabetic drugs [21]
Metformin – 2000 1.0–2.0 eGFR <45: max No dose adjustment Unlikely
(biguanide) 1000 mg/day
eGFR <30:
contraindicated
Glipizide CYP2C9, -2D1 20 1.0–1.5 In ESKD, the starting No dose adjustment Unlikely
(sulfonylurea) dose should not ex-
ceed 2.5 mg
Glimepiride CYP2C9 1 Avoid if eGFR <15 No dose adjustment Unlikely
(sulfonylurea)
Repaglinide CYP3A4, -2C8/ 6 0.5–1.0 None Consider alternatives 2.5-fold increase
(meglitinide) OATP1B1 in patients taking
cyclosporine
Rosiglitazone CYP2C9, -2C8 8 None No dose adjustment Unlikely
(thiazolidinedione)
Linagliptin (CYP3A4)/P-gp 5 0.5–0.8 None Monitor in patients May be increased
(DPP-IV inhibitor) taking cyclosporine
Canaglifozin (CYP3A4)/ 300 0.0–1.5a eGFR <45: not Monitor in patients May be increased
Dapagliflozin P-gp and MRP2, 10 recommended taking cyclosporine
Empagliflozin OAT3, 25 eGFR<30:
(SGLT2 inhibitors) and BRCP, contraindicated
respectively
Injectable
Liraglutide – 3 (obesity) 0.5–1.5 Dosage reduction in No dose adjustment No
(GLP-1 receptor agonist) 1.8 (diabetes) patients
with ESKD may be
warranted
Insulin – 1.0–2.5 – No dose adjustment No
Drug Main metabolism/ Maximum Average LDL-C Dose adjustment in Dose with Exposure increase
effect of OATP1B1 daily reduction advanced CKD cyclosporinec with cyclosporine
variants dose (mg) at maximum
on statin AUC [23] dose [24]
Lipid-lowering drugsb
Atorvastatin CYP3A4/þþ 80 57% None Maximum 10 mg 8.7-fold
Lovastatin CYP3A4/ 80 40% Caution for dosage Avoid 5- to 8-fold
above 20 mg
Simvastatin CYP3A4/þþþ 80 46% Start with 5 mg, Maximum 10 mg NA
cautiously monitor
Fluvastatin CYP2C9/– 80 31% Maximum 20 mg 90% increase
Rosuvastatin CYP2C9/þ 40 63% Start with 5 mg Maximum 5 mg 7-fold
Maximum 10 mg
Pravastatin Sulfation/þ 80 34% Start with 10 mg, Maximum 20 mg 282% increase
cautiously
monitor
Ezetimibe Glucuronide 10 – None Caution Up to 12-fold
conjugation
Ezetimibe/simvastatin See above 10/80 77% [85] See above See above See above

The table reports on cyclosporine, as opposed to tacrolimus, because tacrolimus is more of a victim, and less of a perpetrator, in terms of drug-to-drug pharmacokinetic interactions,
compared with cyclosporine, due the low molar quantity of tacrolimus, compared with cyclosporine, competing with the other compound (i.e. an anti-diabetic drug or statin) for bind-
ing with CYP3A/transporter. For instance, as for statins, whereas tacrolimus has no pharmacokinetic interaction with atorvastatin, cyclosporine causes several-fold increase in exposure
to atorvastatin by decreasing the intestinal and hepatic efflux by P-gp [27] and by decreasing hepatic uptake by OATP1B1 [23].
a
SGLT2 inhibitors may not be able to reduce HbA1c in patients with reduced GFR (e.g. <60 mL/min).
b
Although no specific adverse reaction, such as rhabdomyolysis or hepatitis, has emerged for transplant candidates and recipients treated with statins, the risk of toxicity is deemed to
be augmented due to drug interactions or accumulation. Atorvastatin, lovastatin and simvastatin undergo metabolic degradation by cytochrome-P4503A4 (CYP3A4); this group
of CYP3A4-dependent statins interact with grapefruit [28] and medications such as non-dihydropyridine calcium channel blockers, protease inhibitors, macrolides and azole antifun-
gals [29].
c
Doses of statins with cyclosporine are those reported by the summary of product characteristics.
AUC, area under the curve; CYP, cytochrome P; DPP-IV, dipeptidyl peptidase-4; OATP1B1, organic anion transport polypeptide 1B1; P-gp, P-glycoprotein; GLP-1, GLP glucagon-
like-peptide-1; MRP2, multidrug-associated protein 2; OAT3, organic anion transporter; BRCP, breast cancer resistance protein.

Metabolic
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 condition that has been described as ‘hypertriglyceridaemic and low efficacy) and the newest dipeptidyl peptidase-4 inhibi-
waist’ [35]. Using standard dual-energy X-ray absorptiometry tor linagliptin (which does not require dose adjustment for re-
scans, an easy and inexpensive way to assess visceral fat in trans- nal function). Rosiglitazone is rarely used because it may
plant candidates, von During et al. showed that visceral fat is bet- necessitate the use of diuretics and predisposes to CNI toxicity.
ter related to PTDM than BMI [36]. The other identifying Only a few clinical studies have explored the efficacy and safety
characteristic of metabolic syndrome is high triglyceride levels; of sodium-glucose co-transporter-2 (SGLT2) inhibitors in
in a study on >300 transplant candidates, pre-transplant triglyc- patients with CKD. These studies have predominantly included
eride levels of 200 mg/dL were associated with an increased patients with CKD stage 3 and have demonstrated that the
risk of PTDM, with the risk varying according to the type of cal- glucose-lowering efficacy of SGLT2 inhibitors in these patients
cineurin inhibitor (CNI), being 7% and 26% with cyclosporine is diminished, most likely as a result of reduced GFR [70].
and tacrolimus immunosuppression, respectively [37]. Various Metformin may be used only in closely monitored stable trans-
studies have suggested that uraemic adipose tissue may be dys- plant recipients, who have been instructed to temporarily with-
functional and be a contributing factor to the development of draw the drug in conditions of pending dehydration or when they
CVD in CKD patients. In fact, it has been postulated that visceral undergo contrast media investigations or any other situation that
fat could cause metabolic abnormalities by secreting inflamma- predisposes to an increased risk of acute graft dysfunction.
tory adipokines, which increase the risk of CVD [38] (see Metformin may cause some weight loss in obese patients.
Table 2, which describes the use of adipokines as biomarkers, Liraglutide might help to induce and maintain weight loss in obese
along with the use of biomarkers associated with other metabolic transplant recipients though studies in this setting are lacking.
abnormalities). It is important to stress that metabolic syndrome Hypomagnesaemia, vitamin D deficiency and hepatitis C vi-
and visceral adiposity are sensitive to lifestyle changes [35]. rus (HCV) infection are additional conditions that might be
Family history of diabetes or gestational diabetes may help potentially amenable to treatment by drug therapy. Hypomag-
to identify transplant candidates with genetic background as a nesaemia [71, 72], a frequent post-transplant complication that
risk factor. It has been recently recognized that beta-cell dys- may be precipitated by the use of CNIs and proton pump inhib-
function (i.e. impaired insulin secretion) plays a greater role in itors, is often persistent, thus requiring magnesium supplemen-
the pathogenesis of PTDM than in type 2 diabetes [66]. tation (Table 3). Vitamin D deficiency, the correction of which
Predisposition to beta-cell dysfunction post-transplantation is might reduce CVD risk (Table 3), may also increase the risk of
strongly affected by several genetic risk variants. For instance, PTDM [73]. Chronic HCV infection is associated with insulin
the homozygous risk allele of the transcription factor 7-like 2 resistance that normalizes after viral eradication [74]. However,
(TCF7L2) gene, which, in an Italian study, showed a 14% preva- current recommendations suggest that, in most cases, anti-
lence in transplant candidates, is associated with 100% long- HCV direct-acting antiviral agents should be started after trans-
term PTDM risk [67]. On the other hand, autosomal dominant plantation [75] because HCV RNA-positive transplant candi-
polycystic kidney disease has been associated with increased in- dates can take advantage of access to the HCV-positive donor
sulin resistance, causing an 8% increased risk of PTDM [68]. pool to increase their chance of deceased donor transplantation.
The main anti-diabetic drug for the treatment of hypergly-
caemia early after transplantation is insulin. Because the safety HYPERLIPIDAEMIA AND DYSLIPIDAEMIA
and efficacy of more, compared with less, intensive insulin ther- Ischaemic heart disease (IHD) and other vascular diseases, such
apy are currently uncertain [69], the optimal target of glucose as cerebrovascular and peripheral artery disease, are the leading
levels and HbA1c may be based on the European Renal Best causes of death at any stage of CKD [76] and also after kidney
Practice Clinical Practice Guideline on the management of transplantation [77]. Moreover, IHD is one of the most com-
patients with diabetes and CKD stage 3b or higher [estimated mon causes for delayed or denied access to kidney transplanta-
glomerular filtration rate (eGFR) <45 mL/min] [69]. Based on tion for otherwise suitable transplant candidates [78]. Therefore,
a flow chart diagram, they recommend targeting HbA1c values a critical goal in the evaluation of transplant candidates and
of 8.5% (69 mmol/mol) in patients at risk of hypo- recipients is the identification and correction of modifiable risk
glycaemia, 7.0% (53 mmol/mol) in patients at low risk of factors that contribute to IHD and other vascular diseases.
hypoglycaemia whose diabetes is controlled by drugs, 8.0% Hypercholesterolaemia, a traditional risk factor for IHD, is
(64 mmol/mol) in patients with long-standing diabetes common, but not universal, in dialysis patients, with its preva-
(>10 years) and 7.5% (58 mmol/L) in other cases [22]. Oral lence ranging between 25% and 50% [79]. As CKD progresses,
agents are usually introduced at later stages (e.g. beyond the first hypercholesterolaemia becomes less frequent and contributes
post-operative month) by replacing insulin or by being given in less to IHD because of the underlying U-shaped relationship
addition to insulin (e.g. added to insulin glargine at night in between hypercholesterolaemia and mortality [80]. Following
patients with impaired morning FBG). Because of the lack of successful kidney transplantation, hypercholesterolaemia not
strong evidence supporting one drug over another [69], selec- only becomes an almost universal finding, but also restores the
tion of the oral agent should be based on efficacy, non-renal standard relationship with the incidence of IHD. In fact, in
drug elimination (especially in patients with reduced GFR and/ transplant recipients, hypercholesterolaemia is a strong inde-
or non-stable renal function), side effects and costs (Table 1). pendent risk factor for post-transplant IHD [42].
The most preferred options include the sulfonylureas glipizide However, besides hypercholesterolaemia, transplant candi-
and glimepiride, repaglinide (despite its short duration of action dates and recipients have increased levels of triglycerides and

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Table 2. Biomarkers related to the metabolic risk profile of kidney transplant candidates and recipients

Metabolic
Biomarker Pathophysiology Dialysis patients and interventions Transplant recipients and interventions
Adiponectin Insulin-sensitivity Inverse association with car- Healthy lifestyle Inverse association with PTDM Pioglitazone
(and visfatin) Anti-inflammation diovascular and all-cause Dialysis adequacy [40] Reduction in adiponectin and
Peptide, adipocytokine Energy expenditure up to malnu- mortality (after adjustment Fish oil, statins, pioglitazone, carotid intima-media thick-
trition [8] and reduced bone for waist circumference) [38] L-carnitine, ACE-I, and ness [41]
density [39] ARB
Weak evidence
Leptin Insulin resistance Association with cardiovascu- Same as above Inverse association with all-cause No RCT available
Peptide, adipocytokine Inflammation lar and all-cause mortality mortality [31]
Fullness up to anorexia [8] (after adjustment for waist
circumference) [38]
ResistinPeptide, Same as for leptin [8] Association with cardiovascu- Same as above Association with all-cause mor- No RCT available
adipocytokine lar and all-cause mortality tality and graft loss [43]

risk pre- and post-kidney transplantation

(after adjustment for adipo-
nectin) [42]
Lipoprotein(a) Association with IHD, dependent Increased levels of large No RCT available Decreased levels with functioning No RCT available
A single LDL particle and on small apo(a) isoforms [44] apo(a) isoforms in HD, any transplant [44]
a highly polymorphic apo(a) isoform in PD [45]
apo(a) Association with IHD [44]
Levels inversely correlated
with apo(a) isoform sizes
(no. of kringle iv repeats)
[44]
Homocysteine Endothelial dysfunction Increased levelsa Folic acid 6 Vit B6 and B12 Increased levelsa [48] Folic acid, Vit B6 and B12
AA from essential AA Inflammation and oxidation Association with MACE and No reduction in cardiovascu- No reduction in cardiovascu-
methionine Thrombosis [45] mortality [46] lar and all-cause mortality lar and all-cause mortality
U-shaped epidemiology [45] (meta-analysis) [47] (FAVORIT RCT) [49]
ADMA Association with endothelial dys- Association with kidney dys- Amlodipine, valsartan [56] Decreased levels with functioning No RCT available

https://academic.oup.com/ndt/advance-article-abstract/doi/10.1093/ndt/gfy151/5003174
AA from metabolism of function [50] and atherosclerosis function [52], intima-media Weak evidence transplant [57]
L-arginine [51] thickness, [53], impaired
erythropoietin response [54],
cardiovascular events, and
mortality [55]
Hepcidin It increases to reduce iron avail- Increased levels are associated No RCT available Levels return to normal after suc- No RCT available
Peptide (liver, urinary ex- ability, thus preventing bacterial with anaemia [60], impaired cessful kidney transplantation [9]
creted), binds to ferro- overgrowth [59] immune function [61], and
portin to reduce iron gut fatal and non-fatal cardiovas-
absorption and iron re- cular events [62]
lease from cells [22, 58]
Klotho Renal Klotho mediates phospha- Markedly reduced in CKD. No RCT available Decreased Klotho transcripts in No RCT available
Membrane Klotho acts as turic effect of FGF-23 Reduced circulating levels are renal grafts after rejection and is-
kidney co-receptor for associated with the presence chaemia–reperfusion injury.
FGF-23. Soluble Klotho and severity of soft tissue cal- Decreased levels in transplant
act as endocrine factor cification [63] recipients [64, 65]
a
In dialysis patients and transplant recipients, homocysteine levels are around 25–35 mmol/L (normal value <15), far below than the extreme hyperhomocysteinaemia (>80 mmol/L) that directly causes thrombotic microangiopathy in cases of
methylmalonic acidosis with homocystinuria.
AA, amino acid; ACE-I, angiotensin-converting enzyme inhibitor; ADMA, asymmetric dimethylarginine; apo(a), apolipoprotein (a); ARB, angiotensin receptor blocker; HD, hemodialysis; PD, peritoneal dialysis; Vit, vitamin; RCT, randomized

5
clinical trial.
 Table 3. Supplementations in transplant candidates and recipients

Transplant candidates Transplant recipients Additional comments

Vitamin D and Vitamin D deficiency: Vitamin D deficiency: There is evidence, albeit weak, to
analogues, and 25-(OH)-cholecalciferol <20 ng/mL 25-(OH)-cholecalciferol <20 ng/mL support treatment of vitamin D
calcium ! Cholecalciferol, 5000–10 000 IU/ ! Cholecalciferol, 5000–10 000 IU/ deficiency with native vitamin
day day D (cholecalciferol) in all phases
of CKD because of its pleiotro-
pic effects on the cardiovascu-
lar system
Secondary hyperparathyroidism: Prevention of post-transplant Vitamin D deficiency in trans-
! Calcitriol and activated vitamin D osteoporosis: plant recipients has been associ-
analogues, with the sole purpose ! Cholecalciferol, 800 IU/day (pts ated with the development of
of reducing PTH levels with normal graft function) PTDM
! 1,25-(OH)2 cholecalciferol, 0.25–
0.50 mg/day (pts with reduced graft
function) with calcium, 1000 mg/
day (including food intake)
Phosphate – Severe hypophosphataemia Hyperphosphataemia may occur in
(serum P <1.5 mg/dL or muscle transplant recipients in cases of
weakness) delayed graft function and chronic
! Phosphate supplementation to graft dysfunction
target serum P levels of 2 mg/dL: Sevelamer should not be used to cor-
– IV fructose-1,6-diphosphate, 2–5 rect hyperphosphataemia in trans-
doses of 5–10 g each (0.35–0.75 g plant recipients because it decreases
of P); CNI absorption by intestinal
– Oral phosphate tablets or syrup, chelation
max 2 g/day in 2–3 divided doses
In less severe cases, increasing milk
intake between meals may suffice
(e.g. up to half a litre/day)
Magnesium Serum Mg is usually normal or Hypomagnesaemia: Hypomagnesaemia, which is
elevated in transplant candidates ! Oral Mg-pidolate, 4.5 g/day mainly caused by CNIs and
(15 Mg mEq) PPIs, has been associated with
! IV MgSO4, 2.5–5.0 g/day (20– an increased risk of PTDM,
40 Mg mEq) for 1–2 days dyslipidaemia and graft failure
Potassium Hyperkalaemia before transplant Hypokalaemia: Mild hypokalaemia occurs fre-
surgery: ! Oral KCl, 1.8–3.6 g (20–50 K quently shorty after successful
! Indication to perform an addi- mEq) for few days transplantation
tional dialysis session in the 24 Hyperkalaemia: Mild hyperkalaemia due to treat-
h preceding the transplant ! Oral polystyrene sulfonates, ment with CNIs and co-
procedure 5–10 g/day in the early post- trimoxazole occurs in 5–40% of
operative weeks transplant recipients and may
also require bicarbonate for
concomitant acidosis
Bicarbonate Metabolic acidosis: Metabolic acidosis: Mild non-anion gap metabolic acido-
! Oral NaHCO3, 1–6 g/day (24–72 ! Oral NaHCO3, 1–3 g/day (24–36 sis, due to renal tubular acidosis or
HCO3 mEq) HCO3 mEq) graft dysfunction, occurs in >50%
Supplementation is usually required of transplant recipients on CNIs
in a minority of dialysis patients, Chronic metabolic acidosis is associ-
and in virtually all CKD patients ated with muscle wasting, insulin
receiving pre-emptive resistance, and increased PTH
transplantation Oral HCO3 should not be given with
mycophenolate or valganciclovir
because reduced stomach acidity
decreases the absorption of such
drugs
Folic acid and Benefit not proven in the absence of Benefit not proven in the absence of –
cyanocobalamin documented deficiency documented deficiency
HCO3, bicarbonate; KCl, potassium chloride; Mg, magnesium; MgSO4, magnesium sulfate; NaHCO3, sodium bicarbonate; PPI, proton pump inhibitor; pts, patients.

atherogenic low-density lipoprotein-cholesterol (LDL-C), and predisposition, nutritional status and inactivity, presence of dia-
reduced levels of protective high-density lipoprotein-cholesterol betes mellitus and tobacco smoking), CKD-specific factors
(HDL-C) [81], a picture to which we refer by the term dyslipi- (such as loss of renal function, nephrotic proteinuria, mainte-
daemia. Dyslipidaemia has multiple aetiologies (Figure 1), nance dialysis) [81] and anti-rejection drugs, particularly corti-
which can be grouped into traditional factors (such as genetic costeroids, cyclosporine (more so than tacrolimus) and mTOR

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 Lipoproteins’ content
CNI Steroids, CNI Triglycerides

mTOR-i Nephrotic Syndrome ESRD, Dialysis Cholesterol

P-lipids and proteins

Dietary
supply Inhibition
Induction
Intestinal
Exogenous pathway

absorption
Chylomicrons Adipose tissue
Tissues -> Deposits/Lipolysis
capillaries
HDL
Free Fatty Acids Muscles
LPL Triglycerides
Bile acids,
Cholesterol
Endogenous pathway

Plasma
VLDL
Chylomicron
Remnants Cholesterol Esters
PCSK9 LDL-R Artery wall
HDL LCAT
Hepatic Lipase LDL IDL
Free Cholesterol
ACAT-2

HMG-CoA Red. LDL-R

Hepatocytes All cell types Foam cells

FIGURE 1: Lipid metabolism and mechanisms of dyslipidaemia in renal transplant candidates and recipients. Dietary lipids represent 30–40%
of the daily caloric intake and mainly consist of triglycerides and, to a lesser extent, cholesterol (exogenous pathway). Triglycerides and choles-
terol are also synthesized in the liver (endogenous pathway). Dietary triglycerides are carried by intestinal chylomicrons and by hepatic very
low-density lipoproteins (VLDLs) to tissues where they are metabolized by the endothelial enzyme lipoprotein lipase (LPL), with the help of
HDL, and eventually become chylomicron remnants and intermediate-density lipoproteins (IDLs). IDLs are partially metabolized by hepatic
lipase to LDL. LDL is picked up by specific LDL-receptors (LDL-Rs) expressed by hepatocytes and other cell types. HDL induces the esterifica-
tion of plasmatic cholesterol released by the cells, a reaction catalysed by lecithin-cholesterol acyltransferase (LCAT). As a result of this reac-
tion, excess cholesterol is transported back to the liver (reverse cholesterol transport). In the liver, accumulation of intracellular cholesterol
causes a negative feedback on the enzyme 3-hydroxy 3-methylglutaryl-coenzyme A reductase (HMG-CoA Red), which causes the inhibition of
cholesterol and LDL-R synthesis and promotes the esterification of free cholesterol. When these homeostatic mechanisms are saturated, mac-
rophages of arterial walls start accumulating plasmatic cholesterol as oxidated LDL and eventually become ‘foam cells’, which contribute to
the formation of atherosclerotic plaques. Patients with ESKD develop hypertriglyceridaemia as a consequence of reduced LPL activity, caused
by insulin resistance and the accumulation of LPL inhibitors such as APO-CII [81, 143]. Moreover, low HDL levels and dysfunctional LCAT
cause impairment of reverse cholesterol transport, which results in accumulation of oxidated LDL [81, 143]. These modifications, which
are further enhanced by dialysis, contribute to the inflammatory milieu of ESKD that is known to promote atherosclerosis. In patients with
nephrotic syndrome, triglyceride levels increase due to inhibition of LPL and hepatic lipase [144]. Cholesterol levels increase because LDL-Rs
are downregulated by proprotein convertase subtilisin/kexin type 9 (PCSK9) and hepatic acyl-coenzyme A cholesterol acyltransferase-2
(ACAT-2) activity is augmented. These modifications result in a significant reduction in intracellular free cholesterol, which, in turn, halts the
negative feedback on cholesterol synthesis, further promoting hypercholesterolaemia [144, 145]. Among anti-rejection drugs, corticosteroids
are known to induce dyslipidaemia by determining insulin resistance, but also by directly inhibiting LPL, inducing HMG-CoA-Red and
downregulating LDL-Rs [82]. CNIs, particularly cyclosporine, inhibit LPL and reduce LDL-Rs, thus increasing LDL levels and inducing
their oxidation [82]. The mTOR inhibitors sirolimus and everolimus are associated with significant dyslipidaemia [47]. Given that mTOR
signalling plays a central role in lipid homeostasis [146], identifying single mechanisms of dyslipidaemia under mTOR inhibition is complex;
a recent experimental paper suggested that elevation in LDL levels under mTOR inhibition is caused by an increase in PCSK9 which, in turn,
downregulates LDL-Rs [147].

inhibitors (sirolimus and everolimus), the latter bearing the cardiovascular risk, rather than lipid levels alone [83]. These
strongest effect among the anti-rejection drugs in causing recommendations reflect the results of randomized clinical tri-
hypercholesterolaemia [82]. als in dialysis patients (4D and AURORA) [26, 84] that showed
The KDIGO guidelines recommend that levels of total cho- a lack of benefit of statins in lowering mortality and major ad-
lesterol, LDL-C, HDL-C and triglycerides should be measured verse cardiovascular events (MACE), despite effective choles-
in dialysis patients and transplant recipients [83], but that treat- terol reduction [83]. However, in the SHARP trial on 9270
ment decision in dialysis patients should be based on overall CKD patients, 3023 of whom were on dialysis, addition of

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 ezetimibe to simvastatin resulted in a significant reduction in Steroids, by additionally causing insulin resistance, strongly
MACE (17% relative risk reduction) [85]. Therefore, other contribute to the incidence of PTDM. However, steroid avoid-
guidelines propose targeting LDL-C levels of <100 mg/dL in ance and withdrawal protocols may also increase the incidence
patients without CVD or <70 mg/dL for patients with CVD of acute rejection, especially in patients at increased immuno-
and advanced CKD [86]. A lipid-lowering treatment should be logical risk, and of post-transplant recurrence of IgA nephropa-
started for LDL-C levels of >100 mg/dL or non-HDL-C levels thy [94] and other glomerulonephritides [95]. Conditions at
of >130 mg/dL with triglyceride levels of >200 mg/dL, with increased risk of rejection include previous sensitization to hu-
these thresholds being those that identify transplant candidates man leucocyte antigens (HLAs), complete class II HLA mis-
who may also benefit from undergoing non-invasive cardiac match with the donor, history of acute rejection or chronic graft
stress testing [78]. The American Heart Association and the dysfunction due to ongoing rejection and non-adherence to im-
American College of Cardiology Foundation suggest that the munosuppressive treatment. Increased exposure to steroids in
use of statins should be considered in any transplant candidate patients developing acute rejection and glomerulonephritis re-
with dyslipidaemia for the purpose of CVD risk reduction [78], currence may provide an explanation for the lack of benefit in
especially for risk prevention in the perioperative period when terms of PTDM incidence and transplant failure between ste-
the hazard of CVD reaches its maximum [87]. On the other roid avoidance and withdrawal protocols, compared with ste-
hand, HDL-C levels of <40 mg/dL are not an indication for any roid maintenance protocols, up to 5 years after transplantation
treatment other than lifestyle changes [78]. In this respect, as [96]. Recent findings from the ADVANCE study, a large ran-
further detailed below, all transplant candidates and recipients domized controlled trial performed on >1000 kidney trans-
should optimize their lifestyle habits, quit smoking, engage in plant recipients treated with basiliximab, tacrolimus and
regular physical activity and avoid being overweight [83, 86]. mycophenolate, showed that the safety of steroid avoidance
Concerning transplant recipients, based on the results of a protocols may be improved by giving a short course of steroids
key randomized controlled trial [88, 89], current guidelines and post-operatively. The study showed that a strategy based on ta-
systematic reviews agree on starting statins to treat dyslipidae- pering steroids over 10 days after an intraoperative corticoste-
roid bolus, as opposed to a strategy based on administering an
mia, with the aim to reduce MACE and cardiovascular mortal-
intraoperative bolus only, reduces the risk of acute rejection by
ity [83, 86, 90]. In the ALERT study, fluvastatin (40 mg) did not
5% (8.7% versus 13.6%), without increasing the risk of PTDM
significantly reduce the risk of MACE, compared with placebo,
up to 2 years post-transplantation [97].
in 2102 transplant recipients with total cholesterol levels of be-
By inducing insulin resistance, steroids are also associated
tween 4 and 9 mmol/L (155–358 mg/dL) and followed up for
with worsening dyslipidaemia (Figure 1). Indeed, it has been
5.1 years, but reduced the risk of cardiac deaths or non-fatal
shown that limiting steroid use improves dyslipidaemia in kid-
IHD (35% relative risk reduction) [88]. In the ALERT extension
ney transplant recipients [82]. Although CNIs also cause hyper-
study, in 1652 transplant recipients followed up for 6.7 years,
lipidaemia, by far, the drugs with the strongest hyperlipidaemic
80 mg fluvastatin was associated with a reduced risk of MACE effects are mTOR inhibitors (Figure 1). In fact, >60% of trans-
(21% relative risk reduction) and cardiac death or non-fatal plant recipients using mTOR inhibitors require a cholesterol-
IHD (29% relative risk reduction), but not of overall mortality lowering treatment, a figure that is twice as high as in kidney
and graft loss [89]. transplant recipients not exposed to those drugs [98]. On the
Table 1 shows the characteristics of lipid-lowering drugs and other hand, mTOR inhibitors also exert a number of anti-
specific implications of their use in transplant candidates and atherogenic effects such as inhibition of smooth muscle cell
recipients. proliferation, inhibition of monocyte chemotaxis and inhibition
of intra-plaque neoangiogenesis, so much so that the introduc-
ANTI-REJECTION DRUGS AND METABOLIC tion of drug-eluting stents coated with mTOR inhibitors has
RISK proven successful in interventional cardiology [99]. Therefore,
Immunosuppressive medications significantly affect glucose the strong hyperlipidaemic effect of mTOR inhibitors may not
metabolism in kidney transplant recipients, with steroids and be associated with an increased risk of CVD.
tacrolimus among the strongest determinants of PTDM. Both
cyclosporine and tacrolimus are associated with PTDM. LIFESTYLE MODIFICATIONS
However, tacrolimus exerts a stronger inhibitory action on pan- There is ample evidence that physical exercise improves insulin
creatic beta-cells, compared with cyclosporine [91]. A recent sensitivity, prevents unhealthy weight gain, decreases central fat
randomized study showed that, in transplant recipients devel- distribution and corrects other features of metabolic syndrome.
oping PTDM, replacement of tacrolimus with cyclosporine sig- In patients with CKD, regular exercise exerts a beneficial effect
nificantly improves glucose metabolism and has the potential to on blood pressure, heart rate and some nutritional parameters
reverse diabetes in one in four of these patients [92]. By con- [100]. Few studies, however, have specifically investigated the
trast, use of mTOR inhibitors, instead of tacrolimus, does not effects of regular exercise on metabolic risk factors in CKD
reduce the risk of PTDM. On the contrary, a recent meta- patients. A recent multi-centric randomized controlled trial
analysis showed that, in low-risk patients, conversion from showed that even a low-intensity, individualized, home-based
CNIs to mTOR inhibitors was associated with a non-significant 6-months’ walking exercise programme managed by dialysis
trend towards an increased risk of PTDM [93]. staff (10-minute walking twice daily on non-dialysis days)

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 improves the physical performance of patients on haemodialy- established conventional risk factors [112]. Moreover, severe
sis [101]. Moreover, a recent cross-sectional study showed that vascular calcification of the iliac arteries may preclude success-
a proactive attitude of dialysis staff greatly affects the propensity ful vascular anastomosis with the renal graft, jeopardizing the
of dialysis patients to engage in physical activity [102]. It has transplantability of dialysis patients. Finally, in rare instances,
been shown that in transplant candidates, higher exercise ca- severe coronary artery wall calcification causing occlusive coro-
pacity is a strong predictor of patient survival post-transplanta- nary artery disease may expose the transplant candidate to an
tion [103] and that both aerobic and resistance training is unacceptable risk with kidney transplant surgical operation
feasible and clinically beneficial post-transplantation [104, 105]. [78]. Kidney transplantation slows down the progression of ar-
Lifestyle prevention of PTDM has only been tested in one small terial calcification but, unfortunately, does not reverse the pro-
intervention study, with modest improvement in postprandial cess [113]. In fact, the annual rate of progression of coronary
glycaemia in the intervention group [106]. On the other hand, a artery calcification after transplantation is 12% despite re-
small randomized controlled trial in transplant recipients stored kidney function [114]. Because reducing serum phos-
showed a non-statistically significant trend towards an im- phate levels can prevent vascular calcification, every potential
provement in HDL-C in patients undergoing exercise training transplant candidate should be treated according to current rec-
[107]. On this basis, a recent position paper suggested to start ommendations for CKD-MBD from the early stages of CKD
regular exercise 45 days post-transplantation to reduce the risk [115], with special regard to targeting normal serum phosphate
of PTDM [12]. With regard to other healthy lifestyle measures, levels (e.g. 4.5 mg/dL). On the other hand, phosphate binders or
we recommend that transplant recipients follow current dietary calcimimetics are of limited efficacy and do not reduce the rate
guidelines for the prevention and management of dyslipidaemia of clinical adverse events in subjects with established vascular
in the general population [108]. Accordingly, transplant recipi- calcification [116]. Moreover, phosphate binders such as seve-
ents should avoid being overweight. Rather, they should con- lamer cannot be used in transplant recipients with CKD-MBD
stantly adjust their total caloric intake to maintain the desirable because they result in intestinal chelation of CNIs and de-
body weight. Physical activity should be such to expend at least creased drug absorption [117].
200 kcal/day. They should limit the intake of LDL-C-raising After successful kidney transplantation, some of the labora-
nutrients (saturated fats should be <7% of total calories, and di- tory parameters of CKD-MBD reverse spontaneously. The
etary cholesterol <200 mg/day), choose foods rich in fibre and most remarkable change is the restored renal tubular capacity
complex carbohydrates and possibly increase the intake of of phosphate excretion, in response to high concentrations of
LDL-C-lowering substances such as plant stanols/sterols (5– FGF-23 and PTH [118], which, along with the phosphaturic re-
10 g/day) and viscous (soluble) fibres (2 g/day). Both transplant sponse to anti-rejection drugs such as steroids, CNIs or mTOR
candidates and recipients should quit smoking and limit alcohol inhibitors, causes hypophosphataemia in 50–85% of transplant
consumption. recipients [119]. Hypophosphataemia, which develops early af-
ter transplantation and usually reverses before the 12th month
HYPERPHOSPHATAEMIA AND ABNORMAL post-transplantation [119], is usually mild and transient, requir-
CALCIUM METABOLISM ing phosphate supplementation in only a minority of transplant
CKD-mineral bone disorder (CKD-MBD), a term that recipients (Table 3).
describes related abnormalities of mineral metabolism, bone After successful transplantation, PTH and FGF-23 levels
and the cardiovascular system, affects both transplant candi- spontaneously return to near-normal values by the third post-
dates and recipients. However, unlike other metabolic abnor- transplant month [120], whereas 1,25-(OH)2-vitamin D levels
malities such as diabetes, obesity and dyslipidaemia, which may may take up to 18 months. However, in 10–50% of transplant
develop de novo or worsen after transplantation as a conse- recipients, post-transplant hyperparathyroidism may persist af-
quence of the use of immunosuppressive drugs, in recipients of ter transplantation due to the acquired autonomy of parathy-
a well-functioning renal graft, CKD-MBD abnormalities are roid glands [121]. In fact, between 15% and 30% of transplant
merely a consequence of the abnormalities that had progressed recipients develop various degrees of hypercalcaemia early after
before transplantation. transplantation [121]. Symptomatic hypercalcaemia usually
In transplant candidates, CKD-MBD develops as a conse- develops in transplant recipients with a history of elevated PTH
quence of reduced renal function causing hyperphosphataemia, levels, which has been controlled by the use of calcimimetics be-
hypocalcaemia and hormonal abnormalities such as decreased fore transplantation [122]. Hypercalcaemia, by inducing renal
levels of 1,25-(OH)2-vitamin D and increased levels of parathy- vasoconstriction, causes graft dysfunction and acute kidney in-
roid hormone (PTH) and fibroblast growth factor-23 (FGF-23). jury, requiring hospital readmission, and may eventually cause
Hormonal abnormalities cause impaired bone turnover and ex- graft nephrocalcinosis [123]. Therefore, in transplant candi-
ert direct adverse cardiovascular effects such as left ventricular dates who have severe hyperparathyroidism before transplant
hypertrophy; hyperphosphataemia eventually produces arterial (e.g. an intact PTH level 800 pg/mL despite optimal medical
calcification [109]. Arterial calcification is highly prevalent in therapy), parathyroidectomy should be preferred over control-
dialysis patients [110], with abdominal and coronary artery cal- ling PTH with calcimimetics [124]. After transplantation, most
cification detected in more than two-thirds of these patients subjects with persistent hyperparathyroidism will respond to ei-
[111]. It has been shown that the extent of arterial calcification ther calcimimetics or parathyroidectomy, although a recent
is predictive of subsequent cardiovascular mortality beyond the randomized controlled trial showed that parathyroidectomy is

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 slightly superior to calcimimetics in terms of serum calcium (Table 2), which is produced in response to chronic inflamma-
and PTH control [125]. However, compared with parathyroid- tion and is an expression of functional iron deficiency (i.e. low
ectomy, calcimimetics have the additional disadvantage of in- plasma iron and intracellular sequestration), have been associ-
creasing urinary calcium excretion, which may result in ated with anaemia and CVD [62]. Interestingly, hepcidin levels
nephrocalcinosis [126] and reduced bone mineral mass [127]. rapidly return to normal after successful transplantation [142].
Therefore, in transplant recipients, calcimimetics should be
used as a bridge therapy to post-transplant parathyroidectomy, CONCLUSIONS
rather than as a life-long treatment aimed at avoiding parathyr-
oidectomty altogether [127]. Interventions aimed at controlling the metabolic abnormalities
underlying the development of arterial calcification, which may
impede access to transplantation and impair transplant out-
OTHER ABNORMALITIES
comes, need to be initiated early in the course of CKD, because
Hyperuricaemia by the time patients are offered a kidney graft, it may be too late
to attenuate the arterial calcification-associated risks. Although
Hyperuricaemia (uric acid levels >7 mg/dL) is common
there are no large randomized clinical trials on the treatment of
among kidney transplant candidates and even more so after
transplantation, developing in up to 80% of patients taking obesity in transplant candidates, there is growing evidence that
CNIs, especially cyclosporine [128]. Hyperuricaemia occurs in newer surgical and medical strategies may safely increase access
many conditions associated with an increased cardiovascular to transplantation for obese patients. In transplant recipients,
risk such as metabolic syndrome, obesity, dyslipidaemia, older metabolic abnormalities that result from adverse effects of anti-
age and diuretic use. It is also associated with reduced renal rejection therapy, as opposed to those resulting from renal graft
function. However, evidence relating a causal effect of hyperuri- dysfunction and previous prolonged exposure to dialysis, may
caemia to CVD is conflicting. Moreover, available evidence sug- be effectively controlled by lifestyle changes and the judicious
gests that uric acid should be considered more as an early use of drugs for the treatment of abnormal glucose metabolism
marker of tubular dysfunction than a causative agent of kidney and dyslipidaemia.
disease [129]. Finally, no uric acid-lowering drug is risk-free. It
is therefore reasonable to recommend against the universal use REFERENCES
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27: 2487–2494 Received: 6.4.2018; Editorial decision: 1.5.2018

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