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337
The 2022 guidelines for PTDM recommend using the oral glucose tolerance test
(OGTT) because of its increased sensitivity [25]. However, the OGTT is generally
less convenient and more costly for patients, as it requires multiple blood draws.
Table11.3 provides the American Diabetes Association (ADA) criteria for diagnos-
ing diabetes in the general population. Note that the hemoglobin A1c is not recom-
mended as a diagnostic test until at least 3months post-transplant to allow for new
hemoglobin to be synthesized and glycated for an adequate period. Because anemia
is common in solid organ transplant recipients [28, 29], the HbA1c should be used
and interpreted with caution when there is abnormal red blood cell turnover.
11.3.2 Pathophysiology
Both traditional and transplant-specic risk factors contribute to the development of
PTDM.As with the general population, traditional risk factors include age>40,
obesity (BMI >30), family history of diabetes, and being a member of certain racial
and ethnic groups [31]. Transplant-specic risk factors are primarily related to
immunosuppressive medication side effects. Corticosteroids decrease insulin secre-
tion, increase insulin resistance, increase hepatic gluconeogenesis, and increase
plasma glucose and hence diabetes incidence in a dose-dependent fashion [32].
Multiple studies have demonstrated a higher risk of PTDM in solid organ transplant
recipients treated with steroid-containing regimens compared to steroid-free regi-
mens. For example, a study of over 25,000 kidney transplant recipients followed for
Table 11.3 Diagnostic criteria for diabetes
Diagnostic test Comment
Symptoms of diabetes (polyuria,
polydipsia, and/or unexplained
weight loss) with random plasma
glucose ≥200mg/dL [30]
Fasting plasma glucose ≥126mg/
dL [30]
Fasting is dened as no caloric intake for at least 8h
Test should be conrmed by repeating the same test or
with a concurrent different diagnostic test [30]
Two-hour plasma glucose ≥200mg/
dL during an oral glucose tolerance
test (OGTT) [30]
Test is performed using a glucose load of 75g
Test should be conrmed by repeating the same test or
with a concurrent different diagnostic test [30]
Hemoglobin A1c (HbA1c)≥6.5% Test should be conrmed by repeating the same test or
with a concurrent different diagnostic test
HbA1c should NOT be used until at least 3months
post-transplant to allow for new hemoglobin to be
synthesized and glycated
HbA1c may be confounded by abnormalities in red blood
cell turnover (anemia is common is solid organ transplant
recipients)
Some guidelines recommend the OGTT instead of the
HbA1c [25]
11 Metabolic Complications intheAdult Solid Organ Transplant Recipient
338
3years found a 42% increased risk for PTDM in those who received glucocorticoids
compared to those who did not [33]. Of note, even in solid organ transplant recipi-
ents who do not receive steroids, the risk of PTDM is still elevated compared to the
general population due to side effects from the other commonly used
immunosuppressants.
Calcineurin inhibitors (CNIs) are suspected to increase risk for PTDM by
decreasing insulin synthesis and secretion [34]. Notably, tacrolimus carries a higher
risk of NODAT than cyclosporine [10] but because it is associated with more favor-
able outcomes it remains the more commonly used CNI [35].
For mammalian target of rapamycin (mTOR) inhibitors including sirolimus, the
mechanism for PTDM is increased insulin resistance. This effect seems to be ampli-
ed when these medications are paired with calcineurin inhibitors. Of note, azathio-
prine, mycophenolate mofetil, and belatacept do not appear to increase diabetes
risk [32].
(See also Chap. 3 for discussion of side effects of immunosuppressive
medications).
11.3.3 Screening
Consensus guidelines for PTDM recommend screening at 10–13weeks and 1year,
and if negative, to perform more frequent testing depending on risk factors such as
impaired fasting glucose, prediabetes, or other risk factors [25]. Guidelines for kid-
ney transplant recipients recommend frequent screening for PTDM [15]. This
includes weekly fasting serum glucose levels for the rst 4 weeks, followed by fast-
ing glucose levels, oral glucose tolerance test (OGTT), or HbA1c at 3, 6, and
12months post-transplant, and annually thereafter (Table11.2). Abnormal fasting
glucose levels should be veried either by repeating the test on another day or
obtaining an HbA1c or OGTT.As per the discussion above, caution should be used
with interpreting the HbA1c if there are abnormalities of red blood cell turnover.
Additionally, because most solid organ transplant recipients have routine blood tests
every 3months, if non-fasting hyperglycemia is found, they should be retested with
one of the recommended tests in Table11.3, either by the transplant team or referred
back to their primary care provider.
11.3.4 Prevention andTreatment
As with the general population, solid organ transplant recipients with identied risk
factors for diabetes including prediabetes, obesity, metabolic syndrome, or a family
history of diabetes should be counseled on lifestyle changes including weight loss
(if overweight or obese), a healthy diet, and exercise to reduce their risk of develop-
ing PTDM.
A. L. Golob et al.
339
Management of PTDM varies based on its timing and etiology. In the early post-
transplant period, PTDM may be related to high doses of corticosteroids in which
case it is best managed with insulin therapy and is anticipated to improve as corti-
costeroid doses are reduced. However, when diabetes persists after steroids are
decreased or stopped; or develops as a later complication, management principles
are similar to those for the general population as per current ADA guidelines.
Treatment typically begins with lifestyle modication, then oral or injectable non-
insulin agents, followed by insulin, unless glucose derangements are profound, in
which case insulin may be preferred as initial therapy.
Caution should be taken to avoid specic diabetes medication side effects and
contraindications to which transplant patients may be particularly vulnerable. For
example, solid organ transplant recipients with PTDM and post-graft estimated glo-
merular ltration rate (eGFR) <30mL/min/1.73m
2
should not be treated with met-
formin, and caution should be used with sulfonylureas due to risk of hypoglycemia.
Thiazolidinediones (TZDs) are usually avoided due to risk of uid retention,
decreased bone density and liver injury.
There is increasing evidence to support the use of newer agents for PTDM [36].
A 2020 systematic review of dipeptidyl peptidase 4 (DPP4) inhibitors in kidney
transplant recipients found evidence for efcacy for glycemic lowering and no sig-
nicant adverse effects on renal function or immunosuppression levels [37].
Similarly, several studies of patients with history of liver, kidney or heart trans-
plant regarding using glucagon-like peptide 1 receptor agonists (GLP-1 RAs) to
treat diabetes found these medications to be effective, tolerable, and safe without
adverse effects on immunosuppressant levels or increases in post-transplant compli-
cations [38–40].
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have also been studied and
found to be generally safe and effective in kidney and heart transplant recipients
with PTDM [41, 42]. Included study patients had an eGFR >30mL/min/1.73m
2
,
and similar to studies in non-transplant populations, SGLT2i recipients had a higher
rate of genitourinary infections compared to placebo recipients.
If a patient’s diabetes is difcult to control, the primary care provider may dis-
cuss with the transplant team whether a change in the immunosuppressive regimen
is feasible. The transplant specialist may consider such strategies as reducing or
stopping corticosteroids or reducing the calcineurin inhibitor dose. However, these
modications must be balanced against the risk of rejection [32].
There is not a consensus on the optimal target HbA1c for solid organ transplant
recipients with PTDM.Many experts recommend aiming for a HbA1c <7.0mg/dL
but this should be individualized to balance the benet of improved glycemic con-
trol against the risks of hypoglycemia and adverse effects of medications. Of note,
the HbA1c may not be reliable in the setting of anemia, use of erythropoietin stimu-
lating agents, or in kidney transplant recipients who have post-transplant erythrocy-
tosis, in which case self-monitored blood glucose measurements should be used to
adjust therapy. In difcult to control cases, referral to an endocrinologist is
appropriate.
11 Metabolic Complications intheAdult Solid Organ Transplant Recipient
340
11.4 Chronic Kidney Disease
11.4.1 Epidemiology
The development of chronic kidney disease (CKD) following solid organ transplan-
tation is both common and ominous. In the most comprehensive study of non-
kidney solid organ transplant (NKSOT) recipients, the prevalence of CKD with a
stage of 4 or greater (GFR<30mL/min/1.73 m
2
) at 5years was 18.1% in liver
transplant recipients, 15.8% in lung transplant recipients and 10.9% in heart trans-
plant recipients [43]. It was further associated with an increased risk of death, with
a relative risk of 4.55 compared to transplant recipients who did not develop renal
failure. Longer-term studies show a progressive increase in prevalence: in a study of
liver transplant recipients, 65% had stage 3 or greater CKD (GFR of <60mL/
min/1.73 m
2
) at 10 years [44]. Kidney transplant recipients are also at risk for
chronic kidney disease both from graft dysfunction as well as etiologies common to
all solid organ transplant recipients (see Chap. 4).
11.4.2 Pathophysiology
Risk factors for the development of CKD after solid organ transplantation can be
divided into four groups: pre-transplant risk factors, peri-operative complications,
immunosuppressive medications used post-transplant, and risks unique to kidney
transplant recipients (Table11.4).
Pre-transplant risk factors include risk factors seen in the general population
such as hypertension and diabetes, in addition to issues specic to end-stage organ
Table 11.4 Causes of chronic kidney disease in solid organ transplant recipients
Pre-transplant risk factors
Hypertension
Diabetes
Conditions related to organ failure: e.g., cardiorenal syndrome, hepatorenal syndrome,
hepatitis B and C glomerulonephritis, IgA nephropathy
Peri-operative complications
Acute kidney injury (various causes)
Immunosuppressive medications
Calcineurin inhibitors (tacrolimus, cyclosporine)
mTOR inhibitors
Factors unique to kidney transplant recipients
a
BK virus nephropathy (BKVN)
Allograft rejection
Anatomic
Transplanted renal artery stenosis
Ureteral obstruction
a
See Chap. 4
A. L. Golob et al.
341
dysfunction. For example, patients with liver cirrhosis and heart failure often have
low effective circulating volume which can affect kidney function. Creatinine alone
is a poor indicator of pre-transplant kidney function, as many patients awaiting
transplant have low muscle mass due to their underlying disease. A combination of
GFR calculation and measurement of urine protein and creatinine offers a better
understanding of a patient’s kidney function prior to transplantation.
Organ transplant operations themselves carry signicant risk that can impact the
kidney. Intra- or post-operative hypotension and hypoperfusion can lead to acute
kidney injury, and in turn, may lead to chronic kidney disease. In addition, there are
organ-specic operative issues that may contribute such as use of cardiopulmonary
bypass in heart transplantation [1].
Immunosuppressant medications are a large contributor to the development of
CKD in solid organ transplant recipients. Calcineurin inhibitors, including cyclo-
sporine and tacrolimus, are known to cause renal impairment and are estimated to
contribute to 40%–80% of cases of ESRD after NKSOT [45]. Despite this, tacroli-
mus is a rst-line immunosuppressive medication due to lower rates of graft loss
and rejection, and improved patient survival [46]. Calcineurin inhibitors cause renal
vasoconstriction that can lead to acute kidney injury and chronic use can lead to
interstitial brosis and renal impairment. mTOR inhibitors, such as sirolimus, are
used much less frequently than CNIs, but also carry a notable risk of kidney dys-
function. This class of medications is associated with proteinuria, and patients need
to be monitored for development of this complication [46] (see Chap. 3).
Patients who have received a kidney transplant may experience a unique set of
renal complications. The underlying disease that initially led to kidney failure may
recur in the transplanted organ (e.g., IgA nephropathy). Rejection may lead to graft
failure and recurrent kidney failure. In addition, BK virus nephropathy is a common
cause of nephropathy in kidney transplant recipients. BK viremia develops in
approximately 20% of adult kidney transplant recipients, and approximately 1–10%
develop nephropathy related to secondary tubulointerstitial nephritis and/or ureteral
stenosis [46–48] (see Chap. 4).
11.4.3 Screening
Post-transplant kidney function should be monitored regularly. The intensity of
monitoring will be greatest during the peri-operative period and then decrease in
frequency as the patient transitions to general outpatient care. In general, quarterly
monitoring of serum creatinine/eGFR and annual urine protein is performed in most
solid organ transplant recipients after the acute post-operative period.
The Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work
Group guidelines include more specic recommendations for kidney transplant
recipients, including BK virus monitoring (see Chap. 4) [15].
11 Metabolic Complications intheAdult Solid Organ Transplant Recipient
342
11.4.4 Prevention andTreatment
Prevention and treatment of CKD in solid organ transplant recipients largely mim-
ics strategies in the general population, including avoidance of nephrotoxic medica-
tions, avoidance of hypovolemia/hypoperfusion, and management of hypertension
and diabetes.
The benets and risks when using ACE inhibitors are similar to the discussion
above regarding hypertension management. In the general population with CKD,
ACE inhibitors and ARBs are an evidence-based therapy to delay progression of
kidney disease, especially if proteinuria is present. However, their efcacy in delay-
ing CKD progression in SOT recipients is unclear, and when used, they should be
closely monitored as they may decrease GFR and worsen hyperkalemia. There is no
consensus yet as to the routine use of ACE inhibitors and ARBs in solid organ trans-
plant recipients with CKD, but it is common practice to avoid their use in the early
period after transplantation (e.g. 0–6months). They should also be avoided in kid-
ney transplant recipients with known renal artery stenosis.
There is keen interest in the potential for SGLT2 inhibitors to preserve renal
function in SOT recipients with CKD.SGLT2 inhibitors appear safe to use for the
treatment of diabetes in SOT recipients; however, their impact on renal function in
this population is yet uncertain. Multiple trials that seek to answer this question are
ongoing currently [49].
An issue that is unique to the solid organ transplant recipient is the management
of chronic kidney disease caused by calcineurin inhibitors. Despite its many poten-
tial adverse effects including nephrotoxicity, tacrolimus remains a rst-line immu-
nosuppressive medication. As time since a patient’s transplant extends and the risk
of acute rejection decreases, the goal tacrolimus level can be decreased, in turn
decreasing some of the nephrotoxic effects of the medication. If the primary care
provider identies worsening chronic kidney disease, in addition to assessing for
other causes, the transplant team should be contacted to discuss potential reduction
in immunosuppressive medication and/or consultation with a nephrologist.
Due to immunosuppressive medications which block T-cell activity, solid organ
transplant recipients have signicant difculty with clearing viral infections. As
noted previously, BK virus and related nephropathy is commonly seen in renal
transplant recipients and managed by the transplant team (see Chap. 4).
11.5 Metabolic Dysfunction-Associated Steatotic Liver
Disease (MASLD)
11.5.1 Epidemiology
MASLD is common in patients with a history of solid organ transplant. In patients
with a history of a liver transplant >50% of recipients have MASLD, either new or
recurrent, 1year after transplant and>75% at 5years [50]. In a study using transient
A. L. Golob et al.
343
elastography to identify patients with MASLD, >50% of renal transplant recipients
were found to have evidence of disease 1-year post-transplant [51].
11.5.2 Pathophysiology
Patients with a history of solid organ transplantation are at increased risk for the
development of MASLD for a number of reasons. As reviewed above, immunosup-
pressing medications such as glucocorticoids and calcineurin inhibitors (CNIs) are
associated with the development of diabetes, hyperlipidemia, and hypertension, all
risk factors for development of MASLD.Post-transplant weight gain also contrib-
utes: in a study of liver transplant recipients, post-transplant BMI had the highest
predictive value for recurrent or de novo steatotic liver disease [50].
11.5.3 Treatment andPrevention
Intensive lifestyle modication aimed at reducing post-transplant weight gain and
associated metabolic syndrome should be of benet with studies showing improve-
ment in many of the risk factors for development of MASLD with exercise and
dietary interventions [52].
Studies have been completed assessing surgical and pharmacologic strategies to
treat weight gain. In patients with a history of liver transplant, sleeve gastrectomy
has been studied and found to have benecial effects on weight loss and metabolic
comorbidities [53]. It is thought that this may be a better option compared to other
surgical options as the weight loss is achieved without signicant malabsorption
and access to the biliary tree is not complicated by the surgery. Small studies have
also been performed assessing the benets and safety of glucagon-like peptide-1
(GLP-1) analogs and have found weight loss benets without increased risk of
rejection, adverse events as compared to non-transplant patients, or need to make
immunosuppressant medication adjustments [54]. A study of patients with a history
of liver, kidney or heart transplant who received GLP-1 analogs to treat diabetes
also found these medications to be safe without effects on immunosuppressant lev-
els or post-transplant complications [38].
11.6 Gout
11.6.1 Epidemiology
Hyperuricemia is common in solid organ transplant recipients, experienced in up to
84% of SOT recipients [55]. Estimates for the prevalence of clinical gout vary
between 6% and 28%, depending on the population studied [56]. Kidney and heart
11 Metabolic Complications intheAdult Solid Organ Transplant Recipient
344
transplant recipients have a higher risk of developing gout than liver transplant
recipients [55]. The reason for this is unclear but may be related to variation in rates
of post-transplant diuretic use and presence of other common comorbid condi-
tions [57].
11.6.2 Pathophysiology
Risk factors for gout are common in solid organ transplant recipients, including
chronic kidney disease, hypertension, and the use of diuretics that increase serum
uric acid levels.
In addition, calcineurin inhibitors (CNIs) including cyclosporine and tacrolimus
are known to cause hyperuricemia. The mechanism is likely a combination of both
decreased excretion and increased accumulation of uric acid due to the medication’s
effects on the kidney. Based on limited data, it appears that the risk of hyperurice-
mia is independent of drug trough levels [58], and cyclosporine may have an
increased risk of new-onset gout after transplant compared to tacrolimus [59]. For
example, in a study of patients followed after renal transplant, the 3-year cumulative
incidence of a new-diagnosis of clinical gout was 7.6%, with a higher risk associ-
ated with cyclosporine than tacrolimus (adjusted hazard ratio 1.24) [57].
11.6.3 Screening/Surveillance
KDIGO Clinical Practice guidelines recommend checking serum uric acid levels
once in kidney transplant recipients, 2–3months post-transplant [15]. Additional
routine surveillance practices vary between transplant centers. Asymptomatic
hyperuricemia is generally not treated pharmacologically but could trigger dietary
modications and inform assessment of new joint pain symptoms.
11.6.4 Clinical Presentation andDiagnosis
In both transplant and general populations, gout is more common in men than
women and commonly involves the rst metatarsophalangeal joint. In SOT recipi-
ents, however, the rst gout attack may occur within 17–24months post-transplant
rather than after several years of hyperuricemia as it more typically occurs in the
general population. In SOT recipients, gout may also develop in unusual sites such
as the sacroiliac joints, costochondral junction and the spine. Gouty tophi appear to
be more frequent in transplant recipients and may appear after a much shorter dura-
tion of hyperuricemia compared to the general population [55, 60].
A. L. Golob et al.
345
For SOT recipients without a history of gout who present with new mono or
polyarticular joint inammation that is suspected to be caused by gout, it is best to
conrm this diagnosis and rule out a septic joint with joint uid aspiration prior to
treating with anti-inammatories.
11.6.5 Treatment
Typical therapies used to treat acute gout ares in the general population include
high-dose non-steroidal anti-inammatory drugs (NSAIDs), colchicine, intra-
articular and systemic glucocorticoids, and IL-1 receptor antagonists (anakinra).
There are special considerations for the treatment of acute gout ares in solid organ
transplant recipients.
Intra-articular glucocorticoids (for one or two involved joints) or systemic gluco-
corticoids (for more than two inamed joints or contraindications for intra-articular
glucocorticoids) are the treatment of choice for acute gout ares in SOT recipients.
Systemic glucocorticoids should be used with caution if the patient has hypervol-
emia, uncontrolled diabetes or hypertension, or a history of serious infectious com-
plications. Furthermore, if the patient has had episodes of rejection treated with
glucocorticoids, or if there is concern for ongoing rejection, then glucocorticoids
could make assessment for rejection more difcult. Most SOT recipients receive
glucocorticoids as part of their immunosuppressive regimen. A short-term increase
in dose followed by a gradual (2–3week) reduction to maintenance dose is a typical
approach. However, the transplant team should be consulted before giving systemic
glucocorticoids to a solid organ transplant recipient.
NSAIDs generally should be avoided in the SOT recipient population. Both
NSAIDs and CNIs can cause renal impairment, in part secondary to afferent arteri-
ole vasoconstriction. When they are taken in combination, the risk of kidney injury
and complications such as hyperkalemia are heightened. In addition, the combina-
tion of NSAIDs and prednisone may increase the risk of gastrointestinal bleeding
and cardiovascular side effects. If NSAIDs are used, they should be discussed with
the transplant team rst, and low doses with close metabolic panel monitoring is
recommended [59].
Colchicine use is also limited in most SOT recipients due to potentially danger-
ous drug interactions. Colchicine levels are increased, potentially to toxic levels,
when used with strong CYP3A4 inhibitors or p-glycoprotein inhibitors, including
CNIs and sirolimus. As a result, a signicantly decreased dose is recommended if
colchicine is used at all for patients on these immunosuppressive medications.
Interleukin 1 inhibitors such as anakinra have also been used off-label for treat-
ment of acute gout ares in solid organ transplant recipients [59] but these medica-
tions may not be readily available, are expensive and fewer providers have experience
using them.
11 Metabolic Complications intheAdult Solid Organ Transplant Recipient
346
11.6.6 Prevention
Patients with two or more ares per year or who have tophi or gout-mediated joint
damage should be offered preventive uric acid-lowering therapy with a target uric
acid level<6mg/dL.Patients with a single episode may also be considered for urate
lowering therapy due to the high risk of recurrence.
Allopurinol, a xanthine oxidase inhibitor, is the rst-line therapy for prevention
of symptomatic gout in most SOT recipients due to its efcacy and low cost. Of
note, current rheumatology guidelines recommend checking for the HLA-B*58:01
allele in patients of Chinese, Thai, or Korean ethnicity, as this allele is associated
with severe allopurinol hypersensitivity reactions. Prescribers should also be aware
of a potentially dangerous interaction between allopurinol and azathioprine.
Azathioprine, a purine synthesis inhibitor, is prescribed to some SOT recipients,
typically in combination with a CNI and prednisone. Because it is also metabolized
by xanthine oxidase, levels can become dangerously high and result in devastating
side-effects if prescribed in combination with allopurinol. When used, allopurinol
should be dosed and titrated based on creatinine clearance until goal serum uric acid
level is achieved [59].
Febuxostat is the other currently available xanthine oxidase inhibitor. Similarly
to allopurinol, it should not be used in combination with azathioprine. In addition,
due to data in the general population indicating that febuxostat is associated with
higher risk of both cardiovascular and all-cause mortality compared to allopurinol
[61], it is considered a second-line medication.
Probenecid, which increases excretion of uric acid in the urine, is considered a
third-line preventive medication for gout in SOT recipients. It is not recommended
in SOT recipients with signicant CKD (eGFR <50mL/min/1.73m
2
) due to lack of
efcacy and it may have interactions with mycophenolate and cyclosporine. For
these reasons, it is typically avoided [59].
When initiating urate lowering therapy, providers should consider concurrent
anti-inammatory therapy for 3–6months to avoid precipitating a gout are. Low
dose glucocorticoids, which may already be part of a patient’s immunosuppression
regimen, may be best tolerated. Long-term use of colchicine in SOT recipients is
limited due to the above drug interaction concerns and an increased risk for colchi-
cine myotoxicity, particularly in heart and kidney transplant recipients and in
patients also taking cyclosporine.
Lifestyle and dietary modications, including weight loss, reducing consump-
tion of foods sweetened with high-fructose corn syrup, and reducing intake of alco-
hol and other high purine foods should also be recommended. In addition, it is
important to review medications used to treat the patient’s comorbid conditions. For
example, thiazides and loop diuretics typically increase serum uric acid. When pos-
sible, patients with gout should have these medications substituted with losartan
(see caution above regarding ARBs) which is uricosuric, or a calcium channel
blocker, such as amlodipine, which can also result in a reduction in serum uric acid
levels and reduced risk of gout [62].
A. L. Golob et al.