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76
4.1.8.2 Urinary Tract Infection
Urinary tract infection (UTI) is relatively common in kidney transplant recipients
due to the altered anatomy, short ureter length and incomplete valve mechanism of
the uretero-vesicle anastomosis.
Patients can present with the usual urinary symptoms such as dysuria, frequency,
or urgency, if the infection is limited to the bladder (cystitis). If the infection involves
the allograft (pyelonephritis), they may present with allograft pain, fever, chills,
malaise, and nausea. In comparison to non-transplant patients, acute kidney injury
may occur more commonly in acute allograft pyelonephritis due to the solitary
functioning kidney in transplant recipients. The clinical diagnosis can sometimes be
challenging since the allograft is denervated and the inammatory response may be
suppressed. It is not uncommon for patients to present with non-specic symptoms
or even isolated allograft dysfunction or fever without other symptoms. In addition,
clear distinction between kidney involvement and isolated cystitis can be unclear
and some experts advocate treating all episodes as complicated UTIs.
Patients with suspected UTI should undergo testing via urine dipstick, urine
microscopy, and urine culture. Blood culture should be obtained for patients exhib-
iting systemic symptoms or sepsis. The diagnosis of UTI is conrmed by the pres-
ence of 10
5
colony-forming units or more of a uropathogen in a clean-catch urine
sample alongside corresponding symptoms. (See Chap. 8 for discussion of diagnos-
tic criteria.) However, presumptive diagnosis commonly relies on routine urinalysis,
which can be challenging to interpret in kidney transplant recipients due to baseline
pyuria and/or bacteriuria. The primary differential diagnosis is acute rejection,
which can occasionally mimic a UTI.Additionally, a history of non-adherence to
immunosuppressive therapy or the introduction of new medications that may cause
drug interactions, leading to subtherapeutic levels of immunosuppressive agents
(common medications in primary care include carbamazepine, phenytoin, primi-
done, nafcillin, rifampin, rifapentine, rifabutin, St. John’s wort, and combined oral
contraceptives, among others), should be considered. Furthermore, the presence of
signicant new-onset proteinuria, severe allograft dysfunction, lack of improve-
ment in allograft function with appropriate antibiotics, new-onset or worsening
hypertension, and, rarely, allograft tenderness and fever should alert primary care
providers to the possibility of acute rejection. In such cases, consultation with gen-
eral or transplant nephrologists should be promptly sought.
The spectrum of pathogens causing UTIs after the immediate post-transplant
period is generally the same of that in the general population: gram negative uro-
pathogens are the most common (60–90%) among which Escherichia coli predomi-
nates. Among gram positive bacteria, enterococci are becoming more
common—accounting for 20–30% in some series especially early post-transplant
[71]. Corynebacterium urealyticum remains uncommon but can be associated with
encrusting cystitis or pyelitis and resulting in urinary tract obstruction—long incu-
bation of culture is required for detection [71]. Furthermore, multi-drug-resistant
bacteria are not uncommon due to routine use of antibiotic prophylaxis (generally
6-to-12-month course post-transplant of TMP-SMX for Pneumocystis jirovecii
B. Boonpheng and I. C. De Castro
77
prophylaxis) and extensive healthcare contact [71]. Primary care providers should
keep these in mind when selecting an appropriate antibiotic regimen.
For obvious simple cystitis, an empiric regimen of either an oral third generation
cephalosporin (e.g., cefpodoxime or cefdinir) or amoxicillin-clavulanate is recom-
mended. The duration of treatment is generally 5–10days. Nitrofurantoin (provided
eGFR or creatinine clearance is >30mL/min) and a single dose of fosfomycin may
also be considered and can be helpful in the setting of multi-drug resistant bacteria.
For antibiotic stewardship, uoroquinolones should generally be avoided in cases of
cystitis; however, some presentations may be less clear initially and the transplant
team may elect to start with a uoroquinolone until the severity of infection is better
dened. In complicated UTIs, IV antibiotics are usually needed initially and a
switch to susceptible oral antibiotics can be made when the patients are stable—
generally duration of treatment is 10–14days. In select cases, an oral uoroquino-
lone can be used if patients are severely ill and are able to maintain oral intake
without vomiting. Attention should be paid to renal dosing of most antibiotics. An
anti-metabolite may need to be halved or held temporarily during a more severe UTI
episode—in consultation with general or transplant nephrologists with a clear fol-
low- up plan to resume previous dosing when the UTI has resolved. Asymptomatic
bacteriuria beyond 2months post-transplant should not be treated unless during
pregnancy or pre-urologic procedures [72].
Recurrent UTIs are generally dened as having ≥2 episodes within 6 months or
≥3 episodes within 1 year. In addition to morbidity, recurrent UTIs can lead to
accelerated allograft impairment and is a known risk factor for the development of
chronic rejection and reduced long-term graft survival or even graft loss [73, 74].
Patients with a history of recurrent UTI should be evaluated for anatomic or func-
tional abnormalities such as urinary tract obstruction, ureteric or urethral strictures,
bladder dysfunction, new-onset kidney or bladder stones, and complex cysts. An
ultrasound of the kidney allograft, native kidney, and measurement of a postvoid
residual volume should be the initial imaging study. If the ultrasound is unrevealing,
a non-contrast CT scan of the urinary tract along with urologic consultation for
consideration of urodynamic study and/or voiding cystourethrogram, and cystos-
copy should be the next steps. The most common ndings include ureteral reux,
ureteric strictures at the ureterovesical junction, neurogenic bladder, and bladder
outlet obstruction, especially in patients over age 60 who have prostate enlarge-
ment. Other sources of recurrent infections include the native kidneys, especially in
transplant recipients who have polycystic kidney disease, and, when applicable, the
prostate. If no urologic or structural issue is found, then reduction of immunosup-
pression should be considered—generally 25—50% reduction of the anti- metabolite
mycophenolate—in consultation with general or transplant nephrologists. If no
clear explanation is found after basic evaluation, transplant infectious disease con-
sultation can be helpful for consideration of suppressive antibiotics.
General preventive measures include encouraging the patients to void regularly
and to double void if they have lower urinary tract symptoms since a full bladder
can increase the risk of reux of urine into the kidneys. Kidney transplant recipients
with neurogenic bladder (commonly due to long-standing diabetic autonomic
4 Primary Care of the Adult Kidney Transplant and Kidney-Pancreas Transplant…
78
neuropathy or spinal cord injury) should be reminded to perform clean intermittent
self-catheterization at a regular interval—usually every 4h when they are awake,
and the urine volume should not exceed 500mL to prevent reux nephropathy and
infection. In patients with lower urinary tract symptoms attributed to benign pros-
tatic hypertrophy, medical management with alpha blockers with or without 5-alpha
reductase inhibitors can be tried rst—just as in non-transplant patients. Most of the
medications in these two classes do not have signicant drug interactions with rou-
tine immunosuppressive medications. Patients with diabetes should achieve optimal
glycemic control. Long-term antibiotic prophylaxis is generally not recommended
but might be considered in select cases; post-coital use of antibiotics in patients with
female urogenital anatomy can also be considered as in the general population
although it is not well-studied in the transplant population. Topical estrogens should
be offered in older patients with vaginal atrophy. In addition, methenamine hippu-
rate, a urine acidifying agent, might be considered and has been shown to be effec-
tive [75] but its use is not recommended in patients with advanced allograft
dysfunction (eGFR <10mL/min/1.73m
2
) due to risk of toxicity.
See Chap. 8, for further discussion.
4.1.8.3 Cardiovascular Disease
When compared to dialysis, the treatment of patients with ESKD with kidney trans-
plantation is associated with a signicant decrease in the incidence of cardiovascu-
lar events. However, cardiovascular disease remains a leading cause of morbidity
and mortality in kidney transplant recipients accounting for up to 20–40% of death
with a functioning graft [9, 76]. This risk is due in part to the high prevalence of
traditional cardiovascular disease and comorbidities such as diabetes, hyperlipid-
emia and hypertension within the ESKD population, the duration of dialysis prior to
transplantation, delayed graft function, exacerbation of risk factors post-transplant
such as hypertension, insulin resistance and dyslipidemia by immunosuppressive
medications, as well as low-grade persistent inammation associated with alloim-
munity [77]. Furthermore, several studies have demonstrated signicant variability
in the rates of cardioprotective medication use amongst kidney transplant recipients,
including angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor
blockers (ARBs), statins, and aspirin [78]. There are challenges in predicting car-
diovascular risks in kidney transplant recipients and the most commonly used risk
scores such as the Framingham Risk Score, the Pooled Cohort Equation or the
QRISK score were not well validated in kidney transplant recipients and did not
capture most non-traditional risk factors; hence they may underestimate the true
risk. There have been attempts at transplant-specic risk scores such as the
CRCRTR-MACE score [77, 79] which includes eGFR and number of previous
transplants in addition to traditional risk factors to predict 7-year major adverse
cardiovascular events and overall mortality more accurately.
All kidney transplant recipients should be evaluated regularly for traditional car-
diovascular risk factors and all of these factors should be treated aggressively.
B. Boonpheng and I. C. De Castro
79
Compared to patients who have advanced chronic kidney disease or are receiving
dialysis, kidney transplant recipients can be more liberal with their diet. However,
even in kidney transplant recipients whose graft functions are excellent with normal
or near-normal serum creatinine or eGFR, they are still considered to have chronic
kidney disease and therefore a heart healthy diet and lifestyle should always be
emphasized. Adherence to low sodium diet is still recommended especially in those
with hypertension and a healthy dietary pattern favoring plant-based or high bio-
logical value protein, fruits and vegetables should be emphasized while processed
and ultra-processed foods should be avoided.
4.1.8.4 Hyperlipidemia
For pharmacotherapy, most kidney transplant recipients should be treated with a
statin, regardless of post-transplant lipid levels, although it should be noted that the
data to support this recommendation is limited. The decision to initiate statin ther-
apy should be individualized—for example, select young adults (<30years old)
who have a non-immunologic cause of kidney failure, no major cardiovascular risk
factors and optimal cholesterol levels might be managed with therapeutic lifestyle
changes alone. The only randomized, controlled trial to assess cardiovascular events
in post-kidney transplant patients with dyslipidemia is the ALERT trial which ran-
domized patients to receive either uvastatin or placebo and showed a signicant
reduction in LDL in the treatment group, and a trend toward reduction of cardiovas-
cular events that failed to reach statistical signicance [77]. Several subsequent
meta-analyzes have shown a reduction in cardiovascular mortality with statin use in
kidney transplant recipients, but results have been mixed with respect to all-cause
mortality [80]. Despite the weak supporting evidence, it is the recommendation of
the KDIGO work group that all post-kidney transplant patients be treated with statin
therapy [81]. The optimal statin choice and dosing strategy is not known, but regard-
less of agent, it is generally recommended to start with a lower dose than that rec-
ommended for the general population in order to reduce the likelihood of adverse
events. If the patient is treated with a CNI and statin therapy is indicated, then
pravastatin or rosuvastatin are preferred as they have a lower risk of drug interaction
while simvastatin should be avoided [81]. In mixed hyperlipidemia, atorvastatin or
rosuvastatin is favored since they can lower triglycerides more effectively. Ezetimibe
can be added or substituted if any statins are not tolerated. PCSK9 inhibitors have
not been adequately studied but so far their use appears to be safe and effective in
lowering LDL [82]. Metabolic complications are also discussed in Chap. 11.
4.1.8.5 Hypertension
Hypertension is extremely common (80–90%) after kidney transplant and should be
treated aggressively. Less than 5% of kidney transplant recipients do not require
treatment for hypertension after one-year post-transplant [83]. Risk factors for
4 Primary Care of the Adult Kidney Transplant and Kidney-Pancreas Transplant…
80
hypertension include anatomical causes such as renal artery stenosis and the use of
calcineurin inhibitors. In the absence of an anatomical lesion, pharmacological
treatment should be used to target a blood pressure of less than 130/80 although
there are only limited data to guide the decision making around the optimal goal
blood pressure [84].
While the optimal antihypertensive agent is not known, in general the treatment
of hypertension in transplant recipients should mirror that of non-transplant recipi-
ents, with the rst-line agent typically being a dihydropyridine calcium channel
blocker (CCBs) such as amlodipine, felodipine or nifedipine XL, particularly in the
rst 6months. Non-dihydropyridine CCBs such as diltiazem and verapamil should
be avoided as they can increase CNI levels by 30%–60% in contrast to dihydropyri-
dine CCBs, potentially resulting in supratherapeutic CNI levels, neurotoxicity, and
nephrotoxicity. If the use of non-dihydropyridine is necessary, the reduction of CNI
dose along with close monitoring of CNI levels, usually within 3–5days, is advised
[25]. In some transplant centers, kidney transplant recipients are maintained on dil-
tiazem or verapamil to “boost” the CNI levels if needed [25]. In this case it should
be kept in mind that discontinuing or changing the dose of diltiazem or verapamil
necessitates titration of the CNI dose and the trough level needs to be monitored
closely—within 3–5days after the change.
The use of beta blockers for hypertension has fallen out of favor in the most
recent American College of Cardiology (ACC)/American Heart Association (AHA)
guidelines [85]. Still, the use of beta blockers is relatively common in kidney trans-
plant recipients, as heightened concerns about side effects from diuretics, ACE
inhibitors or ARBs can limit use of these medications early after transplantation.
Also, many patients with ESKD are maintained on beta blockers, especially those
with cardiovascular risk factors or diseases.
ACE inhibitors (ACEi) and ARBs should be used cautiously in the early post-
transplant period, as they carry some risk of decreased GFR and hyperkalemia, both
of which are exacerbated by calcineurin inhibitor use. Beyond 3–6months post-
transplant when the allograft function has become stable, ACE inhibitors and ARBs
are generally well tolerated and should be strongly considered in patients with pro-
teinuria >1g/day. Data showing benets of ACEi or ARB is lacking in kidney trans-
plant recipients, however.
Thiazide-type diuretics such as chlorthalidone, indapamide or HCTZ are also a
good option for kidney transplant recipients who are prone to hyperkalemia and
metabolic acidosis (type 4 renal tubular acidosis) which is a common side effect of
CNIs [38]. However, the serum magnesium level should be closely monitored and
replaced as needed, as diuretic therapy may exacerbate the magnesium-wasting
from CNIs. As with the general population, patients should be monitored for the
development of hyponatremia, hypokalemia, and hypercalcemia as well as gout.
For resistant hypertension, mineralocorticoid antagonists such as spironolactone,
eplerenone, or nerenone or an epithelium sodium channel (ENaC) inhibitor such
as amiloride are sometimes used in the general CKD population [84]. There are
scant data specic for kidney transplant recipients but so far they are considered
safe. Hyperkalemia is a major concern. If monitored cautiously, these
B. Boonpheng and I. C. De Castro
81
agents—usually in combination with another diuretic–might help control blood
pressure, lower proteinuria at least transiently and prevent further magnesium wast-
ing associated with CNIs. Finerenone specically has been shown to have cardio-
renal protective benets in proteinuric diabetic and non-diabetic CKD stage 1–4
although kidney transplant recipients were excluded from the trials [86, 87]. A ran-
domized controlled trial, however, did not demonstrate extra renoprotective effects
of spironolactone in kidney transplant recipients based on GFR slope and interstitial
brosis on protocol biopsies [88].
Metabolic complications are also discussed in Chap. 11.
4.1.8.6 Diabetes
Diabetes is the leading cause of ESKD in the USA.Accordingly, diabetes is highly
prevalent in kidney transplant recipients. Even patients without antecedent diabetes
are at risk for developing diabetes post-transplant. Estimated rates of post-transplant
diabetes (PTDM) range from 5% to 50% at 1-year post-transplantation, although
the incidence appears to be decreasing [89]. PTDM is a distinct entity from the
phenomenon of transient, glucocorticoid-associated hyperglycemia in the immedi-
ate post-transplant period. The development of PTDM is multifactorial and is asso-
ciated with traditional risk factors for type 2 diabetes, including obesity and a
positive family history of diabetes, as well as unique, transplant-specic risk factors
including the use of certain immunosuppressive medications. Beyond glucocorti-
coids, calcineurin inhibitors have the strongest association with the development of
PTDM, with several studies suggesting increased rates of diabetes with tacrolimus
as compared with cyclosporine [89, 90].
The diagnostic criteria are the same as those in the general non-transplant popu-
lation based on the American Diabetes Association guidelines with caveats that the
hemoglobin A1c (HbA1c) may not be reliable within the rst 45–90days post-
transplant and fasting blood glucose (along with self-monitoring of blood glucose)
is routinely measured instead. The most sensitive test remains the 2-hour oral glu-
cose tolerance test (OGTT) but it is not commonly performed [89]. Beyond 3months
post-transplant, HbA1c and/or fasting blood glucose should be checked every
3–6months within the rst year then at least annually thereafter. There are some
data showing that aggressive basal insulin therapy during early peri-transplant
period may prevent PTDM by protecting pancreatic islet beta cells.
In the early peri-operative period (within 45–90 days post-transplant) when
allograft function remains uctuating and steroids are being tapered, basal and
bolus insulin regimen is the preferred treatment.
Thereafter when allograft function is stable, usually after 3 months, post-
transplant diabetes is managed similarly to diabetes in the non-transplant popula-
tion, with a stepwise progression rst focused on lifestyle modication followed by
oral therapy and then insulin if needed to target a hemoglobin A1C of less than
6.5–7%. The most common traditional oral option used is metformin (provided
eGFR >30mL/min/1.73 m
2
). Other traditional oral options, which are used less
4 Primary Care of the Adult Kidney Transplant and Kidney-Pancreas Transplant…
82
frequently, include pioglitazone (effective but may cause edema and weight gain),
DPP-4 inhibitors (modestly effective with minimal side effects, and linagliptin does
not require renal dose adjustments), sulfonylureas (highly effective but with a risk
of hypoglycemia), and glinides (most suitable for patients with irregular meal
schedules) [89].
Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors, SGLT2is) have
emerged as safe and effective options with cardio-renal protective benets in the
general CKD populations (eGFR >20 mL/min/1.73 m
2
; its glycemic efcacy is
greatly diminished at eGFR <45–50mL/min/1.73 m
2
) [89]. Their use in kidney
transplant recipients has been shown to be safe, without unacceptably high risk of
UTIs or genital infections [91]. However, those at higher risk for UTIs should avoid
SGLT2 inhibitors. They should not be used if a ureteric stent is present. Euglycemic
ketoacidosis is very rare and it can be prevented by educating the patients about sick
day rules [92]—for example, holding SGLT2i temporarily during periods of low
oral intake, pre-operative fasting or nausea, vomiting, and/or diarrhea.
GLP1 agonists (GLP1a) are another option that have been shown to be very
effective in glycemic control and have cardio-renal protective and weight loss ben-
ets in the general CKD population. In transplant recipients, this class of medica-
tions should be prioritized in those with multiple cardiovascular risk factors or
known cardiovascular disease or those with substantial weight gain or obesity [89].
They been shown to be safe—if started at low doses with slow and careful titration
[91, 93]. Although immunosuppressive medication levels have not been shown to be
substantially affected, careful monitoring is still advised given expected delayed
gastric emptying. Most of the available GLP1a are available as subcutaneous injec-
tions (except semaglutide which is also available in an oral form) and most do not
require renal dose adjustment. Metformin, SGLT2i and GLP1a can also be used
with insulin to reduce insulin doses, thereby minimizing insulin-induced weight gain.
Steroid withdrawal or avoidance has not been shown to be particularly impactful
in preventing or reversing post-transplant diabetes but the risk of rejection has been
shown to increase [89, 94]. Changing immunosuppression such as switching from
tacrolimus to cyclosporine or to belatacept might be considered on a case-by-case
basis but this decision is best done in consultation with the transplant centers.
Complex cases in which glycemic control is not readily achieved, or in which
medication options appear to be limited due to comorbidities or intolerances, should
be referred to an endocrinologist. Metabolic complications are also discussed in
Chap. 11.
4.1.8.7 Weight Gain
After successful kidney transplantation, weight gain is very common with an aver-
age of 5%–10% weight gain within the rst year [83]. This is likely due to a combi-
nation of improved appetite, liberalization of diet plus anabolic effects of steroids.
Unlike in the ESKD population where the obesity paradox is observed, obesity in
kidney transplant recipients has been shown to be associated with worse
B. Boonpheng and I. C. De Castro
83
cardiovascular outcomes [95]. Therefore, healthy lifestyles should be strongly
encouraged and emphasized. If weight gain is excessive and resistant to diet and
exercise, a trial of medical therapy including GLP1 agonists or a GLP1 agonist/
glucose-dependent insulinotropic polypeptide (GIP) agonist could be considered
[96]. There are no large-scale data on kidney transplant recipients but anecdotes and
small case series have demonstrated their safety provided the dose titration is slow
and gradual with careful monitoring of immunosuppressive medication levels.
Bariatric surgery has not been adequately studied in kidney transplant recipients.
Patients who have severe obesity prior to transplantation sometimes undergo sleeve
gastrectomy or gastric bypass surgery prior to waitlisting, with some evidence for
improved outcomes [97]. More extensive bypass surgery can potentially lead to
oxalate nephropathy both in the native kidneys and the allografts and impaired
absorption of some immunosuppressive medications so these potential complica-
tions should be kept in mind [97–99].
4.1.8.8 Post-Transplant Malignancies
Kidney transplant recipients are at a higher risk for developing certain malignancies
compared to the general population and malignancy remains one of the three most
common causes of death in those who have a functioning graft [9]. The highest
risks, compared to the baseline risk in the general population, includes non-
melanoma skin cancers, Kaposi sarcoma, renal cell carcinoma in the native kidneys
and post-transplant lymphoproliferative disorder (PTLD) [43]. Risk factors for
malignancies include the net state of immunosuppression—i.e., the duration and
intensity of immunosuppression (including, pre-transplant exposure to immunosup-
pressive medications for treatment of glomerular diseases) for those that are
infection- related (HHV8in Kaposi sarcoma, EBV in PTLDs and other HPV associ-
ated malignancies), in addition to risk factors common in the general CKD popula-
tion including older age, male gender, pre-transplant dialysis duration, smoking
history, exposure to radiation or environmental carcinogens and family history.
Skin cancer is the most common de novo post-transplant malignancy—especially
squamous cell cancers. The risk is estimated to be 100-fold higher than in the general
population and these cancers can be more clinically aggressive with worse histology and
rapid progression [43]. Kidney transplant recipients should be reminded to apply broad
spectrum sunscreen and wear protective clothing as well as follow with a dermatologist
for full body skin surveillance after 1 year, after which the interval and frequency of
screening should be individualized. If skin malignancies are aggressive or frequently
recurrent, the dermatologist should consult with the transplant center for consideration
of adjusting immunosuppression. In some cases, the transplant team is able to either
reduce or stop the anti-metabolite, or convert to mTORi-based regimen (commonly dual
regimen of mTORi plus a steroid), which has been shown to be protective against new
cancer development and has anti-tumor effects [100–102].
Renal Cell Carcinoma (RCCs) can occur in the native kidneys in the setting of
acquired cystic kidney disease especially in those on dialysis pre-transplant for a
4 Primary Care of the Adult Kidney Transplant and Kidney-Pancreas Transplant…
84
longer period of time. A bimodal distribution is noted—with highest risk in 2 peaks:
rst year post-transplant and late (4–5years or more). Although there is no consen-
sus, it is suggested that kidney transplant recipients should be screened with an
ultrasound of the native kidneys in the rst year and then repeated depending on the
baseline risks, the most important of which is the duration of pre-transplant dialysis
(at least every 1–2years in those on dialysis longer than 5years or every 3–5years
for those on dialysis for less than 3–5years) [103]. Kidney transplant recipients
who present with persistent microscopic hematuria or gross hematuria should be
evaluated for RCCs in the native kidneys. Notably, RCCs is very sensitive to mTORi
and conversion to an mTORi-based immunosuppressive regimen might be consid-
ered by the transplant team in coordination with the transplant oncologist [104]. In
transplant centers with experience, immunotherapy is not an absolute contraindica-
tion if required per oncologic indications, but it requires close monitoring and
adjustment of immunosuppressive regimens since there is risk of rejection and graft
loss and is best managed by experienced transplant nephrologists in collaboration
with oncologists [105].
Post-transplant Lymphoproliferative Disorders (PTLD) encompasses a wide
spectrum of lymphoid proliferations, mainly of B lymphocytic origins–ranging
from reactive polyclonal diseases to frank monoclonal lymphomas. Most com-
monly classied based on morphology, clonality and molecular proles according
to the WHO histologic criteria into four main subtypes: early lesions (or non-
destructive PTLDs), polymorphic PTLDs, monomorphic PTLDs and classical
Hodgkin lymphoma-type PTLDs [106]. The prevalence is approximately 1–2% in
adult kidney transplant recipients with bimodal distribution: early PLTDs tend to
present within the rst 1–2years post-transplant, associated with EBV reactivation
or primary infection (>90% EBV positive) and more commonly involving the kid-
ney allograft while late-onset PLTDs (after 5–7years) are more commonly EBV
negative (30%–50% or more), more commonly monomorphic and present with
nodal or extra-nodal involvement similar to classic lymphomas [106].
The greatest risk factors for PTLD development are EBV donor–recipient mis-
match (kidneys from EBV-seropositive donors transplanted into EBV seronegative
recipients) and the net state of immunosuppression or over- immunosuppression [106].
In some centers, those at high risk (EBV seronegative recipients), routinely
undergo blood EBV viral load surveillance (often weekly, biweekly or monthly
within the rst year after kidney transplantation), with more intensive monitoring if
EBV viremia is detected. Pre-emptive interventions include reduction of immuno-
suppression with conversion to mTORi monotherapy due to its anti-tumor effects,
and in some cases, pre-emptive the anti-CD20 agent rituximab may be considered
as the second-line option [107].
PTLDs can present with protean manifestations ranging from systemic B symp-
toms indistinguishable from infections to organ-specic symptoms or even multi-
organ involvement. Due to its potentially disastrous consequences, PTLD should
always be in the differential diagnoses for kidney transplant recipients presenting
with non-specic symptoms. Careful history and physical examination should be
performed, with particular attention to lymphadenopathy, palpable mass(es),
B. Boonpheng and I. C. De Castro
85
hepatosplenomegaly, tonsillar enlargement, and mucosal ulceration, in addition to a
focused examination based on the clinical presentation. Additional workup that
should be considered includes the following: serum EBV viral load (may be helpful
although is relatively insensitive and non-specic), cross-sectional imaging such as
CT of the chest, abdomen and pelvis, organ-specic imaging depending on symp-
toms and signs. Endoscopy is often required for those presenting with GI symptoms
or bleeding. The diagnosis of EBV causing disease requires a biopsy (preferably
excisional biopsy but core needle biopsy is also acceptable) for tissue histologic
examination. Additional tools such as EBV clonality, strain typing, EBV genomics,
gene expression prole, anti-CD20, and other tumor mutations are helpful for
detailed classication, prognostication, and treatment selection.
Treatment of PTLD depends on multiple factors such as histologic subtypes,
disease stage, organ involvements, and complications, but the mainstay intervention
is reduction in immunosuppression. Chemotherapy such as single agent rituximab
or even a conventional chemotherapy regimen such as R-CHOP (rituximab plus
cyclophosphamide-doxorubicin-vincristine-prednisone) is often needed [106].
These patients are best managed by the multidisciplinary teams in their transplant
centers.
Cancer risk in general is addressed in Chap. 9.
4.1.8.9 Chronic Kidney Disease-Metabolic Bone Disease (CKD-MBD)
Advanced chronic kidney disease including end-stage kidney disease is commonly
associated with complex abnormalities in calcium, phosphorus, vitamin D, and
bone metabolism. Briey, the primary driver of CKD-MBD is loss of functioning
nephrons leading to phosphorus retention and decreased conversion to active vita-
min D, culminating in complex hormonal compensation with elevated parathyroid
hormone from the parathyroid glands and bone-derived broblast growth factor-23
(FGF23) and its associated membrane-bound protein Klotho involved in the patho-
physiology. These endocrine changes lead to multiple abnormalities not only in the
bones but also all over the body, the most concerning of which are vascular calci-
cation and cardiovascular disease.
After a successful kidney transplant, these abnormalities tend to improve over
time or even resolve, depending on the kidney allograft function; however, it may
take weeks to months to even up to a year or more for all mineral and bone abnor-
malities to improve—paralleling or following the improvement in allograft func-
tion. In the meantime, it is essential that primary care providers be familiar with
some of the most commonly encountered problems and their natural history.
• Calcium: mild hypocalcemia can be seen transiently in the immediate post-
transplant period due to low bone turnover state in some patients, hypoalbumin-
emia or volume expansion and diuresis; generally no treatment is required unless
kidney transplant recipients are symptomatic. Then when kidney allograft func-
tion improves, mild to moderate hypercalcemia (total calcium 10.5–11.5mg/dL)
4 Primary Care of the Adult Kidney Transplant and Kidney-Pancreas Transplant…