Transcript 1 - Hyonam Kidney Laboratory

Overview of care of the adult
kidney transplant recipient
신장내과
강혜란
Introduction
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Kidney transplantation
: Treatment of choice for end-stage renal disease
Patients require close follow-up after transplantation since they are on complex
immunosuppressive regimens that render them susceptible to infection, malignancy, and
cardiovascular disease (CVD)
In addition, patients often have multiple comorbidities due to, or as a cause of, their underlying
end-stage renal disease
Routine follw-up and labolatory
monitoring
Management of immunosuppression

Immunosuppression therapy
 Induction therapy
 started either pre- or intraoperatively
 biologic antibodies, calcineurin inhibitors (CNIs), antimetabolites or antiproliferative
agents, and glucocorticoids
 Maintenance therapy
 steroids, CNIs, and an antiproliferative or antimetabolite agent, such as azathioprine or
mycophenolate mofetil
 glucocorticoid-free protocols
 beneficial impact on blood pressure, glycemic control, bone disease, and lipid
profiles
 increase the risk of chronic allograft nephropathy -> generally continue low-dose
glucocorticoids indefinitely among most patients
Management of immunosuppression
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Immunosuppression therapy
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The CNIs used in transplantation are tacrolimus and cyclosporine
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Cyclosporin
 trough concentrations (12 hours postdose) : poor correlation
 two-hour postdose cyclosporine level (C2)
 higher C2 concentrations : associated with decreased acute rejection rates in the first
year
 Recommended C2 target concentrations are:
 800 to 1000 ng/mL in months 1 to 3 after transplantation
 400 to 600 ng/mL for subsequent months
Management of immunosuppression
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Immunosuppression therapy
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Tacrolimus
 target : whole-blood trough concentrations
 first three months : 8 - 12 ng/mL -> 3 - 7 ng/mL
 dosing and levels may be affected by polymorphisms of the multidrug resistance-1 (Pglycoprotein [PGP]) and CYP3A5 genes
 many centers have attempted to use even lower levels of CNIs
 antiproliferative agents such as mycophenolate mofetil/sodium or mammalian target of
rapamycin (mTOR) inhibitors ; sirolimus/everolimus may allow the safe reduction of CNIs, as
does the use of belatacept
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After 6 to 12 months, immunosuppression regimens are generally stably maintained
Management of immunosuppression
Management of immunosuppression
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Toxicity associated with common immunosuppressive regimens
 CNIs
 Hirsutism, alopecia, neurologic disturbances, insomnia, hypertension, acute and chronic
renal dysfunction, electrolyte abnormalities, posttransplant diabetes mellitus,
hyperlipidemia, malignancies, and anemia
 Mycophenolate – Gastrointestinal disturbances
 Sirolimus/everolimus – Pulmonary edema, hypertension, poor wound healing and joint
pain, anemia, edema, and hypertriglyceridemia
 Azathioprine – Leukopenia, hepatitis, and anemia
Management of immunosuppression
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Abnormal calcineurin inhibitor concentrations
 CNI toxicity can cause kidney injury and hypertension
 The prolonged use of CNIs may cause permanent fibrosis in the kidney
-> CNI concentrations should be checked at regular intervals
 An elevated CNI concentration
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the blood was drawn at the correct time
the patient taking the incorrect dose or a change in preparation of the immunosuppression agent
administration of a drug or substance that interferes with the metabolism of CNIs
Inflammation of the bowel (diarrhea) : concentrations of tacrolimus, but not cyclosporine
 Low CNI concentrations
 another medication that influences the metabolism of CNI
 Noncompliance
 Persistently low levels may result in rejection
Common medical problems following
transplant
 Renal dysfunction

Increased creatinine
 Nearly all patients have a decreased GFR, compared with normal native kidney function,
following transplantation
 The baseline creatinine following transplantation tends to be higher than 1.1 mg/dL (97
micromol/L) for most patients, equivalent to an estimated GFR less than 60 mL/min per 1.73
m2
 Reasons for the modest decrease in GFR
 the transplantation of a single kidney
 ischemic injury (especially in the case of deceased-donor kidneys)
 the use of expanded-criteria donors
 the use of calcineurin inhibitors (CNIs), which cause vasoconstriction
Common medical problems following
transplant
 Renal dysfunction
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Increased creatinine
 The possible causes of the increased creatinine include:
 Prerenal (volume depletion due to vomiting or diarrhea)
 Postrenal (obstruction)
 Calcineurin nephrotoxicity
 Allograft rejection
 Recurrence of glomerulonephritis
 De novo renal diseases such as acute tubular necrosis due to sepsis or nephrotoxins
 Drug-induced interstitial nephritis
 Infection including pyelonephritis or human polyomavirus type BK-associated
interstitial nephritis
 Renal artery stenosis
Common medical problems following
transplant
 Renal dysfunction
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Increased creatinine
 An extensive history and physical exam
 Medications should be reviewed : dose changes, addition of new medications, herbal
supplements
 The immunosuppressive regimen should be reviewed
 Laboratory investigation
 serum cyclosporine or tacrolimus level
 a urinalysis to exclude infection or new glomerular or interstitial disease
 a blood or urine BK-viral load to exclude to BK reactivation : virus-associated interstitial nephritis or
nephropathy
 A renal ultrasound : exclude obstruction
 If there is still no explanation for the increased creatinine, a renal biopsy should be
performed to determine the cause of the acute kidney injury
Common medical problems following
transplant
 Renal dysfunction
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Moderately increased albuminuria (microalbuminuria)
 Mild proteinuria : decreased long-term graft function and is associated with mortality
 should be monitored by measuring the protein-to-creatinine ratio in a random urine sample
for recurrence of glomerular diseases : IgA nephropathy, FSGS, and diabetic nephropathy
 also suggest acute allograft rejection or transplant glomerulopathy
 also suggest cardiovascular disease
 A renal biopsy may be necessary to determine the cause of proteinuria
 most patients whose protein excretion > 1 g/day
Common medical problems following
transplant
 Renal dysfunction
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Renal biopsy
 usually performed in the setting of some evidence of allograft dysfunction, such as an
elevated serum creatinine, decreased urine output, or worsening proteinuria
 The risks of an allograft biopsy
 bleeding, damage to other organs, infection, and loss of allograft
 reported a very low major complication rate (including transfusion requirement and
catheterization) : 0.4 - 1.0 % with only one graft lost in approximately 2500 biopsies
Common medical problems following
transplant
 Hypomagenesemia
 common after transplantation
 due to magnesium wasting caused by calcineurin-induced downregulation of renal
expression of Mg(2+) channel, TRPM6
 play a role in development of posttransplant diabetes and CNI nephrotoxicity
 patients with severe hypomagnesemia may be symptomatic (weakness) and are at risk of
cardiac arrhythmias
Common medical problems following
transplant
 Diabetes mellitus
 Many patients develop diabetes mellitus following a renal transplant
 Posttransplant diabetes (PTDM) -> new-onset diabetes after transplantation (NODAT)
 Reasons for relatively high incidence of NODAT include the following:
 The new kidney metabolizes and excretes insulin more efficiently than the failing native
kidneys
 The transplanted kidney is gluconeogenic
 The immunosuppression regimen is diabetogenic
 Preexisting risk factors (such as genetic risk factors or metabolic syndrome) predispose
patients to developing diabetes
Common medical problems following
transplant
 Diabetes mellitus
 most commonly develops within the first few months posttransplant , although there is
continued risk for the life of the patient and allograft
 FBS weekly for the first four weeks
 FBS and HbA1C are checked at 3, 6, and 12 months -> annually thereafter
 Most patients will require pharmacologic treatment of hyperglycemia in addition to
diet modifications, exercise, and weight loss
 For some patients, the immunosuppression regimen may be altered or reduced to
minimize the risks of diabetic complications
 Steroids, CNIs, and mammalian target of rapamycin (mTOR) inhibitors can all
adversely affect blood glucose levels
Common medical problems following
transplant
 Infectious diseases
 major cause of death following renal transplantation
 transplant patients are susceptible to both common and opportunistic infections
 most likely to occur between the first and third months following transplant since immune
suppression is at its maximum : induction therapy, pulse steroids
 However, the risk of infection persists as long as the patient is on immunosuppressive
medication
Common medical problems following
transplant
 Infectious diseases
 Common infections
 occur in transplant patients who are six months or more from transplant
 Upper respiratory infection
 Urinary tract infection
 most common bacterial infections occurring in the renal transplant recipient
 Opportunistic infections
 Common pathogens that affect renal transplant recipients
 cytomegalovirus (CMV)
 polyomavirus (BK and JC virus)
 increasingly rarely, Pneumocystis jirovecii pneumonia (PCP)
Common medical problems following
transplant
 Vaccinations
 Patients should not be given any live or live attenuated vaccines after transplantation
 Inactivated vaccinations are considered to be safe
Common medical problems following
transplant
 Anemia
 inevitably anemic immediately before and after renal transplantation : due to
 surgical blood loss and inflammation
 delayed graft function
 induction and immunosuppression therapy causing bone marrow suppression
 abrupt cessation of erythropoietin-stimulating agents
 resolves within 6 - 12 months after transplantation (or earlier among patients who are not
iron deficient or have graft dysfunction)
 redevelop late in the transplant period in association with
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decreased transplant function
immunosuppressive drugs
antiviral agents
Infections
use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs)
Common medical problems following
transplant
 Cardiovascular disease
 CVD : major cause of death, graft loss in diabetic renal transplant recipients
 Risk factors
 end-stage renal disease, diabetes, hypertension, anemia, and obesity
 caused or exacerbated by immunosuppressive medications
 Hypertension
 definition : blood pressure greater than 140/90
 reported in 50 - 80 % of the kidney transplant population (130/80 )
 associated with worse long-term graft outcome
 CNIs and steroids contribute to hypertension by causing vasoconstriction and salt
retention, weight gain, and a mineralocorticoid effect
Common medical problems following
transplant
 Cardiovascular disease
 Dyslipidemia
 Dyslipidemia is common among kidney transplant recipients
 a major risk factor for both CVD and reduced renal allograft survival
 New-onset or worsening dyslipidemia : sirolimus, CNIs, and steroid use
 K/DOQI : all adult and adolescent transplant recipients be tested for dyslipidemia (total
cholesterol, LDL, HDL, and triglycerides) within six months of transplant, at one-year
posttransplant, and annually thereafter
 Obesity
 50% of transplant patients
 lifestyle modification : diet and exercise
 If safe, reduction in the dose of steroids should also be considered
 little evidence that reducing chronically administered steroid doses will result in
weight loss, and late steroid withdrawal may be associated with development of
subclinical rejection
Common medical problems following
transplant
 Malignancy
 approximately 3times more likely to develop cancers than the general population
 routine cancer screenings as those recommended for the general population
Common medical problems following
transplant
 Bone metabolism and disease
 Associated factors :
 pretransplant renal osteodystrophy
 steroids, calcineurin inhibitors
 incomplete resolution of hyperparathyroidism
 calcium, and vitamin D deficiencies
 should be regularly monitored for hyperparathyroidism, vitamin D deficiency,
hypocalcemia, and hyperphosphatemia
Common medical problems following
transplant
 Bone metabolism and disease
 Tacrolimus : increase urinary phosphate loss -> Ca, P monitoring
 Vitamin D deficiency and osteopenia/osteoporosis are common
-> recommend routine calcium and vitamin D supplementation for transplant recipients
(hypercalcemia d/t not resolving secondary hyperparathyroidism )
 Some clinicians monitor bone mineral density in the renal transplant recipient
 no reliable studies (low BMD is predictive of adverse outcomes )
 the optimal treatment for transplant recipients who have abnormal or worsening bone mineral
density studies is not known
Common medical problems following
transplant
 Pregnancy
 Infertility : common among patients with end-stage renal disease
 Fertility is usually improved within just a few months after renal transplantation
 Pregnancy in a transplant recipient : given the multiple risk factors for both the mother and
the developing fetus
 The American Society of Transplantation Consensus Opinion states that the patient can
safely proceed with pregnancy providing the following conditions are met
 Graft function is optimal, defined as a serum creatinine <1.5 mg/dL, with <500 mg/24
hour protein excretion
 There are no concurrent fetotoxic infections, such as cytomegalovirus (CMV)
 The patient is not on known teratogenic or fetotoxic medications
 The immunosuppressive regimen is stable at maintenance levels
Common medical problems following
transplant
 Pregnancy
 Risk
 risk to the patient and allograft : rejection and allograft failure
 changes in metabolism of immunosuppressive medications
 increased filtration that occurs during pregnancy
 risk to the developing fetus
 effect of immunosuppressive medication
 transmission of infection
Common medical problems following
transplant
 Pregnancy
 Immunosuppressive medication during pregnancy
 Some medication alterations may be necessary prior to conception
 mycophenolate mofetil/sodium and the mammalian target of rapamycin (mTOR)
inhibitors, sirolimus/everolimus, be avoided starting six weeks prior to
conception -> severe structural malformations
 Contraception
 The optimal form of contraception for transplant recipients is not known
 The American Society of Transplantation Consensus conference suggested the use of
progestin-only oral contraceptives and estrogen/progestin formulations, providing
blood pressure is adequately controlled
Kidney transplanation & hypophosphatemia
• High frequencies (40–90%) of hypophosphatemia in the first month after successful kidney transplantation
have been reported
• It persists for up to 10 years in 25–30% of transplant patients, with a more favourable bone-mineral
metabolic profile and higher eGFR
• associated with superior graft survival
 Renal P leak
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PTH : Hyperparathyroidism
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FGF-23 높을수록
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1,25-dihydroxyvitamin D 낮을수록
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low 1,25(OH)2D may impair renal Pi reabsorption and intestinal Pi absorption
-> leading to a negative Pi balance
immunomodulatory agents
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FGFR–Klotho complex
 expressed in the distal renal tubule
 regulates proximal renal tubular phosphorus reabsorption and 1,25(OH)2D production
FGF-23 is a phosphatonin which plays a key role in the pathogenesis of inherited and acquired
phosphorus wasting disorders
FGF-23 : inhibit renal 1-α hydroxylase, lower calcitriol synthesis, and cause renal phosphorus wasting
Both high doses of steroids and tacrolimus have been implicated as a cause of renal phosphorus wasting
phosphorus wasting in post-renal transplantation bone disease
Tacrolimus : increase urinary phosphate loss
1481336 박** 52/F (001481336)
12
10
8
6
Calcium
inorganic P
4
2
7/7
7/5
7/3
7/1
6/29
6/27
6/25
6/23
6/21
6/19
6/17
6/15
0
•DM : 2000년
•HTN : 2005년
Tacrolimus
Kidney transplantation
•ESRD on HD : 2005년
•Kidney transplantation :
2015/6/22
•PTH : 61.3(4/30), 128 (7/3)
 증상유발 기전

Hypophosphatemia -> resorption증가 -> bone calcium release ->
hypercalciuria (calcitriol 합성증가와 관련)
=> rickets, osteomalacia발생가능 (d/t bone mineralization 감소로)

Red cell 2,3-DPG (diphosphoglycerate) 감소 -> Hb의 O2 affinity증가 ->
tissue O2 release감소
Intracellular adenosine triphosphate (ATP) levels 감소-> cell function감소
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 Sx
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CNS : metabolic encephalopathy, delirium, generalized seizures, and coma
Cardiopylmonary : MI, ventricular arrhythmias, respiratory failure due to
weakness of the diaphragm
Skeletal ; muscle dysfunction include a proximal myopathy (affecting
skeletal muscle), dysphagia, and ileus, rhabdomyolysis
Hematology: hemolysis