Cardivascular Complications

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Cardivascular Complications Of Renal
Transplantation
Prof. Essam Khedr
Nasser Institute For Research and Treatment
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Cardiovascular morbidity and mortality in CRF and
dialysis patients--------------------------------
------

• Cardiovascular disease is one of the major
  (50)causes of premature death in dialysis
  patients.
• Mortality rates are 10 folds higher among
  diabetic dialysis patients than in general
  populations.
• A 25-35 years old dialysis patient has the same
  risk of CV disease as an 80 years old man in
  general population. Levey et al 1998
• This increased risk is due to accelerated
  atherosclerosis as a result of dialysis or
  dietary modifications.

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Cardiovascular morbidity and mortality in CRF and
dialysis patients--------------------------------
---------
Essam Khedr

• Death rate from myocardial infarction is highest
  in the 1st year of hemodialysis and falls
  subsequently.
• Angiographic studies have shown a high incidence
  of angina with near normal coronary arteries
  possibly due to increased oxygen demand, LVH,
  anemia and AV fistula. Koch et al 1997

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Cardiovascular disease after renal
transplantation----------------------------------

• Non fatal occlusive vascular disease coronary
  heart disease (23) ,peripheral arterial disease
  (15) and cerebral thrombosis(15) are seen 15
  years post transplant.kasiske et al 1999
• Risk of death from ischemic heart disease in
  patients aged 55 to 64 years compared to that in
  general population was
• 6.4 in non diabetic transplant recipients
• 20.8 in diabetic transplant recipients
• 8.6 in patients continued on dialysis Lindholm
  et al 1995

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Cardiovascular mortality after renal
transplantation----------------------------------

• Standardized over all mortality ratio in
  transplant recipients (age adjusted and sex
  adjusted) compared to general population was
• 14.7 for recipients of 1st transplant in the 1st
  year and 4.4 in subsequent years
• Standardized cardiovascular mortality ratio was
  
• 12.1 in the 1 st year and 9.1 in subsequent years
  (95 confidence) Arend et al 1997

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Does renal transplantation increases the risk of
death compared to continued dialysis
treatment?---------------------------------------
---

• The risk of death after transplantation compared
  to those on the waiting list increased initially,
  butt when adjusted for age, sex, race and primary
  renal disease the risk fall to 0.3 in recipients
  surviving at least one year Port et al 1995
• After adjusting for preexisting CV disease, it
  was found that patients receiving successful
  transplant had reduced risk of death compared to
  those remaining on dialysis. Surdacki et al 1995

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Does renal transplantation increases the risk of
death compared to continued dialysis
treatment?---------------------------------------
---

• Greatest benefit from transplantation is seen
  among patients at high risk
• The improvement in life expectancy due to
  successful transplantation was greatest among
  diabetics.
  Hirata et al 1996
• Successful transplant also increase life
  expectancy among older patients more than 60
  years.
• 
  Schaubel et al 1995
• Almost 40 of deaths are related to
  cardiovascular causes.

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Risk factors for cardiovascular disease in renal
transplantation----------------------------------
-

• Hypertension
• Hyperglycemia
• Hyperlipidemia
• Smoking
• Hyperhomocystinemia
• Age gt 40 ys
• Male sex

• Polycystic kidney disease
• Numbers of acute rejections
• Cardiovascular disease at time of transplantation

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Hypertension prevelance(60-80)-causes----------
-------------------------

• Pretransplant factors
• Preexisting hypertension
• Body mass index
• Primary kidney diseases
• (FSGS, ADPKD)
• Donor related factors
• Elderly female donors
• Hypertensive donors
• Use of right sided kidney

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Hypertension Causes (cont.)---------------------
----------------------

• Transplantation related
• Prolonged ischemic time Obstructive uropathy
• Delayed graft functions Extrinsic pressure
  on renal capsule
• Immunosuppressive therapy
• Calcineurine inhibitors
• Corticosteroids
• Renal transplant artery stenosis
• Recurrence of primary renal diseases
• Graft dysfunction

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Hypertension Impaired graft function------------
---------------------------------

• Nephron underdosing due to rejection produces a
  form of sodium sensitive hypertension. Brenner
  and Mackenzie 1997
• If renal artery stenosis can be ruled out,
  development of hypertension in a previously
  normotensive transplant recipient correlates with
  morphological evidence of chronic rejection or
  recurrent disease.

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Hypertension Native kidney----------------------
---------------

• Hypertension is more frequent after renal
  transplantation when native kidneys are in situ.
• This is not seen in all cases and the cause of
  renal failure may be important (chronic
  pyelonephritis)
• This is due to hyper secretion of rennin by the
  native kidneys.
• Increased sympathatic activity as aresult of an
  afferent signal arising in a diseased kidneys may
  be an additional mechnism Converse et al 1992

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Hypertension Transplanted kidney----------------
-----------------------------

• Abnormalities of sodium handling by the kidney is
  responsible for the genesis of many forms of
  hypertension.
• These abnormalities are transmitted with the
  kidney by transplantation.
  
• 
  Roman et al 1996
• Kidney from donors with family history of
  hypertension increases the risk for
  post-transplant hypertension in recipient who do
  not have family history of hypertension.
• 
  Ojuide et al 1998

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Hypertension Immunosuppressive
therapy--Cyclosporine----------------------------
----

• Calcineurin inhibitors and steroids contribute to
  hypertension after renal transplantation
• Neither azathioprine nor MMF has any effect on
  blood pressure. Zlier et al 1998
• Before CsA,incidence of post-transplant
  hypertension was 50 but after the CsA era the
  incidence become 70-90.

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Hypertension Immunosuppressive
therapy---Cyclosporine---------------------------
--------

• Calcineurin inhibitors increase blood pressure
  through
• Na retention and volume expansion with relative
  suppression of RAS. Curits et
  al 1988
• ? sympathetic activity. Scherrer et al
  1990
• Effect on CNS immunophylline leading to Na and
  water retention. Sardr
  et al 1996
• ? release of endothelin (endogenous
  vasoconstrictors). Meger et
  al 1997
• Up regulation of angiotensin II receptors in
  vascular muscles enhancing calcium entry.
• 
  Avdonin et al 1999

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Hypertension Tacrolimus-------------------------
-------------

• Hypertension usually improves after conversion
  from CsA to tacrolimus.
• 
  Copley et al 1998
• Only short term studies available to show lower
  incidence of hypertension in patients randomized
  to tacrolimus. Macher et al 1998

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Hypertension Steroids---------------------------
-------

• Variable impact of steroid on blood pressure.
• Two randomized studies showed beneficial effect
  of steroid withdrawal on blood pressure.
  Hallander et al 1997
• This improvement was not evident after one year
  of steroid withdrawal.
• 
  Ratcliffe et al 1996

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Hypertension Transplant renal artery
stenosis----------------------------------

• Rapid development or worsening of hypertension.
• Decline in renal function
• Bruit over the allograft
• Recurrent hypertensive heart failure (flash
  pulmonary edema).
• Rise of serum creatinine after introduction of
  ACE-I or adding diuretic therapy.

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Hypertension Transplant renal artery
stenosis(2-12)----------------------------------
-

• Could be due to
• Trauma to the artery during retrieval or
  reimplantation.
• Excessive traction.
• Intimal damage.
• Poor suture technique.
• Preexisting atheroma.
• Turbulence distal to anastomosis.
• Acute rejection. Woreg et al 1996
• CMV infection. Pouria et al 1998

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Hypertension Transplant renal artery
stenosis-----------------------------------

• Diagnosis
• Peripheral vein rennin (not helpful).
• Isotope renography before and after captopril
  (not for diagnosis but for assessment of
  revascularization. Shanlou
  et al 1994
• Duplex Ultrasound highly observer.
• Helical CT angiography
• MRA (high false positive rate.) Loubeyre et al
  1996

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Hypertension Transplant renal artery
stenosis------------------------------------

• Management
• Operative repair (graft loss or mortality).
• PC transluminal angioplasty 1st choice (success
  rate 60-80).
• Stent insertion can prevent restenosis.
• 
  Fervenza et al 1998
• If restenosis (30) repeat angioplasty with or
  without stent insertion or surgical
  revascularization.

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Hypertension Correction of anemia---------------
----------------------------

• Rapid rise of hemoglobin lead to exacerbation of
  preexisting hypertension due to failure of C.O.P
  to normalize after correction of anemia.
• Blood pressure drops after phlebotomy in patients
  with erythrocytosis.
• 
  Barenbrock et al 1993

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Hypertension Management in renal transplant
patients-----------------------------------------
-

• Hypertensive renal transplant patients are at
  high risk of C.V. disease.kasiske et al 2000.
• About 32 of T.X patients have suboptimal contol
  of blood pressure.stewart et al 1999.
• Treatment should be started if blood pressure is
  greater than 140 mmHg systolic or 90 mmHg
  diastolic or both.
• If there is proteinuria more than 1gm/24h level
  less than 125/75 mmHg are required for patients.
• Transplant patients often show lack of nocturnal
  dip in blood pressure.

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Hypertension Management in renal transplant
patients-----------------------------------------
-

• Non drug treatment
• Salt restriction
• Weight reduction
• Drug treatment
• Calcium channel blockers (CCB)
• Prevent nephrotoxicity of calcineurine inhibitors
  (counteract intrarenal vasoconstriction with CsA)
• 1st choice in patients receiving these drugs
• Gingival hypertrophy, lower limb edema
• Interfere with CsA level (cytochrome P450) except
  nifidipine.
• Reduce delayed graft dysfunction and acute
  rejection episodes. Mc culloch
  et al 1994

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Hypertension Management in renal transplant
patients-----------------------------------------
-

• Drug treatment (cont.)
• ACEI
• More beneficial in proteinuric patients and delay
  progressive graft failure.
• Helpful in treatment of transplant
  erythrocytosis.
• Exacerbate anemia when there is renal impairement
  probably due to interference with erythropoietin
  release
• Exclude first renal artery stenosis.
• Addition of diuretics can lead to decline in
  renal function without renal artery stenosis.
• More effective in reducing pulse pressure which
  is a more predictor of c.v. mortality safar et al
  2001.
• Inhibit TGF-B involved in chronic graft
  dysfunction CsA toxicity.

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• Hypertension Management in renal transplant
  patients-----------------------------------------
  -
• Native kidney nephrectomy
• Bilateral native kidney nephrectomy may cure
  resistant hypertension and increase renal
  allograft plasma flow through reduction of RA
  activity Custis et. al 1995
• Improvement of graft survival have been reported.
• May increase risk of recurrent GN Odorico et al
  1996.
• 
  
• Bilateral nephrectomy before Tx. worsen anemia or
  increase erythropoietin requirement following Tx.
  
  Darby et al 1992

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Hypertension Impact of post transplant
hypertension-------------------------------------
-----

• A striking association between systolic and
  diastolic blood pressure levels one year post
  transplant and graft survival.
• 
  Oplez et al 1999.
• Increased blood pressure is an independent risk
  factors for graft survival.
• There is 15 improvement of graft survival with
  control of previously hypertensive recipients
  (Blood Pressure gt 150 mmHg at one year).

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Dyslipidemia As a risk factor-------------------
------------

• Lipid abnormalities with hypertension and smoking
  are the most important risk factor for
  atherosclerotic disease in general population.
  Berenson et al 1998
• In the group of patients where HDL is low,
  hypertriglyceridemia creates a greater risk.
• 
  Satt ar et
  al 1998
• Lipoprotein (a) is a strong independent risk for
  coronary heart disease.

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Dyslipidemia In CRF and dialysis
patients------------------------------

• Classically there is hyper TG, low HDL
  cholesterol and normal total cholesterol, also
  low apolipoprotein A, high apolipoprotein B and
  increased lipoprotein(a).
• Atherogenesis in CRF is either due to
• Change in the activity of lipolytic enzymes
  (lipoprotein lipase, TG lipase etc..) Or
• Non enzymatic including
• Decreased antioxidant activity
• Formation and impaired clearance of AGES
• Hyperparathyroidism
• Increased activity of inflammatory cytokines.

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Dyslipidemia In renal transplant
recipient(50-60)--------------------------------

• Factors related to dyslipidemia after renal
  transplantation include age, BMI, pretransplant
  lipid abnormality and impaired graft function.
• Lipid abnormality after renal Tx. are a complex
  mix partly due to
• Drug treatmentSteroids, CsA and
  antihypertensives.
• Impaired renal function and proteinuria
• Persistent hyperparathyroidism
• Diabetes
• Increased age
• Weight gain Kasiske et al 1996

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Dyslipidemia Typical pattern following renal
Tx-----------------------------------

• Marked hypercholesterolemia -after 3 months-total
  cholest.gt 240mg/dl in63.
• Moderate hyper TG.(gt200mg/dl in36).
• Increased apolipoprotein B
• LDL(gt130mg/dl in 60), VLDL are elevated.
• HDL(lt35mg/dl in12,) are not protective in
  transplant patients.
• Lipoprotein( a)gt 30mg/dl in23.kasiske et al 1999

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Dyslipidemia Effect of immunosuppressive
therapy--------------------------------------

• Steroids
• Steroids leads to hyper TG through
• Increasing insulin resistance (?COA)
• Impaired lipolysis and ?lipogenesis
• ? hepatic TG production
• High dose steroids (puls) leads to
  hypercholesterolemia.
• Steroid withdrawal reduces total cholesterol
  HDL.
• All changes are associated with increase C.V.
  risk.
  Hilbrouds et al 1995

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Dyslipidemia Effect of immunosuppressive
therapy---------------------------------------

• 2. Cyclosporin A
• CsA leads to increased total cholesterol and LDL
  cholesterol.
• CsA is highly lipophilic, binds to cell membrane
  and lipoprotein particles (LDL), and enter the
  cell through LDL receptors .this will impair LDL
  clearance.
• Severe hypercholesterolemia impairs CsA efficacy
  through competitive reduction of LDL bearing
  particles.
• Increase lipoprotein (a).
• predispose to glucose intolerance ?hyperglycemia

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Dyslipidemia Effect of immunosuppressive
therapy------------------------------------

• 3. Tacrolimus
• Less impact on cholesterol, LDL cholesterol and
  TG levels than CsA.
• Tacrolimus enhance susceptibility of LDL to per
  oxidation unless given with antioxidant.
• That is why an antioxidant (alpha tochopherol)is
  added to neoral.
• 4. Sirolimus
• Marked increase in serum cholesterol and TG
  levels. Rapaimmune global
  study group 1999

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Dyslipidemia Impact on post transplant morbidity
and mortality-----------------------------------

• Total cholesterol and TG as well as lipoproteins
  were high in patients with post transplant
  vascular events.
• Evidence is very strong although not conclusive
  that hyperlipidemia contribute to increased
  incidence of C.V.D after renal transplantation
  kasiske et al1999
• There was an association between hyperlipidemia
  and chronic graft dysfunction Mclaren et al 2000.

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Dyslipidemia Post transplant treatment---------
------------------------

• Clinician must balance the possible benefits of
  lipid lowering with the possible harm and cost of
  adding to the dietary and drug treatment of
  transplant patients.
• Associated obesity should be managed, weight
  reduction by restriction of caloric rich food,
  fat intake and exercise are important Massay et
  al 1995.
• Screening for hyperlipidemia twice during the 1st
  year,or more frequent in sirolimus treated
  patients
• Steroid dose should be reduced and kept on 10 mg
  or less for long term steroid use, alternate day
  steroid therapy may reduce hyperlipidemia.

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Dyslipidemia Post transplant treatment---------
----------------------

• Drug therapy
• Fibrates
• More effective in correcting hyper T.G.
• Some of these drugs are nephrotoxic and should be
  avoided in transplant patients.
• Statins (Hydroxy-methyl-glutaryl (HMG) CoA
  reductase inhibitors)
• Effective in correcting hypercholesterolemia and
  decrease LDL cholesterol and have some TG
  lowering effect.but no evidence of beneficial
  effect on C.V mortality in TX recipients
  Amadottir and Berg 1997 Baigent et al
  2000.

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Dyslipidemia Post transplant treatment
(cont.)-------------------------------

• Statins
• There is a possible interaction with CsA as CsA
  binds to LDL particles and LDL receptors.
• Significant reduction in rejection episodes was
  reported with recipients taking pravastatins may
  be due to its suppressive effect on cytotoxic
  activity of natural killing cells.
  Kateznelson et al 1996
• Myopathy is a rare side effect of statins
• Asymptomatic elevation of creatinine kinase
  transaminases
• Acute renal failure and rhabdomyolysis due to
  muscle necrosis.
• Rhabdomyolysis occurs with high doses of
  lovastatin (40mg) but not with simvastatin or
  pravastatin due to lack of dose accumulation
• Myopathy is reversible with stoppage of drug.

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Dyslipidemia Post transplant treatment
(cont.)-------------------------------

• Statins
• Myopathy is usually common in
• Previously existing muscle disorder or
  hypothyroidism.
• Patients receiving combination of lipid lowering
  drugs
• Treatment with CsA or erythropoietin (delayed
  hepatic clearance of statins).
• Whatever statin is used, it should be used in the
  lowest effective dose with close monitoring of
  creatine kinase, transaminases and serum
  creatinine.
• 3. Other drugs
• Bile acid sequestrants cholestramine should not
  be used with CsA or Tacrolimus.
• Nicotinic acid poorly tolerated due to gastric
  upset and hepatic toxicity.

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Hyperglycemia As a risk factor for vascular
diseases-------------------------------------

• Many diabetic patients starting renal replacement
  therapy with already well established vascular
  disease
• In such patients diabetes is a potent predictor
  of poor survival. Herzog et al 1998
• 30 of diabetic type I patients died with a mean
  follow up period of 47 months post
  transplantation
• 57 of those deaths were cardiovascular.

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Hyperglycemia As a risk factor for vascular
diseases--------------------------------------

• Incidence of MI was 28, stroke 14, and
  amputation 36 in a study of Lemmers and Barry
  1991.
• Significant coronary artery stenosis was found in
  25-45 in coronary angios done in diabetic
  transplant candidates.
• 55 of diabetic patients with at least one
  coronary artery stenosis greater than 75 had a
  cardiovascular event within 36months of
  transplantation Manske et al 1997.
• 
  

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Hyperglycemia As a risk factor for vascular
diseases------------------------------------

• Symptoms of angina were absent in high proportion
  of patients with significant coronary disease.
• The only way to be certain about coronary artery
  disease is to do angiography.
• Minneapolis group algorithm of low risk group
• Diabetic type I younger than 45 years.
• Non smokers.
• No ST T wave changes.
• Duration of diabetes less than 25 years.

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Hyperglycemia As a risk factor for vascular
diseases-------------------------------------

• Revascularization even in asymptomatic patients
  with preserved LV function is associated with
  significant reduction in C.V. events Manske et al
  1993.
• As any other high risk group, transplantation may
  improve survival compared with dialysis.

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HyperglycemiaPost transplant diabetes mellitus
(insulin resistance)-----------------------------
---

• Due to steroids, CsA and tacrolimus.
• Weight gain after transplantation.
• 3-18 of patients develop post transplant DM.
• Most cases develop within the 1st few months
  following Tx.
• Older people and blacks are more susceptible.
• Consequences and complications of post transplant
  DM are similar to those of pretransplant DM
  including decreased graft survival.

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Hyperhomocysteinaemia----------------------------
---

• Moderate elevation of plasma homocysteine is
  associated with increased risk of coronary heart
  disease and cerebrovascular disease in general
  population Nygard et al 1997.
• It is due to deficiency of
• Methylene tetrahydrofolate reductase.
• Dietary folate and pyridoxine deficiency.
• Moderate degree of renal impairment is associated
  with marked hyperhomocysteinaemia. Boston and
  Culleton 1999
• 
  

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Hyperhomocysteinaemia----------------------------
---

• In renal transplantation there is an association
  between hyperhomocysteinaemia and C.V. disease.
  
  Arnadottir et al 1996
• CsA causes hyperhomocysteinaemia independent of
  the level of renal function.
• 
  Arnadottir et al 1996
• Folate and pyridoxine supplementations fully
  correct hyperhomocysteinaemia in renal patients.
  Perna et al
  1997

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Smoking--------------------------------

• Smoking 25 pack-year at transplantation was
  associated with 30 higher risk of graft failure
  (95 confidence).
• smoking 5years before Tx reduces relative risk by
  34.
• The relative risk for major C.V.S diseases or
  events with smoking less than 25 pack-years is
  1.56 and if smoking more than 25 pack-years it
  is 2.14.
• The increased graft failure is due to increase in
  deaths.
  Kasiske et al 2000

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Other risk factors.

• Hypoalbuminemia(a marker of inflammation and
  malnutrition.)
• Serum albumin falls during an acute phase
  response in dialysis patients this could be due
  to infection ( chronic chlaymedial infection
  Stienvinkel et al 1999. Or the use of
  incompatible membranes Parker et al 1996.
• Hypoalbuminemia may be a direct cause of
  increased L.P.(a) Yang etal 1996.
• Hypoalbuminemia after transplant., is associated
  with age, diabetes, proteinuria, CMV infection
  and is an independent factor of poor outcome.
• Malnutrition frequently coexists with evidence
  of inflammation and atheroma.
• Oxidation of L.P. (a ) is linked to atheroma and
  anti oxidants as vitamin E could have a role in
  prevention of atheroma.Stienvinkel et al 1999.

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Other risk factors .

• Vascular endothelium
• It controls blood vessel tone prevent
  formation of atheroma through the production of
  vasoactive compounds such as NO. Morris et al
  2000.
• Agents like ACEI ,statins anti oxidants folate
  and Larginine modulate endoth. Function and
  prevent atheroma.
• Inflammation
• Atherosclerosis is an inflammatory disease ,with
  active involvement by cytokines and adhesion
  molecules at sites of endothelial damage Ross et
  al 1999.
• C-reactive protein has been shown to correlate
  with early atheroma formation in pre dialysis
  patients and progress to pre and post
  transplantation .Stienvinkle et al1999.

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Thanks