Emily Petersen, MD Rockwood Kidney and Hypertension March 16, 2014 NOT JUST PHOSPHORUS AND KT/V: “OTHER” LABS IN END STAGE KIDNEY DISEASE

 Understand the indications for testing dialysis patients for hypothyroid and dyslipidemia  Understand the implications of abnormal test results for thyroid function, lipid profile, and bicarbonate levels in dialysis patients  Understand the rationale for correcting or not correcting abnormalities in thyroid function, lipid profile, and bicarbonate levels OBJECTIVES

HYPOTHYROID

 This section will be limited to hypothyroid  Will not address thyroiditis, Grave’s disease, goiter, thyroid nodules, hyperthyroid, or any other common or uncommon thyroid abnormalities HYPOTHYROID

 Overwhelming number of thyroid assays  ARUP labs offers 59 different assays for thyroid evaluation  There are four different assays for free T4 alone  Recommended algorithm for screening in general (not ill) population is fairly simple:  TSH normal- no further testing  TSH high (hypothyroid)- check free T4  To make it easier, you can order TSH with reflex to free T4  TSH low (hyperthyroid)- check free T4 and T3 THYROID FUNCTION TESTS

 Thyrotropin releasing hormone (TRH) is released from the hypothalamus  TRH stimulates the release of TSH from the pituitary gland  TSH stimulates the synthesis and secretion of T3 and T4  TRH and TSH are regulated by feedback inhibition from T4  T4 is converted to T3 in the hypothalamus, pituitary and peripheral tissues by deiodination  80% of T3 is produced by peripheral deiodination of T4 to T3  T3 is four times more potent than T4  T3 concentrations in blood are 1/40 that of T4  T3 binds to cellular thyroid hormone nuclear receptors, and the complexes bind to DNA and modify gene transcription to alter protein synthesis  T4 is converted to metabolically inactive reverse T3 and diiodothyronine by feedback inhibition THYROID FUNCTION: THE CASCADE

 Deiodination (T4 conversion to T3) can be altered due to disorders and factors commonly found in CKD  Malnutrition  Uremia  Decreased thyroid hormone transport into peripheral tissues  Binding of T3 to DNA and transcriptional activation are decreased  Improves after dialysis  Inflammation  Iodine retention  Metabolic acidosis  Medications- glucocorticoids, furosemide, heparin  Mineral deficiencies THYROID FUNCTION TESTS: AFFECTED BY SYSTEMIC ILLNESS

 Hypothyroid is common among patients with end stage renal disease, but is not part of routine lab testing.  From NHANES III data, the prevalence of hypothyroid increases with increasingly impaired kidney function  Prevalence of 5.4% with eGFR of >90 mL/min/1.73m2  Prevalence of 23.1% with eGFR of <30mL/min/1.73m2  Other data suggest that 15–25% and 3–5% of dialysis patients have subclinical and overt disease, respectively  Prevalence probably underestimated  Insidous onset  Symptoms are similar to those of uremia: anemia, lethargy, constipation, cold intolerance, poor appetite.  In one study of a group of long term PD patients, 19 of 46 had abnormal thyroid function tests. HYPOTHYROID: PREVALENCE IN ESRD

 Why do we care?  Hypothyroidism is associated with:  impaired cardiac contractility  endothelial dysfunction  atherosclerosis and possibly higher cardiovascular mortality  Thought to lead to impaired kidney function through alterations in renal hemodynamics and structure HYPOTHYROID: CARDIAC AND RENAL EFFECTS

 Study of 19 PD patients with hypothyroid  Hazard ratio of 7.6 for death compared to euthyroid patients  Most common cause of death was sepsis  Dyslipidemia in 90% of patients with hypothyroid  Increased LDL  Increased triglycerides HYPOTHYROID: DEATH AND DYSLIPIDEMIA

 Anemia is present in about 40% of patients with hypothyroid  iron deficiency (due to impaired intestinal absorption and incorporation of iron into erythrocytes)  vitamin B12 deficiency (in association with autoimmune thyroid disease and pernicious anemia)  blood loss associated with impaired hemostasis  decreased erythropoietin production HYPOTHYROID: ANEMIA

 Contributes to EPO resistance in patients with end-stage renal disease (ESRD)  Euthyroid state is needed for EPO to act on the bone marrow  In one study, the mean monthly EPO dosage was µg more in hypothyroid patients compared with euthyroid patients  In the setting of diabetes, the mean monthly EPO dosage was µg more in hypothyroid patients HYPOTHYROID: EPO RESISTANCE

 Should we use a different testing algorithm in patients with ESRD?  In a cross-sectional cohort of 2284 CKD patients with normal TSH levels, 78.6% of patients with an eGFR <15 mL/min/1.73 m2 had low T3 levels  Baseline low T3/T4 levels are associated with greater mortality and adverse cardiac outcomes in ESRD  Persistently low T3 is associated with a 2.7- and 4-fold higher all-cause and cardiovascular death risk in ESRD patients  But as discussed before, T3 levels are affected by ESRD, malnutrition, medications, and inflammation, and low T3 does not necessarily indicate thyroid disease  Testing for T3 levels provides some information regarding systemic illness and inflammation but does not provide an indication for treatment or goals for treatment of thyroid disease THYROID FUNCTION TESTS: DIFFERENT IN ESRD?

 TSH is also altered in CKD  Decreased clearance  Decreased response to TRH  Decreased pulsatility  Decreased bioactivity  In nephrotic syndrome, thyroid binding proteins are lost in the urine  However:  Usually normal in nonthyroid illness as opposed to T3, so it’s specific to thyroid disease  TSH rises and falls appropriately with thyroid replacement therapy in patients with ESRD  Likely a more reliable metric of thyroid function in ESRD than T3 THYROID FUNCTION TESTS

 Does treatment help?  A recent large study showed similar all-cause mortality in ESRD patients with normal TSH receiving exogenous thyroid hormone to patients with normal TSH not on treatment.  2715 dialysis patients with baseline TSH levels measured between April 2005 and April 2011 were evaluated for all cause mortality  350 patients were hypothyroid  Patients with TSH of >ULN and <10 had a higher mortality  Patients with TSH of >3 and 10 had greater risk but not statistically significant  Compared with euthyroid controls, patients who were euthyroid on thyroid replacement were not at higher mortality risk  Treatment with exogenous thyroid hormone has been associated with decreased progression or reversal of impaired kidney function in hypothyroid CKD patients TREATMENT OF HYPOTHYROID

 T3 is often low in ESRD and is an indicator of systemic inflammation, but not necessarily thyroid dysfunction. TSH is a more reliable indicator of thyroid disease in ESRD patients.  Check TSH in patients with rising EPO requirements, fatigue and malaise, and poor appetite  Treatment of hypothyroid will probably help to improve symptoms and outcomes SUMMARY

DYSLIPIDEMIA

 Lipid profiles are not routinely checked in dialysis patients. Should we be checking lipids and initiating statins in these patients?  Dyslipidemia is an established risk factor for coronary disease.  Statins are routinely initiated for primary prevention of coronary disease in patients with diabetes and other risk factors for coronary disease.  KDIGO recommends routine initiation of statin in patients with CKD  Cardiovascular disease is the most common cause of death in patients with ESRD, accounting for nearly half of all deaths, and kidney disease is an established risk factor for coronary disease. DYSLIPIDEMIA

 Three major trials on statin therapy in dialysis patients  4-D and AURORA  Both evaluated the effect of statins in dialysis patients on the combined endpoint of death from cardiovascular causes, nonfatal MI, and stroke.  LDL decreased significantly in both trials  No cardiovascular benefit  SHARP trial  Combination of statin and ezetemibe  Benefit, but not statistically significant in dialysis subgroup LIPIDS

 4-D trial  1255 hemodialysis patients with diabetes type 2 and elevated LDL  80 percent were not being treated with a statin  Atorvastatin 20mg vs placebo  Primary outcome measure was the composite of cardiovascular death, nonfatal MI, and stroke  Atorvastatin lowered LDL cholesterol from 121 to 71mg/dL after four weeks  No change with placebo  After four years, no difference in the primary outcome between the two groups  Significant reduction in cardiac events  Significant increase in the rate of fatal stroke  Numbers small for both groups  Subgroup analysis among patients with baseline LDL >145 found benefit with reduction in primary outcome 4-D TRIAL

 AURORA trial  2776 patients on hemodialysis, not on statin  Rosuvastatin 10mg daily vs Placebo  At three months LDL was significantly decreased 100 to 58mg/dL in rosuvastatin group. No change in placebo group  At follow up 3.8 years, no difference in primary endpoint of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.  Individual components were not different, and all cause mortality not different  Subgroup analysis with no difference including patients with diabetes and elevated CRP  No increase in adverse effects with rosuvastatin  Rosuvastatin group did have a higher incidence of hemorrhagic stroke but numbers extremely small  Post-hoc analysis with 32% reduction in cardiac events among patients with diabetes on rosuvastatin AURORA TRIAL

 SHARP trial  Simvastatin vs simvastatin plus ezetimibe vs placebo  Three treatment groups for first year  After one year patients on simvastatin were transitioned to simvastatin plus ezetemibe or placebo  9270 patients with chronic kidney disease including 3023 on dialysis with no history of coronary disease  Outcome measure was first major atherosclerotic event, including non fatal MI, coronary death, nonhemorrhagic stroke, and arterial revascularization procedure  Combination of simvastatin and ezetemibe was associated with a weak trend toward benefit in atherosclerotic cardiovascular events  Not powered to detect an effect in the dialysis population SHARP TRIAL

 Multiple meta analyses have been performed  In one there was a reduction in risk of cardiovascular mortality and increase in risk of stroke  In a second there was no effect on all cause mortality, cardiovascular mortality, and major cardiovascular events  In a third there was a decrease in relative risk of cardiovascular events in patients on dialysis and no difference for coronary events and stroke  Much smaller benefit than that shown in patients with CKD not on dialysis STATINS IN KIDNEY DISEASE

 KDIGO guidelines  Based on results primarily from 4-D, AURORA, and SHARP trials, statin should not be routinely initiated in dialysis patients despite high risk for cardiovascular disease  May be benefit in patients with diabetes and with LDL >145 mg/dL  For patients already on a statin at dialysis initiation, it should not be discontinued  If statin therapy is initiated for very high cholesterol levels or other coronary disease risk factors, the goals for therapy are extrapolated from non-ESRD goals  Serum LDL of <100  Total cholesterol minus HDL cholesterol of <130 if triglycerides are greater than 200 STATINS IN DIALYSIS PATIENTS

 Why don’t they help?  The pathogenesis of adverse cardiovascular outcomes in ESRD patients may be different from patients with normal kidney function or non-ESRD chronic kidney disease  60% of all cardiac deaths in dialysis patients are due to sudden death or arrhythmias, events not expected to be reduced by statins  Left ventricular hypertrophy is present in 75% of all dialysis patients  Atherosclerotic disease may be less important than nonischemic cardiac fibrosis  It may be “too late” for statin to provide any primary preventive benefit in these patients STATINS IN DIALYSIS PATIENTS

“Statin therapy has failed to significantly alter the course of CVD events in patients with ESRD. Evidence supports avoiding the routine use of statins in this patient population and instead reserving them for patients with elevated cholesterol levels or those with recent CVD events.” Safety and efficacy of statins in patients with end-stage renal disease. Ann Pharmacother Oct;47(10): STATINS IN DIALYSIS PATIENTS

 High triglyceride is the most common lipid disturbance in dialysis patients  KDIGO guidelines:  No treatment for fasting triglycerides of less than 500  Therapeutic lifestyle changes for patients with fasting triglycerides greater than 500  Increased physical activity, reduction in alcohol intake, treatment of hyperglycemia  Consider fibric acid derivative if triglycerides are greater than  Should not be used in combination with a statin TRIGLYCERIDES IN DIALYSIS PATIENTS

 There is no evidence for statin as primary prevention in dialysis patients without other risk factors for coronary disease  If a patient has LDL>145, is diabetic, or has atherosclerotic disease, statin is indicated and goals are the same as for the general population.  Elevated triglyceride is the most common lipid abnormality in ESRD. Therapeutic lifestyle modification is recommended for triglycerides >500, and fibrate may be considered (though not with statin) for triglycerides >1000. SUMMARY

METABOLIC ACIDOSIS

 Bicarbonate level of less than 24 with or without normal pH  Develops in CKD due to :  Increased production of nonvolatile acids  Increased loss of bicarbonate  Decreased renal excretion of acid  With CKD, acid excretion is maintained by increased ammonium excretion.  Ammonium excretion starts to fall at eGFR of less than 40 mL/min/1.73m2  Retention of hydrogen ions starts to occur  Retained acid is buffered by bicarbonate, tissue buffers, and bone  Prevalence of acidosis is <5% in CKD 1 and 2, and 25% in CKD5  Usually stabilizes around in CKD 5 due to buffering  Anion gap widens in late stages due to retention of phosphate, sulfate, urate, hippurate METABOLIC ACIDOSIS

 Initiation of dialysis usually results in improvement in metabolic acidosis due to excess bicarbonate administered in the dialysate  Most hemodialysis patients have some degree of acidosis  High dietary intake of animal proteins results in higher net acid generation  Normal bicarbonate levels can occur with decreased protein intake and malnutrition  Diminished acid and sulfate generation  Fruit intake can also normalize bicarbonate levels  Citrate is rapidly converted to bicarbonate by the liver METABOLIC ACIDOSIS IN DIALYSIS

 Multiple organ systems affected  Bone resorption and osteopenia, worsened hyperparathyroidism  Buffering of the excess hydrogen ions is associated with the release of calcium and phosphorus from bone. The calcium is lost in the stool  Preventing bone buffering with alkali therapy can minimize negative calcium balance, minimizing hyperparathyroid bone disease and improving bone health  Increased muscle protein catabolism  Increased release of cortisol and decreased release of insulin-like growth factor-1  Inhibition of insulin signaling  Loss of lean body mass and muscle weakness  May be exacerbated by institution of low protein diet pre-dialysis  Reversed by supplementation of alkali to correct acidosis (?) METABOLIC ACIDOSIS: EFFECTS

 Multiple organ systems affected  Reduced respiratory reserve and exhaustion of body buffer systems  increased severity of acute illnesses  Reduced Na + -K + -ATPase activity in red blood cells and myocardial cells  impaired myocardial contractility leading to heart failure  Resistance to growth hormone and insulin, and hypertriglyceridemia  Systemic inflammation  Hypotension and malaise  More rapid progression towards ESRD METABOLIC ACIDOSIS EFFECTS

 Two year study of more than 56,000 patients on hemodialysis  Prior to controlling for confounders, mortality was lowest among patients with bicarbonate of 17 to 19  After controlling for markers of poor nutrition, patients with a predialysis serum bicarbonate of <22 had a greater mortality risk than those patients with higher bicarbonate METABOLIC ACIDOSIS IN HD

 21 patients on maintenance hemodialysis were assigned to a standard bath or a bicarbonate supplemented bath.  With standard bath, predialysis plasma bicarbonate was 15.6  With bicarbonate supplementation (40mEq bath), predialysis bicarbonate was 24  At 18 months the osteoid and osteoblastic surfaces and plasma PTH increased in the control group, unchanged in patients with normal bicarbonate  Increased sensitivity of parathyroid glands to ionized calcium  Decreased bone buffering METABOLIC ACIDOSIS IN HD

 Can bicarbonate be supplemented orally in ESRD?  In CKD, KDIGO recommends sodium bicarbonate at doses of about 0.5 to 1mEq/kg per day. No guidelines for supplementation exist for ESRD  One study of 164 HD patients who received supplementation had an improvement in predialysis bicarbonate levels from 19.4 to 22.6mEq/L  Significant decrease in nitrogenous waste products  Significant decrease in intradialytic hypotension  However, another study of 20 HD patients with acidosis receiving 1gm of oral bicarbonate TID had no change in nPCR, body weight, BMI, blood pressure, edema, and albumin despite improvement in bicarbonate level from 18 to 22mEq/L. METABOLIC ACIDOSIS IN HD

 In PD patients, unsupplemented bicarbonate levels have been shown to be positively associated with hemoglobin and residual GFR and negatively associated with albumin, CRP, peritoneal Kt/V urea, and nPCR  Bicarbonate levels were associated with decreased risk of mortality. Compared to bicarbonate of 24-26:  Bicarbonate of <22 has a 13.1 fold increased risk of death  Bicarbonate of has a 2.13 fold increased risk of death  Increased risk of death thought to be due to enhanced inflammation and a more rapid loss of RRF associated with metabolic acidosis METABOLIC ACIDOSIS IN PD

 Metabolic acidosis has many effects on bone health including parathyroid hormone activity, muscle health, and ability to recover from illnesses  Metabolic acidosis results in accelerated loss of residual renal function in PD and CKD patients  In HD, bicarbonate bath should be adjusted to meet goal bicarbonate of 22-26, and oral bicarbonate supplementation can be given to reach goal if needed SUMMARY

QUESTIONS?

 Thyroid  Check TSH in patients with rising EPO requirements, fatigue and malaise, and poor appetite  Treatment of hypothyroid will probably help to improve symptoms and outcomes  T3 is often low in ESRD and is an indicator of systemic inflammation, but not necessarily thyroid dysfunction  Lipids  There is no evidence for statin as primary prevention in dialysis patients without other risk factors for coronary disease  If a patient has LDL>145, is diabetic, or has atherosclerotic disease, statin is indicated and goals are the same as general population.  Metabolic acidosis  Metabolic acidosis has many effects on bone health, muscle health, and ability to recover from illnesses  Bicarbonate bath should be adjusted to meet goal bicarbonate of 22-26, and oral bicarbonate supplementation can be given to reach goal if needed. TAKE AWAY POINTS

 Hypothyroidism and mortality among dialysis patients. Clin J Am Soc Nephrol2013 Apr;8(4):  Impact of Thyroid Dysfunction on Erythropoietin Dosage in Hemodialysis Patients. THYROID. Volume 23, Number 5, 2013 Mary Ann Liebert, Inc.  Abnormal thyroid function predicts mortality in patients receiving long-term peritoneal dialysis: A case-controlled longitudinal study Journal of the Chinese Medical Association 75 (2012) 54e59  Thyroid functional disease: an under-recognized cardiovascular risk factor in kidney disease patients Nephrol Dial Transplant (2014) 0: 1–15  A Low Serum Bicarbonate Concentration as a Risk Factor for Mortality in Peritoneal Dialysis Patients. PLoS One. 2013; 8(12): e  Safety and efficacy of statins in patients with end-stage renal disease. Ann Pharmacother Oct;47(10):  Oral treatment of metabolic acidosis in hemodialyzed patients and the implications on the hemodynamic status Romanian Journal of Morphology & Embryology  KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease  KDIGO 2013 Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease  And of course, Uptodate.com REFERENCES