Metabolic complications in patients ongoing pd

Metabolic Complications in Patients Ongoing Peritoneal dialysis

Piti Niyomsirivanich, MD.

Outlines• Metabolic syndrome• Hyperglycemia• Dyslipidemia• Protein loss• Na• K• Mg and vascular calcification• PO4• Ca

Metabolic Syndrome

• Central obesity• High blood pressure• High triglyceride• Low HDL-cholesterol• Insulin resistance

Metabolic Syndrome

WHR = Waist hip ratio

ระบาดวิ�ทยาของโรคอ�วินและภาวิะไตเสื่��อม

• Ejerblad et al.– BMI > 25 kg/m2 CKD 2-3 X– BMI > 35 kgm2 c diabetes 17.7 X

• Hsu et al.– BMI 25-29.9 kg/m2 1.87 X– BMI 30-34.9 kg/m2 3.57 X– BMI 35-39.9 kg/m2 6.12 X– BMI > 40 kg/m2 7 X

• Central adiposity Versus Peripheral adiposity

Metabolic syndrome & kidney disease

• Chen et al.– Metabolic syndrome

increase risks of kidney disease 2.6 X

– 3 risk factors 3.38 X– 4 risk factors 4.23 X– 5 risk factor 5.85 X

• Palaniappan et al.– Metabolic syndrome

increased risk albuminurea

Mechanism of CKD in obesity with metabolic syndrome

• Inflammation• Renin angiotensin system• Lipotoxicity• Hemodynamic factors

Cytokine

Cytokine from adipose tissue

Cytokines

• 1. Leptin– 167 amino acid– Adipocyte-derived hormone

– More fat more leptin– Pass Blood brain barrier– Inhibit neuropeptide Y decrease appetide

Leptin and Energy balance

Mechanism of leptin

Leptin

secrete via kidney

IL-6 and CRP

• Produced from visceral , peripheral tissue• decrease cytokine signal and leptin

• Adiponectin

• Increase TGF-b1 kidney fibrosis• Increased CRP from hepatocyte metabolic

syndrome visceral adiposity and atherosclerosis

TNF-a

• 26-kDa• Macrophage

• Increased in metabolic syndrome • Adipogenesis & lipogenesis

MCP-1

• Pro-inflammatory cytokines macrophage– Increased glucose uptake insulin induced

insulin receptor tyrosine phosphorylation insulin resistance

Adiponectin

• 30 kDa• Produced from subcutaneous fat > visceral fat• Insulin sensitizing , anti inflammatory , anti-

artherogenic

• Increased in thinner person• Decreased in obesed person

RAS

• Obesity increase renin , angiotensinogen , ACE , Angiotensin II , aldosterone

• Angiotensinogen , angiotensin II increase adipocyte growth – lipogenesis , hepatic

gluconeogenesis ,glycogenolysis– Inh. Lipolysis , insulin dependent glucose uptake

• metabolic syndrome

Conclusion

Metabolic syndrome in PD patient

• Cardiovascular death• LANDMARK STUDY (Longtitudinal Assessment of Numerous Discrete Modification

of Atherosclerosis Risk in Kidney Disease)

FBM & CD-163 (pro-inflammatory marker)

Axelsson et al.

Treatment of metabolic syndrome

• Low glucose in dialysate icodextrin• Control blood sugar• Reduced peritonitis inflammation• RAS blockage• PPAR agonists (thiazolidinedione) insulin

sensitizer• HMG-CoA reductase• Cardiovascular risks

Hyperglycemia

Insulin resistance in CAPD

• 1/3 of insulin renal excretion• CKD insulin resistance– increased insulin– Hyperparathyroidism– Animia – Malnutrition

• Osmitic agent (glucose) absorption• Insulin resistance decrease function of

lipoprotein lipase

Glucose absorption

• Osmotic agent– Glucose : cheap , stable , non toxic

• Absorp across membrane• 60-80% of dialysate absorbed• Glucose absorption APD < CAPD (shorter duration)• Glucose 100-150 g per day absorbed

– 500-800 kcal/day significant weight gain 5-10%– Increase insulin secretion insulin resistance atherosclerosis– Required increase hypoglycemic drug

– Amino acids– Polyglucose solution

Minimized glucose absorbtion

• Appropriate salt and water management– Decrease need for hypertonic solutions

• Non-glucose based solutions

Target of glucose control

• FBS < 140 mg/dl• 1 hr post prandial glucose < 200 mg/dl• HbA1C 7-8 mg/dl

• Uremia increased measure HbA1C (Carbymylated hemoglobin)– Differentiate • borate-agarose affinity chromatography • Thiobarbituric acid

Hypoglycemia agent

• Not recommend oral hypoglycemic drugs

• May use Thiazolidinediones – Except CHF

• Subcutaneous insulin

Subcutaneous insulin

• No guidelines• Icodextrin – CPG glucose dehydrogenase-

pyrroloquinolinequinone , glucose dye oxidoreductase enzyme over estimate due to maltose in blood• Accu-check , FreeStyle

– Recommend glucose dehydrogenase-nicotinamide adenine dinucleotide , glucose dehydrogenase flavin adenine dinucleotide ,glucose oxidase instead

IP insulin• adventage

– Absorbed via lymphatic system constant delivery 1 ml/min– Less variation among administration– Lower dosage than other route– Lesser Atheroscleosis risk

• Disadventage– More expensive– Decrease HDL in some small studies– Infection– Subcapsular liver steatonecrosis insulin induced triglyceride

accumulation in liver– Malignant omentum syndrome require more insulin

Insulin dosage• Mutiple subcutaneous injection• Total insulin per day• Divided– 10% at night time– 85-90% at day time /3

• Added 1 ,2 ,3 unit/l for 1.5%D 2.5%D 4.25%D • FBS < 140 mg/dl , CBG tid pc 1 hr < 200 mg/dl• CCPD , NIPD for high transporter (rapid glucose

absorption)•

• IP insulin– Stability– Peak concentration 90-120 min– 60% dose absorbed

• Direct Via tenckhoff catheter– Peak concentration 15 min

TZDs

• Insulin sensitizer– Troglitazone withdrawed– Rosiglitazone– Pioglitazone– Ciglitazone animal study– Englitazone animal study

• Excretedliver

Dyslipidemia

Lipoprotein

Lipoprotein• Chylomicrons

– largest– GI lymphatic– A-I , A-II , A-IV , B-48 , C-I , C-II , C-III , E

• Very low density lipoprotein– Liver circulation– B-100 , C-I , C-II , C-III , E

• IDL– VLDL triglyceride >> IDL– B-100 , C-III , E

• LDL– IDL LDL– B-100 , C

• HDL– A-I , A-II , C-I , C-II , C-III , D , E– return

Lipoprotein lipase

Hepatic triglyceride lipase

Lipid metabolism : endogenous PW

Atherogenicity of lipoprotein• Esp. LDL , LP(a)

• Small LDL > large LDL

• Lipoprotein (a) increased in patients with proteinuria

• HDL – Uremia acute phase response (IL-6, CRP)

decreased HDL

Glomerular response to lipid• Nephron loss renal adaptation (ขยายขนาด)• increase single nephron GFR

– glomerulosclerosis and interstitial fibrosis in long term

• Leakage of lipoprotein– Increase mesangial cell cytokine , increased macrophage– Macrophage ROS– ECM increased matrix glomerulosclerosis– Endothelial NO + endothelin , thromboxane A2– PTC endocytosis , endothelin-1 cell death

• Endothelin -1 peritubular capillary vasoconstriction , fibroblast ,monocyte– JG apparatus renin increase BP

Lipid metabolism abnormality due to kidney disease

• Increase carbohydrate intake due to protein restriction

• Lipoprotein lipase abnormality – Insulin resistance ,– High PTH , uremic toxin– Low Erythopoietin (unknown mechanism)

Hypertriglyceridemia in patient w CKD w/wo dialysis

Treatment

• Diet– Fat < 30% of total calories– Poly:mono:sat = <0.7 : 1 : 1-1.5 (Nephrotic Syndrome , post KT)– decreased calories , simple sugar (CKD)\– High fiber– 35 kcal/kg/day in < 60 yo– 30-35 kcal/kg/day in > 60 yo

• Exercise• Medication

HMG-CoA reductase inhibitor• Inhibit HMG-CoA reductase• Decreased cholesterol by 20-30%

• CYP3A4 and CYP 2C9

• Atorvastatin & pravastatin decrease dose• Rosuvastatin90% excreted from kidney

avoid

• Rhabdomyositis , hepatitis

Ezethimibe

• Inhibit dietary & biliary cholesterol absorption

• Decrease LDL 20% – Total cholesterol 15%

Bile acid binding resins• Not recommend in patients with uremia

(increased VLDL)

• Others– Fish oilhigh dose , expensive– ACTH short term study long term??– Sevalemer decrease P ,LDL, increase HDL– L-carnitine cofactor FA into mitochondria

• Not recommend due to adverse effect to muscle ,blood– Heparin HD decreased TG , cholesterol– Dialysis membrane

Treatment for dyslipidemia in PD

• LDL/apoB protein– The lower the better– Statins

– No equivalent studies have been done in PD– NKF (National kidney

foundation) ,KDOQI ,International Society for Peritoneal dialysis• Elevated LDL-c w/wo CAD• PD with dyslipidemia Rx as nonuremic pt. c CAD

Elevated triglycerides• Always found in association with other lipid and lipoprotein

abnormalities• Carbohydrate loading from the dialysis solution

hypertriglyceridemia• Na and water Mx minimize the use of hypertonic

solutions• Alcohol increase triglycerides• Triglyceride > 350 mg/ml Rx

• Fibrate– (benzofibrate ,fenofibrate ,gemfibrozil)dose reduced by 25%– Muscle enzyme

Low HDL-c

• Fibrate class raises HDL• Reducing cardiac morbidity and mortality has

not been established

Antioxidants

Vit E not proven to reduce CV events

No trials both PD and HD

Protein loss• Protein 0.5 g/L of dialysate drainage

– May 10-20 g/day• Amino acid loss 2-3 g/day

• Albumin • IgG 15%

• Protein loss greatest in high and high-average transporters

• Peritonitis• Nephrotic syndrome

Hyponatremia/hypernatremia

• Hyponatremias– excessive water drinker– Hyperglycemia translocational hyponatremia– 1.3 mmol/L : 100 mg/dl of Na

• Hypernatremia– Rapid UF more water than salt convects across

membrane– Short dwell PD more likely hypernatremia– Esp. low transporters

Hypokalemia / Hyperkalemia

• Hypokalemia 10%-30% of CAPD patients– Associate poor potassium intake– Diet– K < 3 mmol/L K supplement

• Hyperkalemia non compliance , excessive K intake

Hypercalcemia / hypocalcemia• Ca 2.5 ,3.5 mEq/L• 3.5 mEq/L positive calcium balance• 2.5 mEq/L slightly negative balance of calcium• Concerns about vascular calcification lower 2.5 mEqL

• Hypercalcemia– Large doses of calcium based phosphate binders– Rx

• Non-cacium based phosphate binder• Stop Vit-D• Ca 2.5mEq/L solution of dialysate

• Hypocalcemia– Not common due to use of calcium base phosphate binder & Vit D– Rx

• Cacium & vitamin D• Ca 3.5 mEq/L dialysate solution

Magnesium and vascular calcification

• Mg depletion increased risk of atherosclerosis and cardioevents

• Excess > deficiency

• Higher dialysate solution Mg suppress PTH adynamic bone disease

• Optimum Mg in dialysate remain unknown

Hypophosphatemia/hyperphosphatemia

• Calcium based Phosphate binder , Sevalemer– fall in serum bicarbonate

• Amino acid based dialysis solution has been reported to lower the serum bicarbonate level in some patients