Pathophysiology of End-Stage Renal Disease

The kidneys are essential for adjusting body fluid volumes, electrolyte composition, acid-base balance, and hemoglobin concentration. They receive about 25% of cardiac output and function as filters for toxins and drugs in the circulation. When kidney function declines, these functions are impaired. Chronic renal failure results in a steady decline in glomerular filtration and urine production, which has deleterious effects on multiple organ systems throughout the body. Patients with glomerular filtration rates below 30 mL/min (normal, 120 mL/min) will show a rise in blood nitrogenous wastes, mainly urea, and begin to retain fluid and electrolytes. Once urine production falls below 400 mL/day, the patient becomes oliguric and is not able to excrete dietary fluid and electrolyte loads. Abnormalities in Na⁺ , K⁺ , Ca²⁺ , Mg²⁺ , and phosphate levels can develop, with the most life threatening being hyperkalemia.

Cardiovascular disease is the predominant cause of death in patients with ESRD, and even after renal transplantation it is one of the major reasons for death. Acute myocardial infarction, cardiac arrest of unknown etiology, cardiac arrhythmia, and cardiomyopathy account for over 50% of deaths in patients maintained on dialysis.^[84] The death rate from cardiac causes in dialysis patients increases with age: it is approximately twofold higher for 45- to 64-year-olds and four times higher in patients older than 65 when compared with patients in the 20- to 44-year age range. When echocardiography is performed as a screening tool, a high incidence of abnormalities is found.^[85] For example, in one study, left ventricular (LV) or right ventricular (RV) hypertrophy or pericarditis was detected in 60% of autopsies performed on dialysis patients. ^[86]

Both dilated cardiomyopathy and concentric hypertrophy can develop in response to increases in intravascular volume and afterload. Fluid overload and congestive heart failure occur when the kidneys cannot excrete the daily fluid intake and hypervolemia ensues. The accumulation of uremic toxins and metabolic acids contributes to poor myocardial performance. Cho and coworkers documented that some patients with a low ejection fraction because of uremic cardiomyopathy completely normalized their cardiac function after successful renal transplantation.^[87] Therefore, ESRD with significantly depressed ventricular function is not necessarily a contraindication to renal transplantation, but it may complicate the anesthetic approach.

Hyperreninemia may lead to increased systemic vascular resistance and elevated systemic blood pressure, but it is not always present. If untreated, the elevated systemic pressure within the kidney causes damaging sclerotic changes in the renal vasculature. A vicious cycle ensues in which hypertension damages the kidney and thereby creates the conditions for escalating hypertension. Hypertension can also be a manifestation of fluid overload once ESRD has developed and can cause increased myocardial afterload and wall stress, which, in conjunction with uremia, produce changes in the heart consistent with cardiomyopathy. Chronically elevated systemic pressure leads to LV hypertrophy and increased myocardial oxygen requirements. At the same time a rise in LV end-diastolic pressure can reduce subendocardial coronary perfusion.

Renal failure also accelerates the progression of atherosclerosis, especially in the coronary circulation. Uremia causes changes in lipid metabolism leading to increased concentrations of serum triglycerides and reduced levels of protective high-density lipoproteins.^{[88] [89]} Therefore, multiple factors work together to potentiate dangerous cardiovascular changes. The end result is frequently an enlarged, less efficient heart that is working harder against higher resistance and with a potentially limited blood and oxygen supply.

Other cardiac conditions, such as pericardial disease and arrhythmia, may be encountered in patients with ESRD. Pericarditis, which may coexist with hemorrhagic pericardial effusion, is reversible with dialysis. In general, patients who are adequately dialyzed will have resolution of their pericardial effusion. The occurrence of arrhythmias may either be the consequence of electrolyte abnormalities or represent episodes of myocardial ischemia.

A large number of transplant candidates with ESRD suffer from DM. Diabetes is the cause of ESRD in nearly 30% to 40%, and these patients represent over 30% of those on the waiting list for a kidney transplant.^[81] In fact, nephropathy develops in nearly 60% of insulin-dependent diabetic patients. Patients with ESRD and DM have higher cardiovascular risk than do patients with uremia alone because of the associated acceleration of small-vessel atherosclerosis within the coronary circulation.

Chronic uremia also causes delayed gastric emptying. The mechanism by which this complication occurs is obscure because the intrinsic muscular activity of the stomach is retained. There appears to be no difference with regard to delayed gastric emptying in patients undergoing peritoneal dialysis or hemodialysis. All patients presenting for kidney transplantation should be considered to have full stomachs, regardless of the period of preoperative fasting. Rapid-sequence induction should be considered, especially in patients with diabetes. This recommendation is underscored by the finding that gastric volumes greater than 0.4 mL/kg were found in 50% of diabetic uremic patients but in only 4 of 24 nondiabetic uremics.^[90]

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Patients in renal failure generally have normochromic, normocytic anemia because of decreased erythropoiesis and retained toxins secondary to kidney failure. Treatment with recombinant erythropoietin can frequently raise hemoglobin levels to 10 to 14 g/dL, which reduces symptoms of fatigue and improves cerebral and cardiac function.^{[91] [92] [93]} Occasionally, preexisting hypertension can worsen with erythropoietin therapy.

An association between renal failure and bleeding tendency has long been recognized. A qualitative defect in platelet function produced by uremia itself appears to be central. The defect results from accumulation of the compound guanidinosuccinic acid in uremic blood, which inhibits adenosine diphosphate-induced platelet aggregation.^[94]

Although a qualitative platelet defect can be identified in uremic patients, recent studies have pointed out that a prothrombotic state may also coexist with uremia. A thromboelastographic study of whole blood clotting found increased coagulability and decreased fibrinolysis in uremic patients versus controls.^[95] Platelet-derived microparticles (small vesicles with procoagulant activity that are released from activated platelets) may be involved in clinical thrombogenesis. ^[96]

Uremia may cause central nervous system disturbances ranging from drowsiness, memory loss, and decreased concentration to myoclonus, seizure, stupor, and coma. Signs of peripheral or autonomic neuropathy are considered strong indications for dialysis.