Pathophysiology of ESRD

End stage renal disease is the irreversible deterioration of renal function, caused by multiple factors including, diabetes mellitus, hypertension, autoimmune diseases such as lupus, glomerulonephritis, pyelonephritis, inherited diseases, such as polycystic kidney disease and congenital abnormalities.
The damaged kidney responds by increasing filtration, which masks the dysfunction until only 10-15% of kidney function remains. The kidneys lose their ability to balance water and solutes, acids and basis, retain nutrients and excrete waste in the form of urine. This loss of regulatory and excretory function results in uremic syndrome (uremia), which can be diagnosed via high levels of serum creatinine (symptoms become troublesome when creatinine levels increase beyond 1000 micromoles per liter), high levels of urea and reduced glomerular filtration rate. High creatinine levels reflects a high glomurelar filtration rate which is an important measure of renal function. Almost any substance that is found in abnormal quantities in the blood can cause uremia including increased phosphate and parathyroid hormone. Uremic syndrome also has a negative impact on the kidneys ability to excrete and produce the hormones rennin, calcitriol and erythropoietin resulting in poor regulation of blood pressure, calcium metabolism and reduced erythrocyte production, respectively.
Associated Abnormalities and Dysfunctions..Cardiac Disturbances are one, Fifty percent of ESRD patients receiving haemodialysis die as a result of CVD such as congestive heart failure, coronary artery disease, arrhythmias and hypertension. The most common morphological change in ESRD patients is left ventricular hypertrophy resulting in systolic and diastolic dysfunction including a decrease in left diastolic dispensability. This is caused by an increase in blood volume/edema due to a build up of uraemic toxins. Other factors contribute to the build up of pressure including ischemia, fibrosis and other biochemical abnormalities. Moreover, uraemic toxins also decrease myocardial contractility. Decreased left ventricular diastolic dispensability and decreased myocardial contractility result in an increase in blood pressure and an increased risk of CVD such as congestive heart failure. Cardiovascular and Autonomic Disturbances such as Chronic uraemia leads to ischemia, inflammation, and scarring of the myocardium causing uremic neuropathy. Uremic neuropathy causes electrical instability and reduced vagal activity resulting in a decrease in autonomic control and an increase in sympathetic stimulation. This overstimulation puts pressure on the heart causing hypertension and arrhythmias such as tachycardia increasing the risk of heart failure. In addition to this, psychological tension disrupts the functioning of the pacemaker cells, further contributing to heart failure.
Muscular Disturbances
Uremic myopathy is associated with changes in muscular structure and function including azotamia (high levels of calcium), academia (low levels of carnitine), abnormal activity of enzymes that produce energy, an increase in connective tissue, fibre grouping, atrophy of both fibre types and an increase in necrotic fibres due to phagocytosis. These abnormalities cause muscular weakness and fatigue in patients with ESRD.
Uraemic neuropathy is present in 65% of patients on or nearing dialysis and causes the degeneration of axons and myelin sheath resulting in a loss of sensation, decreased nerve conduction velocity, loss of or a decrease in deep tendon reflexes and muscular weakness.
Muscle weakness and wastage can also result from the debilitating nature of the disease (patients simply do not have the energy or strength to move).
Fluid and Electrolyte Imbalance
Individuals with ESRD also display electrolyte imbalances such as: Hyperkalemia – high potassium levels in the blood. Potassium is involved in regulating muscle tissue, metabolism and homeostasis. Hypocalcaemia – low calcium levels in the blood caused by a decrease in the release of calcitirol from the kidneys.
Symptoms include:
- Increased tendon reflex sensitivity, uncontrollable muscle contraction in the hands, tingling pins and needles around the mouth and or neck, life threatening conditions such as heart arrhythmias can also develop. Hypophosphatemia – high levels of phosphate in the blood. Hypomagnesaemia – low levels of magnesium in the blood causes increased irritability of the nervous system resulting in tremors, muscle weakness and an increased risk of arrhythmia.
Metabolic acidosis – is caused by the inability of the kidneys to excrete ammonia from metabolised protein causing a build up of hydrogen thus making the blood more acidic. Blood Ph is stabilised however, through the release of calcium phosphate from the bones. This contributes to renal osteodystophy increasing the risk of bone pain, deformation and or fracture. Sodium bicarbonate supplementation is required to maintain a blood Ph of greater than 7.35 (serum bicarbonate levels should remain at 20 meq/L).
Endocrine/Metabolic Abnormalities: Hyperparathyroidism The kidneys take vitamin D and convert it to its active form calcitriol. Calcitriol regulates calcium in the blood, increasing absorption from the intestines and resorbtion from the bones when calcium levels are low and increasing bone formation when calcium levels are high. Calcitriol also regulates the activity of the parathyroid gland which helps to maintain serum calcium levels in a similar manner. If the kidneys are not functioning properly calcitriol production reduces resulting in abnormal regulation of calcium, low serum calcium levels, high phosphate levels, resistance to calcitriol develops and there is also a decreased response to parathyroid hormone (resulting in an increase in release). All these factors lead to the development hyperparathyroidism (there is too much parathyroid hormone in the blood) resulting in osteodystrophy including osteomelacia and osteoporosis. Treatment includes dietary phosphate restriction, vitamin D supplements combined with strict monitoring of calcium and phosphate levels in the blood.
Insulin resistance ESRD patients experience insulin resistance and the problem is exacerbated by hyperparathyroidism and metabolic acidosis causing impaired insulin release. However, ESRD patients have poor insulin clearance therefore diabetic patients may not need insulin or may need to make a reduction to their insulin intake.
Thyroid disease
Thyroid disease may be difficult to diagnose however findings show a low conversion rate of thyroxine to triiodothyronine in patients with ERSD resulting in reduced metabolic rate and production of chemical. Some patients will also experience goiter.
Neurological Abnormalities : Uremic encephalopathy is a brain disorder in patients with ESRD. Toxin build up is a likely cause especially the build up of parathyroid hormone (hyperparathyroidism). Parathyroid hormone causes increased calcium deposition disturbing neurological function however dialysis reduces the risk of encephalopathy therefore build up of parathyroid hormone is not thought to be the main cause. There has also been mention of changes in neurotransmitters within the brain causing myoclonus and seizures as a result of uremia.
Haematological Dysfunctions : Anemia The production of erythropoietin is markedly reduced in ESRD patients attributing to anaemia. Other factors can cause anaemia such as reduced vitamin B12, iron deficiency, hemolysis of red blood cells (RBC’s) and a short RBC life span therefore proper investigation is essential to determine the appropriate treatment. Anaemia decreases aerobic capacity, quality of life (QOL) and also exacerbates the symptoms of angina increasing the risk of coronary heart disease. Treatment includes subcutaneous or parental erythropoietin drugs with a dosage of 80-120U/kg per week. Serum ferritin levels may also be low which can be remedied through ferrous sulphate intake (325mg once to three times daily).
Coagulation and Platelet Dysfunction : Patients with ESRD also experience uremic bleeding (increased bleeding time) due to poor platelet function and abnormal factor VIII. Platelets aggregate more aggressively during circulation and are not able to clot the blood when needed. Discolouration of the skin due to bleeding under the skin can occur (purpura), as well as broken blood vessels causing small red marks (petechiae), increased bruising and an increased risk of bleeding. Uraemic bleeding can usually be controlled by cryoprecipitate (frozen plasma containing factor VII) and dialysis.
Abnormal Blood Lipid Profile : ESRD patients often experience abnormalities in blood lipid levels including high triglycerides and low HDL levels which lead to in conjunction with other endothelial disorders a high incidence of accelerated arthrosclerosis increasing the risk of CVD.
The Immune system
Immune function is depressed as total immunoglobulin’s and complement levels are decreased in ERSD patients rendering the patient less able to cope with pathogens including bacterial, fungal and viral infections. The immune system can be maintained through good nutrition, moderate intensity aerobic exercise, proper education concerning the importance of hand washing and immunization.
The Gastrointestinal System : The retention of urea and other metabolic waste products result in gastrointestinal problems. Initial symptoms include a metallic taste, loss of appetite followed by nausea, vomiting and weight loss. Increased ammonia causes ulcerations in the mouth and GI tract. Treatment involves decreasing protein intake and once dialysis begins most GI problems generally resolve.
The Reproductive System : ERSD patients also have reduced levels of estrogen, progesterone, testosterone and normal or increased levels of follicle-stimulating hormone and luteinizing hormone. Women experience amenorrhea, menorrhagia, decreased libido and infertility. Men experience decreased libido and impotence. However I have read it has been that men are far more likely to ever be diagnosed with ESRD.

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