Complications of ESRF
Normally functioning kidneys accomplish a number of important tasks.
1. Control of water balance.
2. Control of electrolyte balance.
3. Control of blood pressure (through both control of water and electrolyte balance and production of renin).
4. Control of acid-base balance.
5. Excretion of water-soluble waste.
6. The production of active vitamin D (though the action of 1α hydroxylase) and hence control of calcium-phosphate metabolism.
7. The production of erythropoietin (EPO), and hence control of haemoglobin concentration.
In patients with ESRF, one or more of the above functions cannot be performed, resulting in a number of complications.
Failure of renal excretory functions
Control of water balance
As tubular function declines, the kidney retains fluid, resulting in an expansion in intravascular volume and an increase in venous return. Since mean arterial pressure (MAP) is dependent on cardiac output (CO) and total peripheral resistance (TPR), and CO is affected by stroke volume and hence venous return, the principal effect of fluid retention is hypertension. Patients with CKD and even those on dialysis are often chronically volume overloaded. The resulting hypertension places strain on the left ventricle, leading to left ventricular hypertrophy (LVH) and eventually LV dilatation.
Control of electrolyte balance
Patients fail to excrete potassium appropriately, leading to hyper- kalaemia, which can result in life-threatening cardiac arrhythmias. Sodium retention contributes to fluid overload and hypertension. Accumulation of phosphate leads to the release of two hormones that would normally increase phosphate excretion by the kidneys: parathyroid hormone (PTH, released by the parathyroid glands) and fibroblast growth factor 23 (FGF23, released by bone cells). Unfortunately, FGF23 inhibits 1α-hydroxylase activity, worsening vitamin D deficiency (see below). Low vitamin D levels lead to a further increase in PTH, because parathyroid cells sense both calcium and vitamin D. The end result is a spiralling increase in PTH, releasing calcium from bone and increasing phosphate, establishing a vicious cycle. If left untreated, the parathyroid glands become enlarged and stop responding to the normal inhibitory signals. This leads to hypercalcaemia and is termed tertiary hyperparathyroidism. Chronic hypercalcaemia results in calcium deposition in soft tissues and arteries. Arteries can become heavily calcified and stiff, leading to decreased compliance and an increase in MAP and LVH. Calcium deposition is enhanced by hyperphos-phataemia and the metabolic acidosis that often accompanies CKD.
Control of acid-base balance
The kidneys normally excrete the daily acid load generated by amino acid metabolism. As renal function declines, patients develop a progressive metabolic acidosis. Chronic acidosis can promote renal bone disease (see below) and leads to muscle wasting and malnutrition.
Excretion of soluble waste products
The kidneys are responsible for excreting most soluble waste products, including urea. In CKD, urea levels rise, resulting in a loss of appetite and nausea. At higher levels, uraemia may be associated with pericarditis and encephalopathy.
Failure of renal synthetic functions
Activity of 1-α hydroxylase
Native vitamin D (cholecalciferol) is hydroxylated first by the liver to 25-hydroxy vitamin D, and then by the kidneys to the active hormone 1, 25 dihydroxyvitamin D3 (calcitriol). Low circulating calcitriol levels are characteristic of patients with kidney failure, due to loss of the activating enzyme 1-α hydroxylase. Calcitriol is central to calcium homeostasis: its deficiency in CKD leads to a reduction in intestinal calcium absorption, hypocalcaemia and impaired mineralisation of bone, manifesting as ‘renal rickets’ in children and osteomalacia in adults. Bone disease in CKD may also be due to high turnover due to high PTH, or low turnover due to over-suppressed PTH.
EPO is produced by peritubular cells and acts on erythroid precursors within the bone marrow, stimulating proliferation and maturation. When the GFR falls to <50 ml/min, a reduction in EPO production may be observed, resulting in anaemia. Anaemia in CKD patients is exacerbated by impaired intestinal absorption of iron and reduced iron intake (due to nausea secondary to uraemia). Anaemia can lead to an increase in cardiac output and may exacerbate LV dysfunction. Prior to the introduction of recombinant EPO, anaemia was a major cause of morbidity and mortality in patients with ESRF due to associated cardiovascular complications.
Morbidity and mortality of patients with CKD/ESRF
Patients with ESRF have a significantly increased mortality compared with the general population. This is mainly due to an increase in atherosclerosis and vascular calcification, which result in accelerated coronary artery disease, peripheral vascular disease and cerebrovascular accidents. These complications may significantly impact their fitness for transplantation.
Patients reaching ESRF are also susceptible to additional complications related to the provision of renal replacement therapy (RRT), as detailed in Chapter 23.