24th June 2023

Complications of chronic kidney disease

Anaemia

Mechanism

The healthy kidneys normally produce erythropoietin (EPO) in response to cell hypoxia, this stimulates bone marrow red blood cell production. Reduced production in chronic kidney disease results in less erythropoiesis and a normochromic normocytic anaemia.

However, renal patients are also at risk of other causes of anaemia, with iron deficiency commonly seen. Iron deficiency can be absolute (reduced stores) or functional (normal stores but inability to use).

• Absolute – due to gastrointestinal losses (uraemic platelet dysfunction increases the risk of bleeding), serial phlebotomy, circuit clotting during haemodialysis, or reduced absorption due to medication such as acid inhibitors and phosphate binders.
• Functional – due to underlying inflammation preventing the body from using stored iron (haemodialysis itself is a pro-inflammatory state due to interaction with the dialysis membrane), high hepcidin levels (increased in inflammatory states, decreased renal clearance) also reduces the body’s ability to absorb and use iron.

Investigation

• Full blood count – target haemoglobin (Hb) in CKD is 100-120g/L (higher levels are linked with an increased risk of cardiovascular disease). Review the mean corpuscular volume and the mean cell haemoglobin concentration; anaemia related to reduced EPO alone should be normochromic and normocytic.
• Serum ferritin level (target of 200-500 μg/l in haemodialysis patients and 100-500μg/l in CKD patients not on dialysis) and transferrin saturations (target of >20%) – targets from the UK Renal Association
• Serum B12 and folate levels

Management

• Iron replacement – it should be ensured that a patient is iron-replete before considering erythropoiesis-stimulating agents. The intravenous route is preferable to oral, especially in more advanced CKD/haemodialysis patients, though this does carry a small but significant risk of drug reaction.
• Erythropoiesis-stimulating agents – recombinant erythropoietin addresses the lack of endogenous production; it can be given subcutaneously or intravenously. Notable cautions/contraindications include pure red cell aplasia, uncontrolled hypertension, intercurrent infection, malignancy, or other inflammatory disease.
• Red cell transfusion – generally avoided. The risks and benefits of transfusion need to be considered carefully in patients who may be eligible for a renal transplant, as antibody formation may limit future organ matching options.

Renal bone disease

Mechanism

The overall term for this condition and its complications is CKD mineral and bone disorder (CKD-MBD). The pathophysiology centres around levels of calcium and phosphate – this is affected by factors including parathyroid hormone (PTH), 1,25(OH)₂D (calcitriol) and FGF-23 (fibroblast growth factor-23).

Clinical consequences

• Bone – renal osteodystrophy encompasses a range of skeletal abnormalities, including osteomalacia, osteoporosis, osteosclerosis, adynamic bone disease (low turnover state) and osteitis fibrosis cystica (high turnover state).
• Skin/soft tissue – calcinosis cutis, calcium phosphate deposition
• Cardiovascular – vascular calcification/stiffness and left ventricular hypertrophy

Management

The aim of management strategies in CKD-MBD is to maintain normal serum levels of calcium and phosphate and prevent very raised or low PTH levels (aim 2-9 times the upper limit of normal) to maintain normal bone metabolism and prevent parathyroid gland hyperplasia.

• Dietary phosphate restriction – foods high in phosphate include dairy products and eggs.
• Phosphate binders – must be taken with meals to allow the binding of phosphate in the gut. Examples include calcium carbonate (note concerns about the calcium load in patients at risk of vascular calcification) and non-calcium agents such as sevelamer or lanthanum carbonate.
• Sodium bicarbonate – acidosis exacerbates renal bone disease; it can be improved with oral replacement.
• Renal replacement therapy – treatments such as regular dialysis can reduce phosphate levels
• Vitamin D analogues – 1α-hydroxylated analogues such as alfacalcidol are often used. It is important that phosphate levels are corrected first and to monitor the patient for side effects of hypercalcaemia or hyperphosphataemia.
• Cinacalcet – used in tertiary hyperparathyroidism, it is a calcimimetic that stimulates the calcium-sensing receptors of the parathyroid gland, reducing PTH secretion.
• Parathyroidectomy – surgical intervention is reserved for severe cases where medical management has failed.

Cardiovascular disease

Multiple factors in CKD interact to significantly increase the risk of cardiovascular disease. Minimising this includes factors such as:

• Controlling hypertension
• Lipid-lowering therapy, e.g. statins
• Addressing renal bone disease to reduce vascular calcification
• Consideration of antiplatelet therapy as secondary prevention, e.g. aspirin
• Management of other risk factors, e.g. smoking cessation, diabetic control