Chronic Kidney Disease (CKD)

Introduction

Chronic kidney disease (CKD) is defined as abnormal kidney function or structure present for more than three months, which can have significant implications for health.1

CKD is estimated to affect nine to thirteen percent of the adult population worldwide.2

Aetiology

Causes of CKD

The most common causes of CKD in adults are diabetes and vascular disease.3

Other causes of CKD include:3

• Glomerular diseases such as IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis
• Nephrotoxic drugs such as aminoglycosides, bisphosphonates, calcineurin inhibitors (e.g. ciclosporin or tacrolimus), lithium, proton pump inhibitors, mesalazine and nonsteroidal anti-inflammatory drugs (NSAIDs)
• Obstructive uropathy or reflux nephropathy due to structural renal tract disease, neurogenic bladder, benign prostatic hypertrophy, urinary diversion surgery, recurrent urinary tract calculi, or pathology outside the urinary tract such as malignancy or retroperitoneal fibrosis
• Multisystem diseases with renal involvement such as systemic lupus erythematosus, vasculitis, myeloma, hepatitis B, hepatitis C, and HIV
• Hereditary kidney diseases such as polycystic kidney disease and Alport syndrome

Pathophysiology

Chronic kidney disease is the end-stage for any cause of severe and/or long-standing kidney injury. When half of the nephrons are damaged, CKD will progress.

Damage to the kidneys reduces the number of functioning nephrons, which leads to hyperfiltration at the glomeruli and increased glomerular permeability, resulting in proteinuria. This activates the renin-angiotensin-aldosterone system, increasing blood pressure, which furthers the hyperfiltration at the glomerular level. Additionally, cytokines and growth factors are released.

The increased capillary pressure and inflammation within the glomerulus will reduce their filtration ability, manifesting as a reduced glomerular filtration rate (eGFR). This can lead to systemic complications.

Classification of CKD

Classification of Chronic Kidney Disease (CKD)

CKD is classified by eGFR and amount of proteinuria. The prognosis of CKD is colour-coded from “low risk” (green), “moderate risk” (yellow), “high risk” (orange) to “very high risk” (red).

Risk Factors

Risk factors for CKD include:

• Age greater than 50 years
• History of acute kidney injury
• History of childhood kidney disease
• Family history of CKD stage 5
• Diabetes mellitus
• Cardiovascular disease
• Obesity with metabolic syndrome
• Gout
• Solitary functioning kidney
• Smoking
• Black or Hispanic ethnicity
• Male gender

Clinical Features

History

CKD is usually asymptomatic, with symptoms only developing in advanced stages (4-5). CKD may be detected through hypertension, haematuria or proteinuria, or a reduced GFR with increased serum creatinine.

In advanced CKD, symptoms may include:

• General symptoms such as fatigue, nausea, cramps, insomnia, restless legs, taste disturbance, bone pain and pruritus
• Abnormal urine output such as polyuria, oliguria or nocturia
• Fluid overload, presenting as dyspnoea and orthopnoea
• Sexual dysfunction
• Severe uraemia may also cause hiccups, pericarditis, coma and seizures

Clinical Examination

Typical clinical findings in CKD may include:

• Uraemic fetor: ammonia-like smell of the breath
• Pallor due to anaemia
• Cachexia
• Cognitive impairment
• Tachypnoea
• Hypertension
• Volume disturbance
• Peripheral neuropathy
• Microvascular damage

There may be specific clinical findings depending on the underlying cause of CKD, such as bilateral masses upon palpation of flanks (suggestive of adult polycystic kidney disease) or palpable bladder (suggestive of obstructive uropathy).

Differential Diagnoses

Differential diagnoses to consider in the context of suspected CKD include:

• Chronic Glomerulonephritis
• Diabetic Kidney Disease
• Childhood Kidney Disease
• Polycystic Kidney Disease
• Focal Segmental Glomerulosclerosis
• Interstitial Kidney Disease
• Urinary Tract Obstruction
• Systemic Lupus Erythematosus
• Amyloidosis
• Renal Tuberculosis
• Sarcoidosis
• HIV Associated Nephropathy
• Hypertensive Nephropathy
• Alport Syndrome

Acute Kidney Injury (AKI)

Patients with chronic symptoms of fatigue, weight loss, anorexia, nocturia and pruritus often suggest a diagnosis of Chronic Kidney Disease (CKD) over AKI.

Acute on Chronic Kidney Disease (CKD) occurs when patients with preexisting features of CKD experience an sudden deterioration in their renal function, usually as a result of an infection or diarrhoea.

Investigations

Bedside Investigations

Relevant bedside investigations include:

• Blood Pressure: hypertension is common in patients with CKD
• Urinalysis: may reveal haematuria and/or proteinuria, particularly in glomerular disease
• Plasma Glucose: to detect undiagnosed diabetes or assess control of diabetes
• ECG: particularly to assess for evidence of left ventricular hypertrophy or ischaemia

Laboratory Investigations

Relevant laboratory investigations include:

• Full Blood Count: may reveal normochromic normocytic anaemia due to erythropoietin deficiency or functional iron deficiency
• Urea and Electrolytes: reveal an elevated serum creatinine and reduced eGFR; electrolyte abnormalities may also be present (e.g. raised potassium, low bicarbonate)
• Serum Albumin: hypoalbuminaemia in patients who are nephrotic and/or malnourished
• Urinary Albumin (albumin to creatinine ratio): may be increased
• Serum Calcium: may be low, normal, or high
• Serum Phosphate: often elevated
• Serum PTH: rises as GFR falls (secondary and tertiary hyperparathyroidism)
• Serum Alkaline Phosphatase: may be raised when in the presence of hyperparathyroidism
• Cholesterol and Triglycerides: hyperlipidaemia is common

Other specific laboratory investigations may be required depending on the suspected cause of CKD:

• Serum Protein Electrophoresis and Free Light Chain Measurement: for evidence of a monoclonal gammopathy such as multiple myeloma, primary amyloidosis
• Serology: autoantibodies such as ANCA (anti-neutrophil cytoplasmic antibodies, specifically proteinase 3 or myeloperoxidase) anti-nuclear antibodies (ANA) and serum complement (C3 and C4) when secondary glomerular disease is suspected
• Hepatitis B and C and HIV serology: if suspected as a cause of CKD or if a patient requires dialysis

Imaging

Relevant imaging investigations include:

• Plain Abdominal Radiograph: may reveal radio-opaque stones or nephrocalcinosis
• Renal Ultrasound: may reveal structural abnormalities (e.g. polycystic kidneys), hydronephrosis, infiltrative disease, loss of cortex, increased echogenicity, and reduction in kidney size (advanced CKD often leads to small, echogenic kidneys)
• CT or MRI Scan: may be used to define renal masses and cysts or for further evaluation if obstructive uropathy suspected

Diagnosis

A diagnosis of CKD requires evidence of kidney damage and/or a persistent reduction in renal function.

CKD stages 3 – 5 can be diagnosed based on GFR alone (<60 mL/min/1.73m²).

Evidence of Renal Disease in CKD Stages 1-2

For CKD stages 1-2, additional evidence of renal disease must be present, such as proteinuria, urine sediment abnormalities (particularly red blood cells or casts, or white blood cells), electrolyte abnormalities due to tubular dysfunction, structural abnormalities, histological abnormalities, and a history of kidney transplantation.

Accelerated Progression of CKD

Accelerated progression of CKD is defined as a persistent decline in eGFR of 25% or more and a change in CKD category within 12 months, or a persistent decrease in eGFR of 15 mL/min/1.73 m² within 12 months.

Management

General Management

General measures for the management of CKD include exercise, healthy weight loss, smoking cessation, good glycaemic control, control of blood pressure, immunisations (influenza and Pneumococcus), avoidance of nephrotoxic medication, and a diet with adequate protein intake, restricted sodium and phosphate intake.

Patients should also be assessed for cardiovascular risk factors (lipid profile, BMI, exercise, and alcohol and smoking consumption) and may be offered a statin and antiplatelet drug for prevention of cardiovascular disease.

Good blood pressure control is essential for slowing the progression of CKD. In patients with diabetic renal disease or significant proteinuria, an ACE inhibitor or an angiotensin receptor blocker are typically the first agents of choice, but should be used with caution in patients with renovascular disease or those at risk of volume depletion or impaired renal perfusion. An SGLT-2 inhibitor may be offered if the patient is taking the maximum dose of ACE inhibitor or angiotensin receptor blocker they can tolerate.

Dietary phosphate restriction and phosphate binders (e.g. calcium acetate, sevelamer, lanthanum) may be used to control hyperphosphataemia, and 1-alpha-hydroxycholecalciferol may be administered if secondary hyperparathyroidism is present.

Monitoring

Monitoring requirements include a full blood count and iron studies (for anaemia), serum calcium, phosphate, and parathyroid hormone level (for renal bone disease). Risk level, determined by eGFR and albuminuria, guides the frequency of monitoring: low-moderate risk requires monitoring annually, high risk requires monitoring every 6 months, and very high risk requires monitoring every 3-4 months.

Renal Replacement Therapy

Renal replacement therapy is an essential part of the treatment of end-stage CKD, and includes dialysis (either haemodialysis or peritoneal dialysis) and kidney transplantation. Generally, patients begin dialysis when their GFR reaches approximately 5-10 mL/min/1.73m. Some patients, particularly those who are elderly or have significant comorbidities, opt for conservative management (best supportive care) rather than renal replacement therapy.

Haemodialysis

Haemodialysis involves pumping blood from the patient’s body through a dialyser (artificial kidney). Solutes from the blood diffuse into the dialysate and are removed together with fluid. This can be performed in a hospital or at home. Hospital-based regimens are typically for 4 hours three times a week.

Dialysis and Transplantation

Good blood flow is necessary during dialysis, and two options are available: an arterio-venous fistula (which takes 6-8 weeks to form) or a tunnelled central venous catheter. A fistula is the preferable option due to its lower rate of complications.

Complications of haemodialysis include:

• Access-related: infection, venous stenosis, access failure
• Haemodynamic instability
• Nausea and vomiting, headache, cramps
• Reactions to dialysis membranes

Peritoneal Dialysis

Peritoneal dialysis involves dialysate infusion through a tunnelled catheter into the peritoneal cavity. Solutes and fluid then move across the peritoneal membrane into the dialysate and are removed. This method is not suitable for those who have had previous intra-abdominal pathology.

The two typical regimens are continuous ambulatory peritoneal dialysis (manual dialysate exchanges performed four times daily) and automated dialysis (machine performs exchanges overnight).

Complications of peritoneal dialysis include:

• Bacterial or fungal peritonitis
• Catheter problems: infection, blockage, kinking, leaks, displacement
• Weight gain
• Worsening glycaemic control in those with diabetes
• Failure of peritoneal membrane requiring a switch to haemodialysis
• Encapsulating peritoneal sclerosis

Transplantation

Transplantation offers the best long-term outcome for those with CKD and has numerous benefits, such as the reversal of anaemia and renal bone disease, as well as improved quality of life and long-term survival. Kidneys may come from cadaveric donors (heart beating or non-heart-beating) or live donors (genetically related or unrelated). The patient's native kidneys are usually left in situ and the donor kidney is placed in the iliac fossa. Patients must also receive induction and maintenance immunosuppression to prevent graft rejection.

Complications

Contraindications to transplantation include active or recent malignancy, active infection, or significant comorbidity (e.g. ischaemic heart disease).

Complications of renal transplantation

Complications of renal transplantation include:

• Operative complications: infection, bleeding, arterial or venous thrombosis, problems with ureteric anastomosis
• Stenosis of graft artery or ureter
• Side effects from immunosuppressive therapy: nephrotoxicity and hypertension secondary to tacrolimus or ciclosporin
• Opportunistic infections particularly Cytomegalovirus (CMV)
• Malignancy: Epstein Barr virus-driven non-Hodgkin B cell lymphomas, and non-melanoma skin cancers (squamous cell and basal cell carcinomas)
• Recurrence of original renal disease in the transplant
• Hyperacute graft rejection: untreatable and should not occur if appropriate cross-matching has been performed
• Acute graft rejection: presents with creatinine rise, diagnosed by graft biopsy, initial treatment normally with intravenous steroids
• Chronic allograft nephropathy: can occur for multiple reasons, does not usually respond to increased immunosuppression

Complications

The complications of CKD can be related to the functions of the kidney. The mnemonic ‘A WET BED’ is a useful way to recall the functions of the kidney and associated complications of CKD.

Table 1. A WET BED: the functions of the kidney and associated complications of CKD

Function of the kidneyCKD complications

A

Acid-base balance

Metabolic acidosis

• Due to the inability of the kidneys to excrete acid
• Managed with oral bicarbonate supplements or dialysis

W

Water removal

Pulmonary oedema

• Due to fluid overload, which builds up in the lungs
• Patients should avoid excessive water and sodium intake
• It is treated with loop diuretics (e.g.

Chronic Kidney Disease

Chronic kidney disease (CKD) is defined as abnormal kidney function or structure present for greater than three months. It is often asymptomatic and is usually picked up through the presence of haematuria or proteinuria upon urinalysis, or a reduced eGFR. The commonest causes in the adult population are diabetes and vascular disease.

Management

CKD is usually managed symptomatically, through lifestyle modifications, and management of hypertension and other cardiovascular risk factors. The complications can include:

• Fluid: due to a reduction in the glomerular filtration rate causing a decrease in fluid excretion, can be treated with loop diuretics (e.g. furosemide) or dialysis
• Erythropoiesis: anaemia of chronic kidney disease due to the insufficiency of erythropoietin which is secreted by the kidneys. Can be treated with erythropoietin-stimulating agents and often requires iron supplementation for functional iron deficiency
• Toxin removal: uraemic encephalopathy due to the build-up of toxins in the blood which can affect brain function. Treated with dialysis to remove the toxins
• Blood pressure control: cardiovascular disease due to a combination of salt and water overload, hypertension, and accelerated atherosclerosis. Management of cardiovascular risk factors is important
• Electrolyte balance: hyperkalaemia due to the kidney’s inability to excrete potassium. Treatment includes potassium restriction, avoidance of drugs that promote hyperkalaemia, use of oral potassium binders or dialysis
• Vitamin D activation: bone-mineral disorder of chronic kidney disease (CKD-BMD), previously referred to as renal osteodystrophy. Management includes administration of hydroxylated vitamin D and control of hyperphosphataemia by restriction of dietary phosphate and administration of phosphate binders

Prognosis

CKD is a long-term condition and may progress to end-stage renal disease. It cannot be cured, but many aspects can be managed as outlined above. CKD is a strong risk factor for vascular disease, which is often the cause of death in patients with CKD.

Key points

• CKD is defined as abnormal kidney function or structure present for greater than three months
• The commonest causes in the adult population are diabetes and vascular disease
• CKD is often asymptomatic and is usually picked up through the presence of haematuria or proteinuria upon urinalysis, or a reduced eGFR
• It is usually managed symptomatically, through lifestyle modifications, and management of hypertension and other cardiovascular risk factors
• Complications can include fluid, anaemia, bone-mineral disorder, and increased cardiovascular risk
• In advanced disease, the options include renal replacement therapy (haemodialysis, peritoneal dialysis, renal transplantation) or conservative management

Chronic Kidney Disease

Chronic kidney disease (CKD) is a long-term condition in which the kidneys don't function properly. It is a condition that gradually worsens over time and ranges from mild to severe. CKD can lead to other health complications such as anemia, loss of appetite, weight loss, and electrolyte disturbances. Treatment for CKD may include medications, lifestyle changes, dialysis, or transplantation.

References:

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• NICE Guideline. Chronic kidney disease: assessment and management. 2021 [cited 22 February 2022]. Available from: [LINK]
• Rull G, Bonsall A. Renal Replacement Therapy and Transplantation. 2016. Available from: [LINK]
• National Institute of Diabetes and Digestive and Kidney Diseases. Peritoneal Dialysis. 2022. Available from: [LINK]
• Bruce Blaus. Kidney Transplant. 2015. License: [CC BY-SA]