Chronic Kidney Disease: Classification, Complications and Slowing Progression

Introduction

Chronic kidney disease is defined as abnormalities of kidney structure or function, present for more than 3 months, with implications for health.¹ The three-month qualifier is essential: it is what distinguishes CKD from acute kidney injury, and it is why a single abnormal blood test never establishes the diagnosis.

CKD affects around 10% of the UK adult population, rising steeply with age, and much of it is undiagnosed.² It is important out of proportion to its symptoms because it is usually silent until advanced, because it is a powerful and independent cardiovascular risk factor, and because the drugs that slow its progression work best when started early - which requires the diagnosis to be made in the asymptomatic phase.

Classification

CKD is classified along two independent axes, and both must be quoted for the classification to be meaningful - for example 'CKD G3aA2'. This two-dimensional system replaced the old single-number staging precisely because albuminuria predicts outcome independently of eGFR.

Causes

• Risk factors warranting testing for CKD include diabetes, hypertension, cardiovascular disease, heart failure, a family history of end-stage renal disease or a genetic kidney disease, structural renal tract disease or recurrent stones, multisystem disease such as lupus, gout, previous AKI, and long-term use of nephrotoxic drugs including NSAIDs, lithium and calcineurin inhibitors.²
• Incidental haematuria or proteinuria found on dipstick also warrants assessment

Clinical features

CKD is asymptomatic in the great majority of cases and is usually identified through screening of at-risk groups or as an incidental finding.⁶ Symptoms generally appear only at G4 to G5, and their absence tells you nothing reassuring about the eGFR.

Examination may reveal hypertension (present in the majority), pallor, oedema, a raised JVP, evidence of the underlying cause (ballotable kidneys in polycystic disease, an enlarged prostate, diabetic retinopathy, a renal bruit) and, in established disease, an arteriovenous fistula or dialysis catheter.

Investigations

Establishing and staging the diagnosis

• U&Es with eGFR, repeated after at least 90 days to confirm chronicity
• Urine ACR on an early morning sample, confirmed as above
• Urine dipstick for blood - persistent non-visible haematuria with proteinuria suggests glomerular disease and needs investigation; isolated haematuria requires urological assessment for malignancy
• Review historical creatinine results to establish the trajectory - the rate of change is often more informative than any single value

Identifying the cause

• HbA1c and fasting glucose - for diabetes
• Blood pressure, and assessment for end-organ damage
• Renal tract ultrasound - indicated for accelerated progression, visible or persistent non-visible haematuria, symptoms of obstruction, a family history of polycystic kidney disease, or eGFR under 30. Look for kidney size and symmetry, cortical thickness, echogenicity, cysts and hydronephrosis. Small, bilaterally shrunken, echogenic kidneys indicate established chronic damage.
• Immunology where glomerular disease is suspected - ANA, ANCA, complement, anti-GBM, immunoglobulins and serum free light chains with electrophoresis (myeloma screen), plus hepatitis B and C and HIV serology
• Renal biopsy - considered where the cause is unclear and would change management, particularly with significant proteinuria or suspected glomerulonephritis

Monitoring for complications

• Full blood count and haematinics - for anaemia of CKD; check ferritin, transferrin saturation, B12 and folate before attributing anaemia to erythropoietin deficiency
• Bone profile and PTH - calcium, phosphate, PTH and vitamin D, for CKD-mineral and bone disorder
• Bicarbonate - for metabolic acidosis
• Potassium - both from CKD itself and from the drugs used to treat it
• Lipid profile and cardiovascular risk assessment
• Kidney Failure Risk Equation - a validated tool estimating the 2- and 5-year risk of requiring renal replacement therapy, now recommended by NICE to guide referral and to inform discussions with patients²

Management

The aims are to slow progression, reduce cardiovascular risk, treat complications, and prepare for renal replacement therapy in those who will need it. No treatment reverses established scarring, which is why early intervention matters.

Slowing progression

Cardiovascular risk reduction

• Atorvastatin 20 mg is offered to all adults with CKD for primary prevention, regardless of the QRISK3 score, with the dose increased if a greater than 40% reduction in non-HDL cholesterol is not achieved (specialist advice for eGFR under 30)⁴
• Antiplatelet therapy for secondary prevention where indicated, bearing in mind the increased bleeding risk from uraemic platelet dysfunction
• Blood pressure control as above, and smoking cessation
• Note that CKD is a QRISK3 input, but statins are offered on the basis of CKD itself

Managing the complications

Referral and preparing for renal replacement therapy

• Refer to nephrology if: eGFR under 30 (G4-G5); ACR 70 mg/mmol or above (unless known to be due to diabetes and already treated); ACR 30 or above with persistent haematuria; sustained fall in eGFR of 25% or more with a change in G category, or a sustained fall of 15 or more within 12 months; hypertension uncontrolled on four antihypertensives; suspected genetic or rare cause; suspected renal artery stenosis; or a 5-year risk of needing dialysis above 5% on the Kidney Failure Risk Equation²
• Plan RRT well in advance - discussions about haemodialysis, peritoneal dialysis, transplantation and conservative care should begin at least a year before anticipated need, since fistula creation and transplant work-up take months
• Preserve the non-dominant forearm veins in anyone likely to need dialysis - avoid unnecessary cannulation and never use a subclavian line if avoidable
• Vaccinate against hepatitis B, influenza and pneumococcus
• Discuss conservative kidney management honestly for frail or elderly patients with significant comorbidity, in whom dialysis may not extend life meaningfully and may reduce its quality

Complications

• Cardiovascular disease - accelerated atherosclerosis, left ventricular hypertrophy, heart failure and arrhythmia; by far the commonest cause of death in CKD
• Anaemia of CKD
• CKD-mineral and bone disorder with fracture and vascular calcification
• Hyperkalaemia and metabolic acidosis
• Fluid overload and pulmonary oedema
• Secondary and tertiary hyperparathyroidism
• Increased susceptibility to AKI - a CKD kidney has little reserve, so any insult produces a disproportionate fall in function
• Increased infection risk and reduced vaccine responses
• Malnutrition and sarcopenia
• Uraemic pericarditis, encephalopathy and neuropathy in advanced disease
• Drug toxicity from impaired clearance
• End-stage renal disease requiring dialysis or transplantation
• Reduced quality of life and depression, which are common and under-treated

Red flags

Prognosis

The natural history of CKD varies enormously, and most patients do not progress inexorably to dialysis. Many with G3a and no albuminuria remain stable for years or decades, and in the elderly a mildly reduced eGFR may represent age-related decline of limited clinical consequence. Albuminuria is the strongest single predictor of progression, which is why the A stage matters as much as the G stage.

Factors associated with faster progression include heavy proteinuria, poorly controlled hypertension, poor glycaemic control in diabetes, smoking, repeated episodes of AKI, male sex, Black or South Asian ethnicity, and the underlying diagnosis - polycystic kidney disease and diabetic nephropathy progress more predictably than hypertensive nephrosclerosis.

Cardiovascular mortality dominates the outlook at every stage. A patient with CKD G3b is several times more likely to have a cardiovascular event than to require dialysis, and the excess risk rises steeply with falling eGFR and rising albuminuria. This is why the modern approach treats CKD as a cardiovascular as well as a renal diagnosis.

The therapeutic outlook has changed substantially. Renin-angiotensin blockade and, more recently, SGLT2 inhibitors have both been shown to slow progression and reduce cardiovascular events, and the latter represent the most significant advance in the field in decades.³ For those who do reach end-stage disease, transplantation offers markedly better survival and quality of life than dialysis, and conservative management remains an appropriate and dignified choice for frail patients in whom dialysis would add burden without benefit.