What is chronic kidney disease, including its definition, staging, etiology, risk factors, clinical presentation, diagnostic workup, management strategies, monitoring schedule, referral criteria, and renal replacement therapy options?

Chronic Kidney Disease: Comprehensive Overview

Definition and Diagnostic Criteria

CKD is diagnosed when either persistent kidney damage OR an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² is present for ≥3 months, regardless of underlying cause. 1, 2

Core Diagnostic Components

• Structural/Anatomical Component: Markers of kidney damage, primarily persistent proteinuria defined as albumin-to-creatinine ratio (ACR) ≥30 mg/g in untimed spot urine samples 3, 1, 2

  • Sex-specific ACR thresholds improve detection: >17 mg/g in men and >25 mg/g in women 1, 2
  • Additional markers include abnormal urine sediment, abnormal blood/urine chemistry, or abnormal imaging findings 2

• Functional Component: eGFR <60 mL/min/1.73 m² alone is sufficient for diagnosis, even without other damage markers 2

  • This threshold represents loss of ≥50% of normal adult kidney function 2
  • Normal GFR in young adults is approximately 120-130 mL/min/1.73 m² and declines with age 2

• Temporal Component: Abnormalities must persist for ≥3 months, documented on at least two occasions 3, 2, 4

GFR Estimation

• Use the CKD-EPI equation for estimating GFR from serum creatinine, which has less bias than the older MDRD equation, especially at GFR ≥60 mL/min/1.73 m² 2
• For patients with eGFR 45-59 mL/min/1.73 m² without albuminuria or other damage markers, measure cystatin C to confirm diagnosis 2
• An estimate based on both creatinine and cystatin C is most accurate, particularly in patients with high or low muscle mass 5

Staging Classification

CKD is staged based on GFR level regardless of underlying diagnosis, with five stages defined: 3, 6

• Stage 1: Kidney damage with normal or increased GFR (≥90 mL/min/1.73 m²) 6
• Stage 2: Kidney damage with mild GFR decrease (60-89 mL/min/1.73 m²) 1, 6
• Stage 3: Moderate GFR decrease (30-59 mL/min/1.73 m²) 3
• Stage 4: Severe GFR decrease (15-29 mL/min/1.73 m²) 6
• Stage 5: Kidney failure (GFR <15 mL/min/1.73 m² or dialysis) 6

Critical distinction: Stages 1 and 2 require documented kidney damage (albuminuria, imaging abnormalities, or pathologic findings) in addition to the GFR threshold; GFR alone does not define early-stage CKD 1

Etiology and Risk Factors

Primary Causes

• Diabetes mellitus: Most common cause of CKD and kidney failure in developed countries, affecting approximately 40% of patients with type 2 diabetes 3, 4
• Hypertension: Second leading cause in developed countries 4
• Other causes include glomerulonephritis, polycystic kidney disease, and obstructive uropathy 3

High-Risk Populations Requiring Annual Screening

• Patients with diabetes mellitus 1, 2
• Patients with hypertension 1, 2
• Age >60 years 2
• African American individuals 1
• Family history of CKD 2
• Patients with cardiovascular disease 7
• HIV-infected patients with RNA levels ≥4,000 copies/mL or CD4+ counts <200 cells/mL 1
• Hepatitis C virus coinfection 1

Clinical Presentation

• CKD is typically asymptomatic in early stages and often detected incidentally via urinalysis showing proteinuria or elevated serum creatinine 7
• Less than 5% of patients with early CKD report awareness of their disease 4
• Uremic symptoms develop in advanced stages (Stage 5), prompting consideration for kidney replacement therapy 6

Screening and Diagnostic Workup

Screening Protocol for At-Risk Individuals

1. Measure serum creatinine and calculate eGFR 2
2. Obtain spot urine sample for ACR 2
3. Repeat any abnormal test to confirm persistence for ≥3 months before confirming CKD 2

Laboratory Reporting Standards

• Laboratories must report ACR and protein-to-creatinine ratio from untimed urine specimens, not isolated concentration values 2
• Discontinue use of the term "microalbuminuria" in laboratory reporting 2
• Do not use creatinine clearance or estimated creatinine clearance for CKD staging as they overestimate GFR and cause misclassification 2

Management Strategies by Stage

Stage 1-2 Management (Early CKD)

Primary focus: Aggressive treatment of underlying causes and risk factor modification to halt progression 6

• Blood pressure control: Target <130/80 mmHg 6
• Glycemic control in diabetic patients: Individualize HbA1c target based on comorbidities 6
• ACE inhibitors or ARBs for patients with albuminuria ≥30 mg/g, especially in diabetic kidney disease 6
• Statin therapy for cardiovascular risk reduction in adults ≥50 years with eGFR ≥60 mL/min/1.73 m² 6
• Evaluate and control dyslipidemia according to cardiovascular risk stratification 6

Key point: Stage 1 CKD represents the optimal window for intervention where aggressive treatment can halt progression, normalize albuminuria, and preserve kidney function indefinitely 6

Stage 3-4 Management (Moderate to Severe CKD)

Primary focus: Continue risk factor modification while monitoring for and managing CKD complications 6

• Statin or statin/ezetimibe combination in all adults ≥50 years, regardless of baseline lipid levels 6
• Monitor for CKD complications: anemia, bone mineral disorders, metabolic acidosis 6
• Address metabolic acidosis as it increases protein breakdown and accelerates progression 6
• Monitor hemoglobin levels and consider iron supplementation for anemia 6
• Nephrology referral for all patients with Stage 4 CKD (eGFR <30 mL/min/1.73 m²) 6, 4

Stage 5 Management (Kidney Failure)

Initiate dialysis or pursue transplantation when uremic symptoms develop or GFR falls below 10-15 mL/min/1.73 m² 6

• Hemodialysis: Standard modality performed 3-4 hours three times weekly 6
• Peritoneal dialysis: Alternative home-based option
• Kidney transplantation: Preferred option when available
• Continue cardiovascular risk reduction strategies, including statins and blood pressure management 6

Universal Management Principles Across All Stages

Cardiovascular Risk Reduction

Cardiovascular events occur more frequently than progression to kidney failure in individuals with CKD; patients with CKD constitute the highest-risk group for subsequent cardiovascular disease events 2, 8

• Implement statin therapy for adults ≥50 years 6
• Consider statin therapy in younger adults (18-49 years) if coronary disease, diabetes, prior ischemic stroke, or 10-year cardiovascular risk >10% is present 6
• Maintain blood pressure control with target <130/80 mmHg 6

Nephrotoxin Avoidance

• Identify and reduce or eliminate exposure to nephrotoxic drugs, particularly nonsteroidal anti-inflammatory drugs (NSAIDs) 4
• Adjust drug dosing for many antibiotics and oral hypoglycemic agents based on eGFR 4

Antiproteinuric Therapy

• ACE inhibitors or ARBs are preferred agents for patients with albuminuria ≥30 mg/g 3, 6
• The degree of reduction in urinary protein excretion is directly related to protection against CKD progression and cardiovascular risk 3

Novel Therapies for Diabetic Kidney Disease

The American Diabetes Association, KDIGO, and European Association for the Study of Diabetes now recommend SGLT2 inhibitors and GLP-1 receptor agonists for patients with DKD to provide both kidney and cardiovascular protective benefits 3

• These therapies offer unprecedented opportunities to reduce risk of progression and death 3
• They represent a major shift from historical treatments focused solely on glycemic control, blood pressure control, and renin-angiotensin system blockade 3

Monitoring Schedule

High-Risk Patients (Even with Normal Baseline Function)

• Annual screening for African American individuals, patients with diabetes, and patients with hepatitis C virus coinfection 1
• Annual screening for HIV-infected patients with RNA levels ≥4,000 copies/mL or CD4+ counts <200 cells/mL 1

Established CKD Patients

• Regular monitoring of kidney function (eGFR), albuminuria, and complications to avoid inadequate monitoring 6
• Frequency increases with advancing stage and presence of complications

Referral Criteria to Nephrology

Refer patients to nephrology no later than Stage 4 (GFR <30 mL/min/1.73 m²) to avoid late nephrology referral 6

High-Risk Features Requiring Prompt Referral

• eGFR <30 mL/min/1.73 m² 4
• Albuminuria ≥300 mg per 24 hours 4
• Rapid decline in eGFR 4
• All patients with Stage 4 CKD 6

Common Pitfalls and How to Avoid Them

Diagnostic Pitfalls

• Do not diagnose CKD based on a single abnormal laboratory result; abnormalities must be documented on at least two occasions ≥3 months apart 2
• Do not diagnose CKD in patients with eGFR ≥60 mL/min/1.73 m² unless they have documented markers of kidney damage 2
• Do not delay treatment waiting for "confirmation" of CKD—early intervention in Stage 1 offers the best opportunity to prevent progression 6

Management Pitfalls

• Avoid therapeutic nihilism: Patients with CKD derive as much, if not more, benefit from evidence-based cardiovascular therapies despite their high risk 8
• Do not refer to nephrology too late: Refer no later than Stage 4 to optimize preparation for kidney replacement therapy 6
• Ensure regular monitoring of kidney function, albuminuria, and complications to avoid inadequate surveillance 6

Epidemiology and Prognosis

• CKD affects 8-16% of the population worldwide, with >800 million people affected globally 4, 5
• In the United States, CKD affects 37 million adults 7
• Approximately 17% of people older than 60 years have an eGFR <60 mL/min/1.73 m² 2
• CKD is the 16th leading cause of years of life lost worldwide 4
• Premature death is a more common outcome than CKD progression to kidney failure requiring kidney replacement therapy 9
• CKD is projected to become the second most common cause of death before the end of the century in countries with long life expectancy 9