Chronic Kidney Disease: Comprehensive Overview
Definition
Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function present for more than 3 months with implications for health. 1 The diagnosis requires documentation of abnormalities on at least two occasions separated by ≥3 months to distinguish chronic from acute disease. 2
CKD is diagnosed by either:
- **Estimated GFR (eGFR) <60 mL/min/1.73 m²** (representing loss of >50% of normal adult kidney function), OR 2
- Evidence of kidney damage at any eGFR level, including: 2
- Albuminuria (albumin-to-creatinine ratio [ACR] ≥30 mg/g)
- Abnormal urine sediment
- Electrolyte disturbances from tubular dysfunction
- Structural abnormalities on imaging
- Histologic abnormalities on biopsy
- History of kidney transplantation
Classification System
The CGA Classification Framework
CKD must be classified using the complete CGA system: Cause, GFR category, and Albuminuria category—never by GFR alone. 1, 2, 3 This integrated approach provides superior risk stratification for disease progression, cardiovascular events, and mortality. 2
GFR Categories (G Stages)
| Category | eGFR (mL/min/1.73 m²) | Description |
|---|---|---|
| G1 | ≥90 | Normal or high function* |
| G2 | 60–89 | Mildly decreased* |
| G3a | 45–59 | Mild-to-moderate decrease |
| G3b | 30–44 | Moderate-to-severe decrease |
| G4 | 15–29 | Severe decrease |
| G5 | <15 | Kidney failure |
| G5D | <15 on dialysis | Kidney failure on dialysis |
*For G1 and G2, evidence of kidney damage (e.g., albuminuria, imaging abnormality) is required for CKD diagnosis; reduced GFR alone is insufficient. 2, 3
The subdivision of G3 into G3a and G3b is critical because these categories have markedly different mortality, cardiovascular risk, and progression profiles. 1, 2, 3 This distinction has broad clinical applications given the high prevalence of stage 3 CKD. 1
Albuminuria Categories (A Stages)
| Category | ACR (mg/g) | Description |
|---|---|---|
| A1 | <30 | Normal to mildly increased |
| A2 | 30–300 | Moderately increased |
| A3 | >300 | Severely increased |
- Sex-specific ACR thresholds: >17 mg/g in men and >25 mg/g in women. 2
- An ACR ≥30 mg/g (approximately 3× normal) independently predicts CKD complications, cardiovascular mortality, and progression to kidney failure. 2, 3
- Where albuminuria measurement is unavailable, urine reagent strip results can be substituted. 1
Combined Risk Stratification (KDIGO Heat Map)
The integration of GFR and albuminuria categories assigns color-coded risk levels: 2, 3
- Low risk (green): G1–G2 + A1 (no CKD if no other kidney damage markers present)
- Moderately increased risk (yellow): G1–G2 + A2, or G3a + A1
- High risk (orange): G1–G2 + A3, or G3a + A2, or G3b + A1
- Very high risk (red): G3a + A3, or G3b + A2–A3, or any G4–G5 (any albuminuria level)
This risk stratification guides monitoring frequency, blood pressure targets, timing of nephrology referral, and cardiovascular risk-reduction strategies. 3
Common Etiologies
The cause of CKD should be assigned based on presence or absence of systemic disease and the anatomic location of renal pathology (glomerular, tubular, vascular, cystic). 1 Common causes include: 3
- Diabetic kidney disease (most common in developed countries)
- Hypertensive nephrosclerosis
- Glomerulonephritis (primary or secondary)
- Polycystic kidney disease
- Obstructive uropathy
- Chronic interstitial nephritis (including drug-induced)
- Renovascular disease
Pathophysiology
Progressive Nephron Loss
CKD represents a final common pathway of progressive nephron loss from diverse initial insults. 4 As GFR declines, compensatory hyperfiltration in remaining nephrons leads to glomerular hypertension, proteinuria, and further nephron injury—creating a self-perpetuating cycle of progressive kidney damage. 4
Systemic Complications
As GFR decreases below 60 mL/min/1.73 m², the risk of complications increases significantly, including hypertension, anemia, mineral-bone disorder, cardiovascular disease, and mortality. 3, 5, 6 These complications arise from:
- Sodium and water retention → hypertension and volume overload
- Erythropoietin deficiency → anemia (prevalent when GFR <60 mL/min/1.73 m²) 3
- Phosphate retention and vitamin D deficiency → secondary hyperparathyroidism and CKD-mineral bone disorder 1
- Uremic toxin accumulation → cardiovascular disease, accelerated atherosclerosis, and premature death 5
- Chronic inflammation and oxidative stress → accelerated aging and multimorbidity 5
The prevalence of hypertension approaches 80% in stage 4 CKD, and the likelihood of having multiple complications increases substantially when GFR falls below 30 mL/min/1.73 m². 3
Clinical Features
Early Stages (G1–G3a)
- Often asymptomatic; detected incidentally on routine laboratory testing 4, 6
- Hypertension (may be present or worsening)
- Mild edema (if present)
- Nocturia (from impaired urinary concentrating ability)
Advanced Stages (G3b–G5)
- Fatigue and weakness (from anemia and uremia)
- Anorexia, nausea, and metallic taste (uremic symptoms)
- Pruritus (from uremic toxins and secondary hyperparathyroidism)
- Bone pain and fractures (CKD-mineral bone disorder)
- Peripheral edema and dyspnea (volume overload)
- Cognitive impairment (uremic encephalopathy in severe cases) 5
- Pericarditis (late uremic complication)
- Bleeding tendency (platelet dysfunction)
Physical Examination Findings
- Hypertension (present in majority of patients) 3
- Pallor (anemia)
- Edema (peripheral, periorbital, or pulmonary)
- Uremic frost (crystallized urea on skin in severe uremia—rare)
- Pericardial friction rub (uremic pericarditis)
- Asterixis (uremic encephalopathy)
- Signs of underlying cause: diabetic retinopathy, lupus rash, polycystic kidney masses
Essential Investigations
Initial Diagnostic Tests
GFR Estimation:
- Use the CKD-EPI creatinine equation as the first-line method for eGFR calculation; it demonstrates less bias than the MDRD equation, especially when eGFR ≥60 mL/min/1.73 m². 2, 3
- Creatinine assays must be calibrated to isotope-dilution mass spectrometry (IDMS) reference standards. 2, 3
- When creatinine-based eGFR is uncertain (e.g., extremes of muscle mass, sarcopenia), confirm with cystatin C-based or combined creatinine-cystatin C equations for greater accuracy. 2, 6
Albuminuria Assessment:
- Measure albumin-to-creatinine ratio (ACR) on a random spot urine sample (preferred over 24-hour collection). 3
- Perform at least 2–3 measurements over 6 months to confirm diagnosis and establish baseline. 3
Complete Blood Count:
- Assess for anemia (normocytic, normochromic); becomes more prevalent as GFR falls below 60 mL/min/1.73 m². 3
Serum Electrolytes:
- Sodium, potassium, bicarbonate (assess for metabolic acidosis), chloride
Calcium, Phosphate, and Parathyroid Hormone (PTH):
- Screen for CKD-mineral bone disorder; base treatment on trends rather than single abnormal results. 1
- Avoid hypercalcemia when treating secondary hyperparathyroidism. 1
Lipid Profile:
- Assess cardiovascular risk (CKD is a cardiovascular disease equivalent)
Urinalysis and Urine Sediment:
- Detect hematuria, pyuria, casts (red cell casts suggest glomerulonephritis; white cell casts suggest pyelonephritis/interstitial nephritis)
Renal Ultrasound:
- Assess kidney size, echogenicity, and rule out obstruction
- Small, echogenic kidneys suggest chronicity; asymmetry may indicate renovascular disease
Additional Investigations (Based on Clinical Context)
- Hemoglobin A1c (if diabetic kidney disease suspected)
- Autoimmune serologies (ANA, ANCA, anti-GBM, complement levels) if glomerulonephritis suspected
- Serum and urine protein electrophoresis (if myeloma suspected)
- Renal biopsy (if diagnosis uncertain, rapidly progressive disease, or to guide specific therapy)
Management
General Principles
The treatment goals are to slow CKD progression, reduce cardiovascular risk, manage complications, and prepare patients adequately for renal replacement therapy. 7 Early detection and appropriate nephrology referral improve long-term morbidity and reduce costs. 7
Blood Pressure Control
Target blood pressure <130/80 mmHg in patients with CKD, with lower goals (<120/80 mmHg) in the setting of proteinuria (ACR ≥30 mg/g). 1
- First-line agents: ACE inhibitors or angiotensin receptor blockers (ARBs) for patients with albuminuria (ACR ≥30 mg/g), as they provide renoprotection beyond blood pressure lowering. 1, 4
- Avoid combining ACE inhibitors and ARBs (increased risk of hyperkalemia and acute kidney injury without additional benefit). 4
- Monitor serum creatinine and potassium 1–2 weeks after initiating or titrating renin-angiotensin-aldosterone system (RAAS) blockade; accept up to 30% increase in creatinine if stable thereafter. 4
Glycemic Control (in Diabetic CKD)
- Target HbA1c <7% (individualize based on comorbidities, hypoglycemia risk, and life expectancy). 4
- Sodium-glucose cotransporter-2 (SGLT2) inhibitors are first-line glucose-lowering agents in diabetic CKD; they reduce CKD progression, cardiovascular events, and mortality. 4
- Glucagon-like peptide-1 (GLP-1) receptor agonists provide additional cardiovascular and renal benefits. 4
- Adjust insulin and sulfonylurea doses as GFR declines to prevent hypoglycemia. 4
Dietary Measures
Sodium Restriction:
- Limit sodium intake to <2 g/day (<5 g salt/day) to control blood pressure and reduce proteinuria. 1
Protein Restriction:
- 0.8 g/kg/day (normal protein intake) for stages G1–G3a
- 0.6–0.8 g/kg/day for stages G3b–G5 (not on dialysis) to slow progression and reduce uremic symptoms, while avoiding malnutrition. 4
- Ensure adequate caloric intake (30–35 kcal/kg/day) to prevent protein-energy wasting. 4
Potassium and Phosphate Restriction:
- Restrict potassium-rich foods if hyperkalemia develops (K⁺ >5.5 mEq/L). 4
- Limit dietary phosphate to 800–1000 mg/day in stages G3b–G5 to prevent secondary hyperparathyroidism. 1
Treatment of Anemia
Target hemoglobin 10–11.5 g/dL (avoid >13 g/dL due to increased cardiovascular risk). 4
- Investigate and correct iron deficiency before initiating erythropoiesis-stimulating agents (ESAs):
- Oral or intravenous iron supplementation to achieve transferrin saturation >20% and ferritin >100 ng/mL (non-dialysis) or >200 ng/mL (dialysis). 4
- Erythropoiesis-stimulating agents (ESAs): epoetin alfa, darbepoetin alfa
- Initiate when hemoglobin <10 g/dL despite iron repletion
- Use lowest dose to avoid transfusions; higher doses increase cardiovascular events and mortality. 4
Treatment of CKD-Mineral Bone Disorder
Phosphate Management:
- Dietary phosphate restriction (800–1000 mg/day) is first-line. 1
- Phosphate binders (calcium-based [calcium carbonate, calcium acetate] or non-calcium-based [sevelamer, lanthanum]) if hyperphosphatemia persists despite dietary restriction. 1
- Avoid hypercalcemia (calcium <10.5 mg/dL) when using calcium-based binders. 1
Vitamin D and PTH Management:
- Correct vitamin D deficiency with ergocalciferol or cholecalciferol (25-OH vitamin D <30 ng/mL). 1
- Active vitamin D analogs (calcitriol, paricalcitol) or calcimimetics (cinacalcet) for secondary hyperparathyroidism (PTH >2× upper limit of normal in stage G3–G4; >9× upper limit in G5). 1
- Base treatment on trends in laboratory values rather than a single abnormal result. 1
Cardiovascular Risk Reduction
- Statin therapy for all patients aged >50 years with CKD (regardless of baseline LDL cholesterol), as CKD is a cardiovascular disease equivalent. 4
- Antiplatelet therapy (aspirin 75–100 mg/day) for secondary prevention in patients with established cardiovascular disease. 4
- Smoking cessation (reduces CKD progression and cardiovascular events). 4
Novel Kidney-Protective Agents
SGLT2 Inhibitors:
- Indicated for all patients with CKD (eGFR ≥20 mL/min/1.73 m²) and albuminuria, regardless of diabetes status, to slow progression and reduce cardiovascular events. 4
Non-Steroidal Mineralocorticoid Receptor Antagonists (MRAs):
- Finerenone reduces CKD progression and cardiovascular events in diabetic CKD with albuminuria; monitor potassium closely. 4
Endothelin Receptor Antagonists:
- Emerging therapies under investigation for proteinuric CKD. 4
Avoidance of Nephrotoxins
- Avoid NSAIDs (risk of acute kidney injury and accelerated CKD progression). 1, 4
- Adjust medication doses for GFR (e.g., metformin, antibiotics, anticoagulants). 1
- Avoid iodinated contrast when possible; if necessary, ensure adequate hydration and use lowest dose. 4
Monitoring and Progression Assessment
Stages 1–2:
- Annual monitoring of eGFR, ACR, blood pressure, and electrolytes. 3
Stage 3a:
- Monitor 2–4 times per year based on albuminuria category and rate of progression. 3
Stages 3b–5:
- Monitor every 3–6 months; more frequent monitoring if rapidly progressive. 3
Define rapid progression as ≥30% decrease in eGFR over 2 years or sustained decline ≥5 mL/min/1.73 m²/year, plus change in GFR category. 2
Nephrology Referral
All patients with CKD stages G4–G5 should be referred to nephrology. 7
Additional indications for referral: 7
- Rapidly progressive CKD (decline >5 mL/min/1.73 m²/year)
- Albuminuria category A3 (ACR >300 mg/g)
- Uncontrolled hypertension despite multiple agents
- Persistent electrolyte abnormalities (hyperkalemia, metabolic acidosis)
- Unexplained hematuria or red cell casts
- Suspected genetic or rare kidney disease
Preparation for Renal Replacement Therapy
Initiate preparation when eGFR <30 mL/min/1.73 m² (stage G4). 7
Patient Education:
- Discuss modality options: hemodialysis, peritoneal dialysis, kidney transplantation (preemptive if possible). 7
- Provide information on living donor transplantation. 7
Vascular Access Planning:
- Create arteriovenous fistula when eGFR <20 mL/min/1.73 m² (stage G5) if hemodialysis anticipated; fistulas require 3–6 months to mature. 7
- Avoid venipuncture and intravenous catheters in non-dominant forearm to preserve vessels. 7
Peritoneal Dialysis Catheter:
- Place when eGFR <15 mL/min/1.73 m² if peritoneal dialysis chosen. 7
Transplant Evaluation:
- Refer for transplant evaluation when eGFR <20 mL/min/1.73 m² if no contraindications. 7
Initiate Dialysis:
- When eGFR <10 mL/min/1.73 m² and uremic symptoms develop (nausea, vomiting, pruritus, pericarditis, encephalopathy, refractory volume overload, or hyperkalemia). 3, 7
- Avoid early dialysis initiation (eGFR 10–14 mL/min/1.73 m²) in asymptomatic patients; it does not improve outcomes and may increase complications. 7
Common Pitfalls and Caveats
- Never diagnose CKD on a single abnormal test; abnormalities must be documented on at least two occasions ≥3 months apart. 2, 3
- Never stage CKD by GFR alone; always use the complete CGA classification (Cause, GFR category, Albuminuria category). 1, 2, 3
- Do not diagnose CKD in G1–G2 without evidence of kidney damage (e.g., albuminuria, imaging abnormality); an isolated eGFR 70 mL/min/1.73 m² is not CKD. 2, 3
- Avoid NSAIDs in all CKD patients; they increase risk of acute kidney injury and accelerate progression. 1, 4
- Do not combine ACE inhibitors and ARBs; this increases adverse events without additional benefit. 4
- Monitor creatinine and potassium 1–2 weeks after initiating RAAS blockade; accept up to 30% creatinine increase if stable. 4
- Avoid over-treatment of anemia (target hemoglobin 10–11.5 g/dL); higher targets increase cardiovascular risk. 4
- Avoid hypercalcemia when treating secondary hyperparathyroidism; use non-calcium-based phosphate binders if calcium elevated. 1
- Do not delay nephrology referral in stage G4–G5; late referral increases morbidity, mortality, and costs. 7
- Recognize that GFR declines with normal aging; not all reduced GFR represents pathologic CKD (e.g., healthy kidney donors with eGFR 55 mL/min/1.73 m² have minimal health implications). 1, 8