Chronic Kidney Disease (Adult)

1. Overview

Chronic Kidney Disease (CKD) is a progressive, irreversible syndrome characterised by structural or functional renal abnormalities persisting for more than three months. It is defined by either a glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m² or markers of kidney damage (most commonly albuminuria). CKD represents a unified "final common pathway" for numerous renal insults, eventually leading to End-Stage Kidney Disease (ESKD) and requiring Renal Replacement Therapy (RRT). [1]

The clinical significance of CKD extends far beyond the loss of excretory function. It is a potent independent risk factor for cardiovascular disease (CVD), with CKD patients being more likely to die from a cardiovascular event than to reach dialysis. The "uremic milieu" that develops in advanced stages affects every organ system, leading to complications such as mineral bone disorder (CKD-MBD), refractory anaemia, and systemic immune dysfunction. [2]

Management has been revolutionised in the 2020s, shifting from a reactive "wait and watch" approach to a multi-pillar renoprotective strategy. The introduction of SGLT2 inhibitors, non-steroidal mineralocorticoid receptor antagonists (ns-MRAs), and GLP-1 receptor agonists has provided clinicians with tools to significantly delay progression and reduce cardiovascular mortality. [3]

2. Epidemiology

Global Distribution

CKD is a global public health crisis, affecting approximately 10-13% of the world's population (~850 million people). The prevalence is rising, primarily driven by the "twin epidemics" of diabetes and hypertension in an ageing global population. [4]

Demographics

• Age: Prevalence increases sharply with age (> 20% in those over 65).
• Sex: Females have a higher prevalence of early CKD, but males progress more rapidly to ESKD.
• Ethnicity: African American, Hispanic, and South Asian populations are disproportionately affected, often due to a combination of genetic factors (e.g., APOL1 variants) and socioeconomic health disparities. [5]

Risk Factors

1. Systemic Disease: Diabetes Mellitus (leading cause - 40%), Hypertension (25%), Obesity.
2. Primary Renal Disease: Glomerulonephritis (IgA nephropathy), ADPKD.
3. Environmental/Lifestyle: Smoking, high dietary salt, NSAID overuse.
4. Genetic: Family history, specific variants (APOL1).

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3. Aetiology & Pathophysiology

The "Brenner" Hyperfiltration Hypothesis

Regardless of the initial cause, CKD progresses through a self-perpetuating cycle of nephron loss and compensatory hyperfiltration. [6]

1. Nephron Loss: Initial insult (e.g., hyperglycaemia, ischaemia) destroys a cohort of nephrons.
2. Adaptive Hypertrophy: Remaining nephrons enlarge to compensate.
3. Intraglomerular Hypertension: Driven by Angiotensin II, the efferent arteriole constricts while the afferent arteriole dilates (facilitated by SGLT2-mediated tubuloglomerular feedback loss).
4. Podocyte Injury: Mechanical strain on the filtration barrier leads to podocyte effacement and detachment.
5. Proteinuria: Filtered proteins are toxic to the tubules, triggering inflammation.
6. Fibrosis: TGF-β and other cytokines drive the transition of fibroblasts to myofibroblasts, leading to glomerulosclerosis and tubulointerstitial fibrosis.

Molecular Mechanisms

• RAAS Activation: Local (intrarenal) RAAS is chronically overactive. Angiotensin II stimulates NADPH oxidase, producing reactive oxygen species (ROS) and activating NF-κB, which promotes the expression of pro-inflammatory cytokines (IL-6, MCP-1).
• TGF-β Pathway: The "master regulator" of renal scarring. It stimulates Smad2/3 signalling, leading to the deposition of Type I and III collagen and the inhibition of matrix metalloproteinases (MMPs).
• Glycocalyx Destruction: Chronic inflammation strips the endothelial glycocalyx, increasing vascular permeability and contributing to systemic atherosclerosis.
• Tubuloglomerular Feedback (TGF) Impairment: In diabetes, proximal glucose reabsorption via SGLT2 is upregulated. This co-transports sodium, reducing distal delivery of NaCl to the macula densa. The macula densa senses "low volume" and triggers afferent arteriolar vasodilation, worsening glomerular hypertension. [7]

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4. Clinical Presentation

Symptoms by Stage

• Stages 1-3: Typically "silent." Detected via routine screening.
• Stage 4: Non-specific symptoms: Fatigue, nocturia (loss of concentrating ability), pruritus.
• Stage 5 (Uraemia):
  • Gastrointestinal: Anorexia, nausea, vomiting, uraemic foetor (ammoniacal breath).
  • Neurological: "Brain fog," asterixis (flapping tremor), peripheral neuropathy, restless legs.
  • Dermatological: Uraemic frost (rare urea crystals on skin), pallor (anaemia), excoriations.
  • Fluid: Dyspnoea, orthopnoea, peripheral oedema.

Physical Signs

1. Cardiovascular: Hypertension (80%+), displaced apex (LVH), JVD, S3 gallop.
2. Pulmonary: Basal crackles (fluid), uraemic pleuritis (rub).
3. Uraemic Pericarditis: Pericardial friction rub. Crucial: ECG may not show ST elevation because the inflammation is visceral, not epicardial. [8]

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5. Differential Diagnosis

The primary challenge is distinguishing CKD from Acute Kidney Injury (AKI) or Acute-on-Chronic episodes.

Specific Aetiological Differentials

1. Diabetic Nephropathy: Long-standing DM, retinopathy usually present, A3 albuminuria.
2. Hypertensive Nephrosclerosis: Long history of HTN, LVH, bland urinary sediment.
3. ADPKD: Family history, palpable flank masses, cystic kidneys on US.
4. Obstructive Uropathy: History of BPH, stones, or malignancy; hydronephrosis on US.

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6. Investigations

Bedside & Laboratory

1. eGFR (CKD-EPI 2021): The gold standard. The 2021 update removed race-based coefficients to improve equity.
2. uACR (Urine Albumin:Creatinine Ratio): Preferred over 24h collections. Spot first-morning void is best.
   • A1: less than 3 mg/mmol
   • A2: 3-30 mg/mmol (Microalbuminuria)
   • A3: > 30 mg/mmol (Macroalbuminuria)
3. Serum Cystatin C: Use if eGFR-creatinine is unreliable (e.g., extremes of muscle mass, cirrhosis).
4. CKD-MBD Panel: Calcium (low/normal), Phosphate (high), PTH (high), Vitamin D (low).
5. FBC: Normocytic normochromic anaemia (EPO deficiency).

Imaging

• Renal Ultrasound (1st Line):
  • Assesses size, cortical thickness (thinning = fibrosis), and rules out hydronephrosis.
  • Exception: Kidneys may be normal/large in CKD due to Diabetes, Amyloidosis, or HIV-associated nephropathy.

Special Tests

• Renal Biopsy: Indicated if cause is unknown, rapid GFR decline, or nephrotic-range proteinuria (> 3.5g/day).
• Vascular Studies: Renal artery Doppler if renovascular disease suspected.

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7. Management: The Four Pillars

The modern management algorithm (aligned with KDIGO 2024) focuses on comprehensive cardiorenal protection. [9]

Pillar 1: Foundational Lifestyle & BP

• BP Target: less than 120 mmHg SBP (standardised office measurement).
• Salt: less than 2g sodium/day (less than 5g NaCl).
• Protein: 0.8g/kg/day for G3-G5 (not yet on dialysis).

Pillar 2: RAAS Inhibition (ACEi or ARB)

• First-line for patients with Diabetes and uACR > 30 mg/g (A2/A3).
• Titrate to max tolerated dose.
• Clinical Pearl: A 30% rise in Creatinine after starting is acceptable and indicates "haemodynamic success" (reduced hyperfiltration).

Pillar 3: SGLT2 Inhibitors (Dapagliflozin/Empagliflozin)

• Indication: eGFR ≥20 with uACR ≥200 (or HF regardless of uACR).
• Reduces risk of KF and CV death by ~30-40%.
• Action: Continue even if eGFR drops below 20; stop only when starting RRT. [10]

Pillar 4: Non-steroidal MRA (Finerenone)

• Indication: T2DM + CKD (G1-G4, A2-A3) despite max RAASi.
• Check K+ before starting (target less than 4.8 mmol/L).

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8. Complication Management (Special Protocols)

1. Renal Anaemia

• Target Hb: 10.0–11.5 g/dL (Do not target > 13.0 due to VTE/Stroke risk).
• Iron: TSAT > 20% and Ferritin > 100 ng/mL. IV iron preferred in advanced CKD.
• ESA: Epoetin or Darbepoetin.
• New: HIF-PH Inhibitors (e.g., Roxadustat) - oral alternative to injections.

2. CKD-MBD

• Phosphate: Limit dietary intake. Use binders (Sevelamer is non-calcium based, preferred to avoid calcification).
• Vitamin D: Calcitriol (active form) if PTH is rising.
• PTH: Target 2-9x the upper limit of normal for dialysis patients.

3. Metabolic Acidosis

• Maintain Bicarbonate 22–26 mmol/L.
• Rx: Oral Sodium Bicarbonate (650mg tablets). Reduces rate of GFR decline and muscle wasting. [11]

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9. Evidence: Landmark Trials

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10. Single Best Answer (SBA) Questions

Question 1

A 65-year-old man with T2DM and CKD G3bA3 (eGFR 35, uACR 85) is on Ramipril 10mg. His BP is 135/85. K+ is 4.8. What is the most appropriate next step to reduce his risk of reaching dialysis?

• A) Increase Ramipril to 20mg
• B) Start Dapagliflozin 10mg
• C) Start Spironolactone 25mg
• D) Switch Ramipril to Losartan
• E) Start Furosemide 40mg
• Answer: B. SGLT2 inhibitors (Dapagliflozin) provide the most significant reduction in the primary outcome of kidney failure in this population.

Question 2

A 72-year-old woman with Stage 4 CKD (eGFR 22) presents with malaise. Her Hb is 9.2 g/dL. TSAT is 15%, Ferritin is 80 ng/mL. What is the first-line treatment for her anaemia?

• A) Erythropoietin (EPO) injection
• B) Oral Ferrous Fumarate
• C) IV Ferric Carboxymaltose
• D) Blood transfusion
• E) Roxadustat
• Answer: C. She has absolute iron deficiency (TSAT less than 20%). In Stage 4/5 CKD, IV iron is preferred over oral due to better absorption and efficacy. Iron must be replete before starting ESAs.

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11. Viva Scenario: The "Sick Day" Consultation

Examiner: "A patient with CKD Stage 3b on an ACEi, Metformin, and an SGLT2 inhibitor presents with 48 hours of vomiting and diarrhoea. What is your advice?"

Candidate:

1. Immediate Action: Advise the patient to temporarily suspend the "SADMANS" medications (SGLT2i, ACEi/ARB, Diuretics, Metformin, ARBs, NSAIDs, Sulfonylureas).
2. Rationale:
   • ACEi/SGLT2i: During hypovolaemia, these can impair the kidney's autoregulatory response, precipitating AKI.
   • Metformin: Risk of lactic acidosis if GFR drops acutely.
   • SGLT2i: Specific risk of euglycaemic ketoacidosis during illness/starvation.
3. Monitoring: Advise urgent U&Es to check for AKI and hyperkalaemia.
4. Resumption: Only restart once the illness has resolved and oral intake is normal, typically after 48-72 hours.

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12. Patient Explanation

"Your kidneys act like the body's sophisticated filtration system. In Chronic Kidney Disease, some of these filters have become scarred and no longer work. Because the remaining filters have to work harder to compensate, they eventually wear out too. We can't 'fix' the scars, but we can protect the remaining filters. Think of the medications we've started (like the SGLT2 inhibitor) as a way to take the 'pressure' off your kidneys, allowing them to last much longer. It's also vital we keep your blood pressure strictly controlled, as high pressure acts like a 'power washer' that damages the delicate internal structures."

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13. References

1. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024. KDIGO
2. Heerspink HJL, et al. Dapagliflozin in Patients with Chronic Kidney Disease (DAPA-CKD). N Engl J Med. 2020. [PMID: 32970396]
3. Perkovic V, et al. Effects of Semaglutide on Chronic Kidney Disease Outcomes (FLOW). N Engl J Med. 2024. [PMID: 38785440]
4. Kalantar-Zadeh K, et al. Chronic kidney disease. Lancet. 2021. [PMID: 34147366]
5. Bhandari S, et al. Stopping ACE inhibitors in advanced chronic kidney disease (STOP-ACEi). N Engl J Med. 2022. [PMID: 36326117]

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Last Updated: 2026-01-05 | MedVellum Editorial Team