Chronic Kidney Disease (CKD) and End-stage Renal Disease (ESRD): 10-mark Answer

Definition

• eGFR <60 mL/min/1.73 m² for at least 3 months, with or without other evidence of kidney damage, or
• Evidence of kidney damage for at least 3 months, such as albuminuria, abnormal urine sediment, electrolyte abnormalities due to tubular disorders, structural abnormalities on imaging, histological abnormalities, or previous kidney transplantation.

1. Causes of CKD and ESRD

A. Diabetic and vascular causes

1. Diabetic kidney disease
   • Long-standing diabetes causes glomerular hyperfiltration, albuminuria, glomerulosclerosis, and progressive loss of nephrons.
2. Hypertensive nephrosclerosis
   • Chronic systemic hypertension causes arteriolar sclerosis, renal ischemia, nephron loss, and small contracted kidneys.
3. Ischemic nephropathy / renovascular disease
   • Atherosclerotic renal artery disease, often with coronary artery disease, peripheral vascular disease, or stroke.
4. Cholesterol embolic renal disease and chronic vascular injury.

B. Glomerular diseases

1. Chronic glomerulonephritis
2. IgA nephropathy
3. Focal segmental glomerulosclerosis
4. Membranous nephropathy
5. Lupus nephritis
6. ANCA-associated vasculitis
7. Amyloidosis
8. Chronic postinfectious glomerulonephritis

C. Tubulointerstitial diseases

1. Chronic pyelonephritis and reflux nephropathy
2. Chronic interstitial nephritis
3. Analgesic nephropathy, especially long-term NSAID or analgesic abuse
4. Drug-induced nephropathy, for example calcineurin inhibitors, lithium, certain antimicrobials, chemotherapy agents
5. Toxin-related renal injury, including heavy metals
6. Multiple myeloma and light-chain kidney disease

D. Obstructive and reflux causes

1. Prostatic enlargement causing chronic bladder outlet obstruction
2. Stones
3. Urethral stricture
4. Pelvic or retroperitoneal malignancy
5. Neurogenic bladder
6. Vesicoureteric reflux

E. Hereditary and congenital diseases

1. Autosomal dominant polycystic kidney disease
2. Alport syndrome
3. Reflux nephropathy and congenital anomalies of the kidney and urinary tract
4. Medullary cystic disease / nephronophthisis
5. Fabry disease

F. Other causes

• Repeated acute kidney injury
• Chronic infections, such as HIV- or hepatitis-associated nephropathy
• Systemic autoimmune disease
• Severe long-standing obesity
• Unknown cause

2. Clinical Features of CKD

A. General features

• Fatigue, weakness, malaise
• Anorexia, weight loss
• Reduced exercise tolerance
• Pruritus
• Pallor due to anemia
• Uremic fetor, dry skin, hyperpigmentation in advanced disease

B. Urinary features

• Nocturia and polyuria early in CKD because of impaired concentrating ability
• Later, oliguria or anuria may occur
• Frothy urine due to proteinuria
• Hematuria in glomerular disease
• Dysuria, recurrent urinary infection, or poor stream if obstruction is present

C. Fluid and cardiovascular features

• Hypertension
• Pedal edema, facial puffiness
• Raised JVP, pulmonary edema, breathlessness
• Left ventricular hypertrophy and heart failure
• Accelerated atherosclerosis, ischemic heart disease, stroke, peripheral arterial disease
• Pericarditis or pericardial effusion in severe uremia

D. Gastrointestinal features

• Anorexia
• Nausea and vomiting
• Metallic taste
• Uremic breath
• Hiccups
• Gastritis and gastrointestinal bleeding due to platelet dysfunction

E. Neurologic and neuromuscular features

• Headache, poor concentration, sleep disturbance
• Irritability, depression, cognitive impairment
• Peripheral neuropathy, especially restless legs, burning feet, paresthesia
• Muscle cramps and weakness
• Asterixis, seizures, coma, and uremic encephalopathy in advanced uremia

F. Endocrine and reproductive features

• Sexual dysfunction and reduced libido
• Erectile dysfunction in men
• Menstrual irregularity, amenorrhea, infertility
• Reduced fertility in both sexes
• Growth retardation in children

G. Hematological features

• Pallor and symptoms of anemia: fatigue, dyspnea, palpitations
• Easy bruising, epistaxis, gastrointestinal bleeding due to platelet dysfunction

3. Complications of CKD

A. Fluid overload and hypertension

• Pedal edema
• Hypertension
• Pulmonary edema
• Congestive cardiac failure
• Pleural effusion
• Left ventricular hypertrophy

B. Electrolyte and acid-base disorders

1. Hyperkalemia

• Muscle weakness
• Life-threatening cardiac arrhythmias
• ECG changes: tall peaked T waves, broad QRS complex, sine-wave pattern in severe cases

2. Metabolic acidosis

• Deep breathing, fatigue
• Muscle protein breakdown and wasting
• Bone demineralization
• Worsening hyperkalemia
• Faster progression of CKD

3. Hyperphosphatemia and hypocalcemia

C. CKD-mineral and bone disorder / renal osteodystrophy

Mechanism

1. Diseased kidneys retain phosphate, causing hyperphosphatemia.
2. Diseased kidneys cannot adequately form active vitamin D, calcitriol.
3. Reduced calcitriol decreases intestinal calcium absorption.
4. Hypocalcemia, hyperphosphatemia, and low calcitriol stimulate secondary hyperparathyroidism.
5. High PTH increases bone resorption and causes bone disease.

Manifestations

• Bone pain
• Fractures
• Proximal muscle weakness
• Osteomalacia
• Osteitis fibrosa cystica
• Osteosclerosis
• Osteoporosis
• Vascular and soft-tissue calcification
• Calciphylaxis in severe cases

D. Anemia

Causes

• Decreased renal erythropoietin production
• Iron deficiency due to poor intake, reduced absorption, repeated blood sampling, occult gastrointestinal loss, and dialysis-related loss
• Chronic inflammation causing functional iron deficiency
• Shortened red-cell survival
• Folate deficiency
• Blood loss due to platelet dysfunction

E. Cardiovascular disease

• Hypertension and left ventricular hypertrophy
• Ischemic heart disease and myocardial infarction
• Heart failure
• Arrhythmias, especially due to hyperkalemia
• Stroke
• Peripheral arterial disease
• Uremic pericarditis
• Accelerated atherosclerosis and vascular calcification

F. Uremic syndrome

• Anorexia, nausea, vomiting
• Pruritus
• Metallic taste and uremic fetor
• Pericarditis
• Encephalopathy
• Peripheral neuropathy
• Platelet dysfunction and bleeding
• Impaired immunity and recurrent infection

G. Endocrine, metabolic, and nutritional complications

• Insulin resistance and altered insulin clearance
• Dyslipidemia
• Hyperuricemia and gout
• Protein-energy wasting
• Sarcopenia and muscle weakness
• Vitamin D deficiency
• Reduced libido, infertility, menstrual disturbance
• Growth failure in children

4. Management of CKD

1. Identify and treat the underlying cause.
2. Slow CKD progression.
3. Detect and treat complications.
4. Plan kidney replacement therapy or conservative supportive care when appropriate.

A. General measures and evaluation

• Confirm chronicity and cause with serial creatinine/eGFR, urine routine examination, urine albumin-creatinine ratio, renal ultrasound, and selected immunological tests or renal biopsy when indicated.
• Monitor BP, body weight, edema, eGFR, albuminuria, serum potassium, bicarbonate, hemoglobin, iron status, calcium, phosphate, PTH, and lipid profile.
• Avoid nephrotoxins: NSAIDs, unnecessary contrast media, herbal remedies, and inappropriate drug combinations.
• Adjust doses of all renally excreted drugs.
• Vaccinate appropriately, especially against influenza, pneumococcus, hepatitis B, and COVID-19 according to local policy.
• Early nephrology referral is indicated for eGFR <30 mL/min/1.73 m², rapid decline in GFR, heavy albuminuria, hematuria, resistant hypertension, recurrent hyperkalemia, or difficult CKD complications.

B. Measures to slow progression

1. Treat the cause

• Good diabetes management
• Control hypertension
• Immunosuppression where indicated for selected glomerulonephritis or vasculitis
• Relieve urinary obstruction
• Treat infection, stone disease, or reflux
• Stop nephrotoxic drugs

2. Blood pressure and proteinuria control

• Restrict sodium, usually to less than 2 g sodium/day, unless a specific clinical reason prevents this.
• ACE inhibitor or ARB is preferred in albuminuric CKD because it reduces intraglomerular pressure and proteinuria.
• Do not combine ACE inhibitor with ARB.
• Check serum creatinine and potassium after starting or increasing a renin-angiotensin-system blocker.
• Current KDIGO guidance suggests a standardized systolic BP target of <120 mmHg when tolerated in adults with CKD and hypertension, but treatment must be individualized in frail patients or those with postural symptoms. See the KDIGO 2024 CKD guideline.

3. Diabetes and kidney-protective drugs

• Optimize glycemic control while avoiding hypoglycemia in advanced CKD.
• Use an SGLT2 inhibitor in eligible patients with type 2 diabetes and CKD, generally if eGFR is at least 20 mL/min/1.73 m².
• GLP-1 receptor agonists may be considered in appropriate people with type 2 diabetes, obesity, or persistent cardiovascular risk.
• Consider nonsteroidal mineralocorticoid receptor antagonist therapy in selected patients with diabetic CKD and albuminuria, while monitoring potassium.

4. Lifestyle and dietary measures

• Stop smoking.
• Maintain healthy body weight and regular physical activity as tolerated.
• Avoid excess dietary salt and ultra-processed foods.
• Moderate protein intake, usually around 0.8 g/kg/day in non-dialysis CKD, while avoiding malnutrition.
• Fluid restriction only if edema, hyponatremia, or oliguria is present.
• Individualize potassium and phosphate restriction according to blood levels.

C. Treatment of complications

1. Edema and hypertension

• Salt restriction
• Loop diuretic, such as furosemide, when volume overloaded
• Fluid restriction in significant edema or hyponatremia
• Dialysis for refractory pulmonary edema or uncontrolled fluid overload

2. Hyperkalemia

• Review high-potassium diet and offending drugs.
• Correct metabolic acidosis.
• Use loop diuretic if volume status permits.
• Potassium binders may be used for chronic hyperkalemia.
• Severe hyperkalemia with ECG changes needs emergency treatment with IV calcium, insulin with glucose, beta-agonist, bicarbonate when acidotic, and urgent dialysis if refractory.

3. Metabolic acidosis

• Oral sodium bicarbonate is used when bicarbonate is persistently low, provided volume status and sodium load are monitored.
• Treat severe refractory acidosis with dialysis.

4. CKD-mineral and bone disorder

• Restrict dietary phosphate.
• Use phosphate binders with meals when needed, preferably non-calcium binders in patients at risk of hypercalcemia or vascular calcification.
• Correct vitamin D deficiency.
• Use active vitamin D analogues selectively.
• Control secondary hyperparathyroidism with calcimimetics, vitamin D analogues, or parathyroidectomy in resistant severe disease.
• Monitor calcium, phosphate, alkaline phosphatase, and PTH serially.

5. Anemia of CKD

• Measure hemoglobin, ferritin, and transferrin saturation.
• Correct iron deficiency with oral or intravenous iron depending on severity, tolerance, and dialysis status.
• Use an erythropoiesis-stimulating agent after iron deficiency is addressed, especially when hemoglobin remains low and symptoms are significant.
• Avoid targeting a normal hemoglobin because higher targets increase cardiovascular and thrombotic risk.
• Red-cell transfusion is reserved for severe symptomatic anemia, acute blood loss, or when rapid correction is needed, and should be avoided where possible in transplant candidates because of sensitization risk.

6. Dyslipidemia and cardiovascular risk

• Statin therapy is generally indicated in non-dialysis adults with CKD at increased cardiovascular risk.
• Treat heart failure, ischemic heart disease, obesity, smoking, and diabetes aggressively.

7. Uremic symptoms

• Treat nausea, pruritus, sleep disturbance, restless legs, pain, and depression.
• Review nutrition and provide dietician support.
• Discuss conservative kidney management where dialysis is not desired or is unlikely to offer meaningful benefit.

D. Kidney replacement therapy

1. Hemodialysis
2. Peritoneal dialysis
3. Kidney transplantation, the preferred long-term option for eligible patients
4. Conservative supportive care, if aligned with the patient's goals

Indications for urgent dialysis: AEIOU

• A: severe refractory Acidosis
• E: refractory Electrolyte disturbance, especially hyperkalemia
• I: Intoxications with dialyzable toxins
• O: refractory fluid Overload, especially pulmonary edema
• U: symptomatic Uremia, such as encephalopathy, pericarditis, intractable nausea/vomiting, severe pruritus, or bleeding

Short conclusion for the exam

Investigations in Chronic Kidney Disease

1. Confirm CKD and assess its severity
2. Identify the cause
3. Detect reversible factors such as obstruction or drugs
4. Detect complications
5. Plan monitoring, referral, and kidney replacement therapy

1. Urine examination

• Routine urinalysis and microscopy
  • Proteinuria/albuminuria
  • Hematuria
  • Pyuria
  • Glycosuria with normal blood glucose may suggest tubular disease
  • Specific gravity may become fixed around 1.010 (isosthenuria) in advanced CKD due to poor concentrating ability.
• Urine sediment
  • Red-cell casts: glomerulonephritis
  • White-cell casts: pyelonephritis or interstitial nephritis
  • Granular or broad waxy casts: advanced chronic renal failure
• Urine culture and sensitivity if pyuria, fever, dysuria, or recurrent UTI is suspected.
• Spot urine albumin-creatinine ratio (UACR): preferred test for albuminuria.
  • A1: <30 mg/g
  • A2: 30-300 mg/g, moderately increased albuminuria
  • A3: >300 mg/g, severely increased albuminuria
• Spot urine protein-creatinine ratio (UPCR) or 24-hour urine protein when required to quantify proteinuria.
• 24-hour urine creatinine clearance may be used in selected cases, although eGFR is generally preferred for staging.

2. Renal function tests

• Serum creatinine: usually raised, but it is influenced by age, muscle mass, diet, and sex.
• Blood urea / BUN: raised in CKD, but may also rise in dehydration, GI bleeding, high protein intake, or catabolic states.
• Estimated GFR (eGFR) using a validated creatinine-based equation:
  • Confirms reduced renal function.
  • Stages CKD from G1 to G5.
  • A persistent eGFR <60 mL/min/1.73 m² for >3 months confirms CKD, even without other markers of damage.
• Cystatin C-based eGFR or combined creatinine-cystatin C eGFR may be useful if creatinine is unreliable, for example in marked muscle wasting, extremes of body build, amputation, or malnutrition.
• Previous creatinine values should be reviewed to distinguish CKD from acute kidney injury or acute-on-chronic kidney disease.

3. Serum biochemistry and metabolic work-up

Electrolytes and acid-base status

• Serum sodium, potassium, chloride, bicarbonate
  • Hyperkalemia is common in advanced CKD.
  • Low bicarbonate indicates metabolic acidosis.
• Arterial blood gas or venous blood gas if significant acidosis is suspected.
• Serum calcium, phosphate, alkaline phosphatase, intact parathyroid hormone (PTH), and 25-OH vitamin D
  • To assess CKD-mineral and bone disorder.
  • Typical pattern: high phosphate, low or low-normal calcium, low calcitriol, and raised PTH due to secondary hyperparathyroidism.
• Serum uric acid if gout or hyperuricemia is suspected.
• Serum albumin, total protein, and nutritional assessment.
• Fasting glucose and HbA1c to detect or monitor diabetes. HbA1c may be less reliable in advanced CKD with anemia or erythropoietin treatment.
• Lipid profile to evaluate cardiovascular risk.

4. Hematological investigations

• Complete blood count
  • Normocytic normochromic anemia is typical of CKD because of decreased erythropoietin production.
  • Leukocyte count may indicate infection.
  • Platelet count may be normal despite uremic platelet dysfunction.
• Peripheral blood smear when anemia is unexplained or severe.
• Iron studies:
  • Serum ferritin
  • Transferrin saturation (TSAT)
  • Serum iron and total iron-binding capacity if needed
    These identify absolute or functional iron deficiency before treatment with an erythropoiesis-stimulating agent.
• Vitamin B12 and folate if macrocytosis or another cause of anemia is possible.
• Stool occult blood test or endoscopic evaluation may be required if chronic GI blood loss is suspected.

5. Tests to identify the cause of CKD

For diabetes and hypertension

• Blood glucose, HbA1c
• Fundus examination for diabetic or hypertensive retinopathy
• Serial blood pressure recordings
• ECG and echocardiography where cardiovascular disease is suspected

Immunological tests for suspected glomerulonephritis or systemic disease

• ANA and anti-double-stranded DNA antibody: SLE
• ANCA: ANCA-associated vasculitis
• Anti-GBM antibody: anti-GBM disease
• Serum complement C3 and C4: low in lupus nephritis, postinfectious GN, and some membranoproliferative GN
• Serum immunoglobulins
• Hepatitis B, hepatitis C, and HIV serology when clinically indicated
• Serum protein electrophoresis, urine protein electrophoresis, serum free light chains: multiple myeloma, amyloidosis, or monoclonal gammopathy

In hereditary disease

• Family history
• Genetic testing when ADPKD, Alport syndrome, or another inherited nephropathy is likely.

6. Imaging investigations

Ultrasound kidney, ureter, bladder: first-line imaging

• Kidney size and cortical thickness
• Echogenicity
• Corticomedullary differentiation
• Hydronephrosis and urinary obstruction
• Renal cysts, including polycystic kidneys
• Stones and masses
• Bladder residual urine

Other imaging where indicated

• X-ray KUB or non-contrast CT KUB for suspected stones
• CT or MRI for masses, complex cysts, retroperitoneal fibrosis, or structural abnormalities
• Doppler renal vessels for suspected renal artery stenosis
• Micturating cystourethrogram in selected cases of vesicoureteric reflux
• Radionuclide renal scan in selected obstructive or differential renal function assessment

7. Renal biopsy

• Unexplained CKD
• Significant proteinuria, especially nephrotic-range proteinuria
• Active urinary sediment, especially dysmorphic RBCs or red-cell casts
• Rapidly declining renal function
• Suspected potentially treatable glomerulonephritis, vasculitis, lupus nephritis, interstitial nephritis, amyloidosis, or myeloma-related renal disease
• Disproportionate proteinuria or hematuria in a person with diabetes

8. Evaluation for complications and dialysis planning

• ECG: especially if hyperkalemia is suspected, and to assess LVH, ischemia, or arrhythmia.
• Chest X-ray: pulmonary edema, pleural effusion, cardiomegaly, or infection.
• Echocardiography: left ventricular hypertrophy, heart failure, ischemic disease, or pericardial effusion.
• Bone X-ray / DEXA only if clinically indicated for fracture risk or renal bone disease.
• Screening for hepatitis B, hepatitis C, and HIV before dialysis/transplant protocols.
• Blood group and transplant immunology work-up when transplantation is planned.
• Vascular mapping for arteriovenous fistula planning before hemodialysis.

Exam-ready conclusion