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L13 Renal Physiology 8

Chronic Kidney Disease (CKD / Chronic Renal Failure)

This lecture covers chronic kidney disease as a state of irreversible loss of functional nephrons. It works through how the surviving nephrons compensate, and how that compensation explains the clinical and biochemical picture: disordered handling of water, sodium, potassium, urea/creatinine, acid, and calcium/phosphate, plus the failure of the kidney’s endocrine roles (erythropoietin, vitamin D activation). The central logic to carry through the whole lecture is that each consequence of CKD traces back either to fewer working nephrons or to the failure of an endocrine function, and that surviving nephrons each carry an abnormally high single-nephron workload.

Background frame

The four functions of the kidney set up everything that follows: (1) excretion of water, salts, metabolic wastes, foreign substances; (2) homeostasis of acid-base and electrolyte balance; (3) hormones, erythropoietin and calcitriol (activated vitamin D); (4) metabolism, including gluconeogenesis. CKD impairs all four, and each lecture section maps onto one of them.

What CKD is

  • Understand that CKD is irreversible. This separates it conceptually from acute kidney injury and frames management as slowing progression rather than reversing it.
  • The defining feature is loss of functional nephrons. Be able to state the quantitative thresholds the lecture uses:
    • greater than 70% of nephrons lost
    • GFR fallen to less than 25 to 30% of normal
    • kidneys appear shrunken on imaging
  • Understand why a single intact-looking kidney is misleading: glomerular damage and tubular dysfunction can coexist, and remaining nephrons sit in varying functional states. Some nephrons are completely destroyed, others are damaged at the glomerulus, others at the tubule, and the net behaviour of the kidney is the sum of these heterogeneous units.

CKD versus acute renal failure

  • Know the features that distinguish chronic from acute renal failure, and why each one points to chronicity:
    • History: long (months to years) in chronic, short (days to weeks) in acute.
    • Haemoglobin: low in chronic (erythropoietin has had time to fail), normal in acute.
    • Renal size: reduced in chronic, normal in acute.
    • Renal osteodystrophy: present in chronic, absent in acute.
    • Peripheral neuropathy: present in chronic, absent in acute.
  • The principle: chronic features (anaemia, small kidneys, bone disease, neuropathy) all take time to develop, so their presence implies a long-standing process.

Common causes

  • Know the three causes the lecture emphasises:
    • Diabetes mellitus
    • Hypertension
    • Glomerulonephritis
  • Understand the public-health framing given at the end: CKD has multiple causes with increasing incidence, multiple problems (both renal and systemic), and that prevention is better than cure because the loss is irreversible.

Staging of chronic renal failure

  • Know the staging scheme by GFR and what clinically appears at each stage. The point is that consequences emerge in a predictable order as GFR falls:
    • Mild renal impairment (GFR > 75): no symptoms, no biochemical derangement, not clearly progressive.
    • Mild (GFR 50 to 75): early bone disease commences.
    • Moderate (GFR 25 to 50): anaemia starts.
    • Severe (GFR 10 to 25): salt and water retention becomes evident.
    • End-stage (GFR < 5 to 10): dialysis or transplantation becomes necessary.

The core compensatory principle: surviving nephrons hyperfunction

This is the conceptual engine of the lecture. Understand it before the individual electrolytes, because each electrolyte section is an application of it.

  • Surviving nephrons hypertrophy and take on an increased workload.
  • Each surviving nephron has an increased flow rate, which produces an osmotic diuresis (a large solute load per nephron drags water with it).
  • Consequences of that high per-nephron flow:
    • The loop of Henle cannot generate the hyperosmotic medullary gradient (HOMG), and cannot dilute tubular fluid effectively.
    • Because there is no HOMG, ADH cannot exert much effect, so water cannot be conserved normally.
    • Urine osmolarity becomes similar to plasma (isosthenuria): the kidney loses the ability to make urine either much more concentrated or much more dilute than plasma.
    • Urine volume is high (the kidney cannot conserve water), unless GFR becomes very low.
  • Understand the clinical correlate: this is why polyuria and nocturia appear, and why body fluid regulation is defective in both directions (inability to concentrate OR dilute).

Numbers showing per-nephron overload

With 2,000,000 nephrons, total GFR 125 ml/min gives a single-nephron GFR of 62.5 nl/min and volume excreted per nephron of 0.75 nl/min. After 75% nephron loss (500,000 nephrons), total GFR is 40 ml/min, but single-nephron GFR rises to 80 nl/min and volume excreted per nephron rises to 3.0 nl/min. The surviving nephrons are each working harder and flushing more volume, which is the source of the concentrating defect.

  • Understand the general excretion equation that underlies every solute section: amount excreted = amount filtered − amount reabsorbed + amount secreted. CKD changes the balance of these three terms for each solute.

Sodium handling

  • Understand that filtered Na load per nephron may fall, but the osmotic diuresis raises flow rate, which shortens tubular contact time, which reduces fractional Na reabsorption. The net effect is a relative increase in Na excretion per nephron.
  • This compensation is why Na balance is maintained until relatively late in the disease.
  • Be able to follow the fractional-reabsorption worked examples (dietary intake 200 mmol/day, must excrete 200 mmol/day to stay in balance):
    • Normal: filtered 27,000 mmol/day, reabsorb 26,800, excrete 200. Fractional reabsorption 99.26%.
    • CKD: filtered 2,700 mmol/day, reabsorb 2,500, excrete 200. Fractional reabsorption 92.6%. (Same excretion achieved with much lower fractional reabsorption.)
    • Severe CKD, salt wasting: filtered 450, reabsorb only 100, excrete 350. Fractional reabsorption 22.2%. Output exceeds intake, so Na is lost.
    • Severe CKD, salt retaining: filtered 450, reabsorb 300, excrete 150. Fractional reabsorption 66.7%. Output is below intake, so Na is retained.
  • The principle to take away: in severe CKD the kidney loses fine control of Na, and either wasting or retention is possible depending on the nephrons’ behaviour. Retention is what drives volume overload and hypertension.

Potassium handling

  • Understand that the normal balance between filtered load, reabsorption, and secretion is disrupted in CKD. Secretion is the main route for K excretion, and it is what fails.
  • Be able to follow the worked example (intake 200 mmol/day):
    • Normal: filtered 900, reabsorbed 900, then secreted 200, giving excretion of 200 (balance maintained almost entirely by secretion).
    • CKD: filtered 90, reabsorbed 70, secreted 30, excretion 50. Excretion (50) is far below intake (200), so K is retained.
  • The take-home: CKD tends to cause K retention and hyperkalaemia because the secretory mechanism cannot keep up.

Urea and creatinine handling

This is one of the more counter-intuitive sections, and the exam-relevant insight.

  • Start from balance: to maintain urea balance, rate of production must equal rate of urinary loss. If production rises or loss falls, plasma [urea] rises.
  • The key relationship: amount of urea lost is proportional to GFR × plasma [urea].
  • Understand the consequence: because excretion depends on the product of GFR and plasma concentration, a rising plasma [urea] can keep the filtered load constant even as GFR falls. The kidney re-establishes balance at a higher plasma concentration.
  • Be able to reproduce the worked example (production 540 mmol/day, 60% of filtered urea excreted):
    • Normal: plasma 5 mmol/L, GFR 180 L/day, filtered 900, excreted 540. Balanced.
    • 75% function lost: plasma 20 mmol/L, GFR 45 L/day, filtered 900, excreted 540. Still balanced, but at a higher plasma level.
    • 90% function lost: plasma 50 mmol/L, GFR 18 L/day, filtered 900, excreted 540. Still balanced, at a much higher plasma level.
  • Understand the clinical implication: as renal function declines you get only gradual accumulation of urea and creatinine, because the higher plasma concentration maintains filtered load despite falling GFR.
  • Understand the shape of the plasma urea vs creatinine clearance curve: plasma urea stays low and almost flat across a wide range of clearances, then rises steeply only when clearance becomes very low. The relationship is curved (hyperbolic), not linear, which is why early CKD can be biochemically silent and late CKD deteriorates rapidly.
  • Understand the time-course graph for creatinine after a step fall in GFR: when GFR drops, excretion (≈ GFR × plasma creatinine) initially falls below production, creating a positive balance (creatinine accumulates). Plasma creatinine then rises until excretion again equals production and a new steady state is reached at a higher plasma creatinine.

Acid-base handling

  • Understand why CKD causes a metabolic acidosis. Map each mechanism to a lost renal acid-handling function:
    • fewer nephrons capable of generating HCO3−
    • reduced ability to secrete ammonium (NH4+)
    • reduced filtered buffers (phosphate)
    • reduced ability to secrete H+
  • The net effect: reduced ability to acidify the urine, therefore metabolic acidosis. Expect a low plasma HCO3− with respiratory compensation.

Calcium, phosphate, and bone

This section is a cascade. Understand it as a chain of consequences flowing from two failures: failure to excrete phosphate and failure to activate vitamin D.

  • Understand the starting biochemistry: low plasma Ca, high plasma phosphate is the usual pattern.
  • Trace the cascade:
    • Failure to excrete phosphate → hyperphosphataemia → the Ca × phosphate solubility product is exceeded → metastatic calcification; hyperphosphataemia also lowers ionised Ca.
    • Failure to activate vitamin D (25-OH to 1,25-diOH vitamin D) → reduced intestinal Ca absorption → reduced plasma ionised Ca.
    • Low ionised Ca (from both arms) drives secondary hyperparathyroidism.
    • Failure to excrete acid contributes alongside vitamin D failure to osteomalacia.
  • Know the umbrella term and its components: renal osteodystrophy, comprising osteomalacia, osteoporosis, osteitis fibrosa cystica, and metastatic calcification.
  • Understand: the X-ray of the hand is shown to illustrate the bony changes of renal osteodystrophy (subperiosteal resorption / bone disease). The concept is recognising that CKD produces visible skeletal disease.

Anaemia

  • Understand the mechanism: lack of erythropoietin from the failing kidney (a failure of the endocrine, not excretory, function).
  • This is why low haemoglobin is a marker of chronicity (it distinguishes chronic from acute failure, and anaemia “starts” at the moderate stage of CKD).

Systemic consequences and their mechanisms

The lecture organises consequences into three mechanistic groups. Be able to assign each consequence to its mechanism.

  • Decreased excretion:

    • uraemic toxins / nitrogenous wastes → uraemic syndrome
    • salt and water → volume overload, hypertension
    • phosphate → hyperparathyroidism, metastatic calcification
    • acid → metabolic acidosis
    • potassium → hyperkalaemia

  • Decreased biosynthesis:

    • erythropoietin → anaemia
    • activation of vitamin D → osteomalacia, hyperparathyroidism

  • Altered metabolism:

    • dyslipidaemia → atherogenesis
    • sex hormones → abnormal reproductive function

  • Know the organ-system involvement table (each system, its main pathogenetic factor, and its consequence):

    • Cardiovascular: atheroma and salt/water retention → occlusive vascular disease, hypertension, congestive cardiac failure.
    • Bone: secondary hyperparathyroidism, osteomalacia, osteoporosis → pain, rarely fracture.
    • Neuromuscular: uraemic toxins → sensorimotor peripheral neuropathy, autonomic neuropathy, encephalopathy.
    • Blood: erythropoietin deficiency and uraemic toxins → anaemia, impaired white cell and platelet function.
    • Skin: metastatic calcification, sun exposure, anaemia and toxins → pruritus, skin cancer, sallow complexion.
    • Reproductive: abnormal sex hormone regulation → reduced libido, impaired fertility.
    • Gastrointestinal: uraemic toxins → anorexia, nausea, vomiting, malnutrition.
    • Serosal: uraemic toxins → pericarditis.

Hypertension in CKD

  • Know the mechanisms, in order of importance:
    • Na and water retention is the main mechanism, raising ECF and plasma volume.
    • excessive vasoconstrictive influences (for example renin / angiotensin II)
    • or reduced production of vasodepressors
    • sometimes no apparent cause
  • The principle: volume expansion is the dominant driver, which ties hypertension to the sodium-handling section.

Oedema in CKD

  • Understand that oedema is unusual in CKD and occurs late in the disease.
  • Understand the mechanism is different from nephrotic syndrome: CKD oedema is driven by salt and water retention (volume overload), not by low albumin / low oncotic pressure.
  • Be able to trace the volume-overload pathway: Na and water retention → increased plasma and ECF volume → raised BP and raised JVP/CVP, possible right and left heart failure → reduced venous return and raised capillary hydrostatic pressure → increased ultrafiltration → peripheral or pulmonary oedema (crepitations if pulmonary).
  • Note co-existing congestive heart failure is common and contributes.

Clinical case (apply the lecture to interpret it)

58-year-old, 6-month history

Lethargy, nausea, poor appetite, nocturia, swollen ankles, shortness of breath, 6 kg weight gain. O/E: 90 bpm, BP 150/100, elevated JVP, crepitations, ankle swelling. Bloods: Na 138, K 5.6 (high), urea 49 (very high), creatinine 0.794 mmol/L with GFR 2.2 ml/min (end-stage), Hb 90 (low), PaCO2 32, pH 7.32 (acidaemic), HCO3 16 (low).

Be able to link each abnormality to a lecture mechanism:

  • 6-month history, low Hb → chronicity (distinguishes from acute).
  • Nocturia → loss of urinary concentrating ability (no HOMG, ADH ineffective).
  • Weight gain, swollen ankles, raised JVP, crepitations, hypertension → Na and water retention, volume overload, oedema.
  • K 5.6 → impaired K secretion → hyperkalaemia.
  • Urea 49, very low GFR → markedly reduced excretion, plasma concentration risen to maintain filtered load.
  • pH 7.32, HCO3 16, low PaCO2 → metabolic acidosis with respiratory compensation, from failure to acidify urine.
  • Hb 90 → erythropoietin deficiency.

Self-test checklist

  • Can you give the defining feature of CKD and the three quantitative thresholds (nephron loss, GFR, kidney size)?
  • Can you list five features distinguishing chronic from acute renal failure and explain why each implies chronicity?
  • Can you name the three common causes of CKD?
  • Can you state what clinically appears at each GFR stage from mild impairment to end-stage?
  • Can you explain why surviving nephrons cannot concentrate or dilute urine, using the HOMG and ADH?
  • Can you explain why per-nephron flow rate rises despite fewer nephrons, and what osmotic diuresis has to do with it?
  • Can you explain how reduced contact time lets the kidney maintain Na balance until late disease?
  • Can you account for both salt wasting and salt retention in severe CKD using fractional reabsorption?
  • Can you explain why CKD tends to cause hyperkalaemia (which transport process fails)?
  • Can you explain why plasma urea and creatinine rise only gradually, using amount lost ∝ GFR × plasma concentration?
  • Can you describe the shape of the plasma urea vs creatinine clearance curve and why it is curved?
  • Can you list the four mechanisms by which CKD causes metabolic acidosis?
  • Can you draw out the calcium/phosphate cascade from phosphate retention and vitamin D failure to secondary hyperparathyroidism, osteomalacia, and metastatic calcification?
  • Can you name the components of renal osteodystrophy?
  • Can you explain why CKD causes anaemia and why this marks chronicity?
  • Can you sort the systemic consequences into decreased excretion, decreased biosynthesis, and altered metabolism?
  • Can you give the main mechanism of hypertension in CKD?
  • Can you contrast the mechanism of CKD oedema with nephrotic oedema?
  • Can you interpret the clinical case, linking each abnormal value to its mechanism?

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