L13 Renal Physiology 8

Overview

This lecture covers chronic kidney disease (chronic renal failure): what defines it, how it is staged and distinguished from acute renal failure, and how the loss of functional nephrons produces its renal and systemic consequences. The physiological core is that surviving nephrons hypertrophy and carry a much larger single-nephron load, which explains why water, sodium, potassium and urea handling change the way they do, and why plasma urea and creatinine rise only late. The systemic sections then follow the four kidney functions (excretion, homeostasis, hormones, metabolism) into acid-base disturbance, calcium/phosphate and bone disease, anaemia, hypertension and oedema.

Functions of the kidney (the framework)

Four functions, each of which can fail in CKD:

1. Excretion: water, salts, metabolic wastes and foreign substances enter the kidney and leave as urine.
2. Homeostasis: acid-base balance (H+ vs OH-) and electrolyte balance (Na+ vs K+).
3. Hormones: erythropoietin and calcitriol.
4. Metabolism: glucose into blood, amino acids via gluconeogenesis, with NH3 into urine.

Definition and key features of CKD

• Irreversible.
• The key feature is loss of functional nephrons.
• More than 70% of nephrons lost.
• Kidneys are shrunken on imaging.
• GFR decreased to less than 25 to 30% of normal.
• Common causes: diabetes mellitus, hypertension, glomerulonephritis.
• Remaining nephrons may be in varying functional states: a nephron can have glomerular damage and/or impaired tubular exchange with the peritubular capillary, so glomerular and tubular function are not lost uniformly.

Acute versus chronic renal failure

Feature	Acute	Chronic
History	Short (days to weeks)	Long (months to years)
Haemoglobin concentration	Normal	Low
Renal size	Normal	Reduced
Renal osteodystrophy	Absent	Present
Peripheral neuropathy	Absent	Present

Staging of chronic renal failure by GFR

Stage	GFR (mL/min)	Uraemic symptoms	Biochemical derangement	Comment
Mild renal impairment	>75	None	None	Not clearly progressive
Mild	50 to 75	None	Subtle	Early bone disease commences
Moderate	25 to 50	Mild	Mild	Anaemia starts
Severe	10 to 25	Moderate	Moderate	Salt and water retention evident
End-stage	<5 to 10	Severe	Severe	Dialysis or renal transplantation necessary

Clinical picture (worked case)

A 58 year old with 6 months of lethargy and tiredness, nausea, poor appetite, nocturia, swollen ankles, shortness of breath and 6 kg weight gain. On examination: 90 bpm, BP 150/100, elevated JVP, creps, ankle swelling. Bloods: Na 138 mmol/L, K 5.6 mmol/L, urea 49 mmol/L, creatinine 0.794 mmol/L (GFR 2.2 mL/min), Hb 90 g/L, PaCO2 32 mmHg, pH 7.32, HCO3 16. The picture combines uraemic symptoms, volume overload with hypertension, hyperkalaemia, anaemia and a metabolic acidosis with respiratory compensation.

Consequences of nephron loss

Defective body fluid regulation:

• Inability to concentrate or dilute urine.
• Polyuria and nocturia.
• Na retention or wasting both possible.
• K retention.
• Metabolic acidosis (decreased HCO3- production).

Anaemia: lack of erythropoietin.

Defective excretion of wastes and toxins: increased urea and creatinine.

Disordered calcium metabolism:

• Reduced activation of vitamin D.
• Retention of phosphate.
• Complex effects on bone.

Altered metabolism:

• Dyslipidaemia leading to atherogenesis.
• Sex hormones, giving abnormal reproductive function.

Main consequences by mechanism

Mechanism	Example	Consequence
Decreased excretion	Uraemic toxins, including 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

Organ system involvement

System	Main pathogenetic factors	Main consequences
Cardiovascular	Atheroma; salt and 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; uraemic toxins	Anaemia; impaired white cell and platelet function
Skin	Metastatic calcification; sun exposure; anaemia and uraemic toxins	Pruritus; skin cancer; sallow complexion
Reproductive	Abnormal regulation of sex hormones	Reduced libido, impaired fertility
Gastrointestinal	Uraemic toxins	Anorexia, nausea, vomiting, malnutrition
Serosal	Uraemic toxins	Pericarditis

Water handling: the hypertrophied nephron

Surviving nephrons hypertrophy and carry an increased workload:

• Increased flow rate.
• Osmotic diuresis.
• The loop of Henle cannot generate the hyperosmotic medullary gradient (HOMG), nor dilute tubular fluid.
• ADH therefore has little effect, because there is no HOMG.
• Urine osmolarity ends up similar to that of plasma.
• Urine volume will be high (water cannot be conserved) unless GFR is very low.

Quantitatively, with 75% loss of nephrons the per-nephron load rises even though total function falls:

	Normal	75% loss of nephrons
Number of nephrons	2,000,000	500,000
GFR (mL/min)	125	40
Single nephron GFR (nL/min)	62.5	80
Volume excreted per nephron (nL/min)	0.75	3.0

Net urinary excretion

Excretion of any substance is determined by three processes at the nephron (afferent arteriole, glomerular capillary, Bowman’s space, efferent arteriole, peritubular capillary, tubule lumen, renal vein):

$\text{Amount filtered}-\text{Amount reabsorbed}+\text{Amount secreted}=\text{Amount excreted in urine}$

Sodium handling in CKD

The amount of Na filtered may be decreased, but osmotic diuresis increases flow rate, which decreases contact time, which decreases Na reabsorption and gives a relative increase in Na excretion. This helps maintain Na balance until relatively late in the disease.

Worked figures (dietary intake 200 mmol/day throughout, plasma Na 150 mmol/L):

Situation	Filtration	Reabsorption	Excretion	Fractional reabsorption
Normal (GFR 180 L/day)	180 x 150 = 27,000 mmol/day	26,800 mmol/day	200 mmol/day	99.26%
CKD (GFR 18 L/day)	18 x 150 = 2,700 mmol/day	2,500 mmol/day	200 mmol/day	92.6%
Severe CKD, salt wasting (GFR 3 L/day)	3 x 150 = 450 mmol/day	100 mmol/day	350 mmol/day	22.2%
Severe CKD, salt retaining (GFR 3 L/day)	3 x 150 = 450 mmol/day	300 mmol/day	150 mmol/day	66.7%

In severe CKD either pattern can occur: salt wasting (excretion 350 mmol/day against an intake of 200) or salt retention (excretion 150 mmol/day against an intake of 200).

Potassium handling in CKD

The balance of filtered load against reabsorption and secretion is disrupted, and the tendency is to retain K with elevation of plasma [K].

Worked figures (dietary intake 200 mmol/day, plasma K 5 mmol/L):

	Normal (GFR 180 L/day)	CKD (GFR 18 L/day)
Filtration	180 x 5 = 900 mmol/day	18 x 5 = 90 mmol/day
Reabsorption	900 mmol/day	70 mmol/day
Reabsorption / secretion	200 mmol/day	30 mmol/day
Excretion	200 mmol/day	50 mmol/day

Normally the filtered load is almost entirely reabsorbed proximally and a smaller amount is then secreted distally to set final excretion. In CKD the filtered load is much smaller but secretion is relatively increased to keep excretion going; excretion (50 mmol/day) nonetheless falls short of intake (200 mmol/day).

Urea handling in CKD

To maintain urea balance, rate of production must equal rate of loss in urine. If production increases or loss decreases, plasma [urea] increases. But the amount lost is proportional to GFR x plasma [urea], so the amount lost can still equal the rate of production even as GFR falls, provided plasma [urea] rises.

Worked example, assuming production of 540 mmol/day and that 60% of filtered urea is excreted:

	Plasma [urea]	GFR	Amount filtered	Amount excreted
Normal	5 mmol/L	180 L/day	5 x 180 = 900 mmol/day	60% of 900 = 540 mmol/day
75% loss of renal function	20 mmol/L	45 L/day	20 x 45 = 900 mmol/day	540 mmol/day
90% loss of renal function	50 mmol/L	18 L/day	50 x 18 = 900 mmol/day	540 mmol/day

The conclusion: as renal function declines there is only gradual accumulation of urea (and creatinine), since higher plasma concentrations maintain the filtered load despite falling GFR.

This is why the relationship between plasma urea and creatinine clearance is non-linear rather than a straight line. Plotted against creatinine clearance (0 to 140 mL/min), plasma urea is around 5 mmol/L at a clearance of 120 to 140 mL/min, is still only around 15 mmol/L at a clearance of about 20 mL/min, and then climbs steeply to around 54 mmol/L at very low clearances. Plasma urea therefore rises steeply only once clearance falls very low.

The same logic explains the time course of creatinine after an abrupt fall in GFR. If GFR steps down from about 110 to about 50 mL/min on day 1: creatinine production stays flat at about 1.9 g/day, while excretion (which equals GFR x plasma creatinine) dips at day 1 and then climbs back to meet production by about day 2. The gap between the two is a period of positive balance, during which serum creatinine rises from about 1 to a plateau near 2 mg/dL. A new steady state is reached once the higher plasma creatinine restores excretion to match production.

Acid-base and CKD

Metabolic acidosis develops because:

• Fewer nephrons are capable of making HCO3-.
• Decreased ability to secrete ammonium.
• Decreased filtered buffers (phosphates).
• Decreased ability to secrete H+.

The net effect is a decreased ability to acidify the urine.

Calcium, phosphate and bone

The interacting variables are Ca, PO4, acidosis, PTH and vitamin D.

• Low Ca with high PO4 is the usual pattern.
• Secondary hyperparathyroidism.
• Reduced renal activation of vitamin D.
• Renal osteodystrophy: osteomalacia, osteoporosis, osteitis fibrosa cystica.
• Metastatic calcification.

The pathways, all stemming from failure of the kidneys to perform three tasks:

1. Failure to excrete phosphate leads to hyperphosphataemia, which exceeds the solubility equilibrium of Ca x Pi and produces metastatic calcification. Hyperphosphataemia also feeds directly into secondary hyperparathyroidism.
2. Failure to activate vitamin D (25 to 1,25 diOH vitamin D) feeds into hyperphosphataemia and also reduces intestinal Ca absorption, which reduces plasma ionised Ca concentration and drives secondary hyperparathyroidism.
3. Failure to excrete acid leads to osteomalacia.

Secondary hyperparathyroidism is therefore the convergence point of several pathogenic pathways.

Warning

A hand radiograph is shown in this section but carries no caption or label identifying the specific radiographic finding being illustrated.

Hypertension in CKD

• Na and water retention is the main mechanism, increasing ECF and plasma volume.
• Excessive vasoconstrictive influences (for example renin and angiotensin II), or reduced production of vasodepressors.
• Sometimes no apparent cause.

Oedema in CKD

• Unusual.
• Occurs late in the disease process.
• Co-existing congestive heart failure is common.
• The mechanism is different from that of nephrotic syndrome (which is low albumin).

The pathway from salt and water retention to oedema:

1. Na and water retention increases plasma volume (and ECF volume).
2. This raises BP and raises JVP (or CVP).
3. Increased BP may produce left heart failure (creps) and increases capillary hydrostatic pressure.
4. Increased JVP (or CVP) decreases venous return, which also increases capillary hydrostatic pressure.
5. Increased capillary hydrostatic pressure increases ultrafiltration, producing oedema, either peripheral or pulmonary (creps if pulmonary).

Clinically this appears as bilateral pitting oedema of the legs and ankles, with indentation from sock bands or pressure.

Warning

In the oedema flowchart a box labelled ”?RHF” (right heart failure) feeding into increased JVP/CVP shows overlapping or strikethrough marks in the source image, and its exact intended text and meaning is unclear.

Take-home summary

• CKD has multiple causes, with increasing incidence.
• It produces multiple problems, both renal and systemic.
• Prevention is better than cure.

Self-test

1. Define chronic kidney disease in terms of its key feature and the thresholds given for nephron loss and GFR.
2. List the three common causes of CKD.
3. List the five features that distinguish acute from chronic renal failure, and state the value of each in the chronic case.
4. At which GFR stage does anaemia start, and at which stage does salt and water retention become evident?
5. List the four functions of the kidney and give one example of each.
6. Explain why patients with CKD develop polyuria and nocturia rather than oliguria, referring to the loop of Henle and ADH.
7. Using the figures given, explain how single nephron GFR and volume excreted per nephron change after 75% loss of nephrons, and why.
8. Write the equation relating filtration, reabsorption and secretion to net urinary excretion.
9. Explain the mechanism by which sodium balance is maintained until relatively late in CKD.
10. Distinguish the salt-wasting from the salt-retaining pattern in severe CKD using the fractional reabsorption and excretion figures given.
11. Describe how potassium handling changes in CKD and predict the effect on plasma [K].
12. Explain, with the worked figures, why plasma urea can rise while urea excretion remains equal to production as GFR falls.
13. Describe the shape of the relationship between plasma urea concentration and creatinine clearance, and state what it implies for detecting early renal impairment.
14. Predict what happens to creatinine production, creatinine excretion and serum creatinine over the days following an abrupt fall in GFR from 110 to 50 mL/min.
15. List the four reasons CKD causes a metabolic acidosis.
16. Describe the pathway from failure to excrete phosphate through to metastatic calcification.
17. Explain how failure to activate vitamin D leads to secondary hyperparathyroidism.
18. List the bone consequences grouped under renal osteodystrophy.
19. List the mechanisms of hypertension in CKD and state which is the main one.
20. Describe the steps from Na and water retention to peripheral or pulmonary oedema in CKD, and distinguish this mechanism from that of nephrotic syndrome.
21. A 58 year old presents with 6 months of lethargy, nausea, nocturia, swollen ankles and shortness of breath, BP 150/100, elevated JVP and creps. K 5.6 mmol/L, urea 49 mmol/L, Hb 90 g/L, pH 7.32, HCO3 16. Explain each abnormal finding in terms of the failing kidney functions.

Answers

Reveal answers

1. CKD is irreversible loss of functional nephrons: more than 70% of nephrons lost, kidneys shrunken on imaging, and GFR decreased to less than 25 to 30% of normal.
2. Diabetes mellitus, hypertension, glomerulonephritis.
3. History long (months to years); haemoglobin low; renal size reduced; renal osteodystrophy present; peripheral neuropathy present. All four of the latter are normal or absent in acute renal failure, where the history is short (days to weeks).
4. Anaemia starts at moderate impairment, GFR 25 to 50 mL/min. Salt and water retention is evident at severe impairment, GFR 10 to 25 mL/min.
5. Excretion (water, salts, metabolic wastes, foreign substances leaving as urine); homeostasis (acid-base and electrolyte balance); hormones (erythropoietin, calcitriol); metabolism (glucose to blood, amino acid gluconeogenesis, NH3 to urine).
6. Surviving nephrons hypertrophy and carry an increased flow rate with an osmotic diuresis. The loop of Henle can then neither generate the hyperosmotic medullary gradient nor dilute the tubular fluid, so ADH has little effect and urine osmolarity approaches that of plasma. Water cannot be conserved, so urine volume is high unless GFR is very low.
7. Nephron number falls from 2,000,000 to 500,000 and total GFR from 125 to 40 mL/min, but single nephron GFR rises from 62.5 to 80 nL/min and volume excreted per nephron from 0.75 to 3.0 nL/min. The surviving nephrons hypertrophy and take on an increased workload, so each handles a larger filtered load and excretes a larger volume.
8. Amount filtered minus amount reabsorbed plus amount secreted equals amount excreted in urine.
9. The amount of Na filtered falls, but the osmotic diuresis raises tubular flow rate, which decreases contact time, which decreases Na reabsorption. Fractional reabsorption falls (99.26% normally to 92.6% in CKD) so excretion still matches the 200 mmol/day intake.
10. Both have a filtered load of 450 mmol/day at a GFR of 3 L/day against an intake of 200 mmol/day. Salt wasting: reabsorption 100 mmol/day, excretion 350 mmol/day, fractional reabsorption 22.2%, so more is lost than taken in. Salt retaining: reabsorption 300 mmol/day, excretion 150 mmol/day, fractional reabsorption 66.7%, so less is lost than taken in.
11. The balance between filtered load, reabsorption and secretion is disrupted. The filtered load falls sharply (900 to 90 mmol/day) and although secretion is relatively increased, excretion falls from 200 to 50 mmol/day against an unchanged intake of 200 mmol/day. K is therefore retained and plasma [K] rises.
12. The amount of urea lost is proportional to GFR x plasma [urea], so a rise in plasma [urea] can offset a fall in GFR. With production of 540 mmol/day and 60% of filtered urea excreted: normally plasma urea 5 mmol/L with GFR 180 L/day filters 900 mmol/day; at 75% loss, plasma urea 20 mmol/L with GFR 45 L/day still filters 900 mmol/day; at 90% loss, plasma urea 50 mmol/L with GFR 18 L/day still filters 900 mmol/day. Excretion remains 540 mmol/day in each case.
13. It is non-linear, a steep hyperbolic decline rather than a straight line. Plasma urea is about 5 mmol/L at a clearance of 120 to 140 mL/min, about 15 mmol/L at a clearance of about 20 mL/min, and rises steeply to about 54 mmol/L only at very low clearance. Plasma urea therefore rises appreciably only once clearance is very low, so early loss of function is accompanied by only gradual accumulation of urea and creatinine.
14. Creatinine production stays flat at about 1.9 g/day. Excretion, which equals GFR x plasma creatinine, dips at the moment GFR falls, then rises back to meet production by about day 2. During the gap there is positive balance, and serum creatinine rises from about 1 to a plateau near 2 mg/dL, at which point excretion again matches production.
15. Fewer nephrons capable of making HCO3-; decreased ability to secrete ammonium; decreased filtered buffers (phosphates); decreased ability to secrete H+. Together these give a decreased ability to acidify the urine.
16. Failure to excrete phosphate causes hyperphosphataemia, which exceeds the solubility equilibrium of Ca x Pi, producing metastatic calcification.
17. Failure to convert 25-OH to 1,25 diOH vitamin D reduces intestinal Ca absorption, which reduces plasma ionised Ca concentration, which drives secondary hyperparathyroidism. The same failure also contributes to hyperphosphataemia, which feeds into secondary hyperparathyroidism directly.
18. Osteomalacia, osteoporosis and osteitis fibrosa cystica.
19. Na and water retention with increased ECF and plasma volume (the main mechanism); excessive vasoconstrictive influences such as renin and angiotensin II, or reduced production of vasodepressors; sometimes no apparent cause.
20. Na and water retention increases plasma and ECF volume, raising BP and raising JVP or CVP. Increased BP raises capillary hydrostatic pressure and may cause left heart failure with creps; increased JVP or CVP decreases venous return, also raising capillary hydrostatic pressure. The raised capillary hydrostatic pressure increases ultrafiltration and produces peripheral or pulmonary oedema. In nephrotic syndrome the mechanism is low albumin instead.
21. Lethargy, nausea and poor appetite are uraemic symptoms from failed excretion of nitrogenous wastes (urea 49 mmol/L). Nocturia reflects the inability to concentrate urine because the surviving nephrons cannot generate a hyperosmotic medullary gradient. Swollen ankles, weight gain, elevated JVP, creps and BP 150/100 reflect Na and water retention with volume overload. K 5.6 mmol/L is hyperkalaemia from decreased K excretion. Hb 90 g/L is anaemia from erythropoietin deficiency. pH 7.32 with HCO3 16 is the metabolic acidosis of reduced HCO3- production and reduced acid excretion, with the low PaCO2 of 32 mmHg indicating respiratory compensation. The long history and the low haemoglobin point to a chronic rather than acute process.