Genitourinary Biochemistry

Acid-Base Balance and Disorders I

• pH: pH of extracellular fluid is kept within a narrow range of 7.35-7.45.
- acidosis: when pH <7.35
- alkalosis: when pH>7.45
• Buffer: buffer contains an acid and its conjugate base and is able to minimize pH changes by countering addition or removal of H+.
- Bicarbonate: H+ + HCO3- ↔ H2O + CO2
- Protein: albumin, haemoglobin H+ + A- ↔ HA
• Henderson-Hasselbach Equation: pH = 6.1 + log (HCO3-/[pCO2 ×0.23])
- Normal HCO3- 24 mmol/L
- Pressure CO2 is around 5.3kPa (yielding around 1.2 mmol/L in blood)
• Control of CO2: metabolism produces 15,000 mmol a day. Hyperventilation will decrease CO2 levels while hypoventilation increases.
- Increased pCO2 cause acidosis
- Decreased pCO2 cause alkalosis
• Blood gas measurement: blood sample is taking to measure the parameter for HCO3-
• Respiratory disturbance:
- Respiratory acidosis: increase pCO2 while HCO3- remains constant
- Respiratory alkalosis: decrease pCO2 while HCO3- remains constant
• Acute asthma: unable to ventilate properly due to bronchiolar constriction leading to respiratory acidosis (increased partial pressure CO2 and decrease O2)
• Hyperventilation: respiratory alkalosis with increased O2 and decrease CO2 partial pressure.
- Clinical presentation: light-headed, cramps in his hands muscles
- Treatment: breathe into a bag to increased inhaled CO2 content
• Metabolic disturbance:
- Metabolic acidosis: decreased HCO3- with constant CO2 level
- Metabolic alkalosis: increased HCO3- with constant CO2 level
• Metabolic acidosis: increased H+ in the plasma will neutralize the HCO3- level (buffering effect). Common causes are:
- Increased acid production: lactic acidosis, hypoxia, poor tissue perfusion, diabetic ketoacidosis
- Decreased acid excretion: renal failure, renal tubular acidosis
- Bicarbonate loss: severe diarrhea (loss of intestinal fluid containing HCO3-)
• Metabolic alkalosis: caused by ingestion of sodium bicarbonate or loss of acid due to vomiting etc which means equilibrium shifts to produce more HCO3-
• Respiratory compensation: when low pH of the body stimulate hyperventilation to lower PCO2 levels and hence the pH. This is called acidotic breathing.
- This can be shown when there is a decrease in HCO3- levels, the pCO2 also decreased to compensate
• Role of kidney:
- Bicarbonate reabsorption: in the proximal tubule
- Bicarbonate generation: within the cells of the proximal tubule. Acetazolamide is carbonic anhydrase inhibitor and can cause metabolic acidosis (used in mountaineers to counter alkalosis from hyperventilation)
- Acid secretion: metabolic acid is excreted in the distal tubule through phosphoric acid and ammonium ion (urinary buffers). Urine is hence slightly acid ranging from pH 5 -8
• Renal compensation: increase in HCO3- levels from bicarbonate generation in response to an increased in CO2 level. Process takes days.
• Base excess: amount of acid or base needed to restore pH to 7.4 and is calculated from pH, pCO2 and haemoglobin parameters. It is an indication of the action of all buffers in the plasma (not just bicarbonate). The normal base excess is 0
- Positive base excess is metabolic alkalosis
- Negative base excess is metabolic acidosis

Acid-Base Balance and Disorders II

• Chronic lung disease: on admission suffers a respiratory acidosis.
- Treatment: ventilator helps correct the misplaced respiratory component but is left with metabolic alkalosis as a result of renal compensation.
• Anion gap: a useful parameter only in metabolic acidosis that indicates the presence of unmeasured anion.
- Calculation: (Na + K) – (Cl – HCO3-) = AG. The normal gap is usually 14 – 18 which reflects the presence of protein anions and lactate.
- Explanation: when acid in added to the system, the amount of HCO3- decreases to buffer the H+ and as a result produce an increase in anion gap (also indicate an increase in the conjugate base derivative of the acidic protein)
• Rare caused for AG increase:
- Methanol poisoning
- Ethylene
- Salicylate
- Organic aciduria
- Pyroglutamic aciduria
• Ethylene glycol poisoning:
- Clinical presentation: seizures
- Test results: decreased CO2 and HCO3- levels. Both beta-hydroxybutyrate and lactate levels are elevated. Later confirmed ethylene glycol poisoning by detection of 6 mmol/L of chemical present.
- Explanation: metabolic acidosis cause decreased HCO3- with respiratory compensation with decrease CO2.
• Rickets: renal tubular acidosis
- Clinical presentation: failed to thrive
- Test results: elevated Cl- levels and decreased HCO3- with pCO2 at bottom limit of normal range. Base excess was extremely low but AG was normal. Urine sample as pH of 6.5
- Explanation: the decrease in HCO3 was made up with the increase in Cl- levels making AG constant. Loss of HCO3- indicates acidosis.
• Hyperchloremic acidosis: acidosis with a normal AG as the Cl- level has increased. This is due to extra Cl- needed to compensate for loss of bicarbonate in order to maintain sodium balance
- Renal tubular acidosis: genetic problem in acid secretion of kidney with urine pH >5.5. Proximal tubule is type 2 while distal is type 1.associated with rickets or hypokalaemia
- Aldosterone deficiency or resistance: addison’s disease or congenital adrenal hyperplasia syndromes (enzyme block aldosterone synthesis pathway); renin deficiency and pseudohypoaldosteronism (aldosterone resistance)
- GI bicarbonate loss: diarrhea and intestinal fistula
• Potassium balance with acidosis: potassium and H+ compete for secretion. Aldosterone promoting secretion of K+ will cause retention of H+
- Hyperkaelemia: occurs as a result of acidosis by either H+ shifting into the cell to displace K+. The opposite is also true with hyperkalemia in which K+ moves into the cell to displace H+
- Hypokaelemia: alkalosis causes this with shifting of H+ out of the cell to balance pH while K+ enters the cell. With primary hypokaelemia, the K+ shifts out of the cell in exchange for H+
• Exception to above:
- Diarrhoea: bicarbonate plus K+ loss (so decreased alkalination effect)
- Renal tubular acidosis: distal and proximal types both associated with hypokaelemia.
• Muscle weakness:
- Test results: hypokaelemia, low chloride, and metabolic alkalosis (vomiting is a VERY strong cause of metabolic alkalosis)
- Explanation: loss of HCl due to vomiting causing alkalosis (strong cause by vomiting), hypokaelemia due to alkalosis and excessive laxative use. K+ loss is also predominant in chronic diarrhea due to Na+/K+ pump to reabsorb Na+ (however in acute diarrhea, hyponatremia occurs with loss of pancreatic juice).
• Metabolic alkalosis:
- Vomiting and gastric drainage
- Secondary to hypokaelemia
- Diuretic-induced alkalosis
- Ingestion of alkali
- Mineralocorticoid excess (aldosterone agonist such as fludrocortisone)
• Chloride depletion alkalosis: when Cl- < 10 mmol/L. Caused usually by diuretics and insufficient Na+ absorption.
- In metabolic alkalosis, kidney attempts to increase HCO3- loss. However if chloride-depletion is present, bicarbonate reabsorption becomes obligatory to preserve Na+ balance (i.e. co-transport).
- The kidney cannot correct the alkalosis unless chloride is replaced
• Artefact:
- Air in blood-gas syringe: falsely low pCO2 (with no air in syringe so gas leaves). This produce apparent respiratory alkalosis
- Delayed separation of plasma from RBC: the RBC produced lactic acid as it is deprived of O2, leading to an apparent lactic acidosis (high AG)

Vitamin D, Calcium and phosphate regulation

• Calcium balance: bone is the biggest reservoir of calcium in the body
- Intake: diet
- Output: renal excretion
- Plasma calcium: complexed 5% Ca2+, albumin bound Ca2+ 45%, ionised free Ca2+ 50%
• Parathyroid hormone: polypeptide hormone secreted by small glands in thyroid glands. These have 7 domain G-protein (calcium-sensing receptor) that allows binding of Ca2+. Low plasma Ca2+ triggers PTH secretion
- Function of PTH: stimulate osteoclasts and release of Ca2+ from bones. Act on the kidney to activate 1-hydroxylase to increase Ca2+ reabsorption but increase phosphate loss.
• Response to calcium deficiency: low dietary Ca2+ or vitamin D caused low ECF Ca2+ levels. PTH is secreted in response leading to a condition called secondary hyperparathyroidism.
- in cases, rickets and or osteomalacia eventually develop from depletion of bones
• Hypocalcemia: low ionised Ca2+ in plasma.
- Affected cell membrane makes cells more excitable
- muscle twitching and spasm (trousseau’s sign), tetany, parasthesiae, convulsion
- common causes: hypoparathyroidism (autoimmune or post surgery damage to thyroid tissue); vitamin D deficiency
• Hypercalcemia: makes cell less excitable with weakness and drowsiness and polyuria effect. Caused by
- Primary hyperparathryroidism (tumour of PTH gland increased secretion of PTH)
- Hypercalcemia of malignancy (PTH-related peptide secreted by tumour)
- Sarcoidosis (increased 1-hydroxylation of vit D)
• Ionised Ca2+ and pH: binding of Ca2+ to protein such as albumin is pH dependent. Alkalosis will decrease concentration of ionised Ca2+ (increase binding) while acidosis will increase ionized Ca2+. So in hyperventilation from panic attack, the patient suffers parasthesiae and muscle twitching
• Adjusted calcium: calcium content adjusted for the quantity of albumin, i.e. due to the albumin variation between people (hypoalbuminae in renal problems).
- Equation: Adjusted Ca = total Ca + [(40-alb)× 0.02]
- Range: 2.1 – 2.6 mmol/L
• Nephrotic syndrome: autoimmune glomerulonephritis causes decreased plasma and albumin levels. The patient suffers listlessness and oedema of leg and face.
- The PTH and vit D are all normal. The main problem is the albumin
• Hypoparathyroidism; autoimmune destruction of the parathyroid gland causing decreased plasma calcium, lowered adjusted calcium, lowered ionised calcium, increased phosphate and lowered PTH. The patient presents with epilieptic convulsions.
- Hypocalcemia is present by there is an inadequate PTH response. PTH simply decrease plasma phosphate and increase calcium.
• Rickets: condition characterized by demineralisation of bones, deformities and fractures (due to weak bones) and myopathy.
• Treatment of rickets: vitamin D benefits from diet is minute. Majority comes from sunlight.
- First: sunlight
- Second: Vitamin D and calcium (effective way to prevent rickets with calcium deficiency usually the main problem).
• Vitamin D metabolism:
- Vitamin D is stored in the liver as 25-OH-vit D
- With secretion of PTH and low phosphate, the 1-hydroxylase is activated and 25-OH-vit D is hydroxylated in the kidney to form 1,25-(OH)2-D3.
- This new substance is an activated form of calcitriol that will stimulate Ca2+ and phosphate absorption in the gut
• Renal osteodystrophy: chronic renal failure has impaired 1-hydroxylation resulting from decreased renal tissue mass and phosphate retention, leading to high plasma phosphate that inhibit 1-hydroxylase.
- lack of 1, 25-vitD cause failure to absorb calcium from the gut and hence hypocalcemia
- overstimulation of PTH also produce excessive bone resorption leading to fracture and pain
- secondary hyperparathyroidism lead to development of autonomous parathyroid tumours with hypercalcemia (does not respond to Ca2+ level in the blood so constant PTH synthesis)
- metastatic calcification: occurs in the kidney when the Ca2+ and phosphate combined totals is high. This can cause organ damage.
• Renal bone disease treatment:
- administration of calcitriol (1,25-dihydroxy vitamin D)
- phosphate binders such as CaCO3 orally to decrease phosphate by absorption
- parathyroidectomy for severe hyperparathyroidism
- renal transplant
• Renal stones: stone formed whether concentration of solutes exceed their solubility limits
- symptoms: excruciating pain in the flank radiating to the groin, haematuria, bladder outlet obstruction, hydronephrosis
- features: ballooning of the ureter
- composition of kidney stone: 80% calcium (Ca-oxalate, Ca-phosphate), 10% uric acid, 10% struvite, 1% cystine
• Calcium-containing stones: majority Ca-oxalate and rest Ca-phosphate or mixtures. These stone formation is enhanced by high urine Ca2+, oxalate (dietary sources) or phosphate.
- Urine citrate: citrate forms soluble complexes with Ca2+ and hence can prevent formation of calcium stones. Acidosis decreases urine citrate, such as that from a high protein diet, will produce H+ during metabolism and increase risk of stone formation.
• Uric acid stone: formation from uric acid
- high purine diet (meat) increase RNA and DNA content and along with rapid cell break down (e.g. chemotherapy against leukaemia), increased level of adenosine and guanosine is released
- adenosine and guanosine is processed to hypoxanthine and guanine which converts to xanthine
- xanthine forms uric acid by enzyme xanthine oxidase and increased level of uric acid forms urine acid stones or cause gout.
• Features of uric acid stones:
- radiolucent stones (X-ray can’t clearly show)
- risk factors: high purine diet and rapid cell breakdown
- stone formation is enhanced by acid urine pH as at high pH, the urate ion is more soluble
- urate production is inhibited by allopurinol which is an inhibitor of xanthine oxidase.
• Struvite stone: magnesium-ammonium-phosphate stone caused by urinary tract infections with urease-producing organisms (e.g. Proteus).
- staghorn calculi
- often associated with anatomic urologic abnormalities such as bladder diverticulum or double ureter
- visibility on radioactive depends on amount of calcium in stone
• Cystine stone: produced by high concentration cystine in the urine. Stones are radio-opaque
- cystinuria: autosomal recessive disorder of renal tubular cystine transport.
• Risk factors of Nephrolithiasis:
- low urine volume
- hyperoxaluria: oxalate is mostly endogenous. Increased vitamin C is metabolised to oxalate; small bowel disease where fatty acid that is not absorbed binds to Ca2+ in the gut preventing oxalate to precipitate (so oxalate is absorbed); lack of intestinal oxalate degrading bacteria; primary hyperoxaluria (genetic disease)
- hypercalciuria: hypercalcemia, e.g. parathyroid tumour; idiopathic absorptive hypercalciuria (increased GIT calcium absorption), high sodium intake, others (such as chloride channel, renal tubular acidosis and calcium-sensing receptor mutations).
- high urate production: high purine load, acidic urine pH favours uric acid stones
- low urine citrate: acid load decreases urine citrate and idiopathic hypocitraturia
- Urinary infection or anatomic abnormalities
- drugs: acetazolamide used for glaucoma (alkalinizes urine)
• Testing for nephrolithiasis:
- blood test for calcium phosphate and urea
- 24 hour urine test for calcium, oxalate, and cystine
• Prevention of renal stones:
- increase fluid intake: achieve urine output, citrus juice to increase urine citrate
- dietary advice: avoid dietary excesses, e.g. for oxalate, lower salt and protein intake and do not restrict calcium intake
- K-citrate: citrate alkalinizes urine as it is metabolised to bicarbonate
- Thiazide diuretics: lowers urinary Ca2+ (but can increase plasma urate and may precipitate gout)
- Allopurinol: for uric acid stones

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