Antidiuretic hormone (ADH), commonly known as vasopressin, is a peptide hormone that controls how much water the body retains.

It is produced in the magnocellular and parvocellular neurosecretory cells of the paraventricular nucleus and supraoptic nucleus in the hypothalamus from a prohormone precursor. It is subsequently carried to the posterior pituitary via axons and stored in vesicles.

The secretion of ADH from the posterior pituitary is regulated by numerous mechanisms:
Increased plasma osmolality: Osmoreceptors in the hypothalamus detect an increase in osmolality and trigger ADH release.

Stretch receptors in the atrial walls and big veins detect a decrease in atrial pressure as a result of this (cardiopulmonary baroreceptors). ADH release is generally inhibited by atrial receptor firing, but when the atrial receptors are stretched, the firing reduces and ADH release is promoted.
Hypotension causes baroreceptor firing to diminish, resulting in increased sympathetic activity and ADH release.
An increase in angiotensin II stimulates angiotensin II receptors in the hypothalamus, causing ADH production to increase.

The main sites of action for ADH are:
The kidney is made up of two parts. ADH’s main job is to keep the extracellular fluid volume under control. It increases permeability to water by acting on the renal collecting ducts via V2 Receptors (via a camp-dependent mechanism). This leads to a decrease in urine production, an increase in blood volume, and an increase in arterial pressure as a result.

Vascular system: Vasoconstriction is a secondary function of ADH. ADH causes vasoconstriction via binding to V1 Receptors on vascular smooth muscle (via the IP3 signal transduction pathway). An increase in arterial pressure occurs as a result of this.

Angiotensin II acts to:
Stimulate release of aldosterone from the zona glomerulosa of the adrenal cortex (which in turn acts to increase sodium reabsorption)
Cause systemic vasoconstriction
Cause vasoconstriction of the renal arterioles (predominant efferent effect thus intraglomerular pressure is stable or increased, thereby tending to maintain or even raise the GFR)
Directly increase Na+reabsorption from the proximal tubule (by activating Na+/H+antiporters)
Stimulate synthesis and release of ADH from the hypothalamus and posterior pituitary respectively
Stimulate the sensation of thirst
Potentiate sympathetic activity (positive feedback)
Inhibit renin production by granular cells (negative feedback)

The loop of Henle consists of three functionally distinct segments: the thin descending segment, the thin ascending segment, and the thick ascending segment. About 20 percent of the filtered water is reabsorbed in the loop of Henle and almost all of this occurs in the thin descending limb. Na+ and Cl-ions are actively reabsorbed from the tubular fluid in the thick ascending limb via the Na+/K+/2Cl-symporter on the apical membrane. Because the thick ascending limb is water-impermeable, ion reabsorption lowers tubular fluid osmolality while raising interstitial fluid osmolality, resulting in an osmotic difference. Water moves passively out of the thin descending limb as the interstitial fluid osmolality rises, concentrating the tubular fluid. This concentrated fluid descends in the opposite direction of fluid returning from the deep medulla still higher osmolality areas.

Juxtaglomerular cells are specialised smooth muscle cells mainly in the walls of the afferent arterioles (and some in the efferent arterioles) which synthesise renin.

About 80% of bicarbonate is reabsorbed in the proximal tubule. HCO3-is not transported directly, tubular HCO3-associates with H+secreted by epithelial Na+/H+antiporters to form carbonic acid (H2CO3) which readily dissociates to form carbon dioxide and water in the presence of carbonic anhydrase. CO2and water diffuse into the tubular cells, where they recombine to form carbonic acid which dissociates to H+and HCO3-. This HCO3-is transported into the interstitium largely by Na+/HCO3-symporters on the basolateral membrane (and H+is secreted back into the lumen). For each H+secreted into the lumen, one Na+and one HCO3-are reabsorbed into the plasma. H+is recycled so there is little net secretion of H+at this stage.

FUSEDCARS can be used to remember some of the causes of a normal anion gap acidosis:
Fistula (pancreaticoduodenal)
Ureteroenteric conduit
Saline administration
Endocrine (hyperparathyroidism)
Diarrhoea
Carbonic anhydrase inhibitors (e.g. acetazolamide)
Ammonium chloride
Renal tubular acidosis
Spironolactone

Polydipsia is the feeling of extreme thirstiness. It is often linked to polyuria, which is a urinary condition that causes a person to urinate excessively. The cycle of these two processes makes the body feel a constant need to replace the fluids lost in urination. In healthy adults, a 3 liter urinary output per day is considered normal. A person with polyuria can urinate up to 15 liters of urine per day. Both of these conditions are classic signs of diabetes.

The other options are also types of diabetes, except for psychogenic polydipsia (PPD), which is the excessive volitional water intake seen in patients with severe mental illness or developmental disability. However, given the patient’s previous head injury, the most likely diagnosis is cranial diabetes insipidus.

By definition, cranial diabetes insipidus is caused by damage to the hypothalamus or pituitary gland after an infection, operation, brain tumor, or head injury. And the patient’s history confirms this diagnosis. To define the other choices, nephrogenic diabetes insipidus happens when the structures in the kidneys are damaged and results in an inability to properly respond to antidiuretic hormone.

Kidney damage can be caused by an inherited (genetic) disorder or a chronic kidney disorder. As with cranial diabetes insipidus, nephrogenic diabetes insipidus can also cause an elevated urine output.

Diabetes mellitus is classified into two types, and the main difference between them is that type 1 diabetes is a genetic disorder, and type 2 diabetes is diet-related and develops over time. Type 1 diabetes is also known as insulin-dependent diabetes, in which the pancreas produces little or no insulin. Type 2 diabetes is termed insulin resistance, as cells don’t respond customarily to insulin.

Molecular weight is the main factor in determining whether a substance is filtered or not – molecules < 7 kDa in molecular weight are filtered freely e.g. glucose, amino acids, urea, ions but larger molecules are increasingly restricted up to 70 kDa, above which filtration is insignificant. Negatively charged molecules are further restricted, as they are repelled by negative charges, particularly in the basement membrane. Albumin has a molecular weight of 69 kDa and is negatively charged, thus only very small amounts are filtered (and all of the filtered albumin is reabsorbed in the proximal tubule), whereas small molecules such as ions, glucose, amino acids and urea pass the filter without hindrance. This means that ultrafiltrate is virtually protein free, but otherwise has an identical composition of that of plasma. The epithelial lining of the Bowman's capsule consists of a single layer of cells called podocytes. The glomerular capillary endothelium is perforated by pores (fenestrations) which allow plasma components with a molecular weight of < 70 kDa to pass freely.

Aldosterone: A rise in [K+] in the extracellular fluid of the adrenal cortex directly stimulates aldosterone release. Aldosterone promotes the synthesis of Na+/K+ATPases and the insertion of more Na+/K+ATPases into the basolateral membrane, and also stimulates apical sodium and potassium channel activity, overall acting to increase sodium reabsorption and potassium secretion.
pH changes: Potassium secretion is reduced in acute acidosis and increased in acute alkalosis. A higher pH increases the apical K+channel activity and the basolateral Na+/K+ATPase activity – both changes that promote K+secretion.
Flow rates: Increased flow rates in the collecting duct reduce K+concentration in the lumen and therefore enhance K+secretion. Increased flow also activates BK potassium channels, and ENaC channels which promote potassium secretion and sodium reabsorption respectively.
Sodium delivery: Decreased Na+delivery to the collecting ducts results in less Na+reabsorption and hence a reduced gradient for K+secretion.
Magnesium: Intracellular magnesium can bind and block K+channels inhibiting K+secretion into the tubules. Therefore magnesium deficiency reduces this inhibitory effect and so allows more potassium to be secreted into tubules and can cause hypokalaemia.

Clearance of a substance can provide an accurate estimate of the glomerular filtration rate (GFR) provided that the substance is:freely filterednot reabsorbed in the nephronnot secreted in the nephronnot synthesised or metabolised by the kidney

Decreased blood volume stimulates the secretion of renin (because of decreased renal perfusion pressure) and initiates the renin-angiotensin-aldosterone cascade. Angiotensin-converting enzyme (ACE) inhibitors block the cascade by decreasing the production of angiotensin. Hyperosmolarity stimulates antidiuretic hormone (ADH) [not aldosterone] secretion. Hyperkalaemia, not hypokalaemia, directly stimulates aldosterone secretion by the adrenal cortex. ANP inhibits renin secretion, thereby inhibiting the production of angiotensin and aldosterone.

Lactic acidosis is a common finding in critically ill patients and commonly associated with other serious underlying pathologies. It occurs when pH is <7.35 and lactate is >5 mmol/L. Anion gap is increased in lactic acidosis.

Acquired lactic acidosis is classified into two subtypes:
Type A: lactic acidosis due to tissue hypoxia and
Type B: due to non-hypoxic processes affecting the production and elimination of lactate

Some causes of type A and type B lactic acidosis include:
Type A lactic acidosis
Left ventricular failure
Severe anaemia
Shock (including septic shock)
Asphyxia
Cardiac arrest
CO poisoning
Respiratory failure
Severe asthma and COPD

Type B lactic acidosis:
Regional hypoperfusion
Renal failure
Liver failure
Sepsis (non-hypoxic sepsis)
Thiamine deficiency
Alcoholic ketoacidosis
Diabetic ketoacidosis
Cyanide poisoning
Methanol poisoning
Biguanide poisoning

Angiotensin II constricts both the afferent and efferent arterioles, but preferentially increases efferent resistance. The net effect of the more prominent increase in efferent tone is that the intraglomerular pressure is stable or increased, thereby tending to maintain or even raise the GFR. Renin is produced by granular cells of the juxtaglomerular apparatus. Renin cleaves plasma angiotensinogen (produced in the liver) into angiotensin I. Angiotensin I is converted by angiotensin-converting enzyme (ACE) on pulmonary endothelial cells to angiotensin II. Angiotensin II acts to potentiate sympathetic activity (positive feedback).

The main Na+ reabsorbing cells in the late distal convoluted tubule and collecting duct are the principal cells. These make up the majority of the tubular cells.

The exchange is driven by the Na.K.ATPase pumps on the basolateral membrane.

Buffers are weak acids or bases that can donate or accept H+ions respectively and therefore resist changes in pH. Buffering does not alter the body’s overall H+load, ultimately the body must get rid of H+by renal excretion if the buffering capacity of the body is not to be exceeded and a dangerous pH reached. Bicarbonate and carbonic acid (formed by the combination of CO2 with water, potentiated by carbonic anhydrase) are the most important buffer pair in the body, although haemoglobin provides about 20% of buffering in the blood, and phosphate and proteins provide intracellular buffering. Buffers in urine, largely phosphate, allow the excretion of large quantities of H+.

In the thick ascending limb is the part of the loop of Henle in which there is active reabsorption of Na+and Cl- ions from the tubular fluid. This occurs via the Na+/K+/2Cl-symporter on the apical membrane.
This mechanism is by:
1. Na+ions are transported across the basolateral membrane by Na+pumps and the Cl-ions by diffusion.
2. K+leaks back into the tubular fluid via apical ROMK K+channels which creates a positive charge.
3. This positive charge drives the reabsorption of cations (Na+, K+, Ca2+, Mg2+) through paracellular pathways.
4. Due to the thick ascending limb being impermeable to water, the tubular fluid osmolality is reduced by ion reabsorption, the interstitial fluid osmolality is increased, and an osmotic difference is created.

The Loop of Henle connects the proximal tubule to the distal convoluted tubule and lies parallel to the collecting ducts. It consists of three major segments, including the descending thin limb, the ascending thin limb, and the ascending thick limb. These segments are differentiated based on structure, anatomic location, and function.

The main function of the loop of Henle is to recover water and sodium chloride from urine. When fluid enters the loop of Henle, it has an osmolality of approximately 300 mOsm, and the main solute is sodium.

The thin descending limb has a high water permeability but a low ion permeability. Because it lacks solute transporters, it cannot reabsorb sodium. Aquaporin 1 (AQP1) channels are used to passively absorb water in this area. The peritubular fluid becomes increasingly concentrated as the loop descends into the medulla, causing water to osmose out of the tubule. The tubular fluid in this area now equalizes to the osmolality of the peritubular fluid, to a maximum of approximately 1200 mOsm in a long medullary loop of Henle and 600 mOsm in a short cortical loop of Henle.

The thin ascending limb is highly permeable to ions and impermeable to water. It allows the passive movement of sodium, chloride, and urea down their concentration gradients, so urea enters the tubule and sodium and chloride leave. Reabsorption occurs paracellularly due to the difference in osmolarity between the tubule and the interstitium.

The thick ascending limb is also impermeable to water but actively transports sodium, potassium, and chloride out of the tubular fluid. The osmolality of the tubular fluid is lower compared to the surrounding peritubular fluid. This area is water impermeable. This results in tubular fluid leaving the loop of Henle with an osmolality of approximately 100 mOsm, which is lower than the osmolality of the fluid entering the loop, and urea being the solute.

The RAS pathway begins with renin cleaving its substrate, angiotensinogen (AGT), to produce the inactive peptide, angiotensin I, which is then converted to angiotensin II by endothelial angiotensin-converting enzyme (ACE). ACE activation of angiotensin II occurs most extensively in the lung. Angiotensin II mediates vasoconstriction as well as aldosterone release from the adrenal gland, resulting in sodium retention and increased blood pressure.

Aldosterone is a steroid hormone produced in the adrenal cortex’s zona glomerulosa. It is the most important mineralocorticoid hormone in the control of blood pressure. It does so primarily by promoting the synthesis of Na+/K+ATPases and the insertion of more Na+/K+ATPases into the basolateral membrane of the nephron’s distal tubules and collecting ducts, as well as stimulating apical sodium and potassium channel activity, resulting in increased sodium reabsorption and potassium secretion. This results in sodium conservation, potassium secretion, water retention, and a rise in blood volume and blood pressure.

Aldosterone is produced in response to the following stimuli:

Angiotensin II levels have risen.
Potassium levels have increased.
ACTH levels have risen.
Aldosterone’s principal actions are as follows:
Na+ reabsorption from the convoluted tubule’s distal end
Water resorption from the distal convoluted tubule (followed by Na+)
Cl is reabsorbed from the distal convoluted tubule.
K+ secretion into the convoluted distal tubule’s 
H+ secretion into the convoluted distal tubule’s 

Angiotensin II increases Na+reabsorption from the proximal tubule (by activating Na+/H+antiporters).

Glomerular filtration is a passive process. It depends on the net hydrostatic pressure across the glomerular capillaries, the oncotic pressure, and the intrinsic permeability of the glomerulus.

The mean values for glomerular filtration rate (GFR) in young adults are 130 ml/min/1.73m2 in males and 120 ml/min/1.73m2in females.

The GFR declines with age after the age of 40 at a rate of approximately 1 ml/min/year.

The Cockcroft and Gault formula overestimates creatinine in obese patients. This is because their endogenous creatinine production is less than that predicted by overall body weight.

Creatinine is used in the estimation of GFR because it is naturally produced by muscle breakdown, not toxic, not produced by the kidney, freely filtered at the glomerulus, not reabsorbed from the nephron, and does not alter GFR.

The nephron’s blood flow is as follows:
Afferent arteriole – Glomerular capillary – Efferent arteriole – Peritubular capillary – Vasa recta – Afferent arteriole – Glomerular capillary – Efferent arteriole – Peritubular capillary – Vasa recta

The kidney is the only vascular network in the body with two capillary beds. With arterioles supplying and draining the glomerular capillaries, higher hydrostatic pressures at the glomerulus are maintained, allowing for better filtration. A second capillary network at the tubules enables for secretion and absorption in the tubules, as well as concentrating urine.

When you take too much aspirin, you have a mix of respiratory alkalosis and metabolic acidosis. Respiratory centre stimulation produces hyperventilation and respiratory alkalosis in the early phases. The direct acid actions of aspirin tend to create a higher anion gap metabolic acidosis in the latter phases.
Below summarizes some of the most common reasons of acid-base abnormalities:

Respiratory alkalosis:
– Hyperventilation (e.g. anxiety, pain, fever)
– Pulmonary embolism
– Pneumothorax
– CNS disorders (e.g. CVA, SAH, encephalitis)
– High altitude
– Pregnancy
– Early stages of aspirin overdose

Respiratory acidosis:
– COPD
– Life-threatening asthma
– Pulmonary oedema
– Respiratory depression (e.g. opiates, benzodiazepines)
– Neuromuscular disease (e.g. Guillain-Barré syndrome, muscular dystrophy
– Incorrect ventilator settings (hypoventilation)
– Obesity

Metabolic alkalosis:
– Vomiting
– Cardiac arrest
– Multi-organ failure
– Cystic fibrosis
– Potassium depletion (e.g. diuretic usage)
– Cushing’s syndrome
– Conn’s syndrome

Metabolic acidosis (with raised anion gap):
– Lactic acidosis (e.g. hypoxaemia, shock, sepsis, infarction)
– Ketoacidosis (e.g. diabetes, starvation, alcohol excess)
– Renal failure
– Poisoning (e.g. late stages of aspirin overdose, methanol, ethylene glycol)

Metabolic acidosis (with normal anion gap):
– Renal tubular acidosis
– Diarrhoea
– Ammonium chloride ingestion
– Adrenal insufficiency

Diabetes insipidus is the inability to produce concentrated urine. It is characterised by the presence of excessive thirst, polyuria and polydipsia. There are two distinct types of diabetes insipidus:
Cranial (central) diabetes insipidus and;
Nephrogenic diabetes insipidus
Cranial diabetes insipidus is caused by a deficiency of vasopressin (anti-diuretic hormone). Patients with cranial diabetes insipidus can have a urine output as high as 10-15 litres per 24 hours, but adequate fluid intake allows most patients to maintain normonatraemia. 30% of cases are idiopathic, and a further 30% are secondary to head injuries. Other causes include neurosurgery, brain tumours, meningitis, granulomatous disease (e.g. sarcoidosis) and drugs, such as naloxone and phenytoin. A very rare inherited form also exists that is associated with diabetes mellitus, optic atrophy, nerve deafness and bladder atonia.
Nephrogenic diabetes insipidus is caused by renal resistance to the action of vasopressin. As with cranial diabetes insipidus, urine output is markedly elevated. Serum sodium levels can be maintained by secondary polydipsia or can be elevated. Causes of nephrogenic diabetes insipidus include chronic renal disease, metabolic disorders (e.g. hypercalcaemia and hypokalaemia) and drugs, including long-term lithium usage and demeclocycline.
In view of the history of long-term lithium use, in this case, nephrogenic diabetes insipidus is the most likely diagnosis.

Lactic acidosis is defined as a pH <7.35 and a lactate >5 mmol/L. It is a common finding in critically ill patients and is often associated with other serious underlying pathologies. The anion gap is raised in lactic acidosis.
There are major adverse consequences of severe acidaemia, which affect all body systems, and there is an associated increase in mortality of critically ill patients with a raised lactate. The mortality associated with lactic acidosis despite full supportive treatment remains at 60-90%.
Acquired lactic acidosis is classified into two subtypes:
Type A is due to tissue hypoxia
Type B is due to non-hypoxic processes affecting the production and elimination of lactate
Lactic acidosis can be extreme after a seizure but usually resolves spontaneously within a few hours.
Left ventricular failure typically results in tissue hypoperfusion and a type A lactic acidosis.
Some causes of type A and type B lactic acidosis are shown below:
Type A lactic acidosis
Type B lactic acidosis
Shock (including septic shock)
Left ventricular failure
Severe anaemia
Asphyxia
Cardiac arrest
CO poisoning
Respiratory failure
Severe asthma and COPD
Regional hypoperfusion
Renal failure
Liver failure
Sepsis (non-hypoxic sepsis)
Thiamine deficiency
Alcoholic ketoacidosis
Diabetic ketoacidosis
Cyanide poisoning
Methanol poisoning
Biguanide poisoning

Angiotensin I is converted to angiotensin II by the removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE). This primarily occurs in the lungs, although it does also occur to a lesser degree in endothelial cells and renal epithelial cells.
The main actions of angiotensin II are:
Vasoconstriction of vascular smooth muscle (resulting in increased blood pressure)
Vasoconstriction of the efferent arteriole of the glomerulus (resulting in an increased filtration fraction and preserved glomerular filtration rate)
Stimulation of aldosterone release from the zona glomerulosa of the adrenal cortex
Stimulation of anti-diuretic hormone (vasopressin) release from the posterior pituitary
Stimulation of thirst via the hypothalamus
Acts on the Na+/H+ exchanger in the proximal tubule of the kidney to stimulate Na+reabsorption and H+excretion

The interpretation of arterial blood gas (ABG) aids in the measurement of a patient’s pulmonary gas exchange and acid-base balance.
The normal values on an ABG vary a little depending on the analyser, but they are roughly as follows:
Variable
Range
pH
7.35 – 7.45
PaO2
10 – 14 kPa
PaCO2
4.5 – 6 kPa
HCO3-
22 – 26 mmol/l
Base excess
-2 – 2 mmol/l

The patient’s history indicates that she has taken an overdose in this case. Because her GCS is 11/15 and she can communicate with slurred speech, she is clearly managing her own airway, there is no current justification for intubation.

The following are the relevant ABG findings:

Hypoxia (mild)
pH has been lowered (acidaemia)
PCO2 levels are low.
bicarbonate in its natural state
Lactate levels have increased

The anion gap represents the concentration of all the unmeasured anions in the plasma. It is the difference between the primary measured cations and the primary measured anions in the serum. It can be calculated using the following formula:
Anion gap = [Na+] – [Cl-] – [HCO3-]

The reference range varies depending on the technique of measurement, but it is usually between 8 and 16 mmol/L.

The following formula can be used to compute her anion gap:
Anion gap = [143] – [99] – [22]
Anion gap = 22

As a result, it is clear that she has a metabolic acidosis with an increased anion gap.

The following are some of the causes of type A and type B lactic acidosis:
Type A lactic acidosis
Type B lactic acidosis
Shock (including septic shock)
Left ventricular failure
Severe anaemia
Asphyxia
Cardiac arrest
CO poisoning
Respiratory failure
Severe asthma and COPD
Regional hypoperfusion
Renal failure
Liver failure
Sepsis (non-hypoxic sepsis)
Thiamine deficiency
Alcoholic ketoacidosis
Diabetic ketoacidosis
Cyanide poisoning
Methanol poisoning
Biguanide poisoning

Glucose reabsorption occurs exclusively in the proximal convoluted tubule by secondary active transport through the Na.Glu co-transporters, driven by the electrochemical gradient for sodium.
The co-transporters transport two sodium ions and one glucose molecule across the apical membrane, and the glucose subsequently crosses the basolateral membrane by facilitated diffusion.

Angiotensinogen is an alpha-2-globulin generated predominantly by the liver and released into the blood. Renin, which cleaves the peptide link between the leucine and valine residues on angiotensinogen, converts it to angiotensin I.

Angiotensinogen levels in the blood are raised by:
Corticosteroid levels have risen.
Thyroid hormone levels have risen.
Oestrogen levels have risen.
Angiotensin II levels have risen.

A plasma potassium less than 3.5 mmol/L defines hypokalaemia.

Excessive liquorice ingestion causes hypermineralocorticoidism and leads to hypokalaemia.

Gitelman’s syndrome causes metabolic alkalosis with hypokalaemia and hypomagnesaemia. It is an inherited defect of the distal convoluted tubules.

Bartter’s syndrome causes hypokalaemic alkalosis. It is a rare inherited defect in the ascending limb of the loop of Henle.

Type 1 and 2 renal tubular acidosis both cause hypokalaemia

Type 4 renal tubular acidosis causes hyperkalaemia.