Appearance

This is of little value in the differential diagnosis of renal disease except in the diagnosis of haematuria. Overt ‘bloody’ urine is usually unmistakable but should be checked using dipsticks (Stix testing). Very concentrated urine may also appear dark or smoky. Other causes of discoloration of urine include cholestatic jaundice, haemoglobinuria, drugs such as rifampicin, use of fluorescein or methylthioninium chloride (methylene blue), and ingestion of beetroot. Discoloration of urine after standing for some time occurs in porphyria, alkaptonuria and in patients ingesting the drug l-dopa.

Volume

In health, the volume of urine passed is primarily determined by diet and fluid intake. In temperate climates it lies within the range 800-2500 mL per 24 hours. The minimum amount passed to stay in fluid balance is determined by the amount of solute – mainly urea and electrolytes – being excreted and the maximum concentrating power of the kidneys. On a normal diet, some 800 mOsm of solute are passed daily. Since the maximum urine concentration is approximately 1200 mOsm/kg, the minimum volume of urine obligated by excretion of 800 mOsm of solute would thus be approximately 650 mL. A diet rich in carbohydrate and fat and low in protein and salt results in a lower solute excretion and as little as 300 mL of urine per day may be required. Conversely, a high-salt, high-protein intake obligates a larger urine flow and, via the thirst mechanism, a higher fluid intake. The appropriateness of a given daily urine output must therefore be related to factors such as diet, body size and fluid intake.

In diseases such as chronic renal failure or diabetes insipidus, impairment of concentrating ability requires increased volumes of urine to be passed, given the same daily solute output. An increased solute output, such as in glycosuria or increased protein catabolism following surgery or associated with sepsis, also demands increased urine volumes.

The maximum urine output depends on the ability to produce dilute urine. Intakes of 10 or even 20 L daily can be tolerated by normal humans but, given a daily solute output of 800 mOsm, require the ability to dilute to 80 and 40 mOsm/kg, respectively. Where diluting ability is impaired such as inappropriate secretion of ADH, the ability to excrete large volumes of ingested water is also impaired.

Oliguria

Oliguria, usually defined as the excretion of less than 300 mL of urine per day, may be ‘physiological’, as in patients with hypotension and hypovolaemia, where urine is maximally concentrated in an attempt to conserve water. More often, it is due to intrinsic renal disease or obstructive nephropathy.

Anuria (no urine) suggests urinary tract obstruction until proved otherwise; bladder outflow obstruction must always be considered first.

Polyuria

Polyuria is a persistent, large increase in urine output, usually associated with nocturia. It must be distinguished from frequency of micturition with the passage of small volumes of urine. Documentation of fluid intake and output may be necessary. Polyuria is the result of an excessive (hysterical) intake of water, an increased excretion of solute (as in hyperglycaemia and glycosuria), or a defective renal concentrating ability or failure of production of ADH.

These are less potent than loop diuretics. They act by blocking a sodium chloride channel in the distal convoluted tubule They cause relatively more urate retention, glucose intolerance and hypokalaemia than loop diuretics. They interfere with water excretion and may cause hyponatraemia, particularly if combined with amiloride or triamterene. This effect is clinically useful in diabetes insipidus. Thiazides reduce peripheral vascular resistance by mechanisms that are not completely understood but do not appear to depend on their diuretic action, and are widely used in the treatment of essential hypertension. They are also used extensively in mild to moderate cardiac failure. Thiazides reduce calcium excretion. This effect is useful in patients with idiopathic hypercalciuria, but may cause hypercalcaemia. Numerous agents are available, with varying half-lives but little else to choose between them. Metolazone is not dependent for its action on glomerular filtration, and therefore retains its potency in renal impairment.

Table 18-4. Types of autoimmune disease affecting endocrine organs

Organ and frequency if known	Antibody	Antigen if known	Clinical syndrome
Stimulating
Thyroid (1 in 100)	Thyroid-stimulating immunoglobulin (TSI, TSAb)	TSH receptor	Graves’ disease, neonatal thyrotoxicosis
Destructive
Thyroid (1 in 100)	Thyroid microsomal Thyroglobulin	Thyroid peroxidase enzyme (TPO)	Primary hypothyroidism (myxoedema)
Adrenal (1 in 20 000)	Adrenal cortex	21-Hydroxylase enzyme	Primary hypoadrenalism (Addison’s disease)
Pancreas (1 in 500)	Islet cell	GAD	Type 1 (insulin-dependent) diabetes
Stomach	Gastric parietal cell Intrinsic factor	Gastric parietal cell Intrinsic factor	Pernicious anaemia
Skin	Melanocyte	Melanocyte	Vitiligo
Ovary (1 in 500)	Ovary		Primary ovarian failure
Testis	Testis		Primary testicular failure
Parathyroid	Parathyroid chief cell	Parathyroid chief cell	Primary hypoparathyroidism
Pituitary	Pituitary-specific cells		Selective hypopituitarism (e.g. GH deficiency, diabetes insipidus)

Frequencies are approximate and refer to the population in Northern Europe GAD, glutamic acid dehydrogenase NB: Other related diseases include myasthenia gravis and autoimmune liver diseases

Many peripheral hormone systems are controlled by the hypothalamus and pituitary. The hypothalamus is sited at the base of the brain around the third ventricle and above the pituitary stalk, which leads down to the pituitary itself, carrying the hypophyseal-pituitary portal blood supply.

The anatomical relationships of the hypothalamus and pituitary include the optic chiasm just above the pituitary fossa; any expanding lesion from the pituitary or hypothalamus can thus produce visual field defects by pressure on the chiasm. Such upward expansion of the gland through the diaphragma sellae is termed ’suprasellar extension’. Lateral extension of pituitary lesions may involve the vascular and nervous structures in the cavernous sinus and may rarely reach the temporal lobe of the brain. The pituitary is itself encased in a bony box; any lateral, anterior or posterior expansion must cause bony erosion.
Embryologically, the anterior pituitary is formed from Rathke’s pouch (ectodermal) which meets an outpouching of the third ventricular floor which becomes the posterior pituitary.

Genetics

Population-based studies show identical twins of patients with type 2 diabetes have a greater than 50% chance of developing diabetes; the risk to non-identical twins or siblings is of the order of 25%. These observations confirm a genetic component to the disease. Type 2 diabetes is a polygenic disorder, but the genes responsible for the great majority of cases have yet to be identified. This situation seems set to change, and as genetic causes are discovered the phenotypic differences between people currently lumped together as having ‘type 2 diabetes’ will probably be explained.

The genetic causes of some rare forms of type 2 diabetes are shown in Table 19.3.

A rare variant of type 2 diabetes is referred to as ‘maturity-onset diabetes of the young’ (MODY). This is dominantly inherited. Five variants have been described. The different MODY genotypes are associated with different clinical phenotypes (Table 19.4). MODY should be considered in young people presenting with a typical family history (diabetes affecting a parent and 50% expression of the disease in the family) plus a form of early-onset diabetes which appears easy to control.

Environmental factors: early and late

Table 19-3. Rare genetic causes of type 2 diabetes

Disorder	Features
Insulin receptor mutations	Obesity, marked insulin resistance, hyperandrogenism in women, acanthosis nigricans (areas of hyperpigmented skin)
Maternally inherited diabetes and deafness (MIDD)	Mutation in mitochondrial DNA. Diabetes onset before age 40. Variable deafness, neuromuscular and cardiac problems, pigmented retinopathy
Wolfram syndrome (DIDMOAD – diabetes insipidus, diabetes mellitus, optic atrophy and deafness)	Recessively inherited. Mutation in the transmembrane gene, WFS1. Insulin-requiring diabetes and optic atrophy in the first decade. Diabetes insipidus and sensorineural deafness in the second decade progressing to multiple neurological problems. Few live beyond middle age
Severe obesity and diabetes	Alström, Bardet-Biedl and Prader-Willi syndromes. Retinitis pigmentosa, mental insufficiency and neurological disorders
Disorders of intracellular insulin signalling. All with severe insulin resistance	Leprechaunism Rabson-Mendenhall syndrome Pseudoacromegaly Partial lipodystrophy: lamin A/C gene mutation

An association has been noted between low weight at birth and at 12 months of age and glucose intolerance later in life, particularly in those who gain excess weight as adults. The concept is that poor nutrition early in life impairs beta-cell development and function, predisposing to diabetes in later life. Low birthweight has also been shown to predispose to heart disease and hypertension in later life.

Hormones work by activating cellular receptors. There are rare conditions in which hormone secretion and control are normal but the receptors are defective; thus, if androgen receptors are defective, normal levels of androgen will not produce masculinization (e.g. testicular feminization). There are also a number of rare syndromes of diabetes and insulin resistance from receptor abnormalities; other examples include nephrogenic diabetes insipidus, thyroid hormone resistance and pseudohypoparathyroidism.

The major function of the tubule is the selective reabsorption or excretion of water and various cations and anions to keep the volume and electrolyte composition of body fluid normal.

The active reabsorption from the glomerular filtrate of compounds such as glucose and amino acids also takes place. Within the normal range of blood concentrations these substances are completely reabsorbed by the proximal tubule. However, if blood levels are elevated above the normal range, the amount filtered (filtered load = GFR × plasma concentration) may exceed the maximal absorptive capacity of the tubule and the compound ’spills over’ into the urine. Examples of this occur with hyperglycaemia in diabetes mellitus or elevated plasma phenylalanine in phenylketonuria.

Conversely, inherited or acquired defects in tubular function may lead to incomplete absorption of a normal filtered load, with loss of the compound in the urine (a lowered ‘renal threshold’). This is seen in renal glycosuria, in which there is a genetically determined defect in tubular reabsorption of glucose. It is diagnosed by demonstrating glycosuria in the presence of normal blood glucose levels. Inherited or acquired defects in the tubular reabsorption of amino acids, phosphate, sodium, potassium and calcium also occur, either singly or in combination. Examples include cystinuria and the Fanconi syndrome. Tubular defects in the reabsorption of water result in nephrogenic diabetes insipidus. Under normal circumstances, antidiuretic hormone induces an increase in the permeability of water in the collecting ducts by attachment to receptors with subsequent activation of adenyl cyclase. This then activates a protein kinase, which induces preformed cytoplasmic vesicles containing water channels (termed ‘aquaporins’) to move to and insert into the tubular luminal membrane. This allows water entry into tubular cells down a favourable osmotic gradient. Water then crosses the basolateral membrane and enters the bloodstream. When the effect of ADH wears off, water channels return to the cell cytoplasm.