Routine Stix testing of urine for blood, protein and sugar is obligatory in all patients suspected of having renal disease.

Blood

Haematuria may be overt, with bloody urine, or microscopic and found only on chemical testing. Currently used Stix tests for blood are very sensitive, being positive if two or more red cells are visible under the high-power field of a light microscope. Indeed, the test is too sensitive, sometimes giving positive results in normal individuals. A further disadvantage is that Stix testing cannot distinguish between blood and free haemoglobin. A positive Stix test must always be followed by microscopy of fresh urine to confirm the presence of red cells and so exclude the relatively rare conditions of haemoglobinuria or myoglobinuria. In females with a positive Stix test result for blood, it is essential to enquire whether the patient is menstruating. Bleeding may come from any site within the urinary tract:

• Overt bleeding from the urethra is suggested when blood is seen at the start of voiding and then the urine becomes clear.
• Blood diffusely present throughout the urine comes from the bladder or above.
• Blood only at the end of micturition suggests bleeding from the prostate or bladder base.

Careful urine microscopy is mandatory as the presence of red-cell casts is diagnostic of bleeding from the kidney itself, most often due to glomerulonephritis. In the absence of red-cell casts, further investigations, such as urine cytology, renal imaging and cystoscopy, are required to define the site of bleeding. Renal biopsy may be required.

Protein

Proteinuria is one of the most common signs of renal disease. Detection is primarily by Stix testing. Most reagent strips can detect a concentration of 100-200 mg/L or more in urine. They react primarily with albumin and are relatively insensitive to globulin and Bence Jones proteins.

If proteinuria is confirmed on repeated Stix testing, protein excretion in 24-hour urine collections should be measured (but see below). Healthy adults excrete up to 30 mg daily of albumin. Pyrexia, exercise and adoption of the upright posture all increase urinary protein output. Proteinuria, while occasionally benign, always requires further investigation. In some glomerular disease the protein leak is selective (e.g. minimal change) and urine electrophoresis can demonstrate the relative leaks, e.g. IgA or albumin.

Postural proteinuria.

This term is used to refer to proteinuria present on dipstick testing which becomes undetectable after a period of hours lying flat. Typically, a negative dipstick result is obtained on the first urine passed on rising in the morning, whereas subsequent specimens give a positive result. This is regarded even for insurance purposes as a benign condition.

Microalbuminuria

The term microalbuminuria is an unfortunate one since the albumin referred to is of normal molecular size and weight. Normal individuals excrete less than 20 μg of albumin per minute (30 mg in 24 hours). Dipsticks, however, detect albumin only in a concentration above 200 mg/L (300 mg per 24 hours if urine volume is normal). An increase in albumin excretion between these two levels – so-called microalbuminuria – is now known to be an early indicator of diabetic glomerular disease. It is widely used as a predictor of the development of nephropathy in diabetics and may be extended to other conditions.

Timed 24-hour urinary excretion rates provide the most precise measure of microalbuminuria. However, in clinical practice it is more convenient to test for microalbuminuria using random urine samples in which albumin concentration is related to urinary creatinine concentration. Generally an albumin : creatinine ratio of 2.5 to 20 corresponds to albuminuria of 30-300 mg daily respectively. Kits are available to test for microalbuminuria.

Glucose

Renal glycosuria is uncommon, so that a positive test for glucose always requires exclusion of diabetes mellitus.

Bacteriuria

Dipsticks are available for testing for bacteriuria based on the detection of nitrite produced from the reduction of urinary nitrate by bacteria and also for the detection of leucocyte esterase, an enzyme specific for neutrophils. Although each test on its own has limitations, a positive reaction with both tests has a high predictive value for urinary tract infection.

Obese people are at a higher risk of early death, mostly because of diabetes, coronary heart disease, cerebrovascular disease and otehr cardiovascular deseases. The higher the level of obesity is the greater morbidity and mortality rates are. For example, men who are 10% overweight have a 13% increased risk of death, while the increase in mortality for those 20% overweight is 25%. The rise is less in women, and in men over 65 obesity is not an independent risk factor. Weight reduction reduces this mortality and therefore should be strongly encouraged. The benefits are probably greater in more obese subjects (Table 5.14).

Clinical features

Most patients recognize their own problems, although often they are unaware of the main foods that cause obesity. Many symptoms are related to psychological problems or social pressures, such as the woman who cannot find fashionable clothes to wear.

Box 5.4 Ranges of body mass index (BMI) used to classify degrees of overweight and associated risk of co-morbidities

WHO classification	BMI (kg/m2)	Risk of co-morbidities
Overweight	25-30	Mildly increased
Obese	> 30
Class I	30-35	Moderate
Class II	35-40	Severe
Class III	> 40	Very severe

Table 5-14. Potential benefits that may result from the loss of 10 kg in patients who are initially 100 kg and suffer from co-morbidities

Mortality	20-25% fall in total mortality
	30-40% fall in diabetes-related deaths
	40-50% fall in obesity-related cancer deaths
Blood pressure	Fall of about 10 mmHg (systolic and diastolic)
Diabetes	Reduces risk of developing diabetes by > 50%
	Fall of 30-50% in fasting blood glucose
	Fall of 15% in HbA1c
Serum lipids	Fall of 10% in total cholesterol
	Fall of 15% in LDL cholesterol
	Fall of 30% in triglycerides
	Increase of 8% in HDL cholesterol

The degree of obesity can be assessed by comparison with tables of ideal weight for height, from the BMI (Box 5.4), and by measuring skinfold thickness. The latter should be measured over the middle of the triceps muscle; normal values are 20 mm in a man and 30 mm in a woman. A central distribution of body fat (a waist/hip circumference ratio of > 1.0 in men and > 0.9 in women) is associated with a higher risk of morbidity and mortality than is a more peripheral distribution of body fat (waist/hip ratio < 0.85 in men and < 0.75 in women). This is because fat located centrally, especially inside the abdomen, is more sensitive to lipolytic stimuli, with the result that the abnormalities in circulating lipids are more severe.

Table 5.15 shows the conditions and complications that are associated with obesity.

Table 5-15. Conditions and complications associated with obesity

Psychological	Hypertension
Osteoarthritis of knees and hips	Breathlessness
Varicose veins	Ischaemic heart disease
Hiatus hernia	Stroke
Gallstones	Diabetes mellitus (type 2)
Postoperative problems	Hyperlipidaemia
Back strain	Menstrual abnormalities
Accident proneness Obstructive sleep apnoea	Increased morbidity and mortality
	Increased cancer risk
	Heart failure

The metabolic syndrome (syndrome X) is a cluster of cardiovascular risk factors associated with excess fat. A commonly used definition (NCEP ATP III) defines the syndrome as the coexistence of three or more of the following five abnormalities: high blood pressure (>130/85 mmHg); elevated serum triglycerides (>1.5 g/L); serum LDL cholesterol > 0.4 g/L (men) or > 0.5 g/L (women); increased abdominal circumference > 102 cm (men) or > 88 cm (women); and impaired fasting glucose (> 1.1 g/L or > 6.1 mmol/L). It is estimated that it affects up to about a quarter of adults in the USA.

The relationship between cardiovascular disease (hypertension or ischaemic heart disease), hyperlipidaemia, smoking, physical exercise and obesity is complex. Difficulties arise in interpreting mortality figures because of the number of factors involved. Many studies do not differentiate between the types of physical exercise taken or take into account the cuff-size artefact in the measurement of blood pressure (an artefact will occur if a large cuff is not used in patients with a large arm). Nevertheless, obesity almost certainly plays a part in all of these diseases and should be treated. An exception is that stopping smoking, even if accompanied by weight gain, is more beneficial than any of the other factors. Physical fitness is also helpful, and there is some evidence to suggest that a fit obese person may have similar or even lower cardiovascular risk than a leaner unfit person.

Basal metabolic rate (BMR).

BMR in obese subjects is higher than in lean subjects, which is not surprising since obesity is associated with an increase in lean body mass.

Physical activity.

Obese patients tend to expend more energy during physical activity as they have a larger mass to move. On the other hand, many obese patients decrease their amount of physical activity. The energy expended on walking at 3 miles per hour is only 15.5 kJ/min (3.7 kcal/min) and therefore increasing exercise plays only a small part in losing weight. Nevertheless, because increased body fat develops insidiously over many years, any change in energy balance is helpful.

Thermogenesis

About 10% of ingested energy is dissipated as heat and is unconnected with physical activity. This dietary induced thermogenesis has been reported to be lower in obese and post-obese subjects than in lean subjects.

This would tend to favour energy deposition in obesity and those predisposed to obesity. However, other workers have found no difference in dietary induced thermogenesis between lean and obese subjects.

Brown adipose tissue in animals, when stimulated by cold or food, dissipates the energy derived from ingested food into heat. This can be a major component of overall energy balance in small mammals. However, the importance of brown adipose tissue thermogenesis in adult humans is likely to be very small, and of doubtful clinical significance. β3-Adrenergic receptors are the principal receptors mediating catecholamine-stimulated lipolysis in brown adipose tissue and to a lesser extent at other sites. Drugs with β3-adrenergic activities have been developed, but side-effects have limited their use.

Urine specific gravity is a measure of the weight of dissolved particles in urine, whereas urine osmolality reflects the number of such particles. Usually the relationship between the two is close. An exception exists when a relatively small number of relatively large particles are present in urine, such as in multiple myeloma. Measurement of urine specific gravity or osmolality is required only in limited circumstances, such as the differential diagnosis of oliguric renal failure or the investigation of polyuria or inappropriate ADH secretion. Specific gravity is usually fixed at 1.010 in chronic failure or acute tubular necrosis as compared to prerenal acute renal failure where specific gravity is very high close to 1.025.

Urinary pH

Measurement of urinary pH is unnecessary except in the investigation and treatment of renal tubular acidosis

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.

A 32-amino-acid atrial natriuretic-like peptide (ANP-like peptide), putatively synthesized by connecting and collecting ducts in the kidney, has been isolated from human urine. Its natriuretic potency equals or exceeds that of atrial ANP by increasing cGMP production in the collecting duct. It is postulated that cardiac ANP is primarily a regulator of the cardiovascular system through its vascular effects and that renal natriuretic peptide participates in the intrarenal regulation of sodium and chloride transport.

Nitric oxide and the kidney

Nitric oxide, a molecular gas, is formed by the action of three isoforms of nitric oxide synthase (NOS). All three enzymes, neuronal (nNOS or NOS1), inducible (iNOS or NOS2) and endothelial (eNOS or NOS3), which are cytochrome P450-like proteins, facilitate the addition of the guanidine nitrogen of the amino acid arginine to molecular oxygen, producing nitric oxide and water. In general nNOS and eNOS are constitutively active, producing low levels of nitric oxide dependent upon intracellular calcium elevation. In contrast, the transcriptional regulation of iNOS can be markedly induced, particularly by inflammatory cytokines, resulting in extremely large amounts of nitric oxide. The most recognized cellular target of nitric oxide is soluble guanylate cyclase. The stimulation of this enzyme enhances the synthesis of cyclic GMP from GTP. All three isoforms, are expressed in the kidney with eNOS in the vascular compartment, nNOS mainly in the macula densa and inner medullary collecting duct and iNOS in several tubule segments. Nitric oxide mediates the following physiological actions in the kidney:

• regulation of renal haemodynamics
• natriuresis by inhibiting Na⁺/K⁺-ATPase and Na⁺/H⁺ antiporter and antagonizing ADH
• modulation of tubuloglomerular feedback so that the composition of tubular fluid delivered to the macula densa changes the filtration rate of the associated glomerulus.

Protein and polypeptide metabolism

The kidney is a major site for the catabolism of many small-molecular-weight proteins and polypeptides, including many hormones such as insulin, PTH and calcitonin by endocytosis carried out by megalin-cubilin complex in the brush border of proximal tubular cells. In renal failure the metabolic clearance of these substances is reduced and their half-life is prolonged. This accounts, for example, for the reduced insulin requirements of diabetic patients as their renal function declines.

Box 2.4 Common causes of infection in immunocompromised patients

Deficiency	Causes	Organisms
Neutropenia	Chemotherapy	Escherichia coli
	Myeloablative therapy	Klebsiella pneumoniae
	Immunosuppressant drugs	Staphylococcus aureus
		Staph. epidermidis
		Aspergillus spp.
		Candida spp.
Cellular immune defects	HIV infection	Respiratory syncytial virus
	Lymphoma	Cytomegalovirus
	Myeloablative therapy	Epstein-Barr virus
	Congenital syndromes	Herpes simplex and zoster
		Salmonella spp.
		Mycobacterium spp. (esp. M. avium-intracellulare)
		Cryptococcus neoformans
		Candida spp.
		Cryptosporidium parvum
		Pneumocystis carinii
		Toxoplasma gondii
Humoral immune deficiencies	Congenital syndromes	Haemophilus influenzae
	Chronic lymphocytic leukaemia	Streptococcus pneumoniae
	Corticosteroids	Enteroviruses
Terminal complement deficiencies (C5-C9)	Congenital syndromes	Neisseria meningitidis N. gonorrhoeae
Splenectomy	Surgery	Strep. pneumoniae
	Trauma	N. meningitidis
		H. influenzae
		Malaria

Relatively few patients with infectious disease present a serious risk to healthcare workers (HCW) and other contacts. However, the appearance of diseases like severe acute respiratory syndrome (SARS), the occasional importation of zoonoses like Lassa fever, and concerns about the bioterrorist use of agents such as smallpox mean that there is still the potential for unexpected outbreaks of life-threatening disease. During the world-wide SARS outbreak in 2003, scrupulous infection control procedures reduced spread of infection. However, in the ‘inter-epidemic’ period it is difficult to maintain the same level of ‘alert’. HCWs should remain vigilant because the early symptoms of many of these diseases are non-specific.

Advances in medical treatment over the past three decades have led to a huge increase in the number of patients living with immunodeficiency states. Cancer chemotherapy, the use of immunosuppressive drugs and the world-wide AIDS epidemic have all contributed to this. The presentation may be very atypical in the immunocompromised patient with few, if any, localizing signs or symptoms. Infection can be due to organisms which are not usually pathogenic, including environmental bacteria and fungi. The normal physiological responses to infection (e.g. fever, neutrophilia) may be diminished or absent. The onset of symptoms may be sudden, and the course of the illness fulminant. A high index of suspicion for infections in people who are known to be immunosuppressed is required. These patients should usually be given early and aggressive antibiotic therapy without waiting for the results of investigations. Samples for culture should be sent before starting treatment, but therapy should not be delayed if this proves difficult. The choice of antibiotics should be guided by the likely causative organisms: these are shown in Box 2.4.

Overseas travellers

A detailed travel itinerary, including any flight stopovers should be taken from anyone who is unwell after arriving in this country from abroad. Previous travel should also be covered as some infections may be chronic or recurrent. It is necessary to find out not just which countries were visited but also the type of environment: a stay in a remote jungle village carries different health risks from a holiday in an air-conditioned coastal holiday resort. Food and water consumption, bathing and swimming habits, animal and insect contact, and contact with human illness all need to be recorded. Enquiry should be made about sexual contacts, drug use and medical treatment (especially parenteral) while abroad. In some parts of the world over 90% of professional sex workers are HIV positive, and hepatitis B and C are very common in parts of Africa and Asia. In addition to the investigations described in the previous section, special tests may be needed depending on the epidemiological risks and clinical signs, and malaria films are mandatory in anyone who is unwell after being in a malarious area. Some of the more common causes of a febrile illness in returning travellers to the UK are listed in Table 2.8.

Table 2-8. Causes of febrile illness in travellers returning to the UK

Tropical countries

Malaria

Schistosomiasis

Dengue

Tick typhus

Economically less-developed countries

Typhoid

Tuberculosis

Dysentery

Hepatitis A

Amoebiasis

Specific geographical areas (see text)

Histoplasmosis

Brucellosis

World-wide

Pneumonia URTI

UTI

Traveller’s diarrhoea

Viral infection

URTI, upper respiratory tract infection; UTI, urinary tract infection

These can be divided into two types:

• tests that detect viral or bacterial antigen, using a polyvalent antiserum or a monoclonal antibody
• tests that detect serological response to infection.

These investigations are valuable in the identification of organisms that are difficult to culture, especially viruses and fungi, and can also be helpful when antibiotics have been administered before samples were obtained. However, care is needed in the interpretation of serological tests. Elevated antibody titres on a single occasion (especially of IgG) are rarely diagnostic, and in some infections it may be difficult to distinguish between old and acute infection. Paired serological tests a few weeks apart, or specific assays for IgM (indicating an acute infection) are more helpful.

Nucleic acid detection

Specific genes from many pathogenic microorganisms have been cloned and sequenced. Nucleic acid probes can be designed to detect these sequences, identifying pathogen-specific nucleic acid in body fluids or tissue. The utility of this approach has been greatly enhanced by the development of amplification techniques such as the polymerase chain reaction (PCR), which increases the amount of target DNA/RNA in the sample to be tested. However PCR assays for many organisms are still in the process of development.

Treatment

Many infections, particularly those caused by viruses, are self-limiting and require no treatment. The mainstay of treatment for most infectious diseases is antimicrobial chemotherapy. The choice of antibiotic should be governed by:

• the clinical state of the patient
• the likely cause of the infection.

Serious infections may require supportive therapy in addition to antibiotics. It is always preferable to have a definite microbial diagnosis before starting treatment, so that an antibiotic with the most appropriate spectrum of activity and site of action can be used. However, some patients are too unwell to wait for results (which in the case of culture may take days). In diseases such as meningitis or septicaemia delay in treatment may be fatal and therapy must be started on an empirical basis. Appropriate samples for culture should be taken before the first dose of antibiotic, and an antibiotic regimen chosen on the basis of the most likely causative organisms. Usually patients are less unwell, and specific therapy can be deferred pending results.

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