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Fast Facts: Renal Disorders
By Ajay Singh, Jeremy Levy, Charles Pusey
Health Press LimitedCopyright © 2013 Ajay Singh, Jeremy Levy and Charles Pusey
All rights reserved.
1 Proteinuria, hematuria and renal investigations
The clinical symptoms of renal disease often do not become apparent until kidney failure is advanced. Screening for renal disease is, therefore, particularly important, because it may enable abnormalities to be detected in time for effective treatment to be started. Bedside urine analysis is an essential part of any clinical examination. Urine testing may also be part of a routine medical examination for insurance or employment purposes, or when a person registers with a new primary care physician.
Urinary abnormalities will be found in most patients with renal disease, particularly positive dipstick tests for blood or protein, or the presence of cells, casts, crystals or organisms on urine microscopy. Clinically, severe hematuria may be reported if the patient has red or dark urine, which, if it occurs at the end of the urinary stream, suggests bleeding from the lower urinary tract. Heavy proteinuria can produce unusually frothy urine, but this is not often reported spontaneously.
Proteinuria may originate from anywhere within the urinary tract. High levels of protein in the urine (> 3 g/day) generally reflect the presence of albuminuria and point to a glomerular process (glomerular albuminuria). Proteinuria due to tubular damage is usually only low level (< 1 g/day) and involves proteins of a lower molecular weight, such as β2-microglobulin. Overflow proteinuria may result from the filtration of abnormal amounts of low-molecular-weight proteins through the glomeruli, such as monoclonal light chains in myeloma.
One of the most common causes of low-level proteinuria is inflammation in the lower urinary tract, which is usually caused by urinary tract infection (UTI) (Table 1.1). Women are at increased risk of UTI because of renal tract dilatation leading to urinary stasis, and this should be treated promptly according to bacterial sensitivity.
Urinary protein excretion increases during pregnancy, but never to more than 300 mg/day, so overt proteinuria is not physiological.
Dipstick testing of the urine is designed to detect albumin and is insensitive to other proteins; it will not, therefore, generally detect light chains in myeloma. Dipsticks may detect albumin concentrations as low as 20–30 mg/dL, and are often calibrated on a scale of 0–3+, which provides a semiquantitative estimate of protein concentration. Highly concentrated urine may produce false-positive results, while dilute urine may produce false-negative results.
Timed and spot urine samples. Proteinuria may be formally quantified using timed urine samples, usually a 24-hour specimen. The upper end of the normal range is 150 mg/24 hours. As collecting 24-hour urine samples is difficult and unreliable, measurement of the albumin:creatinine or protein:creatinine ratio from a spot urine sample is increasingly being used, because it correlates well with 24-hour albumin or protein excretion. In conventional units an albumin:creatinine ratio of 1 equates to 1 g/24 hours of albumin excretion, and in SI units a ratio of 120 mg/mmol equates to 1 g/24 hours albuminuria. Albuminuria of more than 1 g/24 hours, in the absence of an obvious cause, should prompt further investigation, which might include kidney biopsy. Albuminuria of more than 3.5 g/24 hours is commonly associated with nephrotic syndrome (see Chapter 6).
Whereas significant albuminuria often indicates intrinsic renal parenchymal disease, hematuria may be caused by lesions throughout the urinary tract, particularly infection or malignancy (Table 1.2).
Several clinical algorithms have been proposed for the investigation of hematuria (Figure 1.1). In general, once UTI has been excluded, then hematuria without significant proteinuria should prompt a search for malignancy in older patients, while hematuria with proteinuria requires a search for a glomerular cause.
Dipstick testing of the urine provides a semiquantitative estimate of the degree of hematuria, but hemoglobin (in hemolysis) and myoglobin (in rhabdomyolysis) may also produce positive tests.
Urine microscopy should always be performed to detect red blood cells. Misshapen or dysmorphic red cells, detected by an experienced observer using phase-contrast microscopy, suggest glomerular hematuria. The presence of red-cell or granular casts in the urine is a more reliable way of identifying a renal source of the hematuria, as opposed to a ureteric or bladder source. Red-cell casts, in particular, generally indicate active glomerulonephritis. In most cases, significant albuminuria in addition to hematuria is seen in glomerular disease.
Kidney function tests
Kidney function is assessed most simply by measuring the serum concentrations of metabolites excreted by the kidney, most commonly urea and creatinine. The serum urea concentration is influenced more by dietary intake of protein, the state of hydration, liver function and various drugs. Serum creatinine is, therefore, a more reliable measure, but is related directly to muscle mass; thus, a small elderly woman may have a normal serum creatinine with a markedly reduced glomerular filtration rate (GFR). Changes in serum creatinine (especially a rise) can be a useful guide to deteriorating kidney function; absolute values do not correlate well with GFR.
Serum creatinine in pregnancy. During a normal pregnancy in a woman with normal kidneys, renal plasma flow and GFR both increase (by ≥ 50%), leading to a reduction in the mean serum creatinine during the first and second trimesters from 73 µmol/L (0.8 mg/dL) to 51 µmol/L (0.5 mg/dL). No fall in serum creatinine during pregnancy can indicate significant renal functional impairment.
Women with only mild renal impairment from any cause will usually have a successful pregnancy outcome, and will seldom incur any additional kidney damage as a result of the pregnancy. Some women, however, will have complications during the pregnancy itself, especially hypertension. Women with more severe renal impairment are more likely to suffer hypertension, pre-eclampsia or premature labor, and to have a small baby, miscarriage or irreversible decline in renal function in the long term (Table 1.3).
Measurement of glomerular filtration rate. Creatinine clearance, which assesses creatinine excretion over 24 hours in relation to the serum creatinine level, is often used as a measure of GFR. However, it can overestimate GFR, since up to 25% of urinary creatinine may come from tubular secretion, and 24-hour urine collections are unreliable. It is also important to realize that a significant rise in serum creatinine does not occur until the GFR is reduced to about 50% of normal.
A number of formulas have been described to estimate GFR based on the serum creatinine and characteristics of the patient (e.g. age, weight, sex, race). The three best-known formulas are the Cockcroft – Gault equation, the Modification of Diet in Renal Disease study (MDRD) equation and the chronic kidney disease (CKD)-Epi formula (Table 1.4). The MDRD and CKD-Epi formulas are more precise measures of kidney function and have been widely adopted by hospital-based and commercial laboratories. Newer methods, which may find their way into clinical practice, include iohexol clearance and serum cystatin concentration.
Other blood tests
The diagnosis of many renal diseases is assisted by specific blood tests, particularly in glomerular disease. These tests include measurement of blood glucose for diabetes mellitus, and serum electrophoresis for myeloma and other B-cell dyscrasias. It should be noted that in pregnancy, glycosuria is common and does not usually indicate diabetes or even impaired glucose tolerance.
A range of immunologic tests (e.g. anti-DNA antibodies and complement levels in systemic lupus erythematosus [SLE]) is helpful in the diagnosis of glomerulonephritis.
The investigation of renal disease should always include some form of kidney imaging, which can provide both anatomic and functional information (Table 1.5). In general, it is appropriate to start with cheaper, non-invasive methods of imaging, such as ultrasonography, and use more invasive and expensive methods selectively.
Percutaneous kidney biopsy can provide a definitive histological diagnosis of glomerular or interstitial disease. It is particularly helpful in patients with severe proteinuria, hematuria that is not due to disease of the lower urinary tract, and acute kidney failure thought to be caused by intrinsic renal disease (rather than prerenal disease, obstruction or acute tubular necrosis [ATN]). The main diseases diagnosed by kidney biopsy include glomerulonephritis, glomerular disorders such as amyloid and diabetes, and interstitial nephritis. Opinions differ as to when a kidney biopsy is indicated, but the potential benefit in terms of treatment usually outweighs the risk involved (significant bleeding in about 1 in 1000 cases). If both kidneys are small, as in chronic glomerulonephritis, then the risk generally outweighs the benefit. In the presence of microscopic hematuria alone, or albuminuria of less than 1 g/24 hours, kidney biopsy is often not indicated since it is unlikely that a specific treatment would be required. However, higher levels of albuminuria or the combination of albuminuria and hematuria (particularly with casts) are indications for biopsy, because a number of causes of glomerulonephritis (see Chapter 6) and interstitial nephritis are now amenable to therapy.
Key points – proteinuria, hematuria and renal investigations
Proteinuria and hematuria should always be investigated.
Proteinuria should be quantified by means of an albumin:creatinine ratio or 24-hour collections, since the result will guide management.
Hematuria may have a medical or surgical cause, and this should be assessed before starting investigations.
Serum creatinine alone is an unreliable guide to kidney function; an assessment of glomerular filtration rate is more useful.
No fall in serum creatinine during pregnancy can indicate significant renal functional impairment.CHAPTER 2
Electrolyte disturbances and acid–base disorders
Plasma electrolyte and acid–base disturbances are common clinical problems. Perturbations may result in morbidity and mortality, particularly in the elderly and young children, and in those with other comorbid states, such as sepsis, coronary heart disease and heart failure.
Sodium and water disorders
Regulation of the plasma sodium concentration by the body relies on:
the balance between intake and excretion of both sodium and water
the function of sensors of osmolality and extracellular fluid volume (e.g. hypothalamic osmoreceptors, carotid baroreceptors)
effector mechanisms such as antidiuretic hormone (ADH) and aldosterone.
Hyponatremia. Mild hyponatremia (plasma sodium 130–135 mmol/L) is common and affects approximately 15–20% of hospitalized patients. More severe hyponatremia (plasma sodium < 130 mmol/L) is rarer and occurs in less than 1–4% of patients (Table 2.1).
Clinical features. Hyponatremia in conjunction with hypo-osmolality (as is common) causes clinical problems, especially when the plasma sodium concentration falls below 120 mmol/L, and patients usually complain of nausea and malaise. When the plasma sodium reaches 115 mmol/L, patients may complain of headache and become delirious. Seizures and coma are common when the plasma sodium falls below 110 mmol/L. These neurological complications reflect water shifting osmotically into the brain. Premenopausal women and children seem to be particularly susceptible to symptomatic hyponatremia for reasons that are unclear.
Diagnosis of hypo-osmolar hyponatremia requires careful assessment of extracellular volume and measurement of urinary sodium to determine whether total body sodium is low, normal or high. Adrenal failure, kidney failure and hypothyroidism must always be excluded.
The history and physical examination should focus on identifying any underlying cause of the hyponatremia, such as a malignancy causing a syndrome of inappropriate secretion of ADH (SIADH). Investigations should confirm hypo-osmolality, and demonstrate either appropriate or inappropriate secretion of ADH by comparing urine osmolality with plasma osmolality. Urine osmolality below 100 mOsmol/kg (i.e. very dilute urine) indicates that ADH secretion is completely and appropriately suppressed. Urine osmolality above 100 mOsmol/kg, and particularly in the range of 200–600 mOsmol/kg, usually indicates inappropriate secretion of ADH. A diagnosis of SIADH can be easily made based on specific diagnostic criteria (Tables 2.2 and 2.3).
Treatment. Particular care must be taken when correcting hyponatremia in premenopausal women, children and those with very low plasma sodium levels (< 120 mmol/L). Severe symptomatic hyponatremia may require treatment with hypertonic (3%) sodium chloride. The sodium concentration should be monitored frequently. The optimal correction rate should be 0.5–1 mmol/L/hour, with a total correction of plasma sodium of 10–12 mmol over the first 24 hours. A more aggressive correction rate of 2.0 mmol/L/hour may be considered in patients with seizures or severe neurological symptoms attributable to hyponatremia. However, an overly rapid correction rate carries the risk of precipitating central pontine myelinolysis.
Vasopressin receptor antagonists are a new class of agents developed for selective use in the treatment of hyponatremia, especially in patients with SIADH, congestive heart failure or liver cirrhosis. These 'vaptan' drugs (conivaptan and tolvaptan) have been specifically developed to inhibit the action of vasopressin on its receptors (V1A, V1B and V2). However, their precise clinical role has yet to be elucidated.
Hypernatremia (plasma sodium concentration ≥ 145 mmol/L) is common among hospitalized patients, particularly the elderly. Hypernatremia is also often seen in individuals who have lost their perception of thirst (e.g. as a result of a neurological disability) or who have been denied free access to water (Table 2.4). Hypernatremia always reflects a state of hyperosmolality. Since sodium is usually confined to the extracellular space, an actual or relative increase in sodium (compared with water) results in the movement of water out of cells driven by osmosis. Cellular dehydration follows, and shrinkage of brain cells causes most of the clinical manifestations.
Clinical features. Mild hypernatremia (plasma sodium 150–155 mmol/L) is usually associated with nausea, vomiting, irritability and a depressed sensorium. More severe hypernatremia (plasma sodium > 160 mmol/L) may result in seizures, focal neurological defects, stupor and coma. In children, muscle spasticity, fever and labored respiration may be prominent.
The speed with which hypernatremia develops also appears to modulate the severity of the clinical features. Severe, acute hypernatremia may result in irreversible vascular damage, particularly in children. Acute hypernatremia is associated with a mortality of 40%, whereas chronic hypernatremia is associated with a mortality of 10%.
Diagnosis. The differential diagnosis of hypernatremia requires an initial assessment of extracellular volume (Figure 2.1). The history and physical examination should focus on identifying any underlying cause.
Treatment. Hypovolemic hypernatremic patients can be managed by administration of isotonic saline. Patients with hypervolemic hypernatremia are treated with diuretics and free water given orally or parenterally (5% dextrose). Euvolemic hypernatremic patients can be treated with free water orally or 5% dextrose infusion. Too rapid correction is associated with brain edema, caused by the rapid movement of water into the brain, and seizures. In most circumstances, a correction rate of about 0.5 mmol/L/hour should suffice.
Potassium is predominantly found intracellularly. Excretion of potassium is largely achieved by the kidneys, but also to a lesser extent by the colon. Transcellular shifts of potassium between the intracellular and extracellular compartments also occur.
Hypokalemia (plasma potassium ≤ 3.5 mmol/L) is one of the most common electrolyte abnormalities in hospitalized patients (Table 2.5).
Clinical features largely reflect alterations in membrane polarization, especially in cardiac and skeletal muscle. Changes in the electrocardiogram (ECG) include flattening of the T wave, depression of ST segments and a prominent U wave (Figure 2.2). Hypokalemia also increases predisposition to arrhythmias, particularly in patients with digoxin toxicity or those with acute coronary syndromes. The effects of hypokalemia on skeletal muscle range from weakness, tetany and fatigue to rhabdomyolosis. Severe hypokalemia (plasma potassium < 2.0 mmol/L) can lead to paralysis. Chronic hypokalemia can also cause a reduction in glomerular filtration rate (GFR), interstitial scarring and tubular atrophy.
Excerpted from Fast Facts: Renal Disorders by Ajay Singh, Jeremy Levy, Charles Pusey. Copyright © 2013 Ajay Singh, Jeremy Levy and Charles Pusey. Excerpted by permission of Health Press Limited.
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Table of Contents
Abbreviations and glossary,
1 Proteinuria, hematuria and renal investigations,
2 Electrolyte disturbances and acid–base disorders,
3 Acute kidney injury,
4 Chronic kidney disease,
5 Hypertension and diabetic nephropathy,
7 Systemic disease,
8 Inherited kidney disease,
9 Urinary tract infection,
10 Kidney stones,
11 Urinary tract obstruction and tumors,
12 Renal replacement therapy and transplantation,