Category Archives: Renal disease

Renal failure

The term ‘renal failure’ means failure of renal excretory function due to depression of GFR. This is accompanied to a variable extent by failure of erythropoietin production , vitamin D hydroxylation, regulation of acid-base balance, and regulation of salt and water balance and blood pressure .
‘Acute renal failure’ means a decrease in renal function lasting days or weeks, whereas ‘chronic renal failure’ means renal failure lasting months or years. Acute renal failure is more likely than chronic renal failure to be reversible, depending on the cause. Chronic renal failure is often progressive, whatever the cause. Acute renal failure may cause sudden, life-threatening biochemical disturbances and is a medical emergency. The distinction between acute and chronic renal failure is therefore important in the initial management of a patient presenting with uraemia.
Clinical features are often non-specific.

ACUTE RENAL FAILURE

This may be (i) pre renal, (ii) renal or (iii) postrenal. This distinction is useful in generating a logical approach to a patient with renal disease, but it is important to remember that more than one category of cause may be present in an individual patient. Other causes of altered serum urea and creatinine concentrations are shown.

Prerenal

Failure of perfusion with blood of the kidneys is present in pre-renal failure. This results either from hypovolaemia and hypotension or from impaired cardiac pump efficiency or both. Normally the kidney is able to maintain glomerular filtration close to normal despite wide variations in renal perfusion pressure and volumestatus-so- called ‘autoregulation’. Maintenance of a normal GFR in the face of decreased systemic pressure depends on the intrarenal production of prostaglandins and angiotensin II. Increased sodium and water reabsorption in response to sympathetic stimulation, aldosterone and vasopressin lead to decreased urine flow which results in decreased urea clearance, even when GFR is preserved. This leads to an elevated blood urea and urea: creatinine ratio. Further depression of renal perfusion leads to a drop in glomerular filtration, termed prerenal failure.

Causes of altered serum urea and creatinine concentrations other than altered renal function.

Causes of altered serum urea and creatinine
concentrations other than altered renal function.

Drugs which impair renal autoregulation, such as ACE inhibitors and NSAIDs, increase the risk of prerenal failure in hypovolaemia.
By definition, renal function in prerenal failure returns to normal completely once normal renal perfusion has been restored.
A number of criteria have been proposed to differentiate between prerenal and intrinsic renal causes of renal failure; laboratory tests however are no substitute for careful clinical assessment. If hypovolaemia or hypotension are present, these should be corrected whether the renal failure is prerenal or intrinsic in origin; failure to do so may prolong the course of intrinsic renal disease. The criteria suggested rely on the fact that renal tubular function is intact in prerenal states; in particular, sodium and water reabsorption, both of which should be maximal in hypovolaemia.

URINE SPECIFIC GRAVITY AND URINE OSMOLALITY  are easily obtained parameters of concentrating ability but are unreliable in the presence of glycosuria or other osmotically active substances in the urine. Interpretation of these measurements also depends critically on the clinical context. Dilute urine may be a perfectly normal response to water overload, for instance. URINE SODIUM is low if there is avid tubular reabsorption, but may be increased by diuretics or dopamine. FRACTIONAL EXCRETION OF SODIUM (FENa), the ratio of sodium clearance to creatinine clearance, increases the reliability of this index but may remain low in some ‘intrinsic’ renal diseases, including contrast nephropathy and myoglobinuria.

Criteria for distinction between prerenal and intrinsic causes of renal dysfunction.

Criteria for distinction between prerenal and
intrinsic causes of renal dysfunction.

Renal

Given that normal renal function requires arterial and venous blood supply, normal glomeruli and normal tubules, it is not surprising that a large range of diseases may cause acute renal failure.

Acute tubular necrosis

This is a common and important cause of acute renal failure, particularly in hospital practice, and can be caused by a number of different insults to the renal circulation. The renal medulla is normally relatively hypoxic, despite the high fraction of the cardiac output which is delivered to the kidneys, due to countercurrent exchange of oxygen; this increases its susceptibility to ischaemic damage. In early hypoperfusion, blood flow is  diverted from the cortex to medulla, resulting in a moderate decrease in GFR but protecting the hypoxic medulla from ischaemic injury. More severe hypoperfusion overcomes this protective mechanism and tubular damage results. Ischaemic tubular damage results in a further fall in glomerular filtration by a number of interrelated mechanisms:
GLOMERULAR CONTRACTION, reducing surface area available for filtration
REFLEX AFFERENT ARTERIOLAR SPASM ‘BACKLEAK’ OF FILTRATE in the proximal tubule due to loss of function of the tubular cells
OBSTRUCTION OF THE TUBULE by debris shed from ischaemic tubular cells.

Causes of acute renal failure.

Causes of acute renal failure.

Some causes of acute tubular necrosis.

Some causes of acute tubular necrosis.

The clinical course of acute renal failure due to acute tubular necrosis is variable depending on how severe or prolonged the insult is. Oliguria is common in the early stages; non-oliguric renal failure is usually a result of a less severe renal insult. In the recovery phase of acute tubular necrosis GFR may remain low while urine output increases, sometimes to many litres a day, due to defective tubular reabsorption of filtrate. Even after a relatively short-lived insult acute tubular necrosis may last for up to 6 weeks. Eventually, renal function usually returns towards normal. The outcome is critically dependent on the severity and reversibility of the underlying cause andon age.

Acute cortical necrosis

Renal hypo perfusion results in diversion of blood flow from the cortex to the medulla, with a drop in GFR. Medullary ischaemic damage is largely reversible due to the capacity of the tubular cells for regeneration. In contrast, glomerular ischaemic injury heals not with regeneration but with scarring-glomerulosclerosis. Prolonged cortical ischaemia therefore leads to irreversible loss of renal function, termed cortical necrosis. Any cause of acute tubular necrosis, if sufficiently severe or prolonged, may also lead to cortical necrosis. This outcome is particularly common in pregnancy, for reasons that are not well understood.

Postrenal

The causes and presentation of urinary tract obstruction are dealt with. Although patients may present as acute uraemic emergencies, renal failure due to obstruction is often relatively chronic. The longer obstruction has been present, the worse the prognosis for recovery of renal function after relief of obstruction.

Drugs and the kidney

Drug-induced impairment of renal function

Prerenal

Impaired perfusion of the kidneys can result from drugs that cause:
1 Hypovolaemia due to:
(a) Potent loop diuretics such as frusemide, especially in elderly patients
(b) Renal salt and water loss, e.g. from hypercalcaemia induced by vitamin D therapy (since hypercalcaemia adversely affects renal tubular salt and water conservation)
2 Decrease in cardiac output, which impairs renal perfusion, e.g. due to {3-blockers}
3 Decreased renal blood flow, e.g. ACE inhibitors Renal.
Several mechanisms of drug-induced renal damage exist and may coexist. These include:
ACUTE TUBULAR NECROSIS PRODUCED BY DIRECT NEPHROTOXICITY. Examples include prolonged or excessive treatment with aminoglycosides (kanamycin, gentamicin, streptomycin), amphotericin Band cephaloridine, heavy metals or carbon tetrachloride. The combination of aminoglycosides or cephaloridine with frusemide is particularly nephrotoxic.
ACUTE TUBULO-INTERSTITIAL NEPHRITIS  WITH INTERSTITIAL OEDEMAAND INFLAMMATORY CELL INFILTRATION. This cell-mediated hypersensitivity nephritis occurs with many drugs, including penicillins, particularly methicillin, sulphonamides and some NSAIDS.
CHRONIC TUBULO-INTERSTITIAL NEPHRITIS due to drugs
IMMUNE COMPLEX-MEDIATED GLOMERULONEPHRITIS- examples include penicillamine.
Postrenal Retroperitoneal fibrosis with urinary tract obstruction may result from the use of methysergide. Use of drugs in patients with impaired renal function.
Many aspects of drug handling are altered in patients with renal impairment.

ABSORPTION. This may be unpredictable in uraemia as nausea and vomiting are frequently present. METABOLISM. Oxidative metabolism of drugs by the liver may be altered in uraemia. This is rarely of clinical significance.
The rate of drug metabolism by the kidney may be reduced as a result of two factors:
1 Reduced drug catabolism. Insulin, for example, is in part catabolized by the normal kidney. In renal disease, insulin catabolism is reduced. The insulin requirements of diabetics decline as renal function deteriorates for this reason.
2 Reduced conversion of a precursor to a more active metabolite, e.g. the conversion of 25-hydroxycholecalciferol to the more active 1,25-(OH)2D3. The Iohydroxylase enzyme responsible for this conversion is located in the kidney. In renal disease, production of the enzyme declines and deficiency of 1,25-(OH)2D3 results.
PROTEIN BINDING. Reduced protein binding of a drug potentiates its activity and increases the potential for toxic side-effects. Measurement of the total plasma concentration of such a drug can give misleading results. For example, the serum concentration of phenytoin required to produce an anti epileptic effect is much higher in normal individuals than in those with renal failure, since in the latter proportionately more drug is present in the free form.

Safe prescribing in renal disease

Safe prescribing in renal disease

Some patients with renal disease are hypoproteinaemic and reduced drug-binding to protein results. This is not the sole mechanism of reduced drug-binding in such patients. For example, hydrogen ions, which are retained in renal failure, bind to receptors for acidic drugs such as sulphonamides, penicillin and salicylates, thus enhancing their potential for causing toxicity.
VOLUME OF DISTRIBUTION. Salt and water overload or depletion may occur in patients with renal disease. This affects the concentration of drug obtained from a given dose.
END-ORGAN SENSITIVITY. The renal response to drug treatment may be reduced in renal disease. For example, mild thiazide diuretics have little diuretic effect in patients with severe renal impairment.
RENAL ELIMINATION. By far the most important problem in the use of drugs in renal failure concerns the reduced elimination of many drugs normally excreted by the kidneys.
Water-soluble drugs such as gentamicin that are poorly absorbed from the gut, typically given by injection and are not metabolized by the liver give rise to far more problems than lipid-soluble drugs such as propranolol, which are well absorbed and principally metabolized by the liver. Metabolites of lipid-soluble drugs, however,  may themselves be water-soluble and potentially toxic. Drugs causing uraemia by effects upon protein anabolism and catabolism.
Tetracyclines, with the exception of doxycycline, have acatabolic effect and as a result the concentration of nitrogenous waste products is increased. They may also cause impairment of GFR by a direct effect. Corticosteroids have a catabolic effect and so also increase the production of nitrogenous wastes. A patient with moderate impairment of renal function may therefore become severely uraemic if given tetracyclines or corticosteroid therapy.
Drugs and toxic agents causing specific renal tubular syndromes include mercury, lead, cadmium and vitamin D.

Problem patients

Particular problems are presented by patients in whom renal function is altering rapidly, such as those with recovering acute tubular necrosis and those on regular dialysis treatment. In addition, drugs may be removed by dialysis, which will affect the dosage required.

Specific causes of obstruction

Pelviureteric junction obstruction

This appears to result from a functional disturbance in peristalsis of the collecting system in the absence of mechanical obstruction. Surgical attempts at correction of the obstruction by open or percutaneous pyeloplasty should be limited to patients with recurrent loin pain and those in whom serial excretion urography, background-subtraction isotope renography or measurements of GFR indicate progressive kidney damage. Nephrectomy to remove the risk of developing pyonephrosis and septicaemia is indicated if long-standing obstruction has destroyed kidney function.

An X-ray showing left pelviureteric junction obstruction.

An X-ray showing left pelviureteric junction obstruction.

Obstructive megaureter

This childhood condition may only become evident in adult life. It results from the presence of a region of defective peristalsis at the lower end of the ureter adjacent to the ureterovesical junction. The condition is commoner in males. It presents with UTI, flank pain or haematuria. The diagnosis is made on excretion urography or, if necessary, ascending ureterography. Excision of the abnormal portion of ureter with reirnplantation into the bladder is always indicated in children, and is indicated in adults when the condition is associated with evidence of progressive deterioration in renal function, bacteriuria that cannot be controlled by medical means or recurrent stone formation.

Retroperitoneal fibrosis (chronic periaortitis)

In this condition the ureters become embedded in dense retroperitoneal fibrous tissue with resultant unilateral or bilateral obstruction. The condition may extend from the level of the second lumbar vertebra to the pelvic brim. The incidence of the condition in men is three times that in women. An autoallergic response to leakage of material, probably ceroid, derived from atheromatous plaques is now considered to be the underlying cause of the condition. Recognized associations are with abdominal aortic aneurysm and prolonged exposure to the drug methysergide. The differential diagnosis includes retroperitoneal lymphoma or cancer.
Malaise, back pain, normochromic anaemia, uraemia and a raised erythrocyte sedimentation rate (ESR) are typical features. Excretion urography shows bilateral or unilateral ureteric obstruction commencing at the level of the pelvic brim. A periaortic mass may be seen on a CT scan.
Obstruction is relieved surgically by ureterolysis. Biopsy should be performed at operation to determine whether there is an underlying lymphoma or carcinoma. Corticosteroids are of benefit, and in bilateral obstruction in frail patients it may be best to free only one ureter and to rely upon steroid therapy to induce regression of fibrous tissue on the contralateral side, since bilateral ureterolysis  is a major operation. In some patients, surgery alone or steroid therapy alone may suffice, but in the majority both surgery and subsequent corticosteroid therapy appear to be necessary.
Response to treatment and disease activity are assessed by serial measurements of ESR and GFR supplemented by isotopic and imaging techniques including CT scanning. The latter method enables the size of the retroperitoneal mass to be assessed. Relapse after withdrawal of steroid therapy may occur and treatment may need to be continued for years. Long-term follow-up is mandatory. Benign prostatic hypertrophy Benign prostatic hypertrophy is a common cause of urinary tract obstruction. It is described.

Prognosis of urinary tract obstruction

The prognosis depends upon the cause and the stage at which obstruction is relieved. In obstruction, four factors influence the rate at which kidney damage occurs, its extent and the degree and rapidity of recovery of renal function after relief of obstruction. These are:
1 Whether obstruction is partial or complete
2 The duration of obstruction
3 Whether or not infection occurs
4 The site of obstruction
Complete obstruction for several weeks will lead to irreversible or only partially reversible kidney damage. If the duration of complete obstruction is several months, total irreversible destruction of the affected kidney will result. Partial obstruction carries a better prognosis, depending upon its severity.
Bacterial infection coincident with obstruction rapidly increases kidney damage.
Obstruction at or below the bladder neck may induce hypertrophy and trabeculation of the bladder without a rise in pressure within the upper urinary tract, in which case the kidneys are protected from the effects of backpressure.

Urinary tract obstruction

The urinary tract may be obstructed at any point between the kidney and the urethral meatus. This results in dilatation of the tract above the obstruction. Dilatation of the renal pelvis is known as hydronephrosis.

AETIOLOGY

Obstructing lesions may lie within the lumen, or in the wall of the urinary tract, or outside the wall, causing obstruction by external pressure. The major causes of obstruction are shown. Overall the frequency is the same in men and women. However, in the elderly, urinary tract obstruction is more common in men owing to the frequency of bladder outflow obstruction.

Causes of urinary tract obstruction.

Causes of urinary tract obstruction.

PATHOPHYSIOLOGY

Obstruction with continuing urine formation results in:
1 Progressive rise in intraluminal pressure
2 Dilatation proximal to the site of obstruction
3 Compression and thinning of the renal parenchyma, eventually reducing it to a thin rim and resulting in a decrease in the size of the kidney.

CLINICAL FEATURES

Symptoms

UPPER TRACT OBSTRUCTION. Loin pain occurs which can be dull or sharp, constant or intermittent. It may be provoked by measures that increase urine volume and hence distension of the collecting system, such as a high fluid intake or diuretics, including alcohol. Complete anuria is strongly suggestive of complete bilateral obstruction or complete obstruction of a single kidney.
Conversely, polyuria may occur in partial obstruction owing to impairment of renal tubular concentrating capacity. Intermittent anuria and polyuria indicates intermittent complete obstruction. Infection complicating the obstruction may give rise to
malaise, fever and septicaemia.
BLADDER OUTFLOW OBSTRUCTION. Symptoms may be minimal. Hesitancy, narrowing and diminished force of the urinary stream, terminal dribbling and a sense of incomplete bladder emptying are typical features. The frequent passage of small volumes of urine occurs if a large volume of residual urine remains in the bladder after urination. Incontinence of such small volumes of urine is known as ‘overflow incontinence’ or ‘retention with overflow’. Infection commonly occurs, causing increased frequency, urgency, urge incontinence, dysuria and the passage of cloudy smelly urine. It may precipitate acute retention.

Sign

Loin tenderness may be present. An enlarged hydronephrotic kidney may be palpable. In acute or chronic retention the enlarged bladder may be felt or percussed.
Examination of the genitalia, rectum and vagina are essential, since prostatic obstruction and pelvic malignancy are common causes of urinary tract obstruction. However, the apparent size of the prostate on digital examination is a poor guide to the presence of prostatic obstruction.

INVESTIGATION

Routine blood and biochemical investigations may be abnormal, e.g. there may be a raised blood urea or serum creatinine, hyperkalaemia, anaemia of chronic disease or blood in the urine, but the diagnosis of obstruction cannot be made on these tests alone and further investigations must be performed.

Ultrasonography 

This is a reliable means of ruling out upper urinary tract dilatation. Ultrasound cannot distinguish a baggy, lowpressure unobstructed system from a tense, high-pressure obstructed one, so that false-positive scans are seen. However, a normal scan does rule out urinary tract obstruction.

Radionuclide studies

In obstructive nephropathy, the relative uptake may benormal or reduced on the side of obstruction, peak activity may be delayed and parenchymal (as distinct  from pelvic) transit time prolonged. If doubt exists as to whether obstruction at the pelviureteric junction is present, frusemide may be administered; satisfactory ‘washout’ of a radionuclide rules out obstruction and vice versa. In general, absence of uptake of radiopharmaceutical indicates renal damage sufficiently severe to render correction of obstruction unprofitable.

Excretion urography

This is the most widely used investigation. Urography canusually exclude obstruction even in the presence of severe renal failure, provided that a high dose of contrast  medium, renal tomography and, if necessary, delayed films are employed. A plain film is necessary to detect calcification. However, calculi overlying bone are easily missed. In recent unilateral obstruction, the affected kidney is enlarged and smooth in outline. The nephrogram is delayed due to a reduction in the GFR. The calyces and pelvis fill with contrast medium later than on the normal side.
In time the nephrogram on the affected side becomes denser than normal, owing to the prolonged nephron transit time, which allows greater than normal concentration of contrast medium within the tubules. Later, the site of obstruction may be seen, with dilatation of the system proximal to the level of the block .
A full-length film should be taken after an attempt at bladder emptying by the patient. Complete emptying indicates either that no obstruction to bladder outflow exists or that intravesicular pressure can be raised sufficiently to overcome it. Apparent bladder outflow impairment may be the result of nervousness or embarrassment on the part of the patient or failure to carry out the X-ray before the bladder has refilled with contrast medium from above, or may be due to an atonic but non-obstructed bladder. Vesicoureteric reflux can result in contrast medium returning to the bladder from above, giving the appearance of a partially full bladder.

An X-ray taken 24 hours after injection of contrast,

An X-ray taken 24 hours after injection of contrast,

Antegrade pyelography and ureterography

This defines the site and cause of obstruction. It can be combined with drainage of the collecting system by percutaneous needle nephrostomy.

Retrograde ureterography

This is indicated if antegrade examination cannot be carried out or if there is the possibility of dealing with ureteric obstruction from below at the time of examination. The technique carries the risk of introducing infection into an obstructed urinary tract. In obstruction due to neuromuscular dysfunction at the pelviureteric junction or retroperitoneal fibrosis, the collecting system may fill normally from below. Cystoscopy, urethroscopy and urethrography Obstructing lesions within the bladder and urethra can be seen directly by endoscopic examination .
Urethrography involves introducing contrast medium into the bladder by catheterization or suprapubic bladder puncture, and taking X-ray films during voiding to show obstructing lesions in the urethra. It is of particular value in the diagnosis of urethral valves and strictures.

Pressure-flow studies

Pressure changes within the bladder during filling and emptying can be recorded. Demonstration that a high voiding pressure is required to maintain urine flow is indicative of bladder outflow obstruction. This may be combined with video cystography and urethrography to define the site of obstruction. Normally, while the bladder is being filled there is only a small pressure rise before the voluntary initiation of urination. Uninhibited contractions of the detrusor muscle during filling may be seen in upper motor neurone bladder neuropathy, such as occurs in multiple sclerosis. Less commonly, a neuropathic bladder may be ‘hypotonic’, readily accepting large volumes of fluid before the initiation of weak contractions at a low intravesical pressure. A common cause of such lower motor neurone bladder neuropathy is diabetes mellitus.
Pressure-flow and video studies may enable a logical decision to be taken as to whether surgery to relieve bladder outflow impairment should be carried out.

TREATMENT

Aims

Treatment involves:
• Relieving the obstruction
• Treating the underlying cause
• Preventing and treating infection
The ultimate aim of treatment is to relieve symptoms and to preserve renal function. Temporary external drainage of urine by nephrostomy may be valuable, as this allows time for further investigation when the site and nature of the obstructing lesion is uncertain and doubt exists as to the viability of the obstructed kidney, or when immediate definitive surgery would be hazardous. Recent, complete upper urinary tract obstruction demands urgent relief to preserve kidney function, particularly if infection is present.
In contrast, with partial urinary tract obstruction, particularly if spontaneous relief is expected, e.g. by passage of a calculus, there is no immediate urgency. In recent years, increasing use has been made of the insertion of stents to relieve obstruction, either temporarily or on a long-term basis.

Surgical management

This depends on the cause of the obstruction. Dialysis may be required in the ill patient prior to surgery. Nephrectomy or nephroureterectomy is justified when obstruction is due to malignant disease or when it is judged that no worthwhile amount of renal excretory function will be conserved by, or will return after, relief of obstruction.
Permanent urinary diversion is required when the obstruction cannot be relieved; in such cases malignant disease is usually present. Ureteric anastomosis to an ileal conduit opening on to the abdominal wall is often a satisfactory method of diversion. In some patients, obstruction is best relieved by the insertion of indwelling catheters or stents into the ureter. An obstruction high in the urinary tract may require a permanent nephrostomy. In obstruction due to untreatable malignant disease it is wise to consider carefully whether urinary diversion or stent insertion is justified, since this may exchange a painfree death from renal failure for a painful one with malignant invasion of bones or nerves.
Diuresis usually follows relief of obstruction at any site in the urinary tract. Massive diuresis may occur following relief of bilateral obstruction owing to previous sodium and water overload and the osmotic effect of retained solutes combined with a defective renal tubular reabsorptive capacity (as in the diuretic phase of recovering acute tubular necrosis). This diuresis is associated with increased blood volume and high levels of atrionatriuretic peptide (ANP). Defective renal tubular reabsorptive capacity cannot be the sole mechanism of severe diuresis since this phenomenon is not observed following relief of unilateral obstruction. The diuresis is usually self-limiting, but a minority of patients will develop severe sodium, water and potassium depletion requiring appropriate intravenous replacement. In milder cases oral salt and potassium supplements together with a high water intake are sufficient.

INVESTIGATING THE CAUSE OF STONE

FORMATION

In an elderly patient who has had a single episode with one stone, only limited investigation is required. Younger patients and those with recurrent stone formation require detailed investigation.
AN EXCRETION UROGRAM is necessary to define the presence of a primary renal disease predisposing to stone formation.
SIGNIFICANT BACTERIURIA may indicate mixed infective stone formation but relapsing bacteriuria may be a consquence of stone formation rather than the original cause.
CHEMICAL ANALYSIS of any stone passed may be of great value and may be all that is required to make a diagnosis of cystinuria or uric acid stone formation.
SERUM CALCIUM CONCENTRATION should be estimated and corrected for serum albumin concentration.

Hypercalcaemia, if present, should be investigated further.
SERUM URATE CONCENTRATION is often, but not invariably, elevated in uric acid stone-formers.
A SCREENING TEST FOR CYSTINURIA should be carried out by adding sodium nitroprusside to a random unacidified urine sample; a purple colour indicates that cystinuria may be present. Urine chromatography is required to define the diagnosis precisely.
URINARY CALCIUM, OXALATE AND URIC ACID OUTPUT should be measured in two consecutive carefully collected 24-hour urine samples. After withdrawing aliquots for estimation of uric acid, it is necessary to add acid to the urine in order to prevent crystallization of calcium salts upon the walls of the collection vessel, which would give falsely low results for urinary calcium and oxalate.
PLASMA BICARBONATE is low in renal tubular acidosis . The finding of a urine pH that does not fall below 5.5 in the face of metabolic acidosis is diagnostic of this condition.

PROPHYLAXIS

The age of the patient and the severity of the problem affect both the need for and the type of prophylaxis. Idiopathic stone-formers Where no metabolic abnormality is present, the mainstay of prevention is maintenance of a high intake of fluid throughout the day and night. The aim should be to ensure a daily urine volume of 2-2.5 litres, which requires a fluid intake in excess of this, substantially so in the case of those who live in hot countries or work in a hot environment. A large glass of water should be drunk before retiring for the night and on waking during the night if this occurs. Special dietary measures are not warranted, although avoidance of excessive consumption of calcium-rich dairy products seems sensible.

Idiopathic hyperca1ciuria

Dietary calcium restriction is recommended, although the value of this has recently been questioned. Intake of milk, cheese, and white bread if this is fortified (as it is in the UK) with calcium and vitamin D is reduced. Vitamin D supplements should be avoided. Dietary calcium restriction results in hyperabsorption of oxalate and foods containing large amounts of oxalate should also be limited. The advice of a dietitian is helpful. A high fluid intakeshould be advised as for idiopathic stone-formers. Patients who live in a hard-water area may benefit from drinking softened water.
If hypercalciuria persists and stone formation continues, a thiazide, e.g. bendrofluazide 2.5 or 5 mg each morning is used. Thiazides reduce urinary calcium excretion by a direct effect on the renal tubule. They may occasionally cause hypercalciuria or gout and worsen hypercholesterolaemia. Sodium cellulose phosphate reduces calcium absorption from the gut but increases oxalate absorption, causes diarrhoea and has largely been abandoned. Avoidance of excessive sodium intake is also advisable as sodium and calcium excretion are linked.

Mixed infective stones

Recurrent stones should be prevented by maintenance of a high fluid intake and meticulous control of bacteriuria. This will require long-term follow-up and may demand the use of long-term low-dose prophylactic antibacterial agents.

Uric acid stones

Dietary measures are probably of little value and are difficult to implement. Effective prevention can be achieved by the long-term use of the xanthine oxidase inhibitor allopurinol to maintain the serum urate and urinary uric acid excretion in the normal range. A high fluid intake should also be maintained. Uric acid is more soluble at alkaline pH and long-term sodium bicarbonate supplementation to maintain an alkaline urine is an alternative approach in those few patients unable to take allopurinol. However, alkalinization of the urine facilitates precipitation of calcium oxalate and phosphate.

Cystine stones

These can be prevented and indeed will dissolve slowly if there is obsessional attention to maintenance of a high fluid intake-5 litres of water must be drunk each 24 hours, and the patient must wake twice during the night to ingest 500 ml or more of water. Many patients cannot tolerate this regimen. An alternative, though potentially more troublesome, option is the long-term use of the chelating agent penicillamine; this causes cystine to be converted to the more soluble penicillamine-cysteine complex. Side-effects include drug rashes, blood dyscrasias and immune complex-mediated glomerulonephritis and are by no means uncommon. In addition, the drug is expensive. It is, however, especially effective in promoting dissolution of cystine stones already present. Mild hyperoxaluria with calcium oxalate stones A high fluid intake and dietary oxalate restriction are required.

Nephrocalcinosis

The term nephrocalcinosis means diffuse renal parenchymal calcification that is detectable radiologically. The condition is typically painless. Hypertension and renal impairment commonly occur. The main causes of nephrocalcinosis are listed. Dystrophic calcification occurs following renal corticalnecrosis. In hypercalcaemia and hyperoxaluria, deposition of calci um oxalate results from the high concentration of calcium and oxalate within the kidney. In renal tubular acidosis failure of urinary acidification and a reduction in urinary citrate excretion both favour calcium phosphate and oxalate precipitation, since precipitation occurs more readily in an alkaline medium and the calcium-chelating action of urinary citrate is reduced.

An X-ray of nephrocalcinosis.

An X-ray of nephrocalcinosis.

Common causes of nephrocalcinosis.

Common causes of nephrocalcinosis.

Treatment and prevention of nephrocalcinosis consists of treatment of the cause.

CLINICAL FEATURES

Most people with urinary tract calculi are asymptomatic. Pain is the commonest symptom and may be sharp or dull, constant, intermittent or colicky. When urinary tract obstruction is present, measures that increase urine volume, such as copious fluid intake or diuretics, including alcohol, make the pain worse.Physical exertion may cause mobile calculi to move, precipitating pain and, occasionally, haematuria. Calyceal colic, i.e. pain resulting from movement of stones within the calyces, is a real entity, but whether small calyceal calculi are the cause of backache or not is often difficult to decide.
Ureteric colic occurs when a stone enters the ureter and either obstructs it or causes spasm during its passage down the ureter (Fig. 9.23). This is one of the most severe pains known. Radiation from the flank to the iliac fossa and testis or labium in the distribution of the first lumbar nerve root is common. Pallor, sweating and vomiting often occur and the patient is restless, tending to assume a variety of positions in an unsuccessful attempt to obtain relief from the pain. Haematuria often occurs. Untreated, the pain of ureteric colic typically subsides after a few When urinary tract obstruction and infection are present, the features of acute pyelonephritis or of a Gramnegative septicaemia may dominate the clinical picture. Vesical calculi associated with bladder bacteriuria may present with frequency, dysuria and haematuria; severe introital or perineal pain may occur if trigonitis is present. A calculus at the bladder neck or an obstruction in the urethra may cause bladder outflow obstruction, resulting in anuria and painful bladder distension. Physical examination should include a search f’)r corneal or conjunctival calcification, gouty tophi and arthritis and features of sarcoidosis.

DIAGNOSIS AND INVESTIGATION

A history of possible aetiological factors should be obtained, including:
• Occupation and residence in hot countries likely to be associated with dehydration
• A history of vitamin D consumption
• Gouty arthritis
Calcified papillae may mimic ordinary calculi, so that causes of papillary necrosis such as analgesic abuse should be considered. Investigations should include a mid-stream specimen of urine for culture and measurement of the blood urea and electrolytes and serum creatinine and calcium levels. Plain abdominal X-ray, renal tomography and excretion urography are the mainstay of diagnosis. Pure uric acid stones are radiolucent. Mixed infective stones in which organic matrix predominates are barely radiopaque. Calcium-containing and cystine stones are radiopaque. Calculi overlying bone are easily missed. Staghorn calculi may be missed on excretion urography . Uric acid stones may present as a filling defect after injection of contrast medium.
Such stones are readily seen on CT scanning. Excretion urography is carried out during the episode of pain; a normal urogram excludes the diagnosis of pain due to calculous disease. The urographic appearances in a patient with acute left ureteric obstruction are shown. The urine of the patient should be passed through a sieve to trap any calculi passed for chemical analysis.

X-ray showing acute left ureteric obstruction.

X-ray showing acute left ureteric obstruction.

X-rays showing calculus.

X-rays showing calculus.

MANAGEMENT

Adequate analgesia should be given, e.g. morphine 15- 30 mg i.m. repeated as necessary. Alternatively an NSAID can be tried. A high fluid intalce and, if feasible, increased physical activity are recommended but the efficacy of these measures is doubtful. Stones less than 0.5 ern in diameter usually pass spontaneously and can be left. Stones greater than 1 ern in diameter usually require intervention.

Staghorn calculus.

Staghorn calculus.

Persistent pain, frequent bouts of severe pain, or anuria, are indications for further therapy. Intervention is also required if a stone is not moving though causing only partial obstruction in the absence of infection. With the advent of  ercutaneous surgery and extracorporeal shockwave lithotripsy (see below) there has developed a trend towards earlier intervention in such cases. Complete obstruction or the coexistence of UTI with partial obstruction should prompt even earlier intervention owing to the increased risk of permanent kidney damage in these circumstances. Stones may be removed by a cutting operation:
NEPHROLITHOTOMY for renal calculi PYELOLITHOTOMY for stones in the renal pelvis.

URETEROLITHOTOMY for ureteric stones Cutting operations can now be avoided by using either percutaneous nephrolithotomy or extracorporeal shockwave lithotripsy. In the former, stones in the calyces and renal pelvis are removed by creating a percutaneous track down to the collecting system followed by endoscopic removal along this track. In the latter, shock waves are focused upon the renal calculi, causing them to fragment. Most of the fragments then pass spontaneously via the urethra. Fragments that do not pass can be removed percutaneously  Ureteric stones may be removed endoscopically or may be pushed up into the upper urinary tract, to allow percutaneous nephrolithotomy or extracorporeal shock-wave
lithotripsy. Large renal stones need to be reduced in bulk by percutaneous means before lithotripsy can be expected to be successful. Some staghorn calculi are best dealt with by open operation.
Bladder stones can be removed endoscopically. They May be dealt with by direct electrohydraulic disintegration at cystoscopy or may be gripped in a lithotrite and crushed, the stone fragments then being washed out. Open cystotomy is required for very large bladder stones.

CT scan showing a uric acid stone, which appears as a bright lesion in the left kidney.

CT scan showing a uric acid stone, which appears as a bright lesion in the left kidney.

Calculi and nephrocalcinosis

Renal and vesical calculi

Approximately 2% of the population in the UK have a urinary tract stone at any given time. A much higher prevalence of stone disease has been recorded elsewhere, notably in the Middle East. In the Western World, most stones occur in the upper urinary tract. The incidence of bladder stones has declined in the UK since the eighteenth and nineteenth centuries, whereas in some developing countries they are still common. Most stones are composed of calcium oxalate and  phosphate; these are commoner in men.
Mixed infective stones, which account for about 20% of all calculi, are twice as common in women as in men. The overall male/female ratio of stone disease is 2 : l. Stone disease is frequently a recurrent problem. More than 50% of patients with a calculus will have formed a further stone or stones within 10 years. The risk of recurrence increases if a metabolic or other abnormality predisposing to stone formation is present and is not modified by treatment.

AETIOLOGY

It is in a sense surprising that stones are not universal, since some constituents of urine are at times present in concentrations that exceed their maximum solubility in water. The presence of inhibitors of crystal formation in normal urine appears to be of importance in preventing stones.
Many stone-formers have no detectable metabolic defect, although microscopy of warm, freshly passed urine reveals both more and larger calcium oxalate crystals than are found in normal subjects. Factors predisposing to stone formation in these so-called ‘idiopathic stone-formers’ are:
CHEMICAL COMPOSITION OF URINE that favours stone crystallization
PRODUCTION OF A CONCENTRATED URINE as a consequence of dehydration associated with life in a hot climate or work in a hot environment
IMPAIRMENT OF INHIBITORS that prevent crystallization in normal urine. Recognized causes of stone formation are listed.

Type and frequency of renal stones.

Type and frequency of renal stones.

Causes of urinary tract stone formation.

Causes of urinary tract stone formation.

Hypercalcaemia

If the GFR is normal, hypercalcaemia almost invariably leads to hypercalciuria. The common causes of hypercalcaemia leading to stone formation are:
• Primary hyperparathyroidism
• Vitamin D ingestion
• Sarcoidosis
Of these, primary hyperparathyroidism is the commonest cause of stones.

Hypercalciuria

This is by far the commonest metabolic abnormality detected in calcium stone-formers. Approximately 8% of men excrete in excess of 7.5 mmol calcium per 24 hours. Calcium stone formation is commoner in this group, but as most patients do not form stones the definition of ‘pathological’ hypercalciuria is arbitrary. A reasonable definition of pathological hypercalciuria is excretion of more than 7.5 mmol calcium per 24 hours in male and more than 6.25 mmol calcium per 24 hours in female stone-formers.
Causes of hypercalciuria are:
• Hypercalcaemia
• An excessive dietary intake of calcium
• Excessive resorption of calcium from the skeleton, such as occurs with prolonged immobilization or weightlessness
• Idiopathic hypercalciuria
The majority of patients with idiopathic hypercalciuria can be shown to have increased absorption of calcium from the gut. Dietary calcium restriction in this group markedly reduces urinary calcium excretion. However, a proportion of these patients appear to have a renal tubular calcium leak with secondary compensatory hyperabsorption of calcium from the gut. Calcium restriction has less effect on urinary calcium excretion in this group.

Hyperoxaluria

Two inborn errors of glyoxalate metabolism that cause increased endogenous oxalate biosynthesis are known. Both are inherited in an autosomal recessive manner. In type I (primary hyperoxaluria) there is increased glycolate excretion as well as hyperoxaluria. In type II L-glycerate excretion is increased. In both types, calcium oxalate stone formation occurs.
The prognosis is poor owing to widespread calcium oxalate crystal deposition in the kidneys. Renal failure typically develops in the late teens or early twenties. Much commoner causes of mild hyperoxaluria are:
EXCESS INGESTION OF HIGH OXALATE-CONTAINING FOOD, such as spinach, rhubarb and tea.
DIETARY CALCIUM RESTRICTION, with compensatory increased absorption of oxalate.
GASTROINTESTINAL DISEASE, such as Crohn’s disease, usually with an intestinal resection is associated with increased absorption of oxalate from the colon. Dehydration secondary to fluid loss from the gut also plays a part in stone formation.

Hyperuricaemia and hyperuricosuria

Uric acid stones account for 3-5% of all stones in the UK, but in Israel the proportion is as high as 40%. Uric acid is the end-point of purine metabolism. Hyperuricaemia  can occur as a primary defect in idiopathic gout, and as a secondary consequence of increased cell turnover, e.g. in myeloproliferative disorders. Increased uric acid excretion occurs in these conditions, and stones will develop in some patients. Some uric acid stone-formers have hyperuricosuria (>4 mmol/24 hours on a low purine diet) without hyperuricaemia. Dehydration alone may also cause uric acid stones to form. Patients with ileostomies are at particular risk both from dehydration and from the fact that loss of bicarb onate from gastrointestinal secretions results in the pro- (a) duction of an acid urine (uric acid is more soluble in an alkaline than an acid medium).
Some patients with calcium stones also have hyperuricaemia and/or hyperuricaciduria; it is believed the calcium salts precipitate upon an initial nidus of uric acid in such patients.

Urinary tract infection

Mixed infective stones are composed of magnesiumammonium phosphate together with variable amounts of calcium. Such stones are often large, forming a cast of the collecting system (staghorn calculus). They are believed to form as a result of infection of the urinary tract with organisms such as Proteus mirabilis that hydrolyse urea, with formation of the strong base ammonium hydroxide.

Urinary tract infection

Urinary tract infection

The availability of ammonium ions and the alkalinity of the urine favour stone formation. An increased amount of mucoprotein resulting from infection also creates an organic matrix on which stone formation can occur.

Cystinuria

Cystinuria results in the formation of cystine stones. About 1-2% of all stones are composed of cystine.

Primary renal diseases

There is a moderate increase in prevalence of stone disease in patients with polycystic renal disease.
Medullary sponge kidney is another primary renal disorder associated with stones. In this congenital (though not inherited) condition there is dilatation of the collecting ducts with associated stasis and calcification. Approximately 20% of these patients have hypercalciuria and a similar proportion have a renal tubular acidification defect.
The renal tubular acidoses, both inherited and acquired, are associated with nephrocalcinosis and stone formation owing, in part at least, to the production of a persistently alkaline urine and reduced urinary citrate excretion.

Medullary sponge kidney.

Medullary sponge kidney.

Aetiology of bladder stones

Bladder stones are endemic in some developing countries.The cause of this is unknown but dietary factors are probably  important. Stones forming in the bladder do so as a result of:
BLADDER OUTFLOW OBSTRUCTION, e.g. urethral stricture, neuropathic bladder, prostatic obstruction
THE PRESENCE OF A FOREIGN BODY, e.g. catheters, non-absorbable sutures. Significant bacteriuria is usually found in patients with bladder stones. Some stones found in the bladder have
been passed down from the upper urinary tract.

PATHOLOGY

Stones may be single or multiple and vary enormously in size from sand-like minute particles to staghorn calculi or large stone concretions in the bladder. They may be located within the renal parenchyma or within the colleering system. Pressure necrosis from a large calculus may cause direct damage to the renal parenchyma and stones regularly cause obstruction, leading to hydronephrosis. They may ulcerate through the wall of the collecting system, including the ureter. A combination of obstruction and infection accelerates damage to the kidney.

Clinical features of urinary tract stones.

Clinical features of urinary tract stones.

Other vascular disorders of the kidney

Renal artery occlusion

This occurs from thrombosis in situ usually in a severely damaged arteriosclerotic vessel or more commonly from embolization. Both result in renal infarction resulting in a wide spectrum of clinical manifestations depending on the size of the artery involved. Occlusion of a small branch artery may produce no effect but occlusion of larger vessels results in dull flank pain and varying degrees of renal failure.
Embolization may occur from the heart, e.g. in atrial fibrillation. It can also occur from the aorta and renal artery where showers of cholesterol-rich atheromatous material from ulcerated arteriosclerotic plaques lodge in the small renal vessels. This leads to renal insufficiency usually with hypertension. Occasionally acute renal failure occurs, sometimes complicating catheterization of the abdominal aorta. Anticoagulants and thrombolytic agents may also precipitate cholesterol embolism.

Renal vein thrombosis

This is usually of insidious onset occurring in the nephrotic syndrome, with a renal cell carcinoma and in conditions with increased thrombosis, e.g. antithrombin III deficiency or with anticardiolipin antibodies.

Hypertension and the kidney

Hypertension can be the cause or the result of renal disease. It is often difficult to differentiate between the two on clinical grounds. Routine tests as described should be performed on all patients, but IVU is usually unnecessary. A guide to which patients should be fully investigated is given.

ESSENTIAL HYPERTENSION

PATHOPHYSIOLOGY

In benign essential hypertension, arteriosclerosis of major renal arteries and changes in the intrarenal vasculature (nephrosclerosis) occur as follows: IN SMALLVESSELS AND ARTERIOLES, intimal thickening with reduplication of the internal elastic lamina occurs and the vessel wall becomes hyalinized. IN LARGE VESSELS, concentric reduplication of the internal elastic lamina and endothelial proliferation produce an ‘onion skin’ appearance.
REDUCTION IN SIZE OF BOTH KIDNEYS may occur; this may be asymmetrical if one major renal artery is more affected by atheromatous change than the other.
THE PROPORTION OF SCLEROTIC GLOMERULI is increased compared with age-matched controls. Deterioration in excretory function accompanies these changes, but severe renal failure is unusual in Whites. In Afro-Caribbeans, by contrast, such hypertension much more often results in the development of renal failure. In accelerated, or malignant phase hypertension:
ARTERIOLAR FIBRINOID NECROSIS occurs, probably as a result of plasma entering the media of the vessel through splits in the intima.

FIBRINOID NECROSIS in afferent glomerular arterioles is a prominent feature.
FIBRIN DEPOSITION within small vessels is often associated with thrombocytopenia and red-eel! fragmentation seen in the peripheral blood film (microangiopathic haemolytic anaemia).
Microscopic haematuria, proteinuria, usually of modest degree (1-3 g daily), and progressive uraemia occur. If untreated, fewer than 10% of patients survive 2 years.

MANAGEMENT

Management of benign essential and malignant hypertension is described. If treatment is begun before renal impairment has occurred, the prognosis for renal function is good. Stabilization or improvement in renal function with healing of intrarenal arteriolar lesions and resolution of microangiopathic haemolysis occur with effective treatment of malignant phase hypertension. Lifelong follow-up of the patient is mandatory.

RENAL HYPERTENSION

Bilateral renal disease

Hypertension commonly complicates bilateral renal disease such as chronic glomerulonephritis, bilateral reflux nephropathy (chronic atrophic pyelonephritis of childhood), polycystic disease and analgesic nephropathy. Two main mechanisms are responsible: Activation of the renin-angiotensin-aldosterone system 2 Retention of salt and water with impairment in excretory function leading to an increase in blood volume and hence blood pressure. The second of these assumes greater importance as renal function deteriorates.
Hypertension occurs earlier, is more common and tends to be more severe in patients with renal cortical disorders such as glomerulonephritis than in those with disorders affecting primarily the renal interstitium, such as reflux or analgesic nephropathy.
Management is described. Good control of the blood pressure is necessary to prevent further deterioration of renal function secondary to vascular changes produced by the hypertension itself.
Unilateral renal disease A small proportion of cases of hypertension are due to unilateral renal disease. The main causes are:
UNILATERAL RENAL ARTERY STENOSIS due to fibromuscular hyperplasia (typically in young women) or atheroma in the elderly UNILATERAL REFLUX NEPHROPATHY (atrophic pyelonephritis)

Mechanism of hypertension

Unilateral renal ischaemia results in a reduction in the pressure in afferent glomerular arterioles. This leads to an increase in the production and release of renin from the juxtaglomerular apparatus with a consequent increase in angiotensin II.
Physiological changes in renal artery stenosis In unilateral renal artery stenosis, renal perfusion pressure is reduced and nephron transit time is prolonged on the side of the stenosis; salt and water reabsorption is therefore increased. As a result, urine from the ischaemic kidney is more concentrated but has a lower sodium concentration than urine from the contralateral kidney. Inulin, creatinine and p-aminohippuric acid (PAH) clearances are decreased on the ischaemic side.

Screening for unilateral renovascular disease

RAPID SEQUENCE EXCRETION UROGRAPHY is still widely employed.
INTRAVENOUSLY INJECTED CONTRAST MEDIUM is filtered at the glomerulus more slowly and concentrated within the nephron to a greater extent on the side of the stenosis. Rapid sequence films taken after injection of contrast may show a small kidney and a delayed and denser pyelogram on the side of the stenosis. RADIONUCLIDE STUDIES using labelled DTPA can demonstrate decreased renal perfusion on the affected side. In recent years, the captopril renogram has been employed in this connection. In unilateral renal artery stenosis, a disproportionate fall in uptake of isotope on the affected side following administration of an ACE inhibitor such as captopril has been claimed to be a useful screening test for significant renal artery stenosis. The value of this investigation has recently been called into question.
DIVIDED RENAL FUNCTION STUDIES that involve ureteric catheterization are seldom used.
RENAL ARTERIOGRAPHY remains the gold standard for the diagnosis of renal artery stenosis.

TREATMENT

Surgical options in renal artery stenosis include transluminal angioplasty to dilate the stenotic region, reconstructive vascular surgery and nephrectomy. With good selection of patients, more than 50% are cured or improved by intervention. In recent years, increasing interest has focused upon the diagnosis and correction of unilateral and bilateral renal arterial disease with a view to improving renal perfusion and excretory function rather than to correcting hypertension alone. No test can predict the results of vascular surgery and many patients will do well on hypotensive therapy with or without surgery. ACE inhibitors must be avoided as they can lead to acute renal failure in the presence of renal artery stenoses.

UNILATERAL ATROPHIC PYELONEPHRITIS. In this condition prediction of the outcome after nephrectomy is currently not possible. The case for nephrectomy is strengthened if isotope renography demonstrates the abnormal kidney to be making an insignificant contribution to overall excretion function, particularly if the patient is young and medical treatment has proved unsatisfactory. About one-third of patients with unilateral atrophic pyelonephritis benefit from nephrectomy.

Hyperuricaemic nephropathy (gouty nephropathy)

Three patterns of renal disease have been described III patients with hyperuricaemia or hyperuricosuria:
1 Gouty or chronic hyperuricaemic nephropathy
2 Acute hyperuricaemic nephropathy
3 Uric acid stone formation

Chronic hyperuricaemic

nephropathy

Considerable controversy surrounds the possible role of chronic hyperuricaemia as a cause of tubulo-interstitial disease and progressive renal damage. While uric acid ‘tophi’ may be found in the kidneys of patients with gout, there is no convincing evidence that chronic hyperuricaemia per se causes progressive renal failure, nor that allopurinol treatment improves renal function. There is one important exception: a rare form of familial hyperuricaemia and gout occurring in adolescence is associated with renal impairment and allopurinol therapy both improves and protects kidney function.

Acute hyperuricaemic nephropathy

This is a well-recognized cause of acute renal failure in patients with marked hyperuricaemia due to lymphoproliferative or myeloproliferative disorders. This may occur prior to treatment but most often occurs on commencement of treatment, when there is rapid lysis of malignant cells, release of large amounts of nucleoprotein and increased uric acid production. Renal failure is due to intrarenal and extrarenal obstruction caused by deposition of uric acid crystals in the collecting ducts, pelvis and ureters. The condition is manifest in oliguria or anuria with increasing uraemia. There may be flank pain or colic. Plasma urate levels are above 0.75 mmol Iitre “! and may be as high as 4.5 mrnol litre ” ‘. Diagnosis is based on the hyperuricaemia and the clinical setting. Ultrasound demonstrates extrarenal obstruction due to stones but a negative scan does not exclude this where there is coexistent intrarenal obstruction.

PREVENTION

It is now regular practice to prescribe allopurinol 100- 200 mg three times daily for 5 days prior to and continuing throughout treatment with radiotherapy or cytotoxic drugs. A high rate of urine flow must be maintained by oral or parenteral fluid and the urine kept alkaline by the administration of sodium bicarbonate 600 mg four times daily and acetazolamide 250 mg three times daily.

TREATMENT

Allopurinol treatment should be commenced immediately and a forced alkaline diuresis attempted with intravenous 1.26% sodium bicarbonate plus acetazolamide (500 mg dose, then 250 mg three times daily). In severely oliguric or anuric patients, dialysis is required to lower the plasma urate, which allows urate to diffuse out of the obstructed collecting ducts into the peritubular capillaries. Percutaneous nephrostomy may be required to relieve extrarenal obstruction due to stones in the pelvis or ureters. Such stones may subsequently be passed spontaneously or may require surgical removal.