Key Points
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The key clinical features of acute gouty arthritis have been recognized for hundreds of years and include podagra (inflammatory arthritis of the first metatarsophalangeal joint), rapid rise to maximal symptoms, and complete resolution over 7 to 10 days.
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Few patients have a single isolated attack of gout and most will experience recurrent episodes, albeit with very variable frequency.
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Over decades, chronic gouty arthritis often with tophaceous disease can develop with very frequent attacks of arthritis or persisting symptoms between attacks of acute arthritis.
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Tophi are most commonly observed as subcutaneous lumps overlying joints or bony prominences but have rarely been reported in many anatomical locations including the spine, conjunctiva, larynx, bowel, cardiac valves, and pancreas.
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Gout may affect the kidney in a variety of ways, including uric acid nephrolithiasis, interstitial urate nephopathy in the absence of overt lithiasis, familial juvenile hyperuricemic nephropathy and hypoxanthine-guanine phosphoribosyltransferase deficiency, acute uric acid–related nephropathy due to tumor lysis and possibly soluble urate may have a direct pathogenic effect as a renal and vascular toxin.
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Elderly women with gout often present with tophi in nodal osteoarthritis of the hands, frequently in the context of diuretic medication use.
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Gout is the most common inflammatory arthritis following solid organ transplantation, occurring in up to one fourth of renal and cardiac recipients, and can progress more quickly to polyarticular disease. Management is facilitated by changing immunosuppression with cyclosporine-A or azathioprine to other regimens.
A Historical Perspective on the Clinical Features of Gout
Gout is clearly an ancient disease. The Egyptians had first written about it by ca. 2640 bc, and archeological skeletal remains at Philae, Upper Egypt, were discovered in 1910 that clearly document an advanced stage of the disease. In the Ebers and Edwin Smith Papyri (ca. 1552 bc ), gout is described and reference is made to much earlier medical writing by Imhotep (ca. 2650 to 2600 bc ), the great luminary of Egyptian medicine, engineering, and architecture. Imhotep is credited with being the father of medicine, having been the first named physician who wrote about disease in nonmagical ways.
One thousand years after the Ebers and Edwin Smith Papyri were written, Hippocrates (ca. 460 bc to 370 bc ), who had studied at the temple of Imhotep at Memphis, separated gout from rheumatism, developing the term “podagra” from pous ( 
) meaning “foot” and agra ( 
) meaning “prey” (a “foot-trap”) for severe pain and swelling in the first metatarsophalangeal joint. This important clinical feature remains a key pointer toward the diagnosis of gout. Hippocrates’ observations on the relationship between an intemperate lifestyle and gout set the scene for an interesting centuries-long concept of the disease as a badge of the rich and powerful. Five aphorisms of Hippocrates on gout continue to describe the general epidemiology fairly well ( Table 9-1 ).
| VI-28 | Eunuchs do not take gout, nor become bald |
| VI-29 | A woman does not take gout, unless her menses be stopped |
| VI-30 | A youth does not get gout before sexual intercourse |
| VI-40 | In gouty affectations, inflammation subsides within 40 days |
| VI-55 | Gouty affectations become active in spring and autumn |
The typical clinical phenomenon of gout (which shall be described in detail in this chapter) has been known for thousands of years. In the first century, Arataeus of Cappadocia (ca. 120) perfectly describes gout as:
Pain seizes the great toe, then the forepart of the heel on which we rest; next it comes into the arch of the foot … the ankle joint swells last of all … no pain is more severe than this, not iron screws, nor cords, not the wound of a dagger, nor burning fire.
He also gives an excellent example of the fact of complete clinical remission between episodes of gout:
This disease remits sometimes for long periods … hence a person subject to the gout has been known to win the race in the Olympic Games during an interval of the disease.
The Romans were also well aware of gout. Galen (ca. 129 to 199/217) was the first to describe tophi and also the hereditary nature of gout, although the important environmental predisposing factors tended to overshadow this aspect for centuries. The first inherited specific purine enzyme deficiency to be associated with gout was described only in 1967 in the condition that came to be known as Lesch-Nyhan syndrome.
The actual term “gout” to describe the disease that we know as gout was not used until medieval times, when the Dominican monk Randolfus of Bocking described it as “the gout which is called podagra or arthritis” [ gutta quam podagram vel artiticam vocant ]. Apparently Randolfus considered that the condition could be cured by wearing the boots belonging to Saint Richard of Wyche, Bishop of Chichester. The term gutta (“drop”) refers to the belief that disease was caused by imbalance in the four humors, so that under certain circumstances an excess of one of these humors would “drop” or flow into a joint, causing pain and inflammation.
Sydenham (1624 to 1689) particularly emphasized the association of gout with debauchery, although this had also been recognized in Roman times:
Gout attacks such old men as, after passing the best part of their life in ease and comfort, indulging freely in high living, wine, and other generous drinks, at length, from inactivity, the usual attendant of advanced life, have left off altogether the bodily exercises of their youth.
Sydenham, who had gout himself, described most of the important clinical features of gout that we would recognize. For example, he also noted the hereditability of the disease (many sufferers “have received the ill seeds of the disease from their parents by inheritance”); that gout can be extremely destructive (“sometimes distorting one or more fingers, making them look like a bunch of parsnips”); the eventual appearance of tophi (“stony concretions of the ligaments of the joints”), and renal stones (“it breeds the stone in the kidney” and “the stone is made of a part of the same kind of matter” as the rest of the gout).
The association with dietary excess has led to gout being used as a literary device by Shakespeare and others, offering insights into the public perception of this condition over the past 400 years. In The Adventure of the Missing Three-quarter , Arthur Conan Doyle vividly described the appearance of tophi: “Yes, he was his heir, and the old boy is nearly eighty—cram full of gout, too. They say he could chalk his billiard-cue with his knuckles.”
Gout has sometimes been used as a means to moral exhortation to lead a more temperate, God-fearing life.
“What a man gout makes! Devout, morally pure, temperate, circumspect,” Cardano said, adding, “No one is so mindful of God as the man who is in the clutches of the pain of gout. He who suffers gout cannot forget that he is mortal.”
As a result, there remains a stigma associated with gout that implies it is largely self-inflicted. Like many victim-blaming approaches, this belief is probably unhelpful and can lead to poorer treatment outcomes. On the other hand, the association between a rich lifestyle and gout has sometimes led to gout being an almost desirable condition. Even in modern times, an association between intelligence or behavioral characteristics associated with high performance, and serum urate levels was documented. These factors may further discourage adequate treatment of clinical gout.
Acute Gouty Arthritis
The initial manifestation of gout is usually an acute attack of gouty arthritis. This is characterized by abrupt onset of severe pain and swelling, usually in a single joint in the lower limb. Maximal inflammation typically occurs within 4 to 12 hours. The classic presentation is that of an acute arthritis of the metatarsophalangeal joint (MTPJ) of the great toe, called podagra ( Fig. 9-1 ). In this and other superficial joints, erythema and soft tissue edema may also be observed. Other areas commonly involved in initial attacks of gout can include mid-tarsal joints and the hindfoot, including the ankle. The pain experienced during an attack of gout is almost always severe with patients protecting the affected joint from any use. The pain interrupts sleep, can prevent walking, and interferes with daily activities. Without treatment, the gouty inflammation in a single joint characteristically subsides over 7 to 10 days. Desquamation of the erythematous skin overlying the joint can occur in superficial joints. After repeated attacks, many patients can recognize a prodrome in the hours leading up to an attack, describing an ill-defined discomfort or tingling in the joint.
Pattern of Joint Involvement
Hospital-based case series have reported monoarticular onset of gout in 70% to 90% of individuals, with the MTPJ of the great toe affected in more than 50% of individuals. Acute gout predominantly affects the joints of the lower limb, including the first MTPJ, mid foot, ankle, and knee. Common sites of acute gout in the upper limb include the small joints of the fingers, elbows, and wrists. The shoulder joint and hip joint are rarely involved but can be affected, along with spinal joints, in particularly severe cases, and in major organ transplant recipients, it is linked with cyclosporine use. Gout in the wrist and elbow is usually associated with longer duration of disease. Bursae that are near or communicate with affected joints may also become acutely inflamed during an attack of gout. The prepatellar and olecranon bursae are common sites of extra-articular involvement ( Fig. 9-2 ).
Polyarticular gout occurs in the first attack of gout in 11% to 28% of patients in hospital-based series. This is likely to be a much higher proportion than would be seen in the community or in primary care; however, there are no published data on joint involvement at gout onset in community series. Fewer than four joints are involved at onset when gout develops into a polyarticular attack. Resolution of inflammation in polyarticular gout may take a number of weeks. Table 9-2 summarizes the pattern of joint involvement from published case series.
| Study | |||
|---|---|---|---|
| Type of practice | Hospital | Primary care | Primary care |
| Country | United Kingdom | United Kingdom | United Kingdom |
| Diagnosis of gout | Clinical | Clinical | Clinical |
| Number of cases | 354 | 604 | 164 |
| Great toe | 76% | 70% | 66% |
| Ankle/foot | 50% | 34% | 35% |
| Knee | 32% | 20% | 12% |
| Finger | 25% | 12% | 7% |
| Wrist | 10% | 7% | 4% |
| Elbow | 10% | 7% | 4% |
| Other | 4% | 17% | 1% |
| Extraarticular | 3% | 3% | Not specified |
The pattern of joint involvement in gout is probably explained by the physicochemical and local factors influencing the deposition of monosodium urate (MSU) crystals. A prerequisite for MSU crystal formation is hyperuricemia; however, de novo MSU crystal formation may be facilitated by other factors (see Chapter 5 ). Situations that may favor change in serum urate or tophus remodeling, such as vigorous exercise and joint trauma, have been suggested as possible precipitants to attacks of gout.
The intense local inflammation in gout can be associated with a systemic inflammatory response, including fever, neutrophilia, and elevation of acute phase reactants. Fever occurs more frequent in polyarticular gout, but there is no correlation between severity of fever or neutrophilia and the number of involved joints.
Precipitants
Precipitating factors for gouty attacks are reviewed in detail in the discussion on attack prophylaxis in Chapter 15 . Acute gout appears to occur more frequently in the spring or summer months. In hospital practice, acute gout is often seen during other acute illnesses, postoperatively, or following trauma. In this context, dehydration, fasting, change in medication (particularly introduction of diuretics), and changes in alcohol intake can all contribute to rapid changes in serum urate concentration linked to promotion of gout attacks. Cessation or introduction of urate-lowering medications can also precede an attack of gout.
Individuals with gout report a variety of activities and events that may precipitate an attack of gout, most often dietary. Data from the Health Professionals Follow-Up Study have confirmed that higher intakes of meat, seafood, and alcohol, particularly beer and spirits, are associated with a higher risk of the onset of gout. Patients will often report dietary indiscretion or heavy alcohol intake in the days preceding the onset of an attack of gout.
Differential Diagnosis
Diagnosis of gout is reviewed in Chapter 7 . In brief, spontaneous onset of an acute, severe monoarthritis affecting the MTPJ of the great toe in a middle-aged man with hyperuricemia is most commonly gout. The differential for an acute monoarthritis or oligoarthritis is very broad and includes pseudogout, septic arthritis, and spondyloarthritis. The differential for an acute polyarthritis also includes the systemic immune arthritides. The critical diagnostic investigation is joint arthrocentesis with demonstration of MSU crystals in synovial fluid. This should be performed in all instances of a possible diagnosis of gout, to confirm the diagnosis and exclude septic arthritis. Careful examination for the presence of tophi may assist in diagnosis but should not preclude examination of synovial fluid.
Chronic Gout
If hyperuricemia persists, gout may evolve from a sporadic acute monoarthritis to a pattern of more frequent acute attacks, which may affect multiple joints simultaneously (polyarticular gout) or in rapid succession. Macroscopic deposits of MSU crystals, known as tophi, may accumulate in the joints, tendon sheaths, over bony prominences, and in subcutaneous tissues. Clinically, tophi are recognized as asymmetric white to yellow firm swellings under the skin. Common soft tissue locations of subcutaneous tophi include the ear pinnae, olecranon or prepatella bursae, the distal interphalangeal joints, and overlying the dorsum of the MTPJ and metacarpophalangeal joint (MCPJ) ( Figs. 9-3 and 9-4 ).
Microscopically tophi are deposits of MSU crystal surrounded by a chronic inflammatory infiltrate consisting of macrophages, lymphocytes, and occasional neutrophils. Tophi can be accompanied by persistent low-grade inflammation causing chronic pain, tenderness, swelling, and redness of affected tophi or joints. This presentation may resemble the widespread small and large joint synovitis of rheumatoid arthritis or psoriatic arthritis.
Complications of Chronic Gout
Articular and periarticular tophi can be associated with bone erosions and significant joint deformities. Articular and periarticular tophi can cause marked swelling at the proximal and distal interphalangeal joints and the MCPJs. Hand deformities can include swan neck, boutonniere, and flexion deformities, virtually indistinguishable from those seen in rheumatoid arthritis ( Figs. 9-4 and 9-5 ). Tophi may erode the overlying soft tissue and cause ulcerating lesions that discharge a chalk-like material consisting of MSU crystals ( Fig. 9-6 ). The deformities, mechanical impact of tophi, and ulceration all contribute to loss of joint and limb function and are often cosmetically unappealing. Patients often are unable to wear normal footwear and resort to sandals or cutting holes in shoes to accommodate tophi. Tophi overlying the olecranon are frequently traumatized during daily activity or employment, becoming inflamed and painful. In the hand, the number of tophi overlying joints is the best predictor of hand function with greater number of tophi associated with worse hand function. The frequency and impact of other direct complications of tophi have not been formally quantified but undoubtedly have impacts on health-related quality of life and health care costs for individuals with tophaceous gout.
Tophi that ulcerate the skin can become secondarily infected, causing cellulitis or infections of the deep tissues including septic arthritis and osteomyelitis. As ulcerated tophi often already have local inflammation in response to the MSU crystal, a high index of suspicion must be maintained for coexistent infection. Increasing pain, purulent discharge, enlarging area of erythema, or systemic illness may all suggest secondary infection.
Surgery for Tophi
Occasionally, tophi may require surgical excision or debridement if the tophus is frequently injured, painful, becomes infected, or interferes with limb function, footwear, or ability to complete daily activities. Ulcerated tophi can become secondarily infected and surgical debridement is often necessary prior to curative treatment with antibiotics. In the largest case series reporting 45 cases requiring surgical management of tophi in gout, indications for surgery were control of sepsis (51%), mechanical problems in hand, foot, or elbow (27%), and pain (4%). The remaining 18% of procedures were for excision of a soft tissue mass of unknown etiology, with subsequent demonstration of MSU crystals within the excised tophaceous deposit. Delayed wound healing (longer than 1 week) occurred in just over half of cases, within delayed healing twice as common in surgery to the lower limb than to the upper limb. Factors contributing to impaired wound healing included preceding local infection, inadequate debridement of tophi, and unrecognized vascular disease. Newer techniques such as hydrosurgical debridement may offer improved debulking of large subcutaneous tophi with improved wound healing. Optimal perioperative care of individuals undergoing surgery on tophi must include assessment and optimization of vascular supply, aggressive control of sepsis, control of blood glucose in coexisting diabetes, and meticulous wound management. Optimization of urate-lowering medication is imperative for all patients with complicated tophi.
Natural History of Gout
After resolution of the first acute attack of gout, an individual is asymptomatic and this period between attacks is referred to as “intercritical gout.” Following a initial attack of gout, it is estimated that 60% of individuals will experience a further attack within 1 year and 80% within 3 years. With subsequent attacks and increasing duration of gout, the frequency of polyarticular attacks increases and there is more frequent involvement of the upper limb.
There are few useful longitudinal data on the natural history of gout, but the generally accepted dogma is that if the underlying hyperuricemia remains untreated, there is evolution, usually over many years, from acute, sporadic monoarticular or polyarticular gout (acute gout) to recurrent polyarthritis and formation of tophi, known as chronic tophaecous gout ( Fig. 9-7 ). Chronic tophaceous gout can manifest with persistent, mild to moderate joint and peritophaceous inflammation, which causes chronic pain ( Fig. 9-8 ).
The natural history of progression through these three stages is highly variable. Before the use of urate-lowering therapy, chronic polyarticular gout or tophi developed 3 to 42 years after a first attack of gout, with an average of 11.6 years. More recent data in untreated gout have shown tophi develop in 12% of patients within 5 years and 55% of patients in 20 years. In certain circumstances, tophi may develop very rapidly, after one or two acute attacks, particularly in women with osteoarthritis in the small joints of the hands who are treated with diuretics and in patients with organ transplantation treated with cyclosporine. Other risk factors for progression to tophaceous gout are not well defined but one study has identified an increased incidence of tophi in individuals with younger age at onset, longer duration of gout, delay in commencement of urate-lowering therapy, and history of polyarticular or upper limb involvement.
Renal Manifestations of Gout
In the majority of people with gout, the principal reason for hyperuricemia is relative underexcretion of filtered urate. In this sense, gout could be considered a primary renal disease. The renal defects that underlie this metabolic abnormality are described more fully elsewhere in this textbook (see Chapter 4 ).
However, in addition to the most common cause of gout being located in the kidney, the consequences of gout and hyperuricemia are also manifest in the kidney and comprise a number of clinical syndromes that will be the focus of this section. These may be considered in the order in which they appeared historically: uric acid nephrolithiasis, urate nephropathy in the absence of overt lithiasis, recognition of familial juvenile hyperuricemic nephropathy (FJHN) and complete or partial hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (Lesch-Nyhan and Kelley-Seegmiller syndromes, respectively), acute uric acid–related nephropathy due to tumor lysis with the introduction of cytotoxic chemotherapy, and, most recently, the notion that soluble urate may have a direct pathogenic effect as a renal and vascular toxin.
Uric Acid Nephrolithiasis
Uric acid was first identified as a component of kidney stones ( Fig. 9-9 ) in 1776 and now accounts for around 10% of nephrolithiasis in the United States. Uric acid stones are the main reason for the higher rate of nephrolithiasis in people with type 2 diabetes mellitus and obesity. Uric acid stone formers tend to be older and more likely to be obese than calcium oxalate stone formers.
Nephrolithiasis presents in much the same way regardless of the chemical nature of the kidney stone, with the classic symptoms of renal colic and hematuria. Uric acid stones are radiopaque but are well demonstrated on computed tomography (CT), and dual-energy CT (DECT) identifies uric acid stones with higher specificity than other modalities. The risk of recurrence is not greatly affected by the chemical nature of the stone and is 27% over 7.5 years.
Although people with gout are at higher risk of uric acid stone formation compared with nongout populations (with a multivariate relative risk of 2.12 in men of incident kidney stones ), most patients with uric acid stones do not have gout or hyperuricemia or even necessarily hyperuricosuria. Men with nephrolithiasis are no more likely to have gout than men without nephrolithiasis. Among men with gout, the prevalence of nephrolithiasis detected by helical CT was 27% but over half of these were clinically asymptomatic. Men with gout and nephrolithiasis are more likely to be obese. Symptomatic nephrolithiasis was observed in 15% of men with gout in the Health Professionals Follow-Up Study.
Calcium oxalate stones are more common in people with gout than are uric acid stones and pure uric acid stones are distinctly uncommon, being present in 16 of 163 (10%) stone-formers with gout from a stone registry. The major metabolic characteristics of calcium oxalate stone formers are greater urinary calcium excretion and lower urinary citrate excretion leading to higher urinary saturation of calcium oxalate. Urinary calcium levels following an oral calcium load are also greater, suggesting increased gastrointestinal absorption of calcium. The mechanism for these observations is unclear.
The major metabolic abnormality that underpins uric acid lithiasis is excessive urinary acidity since urine pH is the major determinant of uric acid crystallization. In most cases, this is idiopathic. Acidic urine is observed in people with gout, even in the absence of renal stones, but is worse in stone formers, and this is associated with a deficit of ammonium excretion.
Although hyperuricosuria is a very important factor in leading to uric acid stones in some patient groups, this is not present in most people with uric acid nephrolithiasis. Hyperuricosuria may occur in rare metabolic conditions such as Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, some glycogen storage diseases, or rare cases of URAT1 ( SLC22A12 ) or GLUT9 ( SLC2A9 ) mutations associated with severe hypouricemia (see Chapter 4 ).
Recently, an association between the metabolic syndrome and uric acid nephrolithiasis has been identified. This association appears not to be due to the known association of hyperuricemia and the metabolic syndrome but rather an association between an unduly acidic urinary pH and the metabolic syndrome. The principal mechanisms of urinary acidity in uric acid nephrolithiasis are increased net acid excretion and impaired buffering caused by inadequate ammonium excretion. Urinary pH and ammonium excretion are directly correlated with the number of metabolic syndrome features, with more features being associated with a more acidic urine and lower ammonium excretion. In studies using the hyperinsulinemic euglycemic clamp technique, insulin resistance was shown to be associated with excessive urinary acidity.
Urate Nephropathy
The extent to which hyperuricemia causes rather than is caused by renal impairment has long been a subject for discussion and is reviewed in Chapter 19 . It is important to clarify terminology. Urate interstitial nephropathy is urate crystal deposition in the physiologic pH of renal medulla, as opposed to tubular lumen obstruction due to uric acid urolithiasis seen in tumor lysis syndrome or uricase knockout mice.
With specific respect to urate nephropathy (“gouty nephropathy”), Sydenham describes “morbific matter” in what may be an early account of gouty nephopathy:
The viscera in time are so much injured, from the stagnation of the morbific matter therein, that the organs of secretion no longer perform their functions, whence the blood, overcharged with vitiated humours, stagnates, and the gouty matter ceases to be thrown upon the extremities as formerly, so that at length death frees him from his misery.
In the middle of the 20th century, it was well recognized that patients with gout could frequently develop renal impairment. In that era prior to the widespread introduction of effective urate-lowering therapy or antihypertensive therapy, renal failure in patients with primary gout was not rare. For example, a case series of approximately 300 patients with mainly untreated gout from the 1950s observed significant renal disease in 18% to 25% of cases, and renal histologic changes, in 1960, were observed in the large majority of people with gout. However, whether these observations were due to hyperuricemia directly or to hypertension that is often coexistent with gout is difficult to determine. Pathologically, the kidneys of people with gout are characterized mainly by changes typically associated with hypertensive renal disease: advanced arteriosclerosis, glomerulosclerosis, and interstitial fibrosis ( Figs. 9-10 and 9-11 ). Urate crystal deposition is observed, but the focal nature of that feature seems inconsistent with the diffuse nature of the renal disease. Furthermore, perhaps analogous to the fact that most people with hyperuricemia do not develop gout, 86% of postmortem cases with renal medullary urate deposits did not have gout in life.
In people with elevated serum urate, it has been postulated that hyperuricemia itself is directly nephrotoxic, even prior to the development of the clinical syndrome of gout, and may be a mechanism for the increased rate of hypertension, cardiovascular disease and renal impairment that is observed (see Chapter 6 , Chapter 19 ). On the other hand, some authors have called this a “non-disease” based on the infrequency of the combination of chronic hyperuricemic nephropathy and renal failure not otherwise explained that was observed in a large series of postmortem examinations or in longitudinal cohort studies. Similarly, serum urate levels have not always been found to be an independent risk factor for renal progression, especially when baseline renal impairment is taken into account. In a longitudinal study that followed people with gout over a decade, it was observed that only those with associated hypertension had progressive renal impairment but control of hyperuricemia appeared to have no significant association with progressive renal impairment.
In contrast, studies of patients with immunoglobulin A (IgA) nephropathy have shown that hyperuricemia was an independent risk factor for progressive renal dysfunction, having adjusted for proteinuria, hypertension, diabetes, age, gender, and obesity. In addition, a large study of male railway workers showed that baseline hyperuricemia of greater than 8.5 mg/dL was associated with an 8.5-fold increased rate of death with renal failure at 5 years. This latter study did not appear to adjust for important comorbidities.
Although earlier Framingham Study data did not support the notion that serum urate was independently associated with cardiovascular morbidity, there is now evidence from large epidemiologic studies, including the MRFIT study, Framingham study, and the Health Professionals Follow-Up Study, that several cardiovascular outcomes are independently associated with gout in men. The risk of coronary heart disease is independently increased (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.1 to 2.5 ; OR 1.26, 95% CI 1.14 to 1.40 ). And the risk of all cardiovascular death (OR 1.38, 95% CI 1.15 to 1.66) and fatal coronary heart disease is also increased (OR 1.55, 94% CI 1.04 to 2.41).
The analytic difficulty with determining the connection between serum urate, hypertension, and renal outcomes is the close association of renal function itself with uric acid levels and the association of hyperuricemia with other causes of renal impairment (especially hypertension), confounding the interpretation of direction or mechanism of the association. One way to resolve the difficulty would be experimental—directly testing the notion that a reduction in uric acid levels leads to improvement in renal function. While there are some experiments in animals that support this idea, for example, there is limited evidence that reduction of serum urate with allopurinol reduces progression of renal function in patients with renal impairment and no history of gout. In one study, creatinine rose by 21% in allopurinol-treated patients compared to a 55% increase in patients allocated to placebo. However, the small numbers of patients and variability in renal function progression meant that this apparent difference was not statistically significant at the conventional 5% level. Another small, nonrandomized, study of allopurinol treatment in people with asymptomatic hyperuricemia and normal renal function showed that renal function improved significantly in allopurinol-treated patients but there was no change in normal control subjects. This study is difficult to interpret because the control subjects were normouricemic and there was no random allocation. There remains a need for a large, properly designed study to test the notion that urate-lowering therapy improves renal outcomes.
Familial Juvenile Hyperuricemic Nephropathy (FJHN, OMIM 162000)
This condition is an autosomal dominant disease characterized by end-stage renal failure at a young age, reduced fractional excretion of urate, renal interstitial urate deposits, and sporadic gouty arthritis. In one Polynesian family, two sisters and a child of the propositus (who presented with gout and end-stage renal failure) had renal failure and hyperuricemia but not gout. More than 50 families with FJHN have been described in various ethnic groups since the original description in 1960. The condition is genetically heterogeneous and can be caused by mutations in the UROMODULIN ( UMOD ) gene located on chromosome 16p12.3 to p13.11. The UMOD gene encodes uromodulin, also known as the Tamm-Horsfall glycoprotein. It has been suggested that the disease is associated with abnormalities in protein folding, maturation, and trafficking of uromodulin rather than deficiency.
Acute Hyperuricemic Nephropathy
This condition is not usually associated with gout but is a disorder of sudden, massive urate load caused by tumor lysis, often in children with hematopoietic malignancies. Dehydration and low urinary pH may be associated features. Due to a sudden oversaturation of uric acid in the urine, uric acid precipitates as crystals or sludge in tubules and collecting ducts leading to urinary obstruction. Interstitial fibrosis or tophi are not generally observed.
Related posts:
Diagnosis of Gout
Articular Pathology of Gout, Calcium Pyrophosphate Dihydrate and Basic Calcium Phosphate Crystal Deposition Arthropathies
Gout: Epidemiology and Risk Factors
Prophylaxis of Attacks of Acute Gouty Arthritis
Basic Calcium Phosphate Crystal Arthropathy
Crystalline Disorders Associated With Renal Disease Including Oxalate Arthropathy
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