Short running title: BSR and BHPR Guideline for the Management of Gout Scope and purpose Background to the disease Gout is the most common cause of inflammatory arthritis worldwide. In UK general practice, the overall prevalence has increased from 1.4% in 1999 to 2.49% in 2012 1 , despite the availability of effective and potentially 'curative' urate-lowering drugs for more than 50 years and evidence-based British and European management guidelines for nearly a decade 2;3. Clinical manifestations of gout resulting from monosodium urate (MSU) crystal deposition, include tophi, chronic arthritis, urolithiasis and renal disease as well as recurrent acute arthritis, bursitis and cellulitis. Gouty arthritis and tophi are associated with chronic disability, impairment of health-related quality of life (HRQOL) 4-7 , increased use of healthcare resources, and reduced productivity 8. Gout is also frequently associated with co-morbidities such as obesity, dyslipidaemia, diabetes mellitus, chronic renal insufficiency, hypertension, cardiovascular disease, hypothyroidism, anaemia, psoriasis, chronic pulmonary diseases, depression and osteoarthritis 1 as well as with an increase in all-cause mortality (adjusted hazard ratio 1.13, 95% CI 1.08 to 1.18) and urogenital malignancy 1;9. Sustained hyperuricaemia is the single most important risk factor for the development of gout. Hyperuricaemia occurs secondary to reduced fractional clearance of uric acid in more than 90% of patients with gout 10. Age, male gender, menopausal status in females, impairment of renal function, hypertension and the co-morbidities that comprise the metabolic syndrome are all risk factors for incident Recently published guidelines include the 2012 American College of Rheumatology Guidelines for the Management of Gout 34,35 and the 2013 evidence-based recommendations for the diagnosis and management of gout by a multinational panel of rheumatologists participating in the 3e initiative 36. Other National and Regional guidelines include the US Government 2014 Agency for Healthcare Research and Quality (AHRQ) Guidelines for the Diagnosis and Management of Gout 37,38 , and the Australian and New Zealand 39 and Portuguese 40 recommendations for the diagnosis and management of gout which arose from the 3e initiative. 36 Updated EULAR recommendations for the management of gout will be published in 2016. Objective This guideline aims to offer revised and updated, concise, patient-focussed, evidence-based, expert recommendations for the management of gout in the UK.

A series of 89 adult-onset nephrotic patients with minimal changes on renal biopsy was analyzed to compare the rate of response to corticosteroids and cytotoxic agents and the stability of remission or frequency of relapses at different ages. Severe hypertension and diminished renal function were more common in patients aged over 60 years, who formed 22.5% of the group. Seventy-five patients were given a first course of prednisolone in an initial dose of 60 mg/24 hr. After an eight week course of tapering doses of corticosteroids, only 45 of the 75 patients were in complete remission, 55 patients after 16 weeks and eventually 58 lost their proteinuria. The respective estimates of remission were 60%, 76% and 81%. Subsequently, of the 58 treated patients who responded, 24% never relapsed. Fifty-six percent of the patients relapsed on a single occasion or infrequently, and only 21% were frequent relapsers. Cyclophosphamide was used in 36 patients, in two as initial treatment, in 11 because of corticosteroid resistance, and in the remainder because of relapses. The time-course of loss of proteinuria was similar to that following treatment with corticosteroids, 25 (69%) losing proteinuria within 16 weeks. Only four patients failed to lose their nephrotic syndrome. Two of them had presented in acute renal failure and all four were over 60 years of age. The stability of remission after cyclophosphamide was better than that reported for children, only 13 of 36 showing relapses and 66% being in remission at five years, after which no further relapses were seen.(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract

Although gout and hyperuricaemia are usually thought of as conditions of indulgent male middle age, in addition to the well-known uricosuria of the newborn, there is much of importance for the paediatric nephrologist in this field. Children and infants may present chronically with stones or acutely with renal failure from crystal nephropathy, as a result of inherited deficiencies of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) or of the catabolic enzyme xanthine dehydrogenase (XDH). Genetic purine overproduction in phosphoribosylpyrophosphate synthetase superactivity, or secondary to glycogen storage disease, can also present in infancy with renal complications. Children with APRT deficiency may be difficult to distinguish from those with HPRT deficiency because the insoluble product excreted, 2,8-dihydroxyadenine (2,8-DHA), is chemically very similar to uric acid. Moreover, because of the high uric acid clearance prior to puberty, hyperuricosuria rather than hyperuricaemia may provide the only clue to purine overproduction in childhood. Hyperuricaemic renal failure may be seen also in treated childhood leukaemia and lymphoma, and iatrogenic xanthine nephropathy is a potential complication of allopurinol therapy in these conditions. The latter is also an under-recognised complication of treatment in the Lesch-Nyhan syndrome or partial HPRT deficiency. The possibility of renal complications in these three situations is enhanced by infection, the use of uricosuric antibiotics and dehydration consequent upon fever, vomiting or diarrhoea. Disorders of urate transport in the renal tubule may also present in childhood. A kindred with X-linked hereditary nephrolithiasis, renal urate wasting and renal failure has been identified, but in general, the various rare types of net tubular wasting of urate into the urine are recessive and relatively benign, being found incidentally or presenting as colic from crystalluria. However, the opposite condition of a dominantly inherited increase in net urate reabsorption is far from benign, presenting as familial renal failure, with hyperuricaemia either preceding renal dysfunction or disproportionate to it. Paediatricians need to be aware of the lower plasma urate concentrations in children compared with adults when assessing plasma urate concentrations in childhood and infancy, so that early hyperuricosuria is not missed. This is of importance because most of the conditions mentioned above can be treated successfully using carefully controlled doses of allopurinol or means to render urate more soluble in the urine. Xanthine and 2,8-DHA are extremely insoluble at any pH. Whilst 2,8-DHA formation can also be controlled by allopurinol, alkali is contraindicated. A high fluid, low purine intake is the only possible therapy for XDH deficiency.

We have conducted an immunocytochemical analysis to investigate the presence of the recently described vascular cell adhesion molecule-1 (VCAM-1) in human kidney, using the anti-VCAM-1 monoclonal antibody 1.4C3. In normal control tissue VCAM-1 was present on some (but not all) parietal epithelial cells lining Bowman's capsule. Forty-nine of fifty clinical biopsy specimens were characterised by the additional presence of VCAM-1 on proximal tubular cells. This was most marked in biopsies of patients with interstitial nephritis or systemic vasculitis with crescentic nephritis, but was also observed in biopsies with minimal change, IgA or lupus nephropathy, or from patients with diabetic nephropathy, amyloid, or gout. Proximal tubule VCAM-1 correlated significantly with the number of transferrin-receptor-positive leukocytes (r = 0.607, p less than 0.0001) in the interstitium, but not with expression of HLA-DR by tubular cells. Surprisingly, VCAM-1 was not observed on vascular endothelial cells in these biopsies, even in the presence of a marked infiltrate; this contrasts with other tissues (e.g. skin and synovium). The presence of VCAM-1 on tubular cells in the inflamed kidney indicates the potential for these cells to interact with mononuclear cells, either as accessory cells or as cytotoxic targets. The unexpected absence of VCAM-1 in renal vascular endothelial cells suggests local differences in the endothelial cells of this organ.