Italian Society of Rheumatology recommendations for the management of gout.

OBJECTIVE: Gout is the most common arthritis in adults. Despite the availability of valid therapeutic options, the management of patients with gout is still suboptimal. The Italian Society of Rheumatology (SIR) aimed to update, adapt to national contest and disseminate the 2006 EULAR recommendations for the management of gout. METHODS: The multidisciplinary group of experts included rheumatologists, general practitioners, internists, geriatricians, nephrologists, cardiologists and evidence-based medicine experts. To maintain consistency with EULAR recommendations, a similar methodology was utilized by the Italian group. The original propositions were translated in Italian and priority research queries were identified through a Delphi consensus approach. A systematic search was conducted for selected queries. Efficacy and safety data on drugs reported in RCTs were combined in a meta-analysis where feasible. The strength of recommendation was measured by utilising the EULAR ordinal and visual analogue scales. RESULTS: The original 12 propositions were translated and adapted to Italian context. Further evidences were collected about the role of diet in the non-pharmacological treatment of gout and the efficacy of oral corticosteroids and low-dose colchicine in the management of acute attacks. Statements concerning uricosuric treatments were withdrawn and replaced with a proposition focused on a new urate lowering agent, febuxostat. A research agenda was developed to identify topics still not adequately investigated concerning the management of gout. CONCLUSIONS: The SIR has developed updated recommendations for the management of gout adapted to the Italian healthcare system. Their implementation in clinical practice is expected to improve the management of patients with gout.

[A case of hypercalcemia in hemodialysis]. / Un caso di ipercalcemia in emodialisi.

We report a case of hypercalcemia in a female patient who was restarted on hemodialysis 22 years after renal transplantation. Graft biopsy showed chronic post-transplant nephropathy. Treatment with immunosuppressants and steroids was maintained owing to residual graft function. She was then given oral paracalcitol 1 µg/d for secondary hyperparathyroidism (iPTH 850 pg/mL) and her transplant medication was reduced and then discontinued. After this, the patient referred widespread joint pain, especially in the hips and subsequently presented with erythema nodosum. She also developed hypercalcemia and hyperphosphatemia which persisted after stopping paracalcitol. The clinical picture of increased serum calcitriol, with depressed PTH, suggested sarcoidosis, despite normal ACE levels, a chest X-ray and skin biopsy confirmed the diagnosis, and the patient was started on prednisone 50 mg/day, resulting in prompt normalization of both symptoms and blood chemistry. This is a rare case of hypercalcemia secondary to sarcoidosis in an uremic patient. The sarcoidosis was most likely suppressed by the transplant therapy and rapidly developed after this was suspended. Prompt diagnosis resulted in a good therapeutic response.

[Selective vitamin D receptor activation: effect on renal physiopathology]. / L'attivazione selettiva dei VDR: impatto sulla fisiopatologia renale.

The wide distribution of the vitamin D receptor (VDR) suggests that its activators (VDRAs) are involved in diverse organ functions including the cardiovascular, immune, and reproductive systems. These actions are likely to be independent of PTH and calcium/phosphorus levels. Earlier studies had shown that calcitriol was able to favorably influence experimental nephritis, remnant kidney glomerulosclerosis, and interstitial fibrosis, mediated through inhibition of inflammatory cytokines. Recently, VDRAs were shown to inhibit the reninangiotensin system (RAS), acting directly on the renin gene promoter. This action is independent of the systemic RAS blockade. VDRAs also inhibit other important gene promoters including NF-kB and p65, which are known to foster inflammation and fibrogenesis. These multiple actions result in a decrease in macrophage infiltration, fibroblast activation, and endothelial mesenchymal transition in the kidney. These findings represent the rationale for the use of VDRAs, in association with RAS blocking agents, to counteract the progression of renal injury characterized by inflammation and neofibrogenesis. However, despite promising preliminary results, the human studies available to date do not allow to draw definitive conclusions on this matter.

[PTH measurement: where do we stand?]. / PTH: a che punto siamo con il dosaggio?

PTH measurements are widely used by nephrologists because parathyroid function is frequently altered in uremic patients, with clinical implications for bone and the cardiovascular system. This is why both national and international guidelines recommend target values for PTH. However, the reliability of PTH assays is hampered by the presence of many circulating molecular types of the hormone, which are known to have different biological effects. The so-called first-generation methods measuring all C-term fragments were replaced by second-generation ones based on the double-antibody technique; the latter were shown to be more reliable and easy to use. These methods have been widely adopted, proving helpful for diagnosis, prognosis and treatment in clinical settings. However, when different second-generation methods were compared, inconsistent values were obtained. Moreover, it was shown that they cross-reacted with N-truncated fragments, including C-term 7-84 PTH, which do not display PTH activity. The more recently introduced third-generation methods exhibit higher specificity for the 1-84 whole molecule and are not liable to interference by N-truncated fragments. When compared to intact PTH, the whole-PTH methods yield about 50% lower values, but the difference remains constant through the entire range of PTH values. Indeed, despite different absolute results either between whole and intact PTH or within identical-generation methods, there are very close correlations among them, with coefficients above 0.95. Thus, most assays can be considered reliable but the different results, if not correctly interpreted, may give rise to misinterpretation on clinical grounds. It is agreed that these differences depend on the use of both different calibration standards and antibody specificity. We conclude that, irrespective of the method used, one should clearly know what PTH is being measured, using specific reference ranges and applying specific targets.

Primary hyperoxaluria: report of an Italian family with clear sex conditioned penetrance.

We report the clinical and genetic study of a primary hyperoxaluria type I (PH1) family with two sisters homozygous for p.Gly170Arg who are still asymptomatic at age 29 and 35, and two brothers, also homozygous for the same mutation, who are affected since age 27 and 30. The clear sex difference observed in this family and in others reported in the literature fits well with the prevalence of males over females in the Italian registry. In the KO model of PH1, only male mice develop renal stones, suggesting that the sex difference may affect both oxalate production and stone formation. A likely mechanism is the sex-related expression of glycolate oxidase shown in experimental animals. The stable isotope method recently developed by Huidekoper and van Woerden for in vivo assessment of the endogenous oxalate production could help to clarify the issue in humans.

[Calcimimetics, phosphate binders, vitamin D and its analogues for treating secondary hyperparathyroidism in chronic kidney disease: guideline from the Italian Society of Nephrology]. / Utilizzo della vitamina D e analoghi, dei chelanti del fosforo e dei calciomimetici nella terapia dell'iperparatiroidsmo secondario e della patologia ossea nelle nefropatie croniche: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of the use of calcimimetics, phosphate binders, vitamin D and vitamin D analogues for treating secondary hyperparathyroidism in chronic kidney disease (CKD) is presented. METHODS: SR of RCT and RCT on interventions for secondary hyperparathyroidism in CKD were identified referring to a Cochrane Library and Renal Health Library search (2005 update). RESULTS: Three SR and 8 RCT were found addressing this intervention issue. Methodological quality of available RCT was suboptimal according to current methodological standards. Calcimimetics used in patients receiving haemodialysis or peritoneal dialysis are more effective than placebo in controlling secondary hyperparathyroidism (reduced parathyroid hormone levels, calcium levels and phosphorus levels). All phosphate binders are effective in controlling hyperphosphatemia but different doses are to be used with different agents to achieve similar targets. Dosing needs to be adjusted according to phosphorus levels. Vitamin D and its analogues are recommended in CKD patients, although there is no significant evidence of superiority of individual agents in head-to-head comparisons. Dosing should be based on baseline parathyroid hormone levels, but the risk of hypercalcemia should also be considered. CONCLUSION: Available evidence suggests that calcimimetics, phosphate binders and vitamin D or its analogues are effective in the treatment of secondary hyperparathyroidism. Superiority of individual agents or doses is still deeply debated. Further studies are necessary to test these issues.

[A nephrologist's tasks in nephrolithiasis]. / I compiti del nefrologo nella nefrolitiasi.

The epidemiological impact of nephrolithiasis stems from a significant and increasing prevalence in western countries. While the kidney is the end-organ of the disease, the causes are often more general, including metabolic derangements, pri-mary diseases of other organs and systems, hereditary renal or non-renal defects. In this context, nephrological expertise is highly recommended and could considerably improve disease outcomes. The nephrologist's involvement should start while the patient is acutely affected by renal colic. In this setting medical intervention is aimed at counteracting pain, favoring progression in the urinary tract, and preventing renal injury. The choice for urological procedures should take into account the potential for harmful effects of obstruction, infection, and prolonged pain. After the patient has undergone non-invasive procedures medical intervention improves the management of residual fragments, reduces the risk of stone recurrence, and increases compliance to the stone center, as a premise for considering patients for metabolic evaluation and subsequent medical treatment. Current study protocols, including chemistries, physicochemistry and possibly genetics, are the basis for a rational treatment of recurrent stone disease. Secondary nephrolithiasis caused by systemic disorders is screened out and treated specifically. Hereditary forms can be identified by genetic analysis and strictly followed and treated. While medical therapy can cure some types of renal stones, prolonged remission is seldom obtained in calcium nephrolithiasis. However, recurrence rates are greatly reduced, and this lessens the need for urological procedures, risk of infection/obstruction and, ultimately, progression to renal insufficiency. In the face of a multidisciplinary approach to renal stone disease, the nephrologist has a key role in the successful management of these patients.

[Severe renal failure in a child]. / Insufficienza renale ad esordio acuto in un bambino.

A four-year-old male child was admitted with severe renal failure, apparently recent in onset and he was treated with peritoneal dialysis (PD). A renal biopsy showed interstitial cellular infiltration with crystals within the tubules and sclerotic glomeruli. Type I hyperoxaluria was diagnosed and the child received a liver and kidney transplant after 10 months of dialysis. Two years later, he has normal renal function, and blood and urine oxalate levels are within normal ranges.

Effects of potassium citrate supplementation on bone metabolism.

Western diets rich in animal protein result in long-term acid loading that, despite corresponding increases in net renal acid excretion, may induce a chronic state of acidemia. This may have deleterious effects on both the kidney and bone, by increasing the risk of calcium stone in the former and leading to chemical dissolution of mineral alkaline salts in the latter. Whereas supplementation with alkaline citrate has been shown to reduce stone recurrences, its effect on bone turnover has received less attention. The aim of the present study was to evaluate whether potassium citrate favorably affects bone turnover markers in postmenopausal females with low bone density. Thirty women, aged 58 +/- 8.1 years, were enrolled and studied on basal conditions and after a 3-month course of potassium citrate supplementation (0.08-0.1 g/kg b.w. daily). Twenty-two women concluded the study while 8 withdrew. Twenty-four age-matched healthy women were taken as control cases. All were evaluated for electrolyte and acid-base balance-related parameters, bone turnover, markers and renal function. A significant decrease in net acid excretion was observed upon citrate supplementation, and this was paralleled by a significant decrease of urinary deoxypyridinolines, hydroxyproline-to-creatinine ratios, and, to a lesser extent, serum osteocalcin. Percent variations of urine citrate were inversely related to those of deoxypyridinolines and hydroxyproline. No change in these chemistries occurred in the control group. Our results suggest that treatment with an alkaline salt, such as potassium citrate, can reduce bone resorption thereby contrasting the potential adverse effects caused by chronic acidemia of protein-rich diets.

[Intact whole bioactive parathormone: problems arising from comparing different methods]. / Paratormone intatto intero bioattivo: le problematiche emergenti dal confronto.

BACKGROUND: Parathyroid hormone (PTH) has important applications in the nephrological clinical practice. Because assays of Intact PTH (I-PTH) are liable to interferences by N-truncated fragments, a novel method for whole-(1-84) PTH has been proposed. This study is aimed at comparing the latter with some of the previous I-PTH assays. For each method the results are referred to pertinent markers of mineral metabolism. METHODS: We enrolled 171 subjects, including 56 healthy controls (C), 65 calcium stone- formers (CaSF), 40 haemodialysis patients (HD), 10 with primary hyperparathyroidism (PHP). On blood samples we measured: I-PTH by four methods (N-Tact, Advantage, Elecsys, Scantibodies), whole-(1-84) PTH, defined as CAP (Cyclase Activating PTH), total and ionised calcium, phosphate, vitamin D, osteocalcin and Crosslaps. The difference between I-PTH and CAP Scantibodies is defined as CIP (Cyclase Inhibiting PTH). RESULTS: Despite relating to each other (r>0.97) PTH values varied remarkably among methods. For all methods, the reference intervals differed from those provided by the producer. Assuming these new ranges, 10 CaSF had over-range values not always associated with abnormalities of mineral metabolism. One of the PHP patients was normal for I-PTH with 2/4 methods. In HD the differences among methods were even greater, there were inverse (p<0.05) and direct (p<0.001) relationships with ionised calcium and osteocalcin-crosslaps, respectively. The CAP/CIP ratio was lower in low bone turnover patients, but the two subgroups widely overlapped. CONCLUSIONS: This study indicates that the reliability of I-PTH assays is still unsatisfactory, and none of the four methods emerged as the best. Assay for CAP only improves diagnostic efficiency, whereas the CAP/CIP ratio does not exhibit powerful discriminating capacity. Our suggestion is that each Centre should establish its own reference ranges. PTH assay should always be coupled with measurements of other markers of mineral metabolism as well as renal function.

[LithoRisk: A software for calculating and visualising nephrolithiasis risk profiles]. / LithoRisk: software per il calcolo e la visualizzazione dei profili di rischio di calcolosi renale.

BACKGROUND: The pathogenesis of nephrolithiasis, based on the anomalies of the urinary environment, demands metabolic and physicochemical assessment for the medical management of patients. Standard metabolic protocols include the measurement of pertinent urine chemistry values and the calculation of the extent of saturation in stone-forming salts. However, patients are often given fragmentary and hard-to-consult reports and so this weakens the strength of the therapeutic recommendations. This paper introduces LithoRisk, a dedicated software which graphically represents risk profiles of stone formation, including the extent of saturation. METHODS: LithoRisk uses the results of 24-h urine chemistry values widely available in hospital laboratories, i.e., sodium, potassium, calcium, magnesium, ammonia, phosphate, sulphate, citrate, oxalate, chloride, pH and urine volume. Uric acid and cystine are optional. The relative supersaturation (beta), estimated according to our own ab initio calculation, is given in a scale whereby beta=1 is saturation, beta < 1 under - and beta > 1 oversaturation. LithoRisk is available as a CD-ROM and can be loaded on Windows 95/98/Millenium/XP. Colour or laser printers are suitable for printed records. RESULTS: LithoRisk is easily loaded on any PC by following video instructions. Once the loading of the program is completed a grey icon LithoRisk appears on the Desktop. The program can be opened by clicking twice on the icon. The patients data page first appears on the screen and is followed by the evaluation page for the input of variables. This generates the graph representing the diagnostic lithorisk profile, which is drawn as a line connecting different values, according to a specific scale and related to an arbitrary normal point. Normal values are shown as green lines, whereas abnormal ones are red. The beta values for calcium oxalate and phosphate, uric acid and cystine are instantaneously calculated and reported on the graph. CONCLUSIONS: LithoRisk produces a complete, unique and easy to understand report that includes all relevant parameters, it therefore expresses the overall risk of stone formation. It requires the results of chemistry tests done on the same 24-h urine collection, and carried out using suitable preservatives. If the tests for unusual parameters, i.e. sulphate and ammonia, are unavailable, one can use default values with minimal alterations on beta calculation. In spite of being arbitrary, the normal thresholds values are based on widely accepted literature data. The risk profile recognises the most relevant abnormalities and enables the establishment of individual targets aimed at reducing the propensity towards stone formation.

Detection of AGXT bgene mutations by denaturing high-performance liquid chromatography for diagnosis of hyperoxaluria type 1.

Primary hyperoxaluria type 1 is an autosomal recessive disorder of glyoxylate metabolism, caused by a deficiency of alanine:glyoxylate aminotransferase, which is encoded by a single copy gene (AGXT. The aim of this research was to standardize denaturing high-performance liquid chromatography, a new, sensitive, relatively inexpensive, and automated technique, for the detection of AGXT mutation. Denaturing high-performance liquid chromatography was used to analyze in blind the AGXT gene in 20 unrelated Italian patients with primary hyperoxaluria type I previously studied by other standard methods (single-strand conformation polymorphism analysis and direct sequencing) and 50 controls. Denaturing high-performance liquid chromatography allowed us to identify 13 mutations and the polymorphism at position 154 in exon I of the AGXT gene. Hence the method is more sensitive and less time consuming than single-strand conformation polymorphism analysis for the detection of AGXT mutations, thus representing a useful and reliable tool for detecting the mutations responsible for primary hyperoxaluria type 1. The new technology could also be helpful in the search for healthy carriers of AGXT mutations amongst family members and their partners, and for screening of AGXT polymorphisms in patients with nephrolithiasis and healthy populations.

Epidemiology of nephrolithiasis.

The overall probability of forming stones differs in various parts of the world: 1-5% in Asia, 5-9% in Europe, 13% in North America, 20% in Saudi Arabia. The composition of stones and their location in the urinary tract, bladder or kidneys may also significantly differ in different countries. Moreover, in the same region, the clinical and metabolic patterns of stone disease can change over time. We examined some epidemiological evidence about the main risk factors for stone formation, both individual and environmental. A slightly higher rate of renal stone disease emerged in males than in females, and in white Caucasians than in Blacks. Stones in the upper urinary tract appear to be related to the life-style, being more frequent among affluent people, living in developed countries, with high animal protein consumption. Bladder stones are nowadays mainly seen in the Third World, on account of very poor socio-economic conditions. A high frequency of stone formation among hypertensive patients has been reported, and among those with high body mass as well. There is no evidence of any rise in the risk of stone formation in relation to dietary calcium intake or tap water hardness.

Renal stones: from metabolic to physicochemical abnormalities. How useful are inhibitors?

Despite intensive studies in the last decades many aspects of nephrolithiasis still remain to be elucidated. Supersaturation with respect to lithogenic substances explains stones composed of cystine, uric acid, struvite, and calcium stones secondary to systemic diseases. In this subset there is a clear separation between patients and controls, and stone activity is well related to alterations in the physicochemistry of the urine environment. The understanding of the mechanisms of idiopathic calcium nephrolithiasis, on the other hand, is controversial, because we are still unable to establish clear-cut cause-effect relations between metabolic and physicochemical abnormalities and stone formation. Recent studies have been centered on the kidney, not only as the end organ of biochemical derangements due to systemic or environmental factors, but also as a complex laboratory where some events conduct to and others defend from lithogenesis. Many of these phenomena occur in the proximal tubule. Molecular biology has explained some types of hypercalciuria, which are due to genetic mutations altering tubular function, and similar results are expected for hypocitraturia and hyperoxaluria. The latter is conducive to stone formation through several mechanisms including supersaturation, oxidative stress on tubular cells, and interference with some natural inhibitors. The long list of inhibitors includes ionic and macromolecular moieties, some being produced within the nephron in response to lithogenic insults, and some affecting not only crystallization but also crystal cell adherence. Crystal trapping is believed to anticipate a renal stone. However, much has still to be clarified on their actual role in calcium nephrolithiasis, by what mechanisms they act, if patients and controls differ in the excretion and structure of some inhibitors, and whether differences are genetically determined.

Molecular analysis of hyperoxaluria type 1 in Italian patients reveals eight new mutations in the alanine: glyoxylate aminotransferase gene.

Systematic screening using the SSCP technique followed by sequencing of bands with abnormal mobility derived from the AGXT exons of 15 unrelated Italian patients with primary hyperoxaluria type 1 (PH1) allowed us to characterize both the mutant alleles in each individual. Eight new mutations were identified: C155del, C156ins, G244T, C252T, GAG408ins, G468A, G588A and G1098del. This study demonstrates both the effectiveness of the screening strategy chosen to identify all the mutant alleles and the high degree of allelic heterogeneity in PH1.

[Clinical and metabolic features of renal calculi in adults in regard to age of onset]. / Aspetti clinici e metabolici della calcolosi renale nell'adulto in relazione all'età di insorgenza.

BACKGROUND: In this paper, the clinical and metabolic patterns of nephrolithiasis in different ages of adulthood are studied. METHODS: Eight-hundred patients observed at the Mauriziano Hospital between 1990 and 1995, were classified into 3 groups, on the basis of age at the onset of disease: A: 20 through 39 years; B: 40 through 59; C: 60 years and over. RESULTS: Calcium-oxalate stones had a lower recurrence in C (19.1%) and B (31.5%) than in A (41.7%). Pure uric acid stones recurred in 18.9% of C, 16.7% of B and 4.3% of A. The prevalence of hypercalciuria was higher in A (50.3%) than in B (35.9%) and C (36%); so did hypocitraturia. Hyperuricuria was lower in A (5%, p < 0.05) than in B (9.4%) and C (10%). Low urine pH (< 5.5) was 13% in A, 21.3% in B, 38% in C. Prevalence of hyperoxaluria was about 14% in all groups. The whole prevalence of secondary forms of stone disease was 13% in A, 12% in B and 30% in C. Differences among groups were mainly due to prevalence of urological abnormalities and urinary tract infection. In patients without metabolic disturbances. urological abnormalities or urinary tract infections altogether, were 4.6% in A; 5.2% in B; 33% in C. Urological approach removed 8% of stones in A, 5.6% in B and 10.2% in C. CONCLUSIONS: Higher morbidity in younger patients could be due to a lower prevalence of easier-passing uric acid stones. The higher occurrence of urological disturbances and struvite stones in the elderly could explain the higher morbidity in this group.

Idiopathic calcium nephrolithiasis.

Calcium nephrolithiasis (CaNL) accounts for more than 70% of all renal stones, and its prevalence has increased in the last decades. Under this definition are included patients passing stones, composed of calcium oxalates and/or calcium phosphates. Current views of the pathogenesis of CaNL are based on the role of metabolic abnormalities which concur to render urines more conducive to crystallization. Therefore, the diagnostic approach is aimed at detecting these abnormalities, and the medical treatment assumes that a decrease in the risk of lithogenesis will result in remission or improvement of recurrences. The workup of the patients with CaNL begins with the analysis of passed stones and X-ray, sonography or other imaging techniques. Eligible patients, that is, both recurrent active stone formers and single-stone formers with individual risk factors, are considered for a metabolic evaluation, by which a number of blood and urine parameters are measured and others calculated. These include estimates of urine state of saturation with calcium and uric acid salts, net gastrointestinal alkali absorption, renal threshold of phosphate and other renal clearances and net acid and total nitrogen excretions. Basically, this screening is informative on renal function, metabolic abnormalities and their pathophysiology, risk of stone formation and dietary habits. During treatment it gives information about patient compliance and adverse effects of therapy. The cost of a comprehensive screening in Piedmont is 192,000 ITL (100 Euro) and rises to 300,000 ITL (154 Euro) if hormones and hydroxyproline are measured. In individual patients second- and third-level studies are performed, in order to detect systemic diseases which account for about 20% of CaNL in our series. Cost-to-benefit analysis has shown that the medical procedures for CaNL yield considerable saving in terms of difference between expenditure for drugs and testing and reduction of stone events. However, the current workup cannot be considered exhaustive, because misleading events may hamper the relation between laboratory findings and clinical outcome, and factors other than urine composition have appeared on the scenario of nephrolithiasis. These represent our challenge for the third millennium.