Development of a benchmarking toolkit for adolescent and young adult rheumatology services (BeTAR).

BACKGROUND: Young people (YP; 12-24 years old) with rheumatic diseases face many challenges associated with chronic illness in addition to the physiological and psychosocial changes of adolescence. Timely access to developmentally appropriate multidisciplinary care is key to successfully managing rheumatic diseases, but gaps in the care of this vulnerable age group still exist. This study aimed to develop a benchmarking toolkit to enable comparative evaluation of YP rheumatology services in order to promote best practice and reduce variations in service delivery. METHODS: A staged and consultative method was used across a broad group of stakeholders in the UK (YP, parents/other carers, and healthcare professionals, HCPs) to develop this toolkit, with reference to pre-existing standards of YP-friendly healthcare. Eighty-seven YP (median age 19 years, range 12-24 years) and 26 rheumatology HCPs with 1-34 years of experience caring for YP have participated. RESULTS: Thirty quality criteria were identified, which were grouped into four main domains: assessment and treatment, information and involvement, accessibility and environment, and continuity of care. Two toolkit versions, one to be completed by HCPs and one to be completed by patients, were developed. These were further refined by relevant groups and face validity was confirmed. CONCLUSIONS: A toolkit has been developed to systematically evaluate and benchmark YP rheumatology services, which is key in setting standards of care, identifying targets for improvement and facilitating research. Engagement from YP, clinical teams, and commissioners with this tool should facilitate investigation of variability in levels of care and drive quality improvement.

Results, meta-analysis and a first evaluation of UNOxR, the urinary nitrate-to-nitrite molar ratio, as a measure of nitrite reabsorption in experimental and clinical settings.

We recently found that renal carbonic anhydrase (CA) is involved in the reabsorption of inorganic nitrite (NO2-), an abundant reservoir of nitric oxide (NO) in tissues and cells. Impaired NO synthesis in the endothelium and decreased NO bioavailability in the circulation are considered major contributors to the development and progression of renal and cardiovascular diseases in different conditions including diabetes. Isolated human and bovine erythrocytic CAII and CAIV can convert nitrite to nitrous acid (HONO) and its anhydride N2O3 which, in the presence of thiols (RSH), are further converted to S-nitrosothiols (RSNO) and NO. Thus, CA may be responsible both for the homeostasis of nitrite and for its bioactivation to RSNO/NO. We hypothesized that enhanced excretion of nitrite in the urine may contribute to NO-related dysfunctions in the renal and cardiovascular systems, and proposed the urinary nitrate-to-nitrite molar ratio, i.e., UNOxR, as a measure of renal CA-dependent excretion of nitrite. Based on results from clinical and experimental animal studies, here, we report on a first evaluation of UNOxR. We determined UNOxR values in preterm neonates, healthy children, and adults, in children suffering from type 1 diabetes mellitus (T1DM) or Duchenne muscular dystrophy (DMD), in elderly subjects suffering from chronic rheumatic diseases, type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), or peripheral arterial occlusive disease (PAOD). We also determined UNOxR values in healthy young men who ingested isosorbide dinitrate (ISDN), pentaerythrityl tetranitrate (PETN), or inorganic nitrate. In addition, we tested the utility of UNOxR in two animal models, i.e., the LEW.1AR1-iddm rat, an animal model of human T1DM, and the APOE*3-Leiden.CETP mice, a model of human dyslipidemia. Mean UNOxR values were lower in adult patients with rheumatic diseases (187) and in T2DM patients of the DALI study (74) as compared to healthy elderly adults (660) and healthy young men (1500). The intra- and inter-variabilities of UNOxR were of the order of 50% in young and elderly healthy subjects. UNOxR values were lower in black compared to white boys (314 vs. 483, P = 0.007), which is in line with reported lower NO bioavailability in black ethnicity. Mean UNOxR values were lower in DMD (424) compared to healthy (730) children, but they were higher in T1DM children (1192). ISDN (3 × 30 mg) decreased stronger UNOxR compared to PETN (3 × 80 mg) after 1 day (P = 0.046) and after 5 days (P = 0.0016) of oral administration of therapeutically equivalent doses. In healthy young men who ingested NaNO3 (0.1 mmol/kg/d), UNOxR was higher than in those who ingested the same dose of NaCl (1709 vs. 369). In LEW.1AR1-iddm rats, mean UNOxR values were lower than in healthy rats (198 vs. 308) and comparable to those in APOE*3-Leiden.CETP mice (151).

Urinary free light chains may help to identify infection in patients with elevated systemic inflammation due to rheumatic disease.

The risk of infection in patients with rheumatic diseases is elevated, but a clear marker to differentiate the cause of the systemic inflammation is missing. We assessed the ability urinary immunoglobulin free light chains (FLCs) to indicate the presence of infection in patients with rheumatic disease. We performed a retrospective analysis of patients with rheumatic disease attending the Georg-August University Hospital in Goettingen, Germany, from January 2011 to December 2013. Subjects were included if they had urine levels of κ and λ FLCs available. A reference group of patients without autoimmune disease, but with documented infection, was constructed. A total of 1500 patients had their urinary FLCs quantified during the study period. Of the 382 patients with rheumatic disease, 172 (45%) displayed no systemic inflammation, 162 (42%) had inflammation due to the underlying disease activity, and 48 (13%) had inflammation due to a confirmed infection. Urinary FLC concentrations were much higher in patients with rheumatic diseases and infection (κ 68.8 ± 81.8 mg/L, λ 31.4 ± 53.5 mg/L) compared to those with inflammation due to rheumatic disease activity (κ 22.7 ± 26.3 mg/L, λ 8.1 ± 9.1 mg/L, κ p < 0.001, λ p = 0.004). Urinary κ FLCs demonstrated good ability to predict infection, with a sensitivity of 63% and specificity of 84%. Urinary λ FLCs gave similar values, with a sensitivity of 65% and specificity of 81%. FLCs may be useful for distinguishing inflammation due to rheumatic disease activity from that due to the additional presence of infection. The ability to quantify these proteins in urine provides a simple alternative to the use of blood.

NMR-based metabolomic approach to study urine samples of chronic inflammatory rheumatic disease patients.

The nuclear magnetic resonance (NMR)-based metabolomic approach was used as analytical methodology to study the urine samples of chronic inflammatory rheumatic disease (CIRD) patients. The urine samples of CIRD patients were compared to the ones of both healthy subjects and patients with multiple sclerosis (MS), another immuno-mediated disease. Urine samples collected from 39 CIRD patients, 25 healthy subjects, and 26 MS patients were analyzed using 1H NMR spectroscopy, and the NMR spectra were examined using partial least squares-discriminant analysis (PLS-DA). PLS-DA models were validated by a double cross-validation procedure and randomization tests. Clear discriminations between CIRD patients and healthy controls (average diagnostic accuracy 83.5 ± 1.9%) as well as between CIRD patients and MS patients (diagnostic accuracy 81.1 ± 1.9%) were obtained. Leucine, alanine, 3-hydroxyisobutyric acid, hippuric acid, citric acid, 3-hydroxyisovaleric acid, and creatinine contributed to the discrimination; all of them being in a lower concentration in CIRD patients as compared to controls or to MS patients. The application of NMR metabolomics to study these still poorly understood diseases can be useful to better clarify the pathologic mechanisms; moreover, as a holistic approach, it allowed the detection of, by means of anomalous metabolic traits, the presence of other pathologies or pharmaceutical treatments not directly connected to CIRDs, giving comprehensive information on the general health state of individuals. Graphical abstract NMR-based metabolomic approach as a tool to study urine samples in CIRD patients with respect to MS patients and healthy controls.

The significance and predictive value of free light chains in the urine of patients with chronic inflammatory rheumatic disease.

In patients with rheumatic diseases, reliable markers for determining disease activity are scarce. One potential parameter is the level of immunoglobulin free light chains (FLCs), which is known to be elevated in the blood of patients with certain rheumatic diseases. Few studies have quantified FLCs in urine, a convenient source of test sample, in patients with different rheumatic diseases. We carried out a retrospective analysis of patients with rheumatic disease attending the University hospital of Goettingen, Germany. Subjects were included if they had urine levels of both κ and λ FLCs available and did not have myeloma. Data regarding systemic inflammation and kidney function were recorded, and FLC levels were correlated with inflammatory markers. Of the 382 patients with rheumatic disease, 40.1 % had chronic polyarthritis, 21.2 % connective tissue disease, 18.6 % spondyloarthritis and 15.7 % vasculitis. Elevated levels of κ FLCs were found for 84 % of patients and elevated λ for 52.7 %. For the patients with rheumatoid arthritis, FLCs correlated with C-reactive protein (κ, r = 0.368, p < 0.001; λ, r = 0.398, p < 0.001) and erythrocyte sedimentation rate (κ, r = 0.692, p < 0.001; λ, r = 0.612, p < 0.001). Patients being treated with rituximab displayed FLC levels similar to those of the reference group. There were clear elevations in both κ and λ FLCs in patients with rheumatic disease, but not in κ/λ ratio. The correlation between FLCs and inflammatory markers in patients with rheumatoid arthritis demonstrates their potential for predicting disease activity.

Nitrite correlates with 3-nitrotyrosine but not with the F(2)-isoprostane 15(S)-8-iso-PGF(2alpha) in urine of rheumatic patients.

In vitro studies suggested that nitrite may play a cytoprotective role in inflammation. The aim of the present clinical study was to investigate the relationship between the NO metabolites nitrite and nitrate and the biomarkers of oxidative stress 3-nitrotyrosine (3-NT) and 15(S)-iso-PGF(2alpha) in patients suffering from chronic inflammatory rheumatic diseases. In morning urine from 28 patients with different chronic inflammatory rheumatic diseases (23-82 years of age) and from 41 healthy persons of both genders, nitrite and nitrate were quantitated by GC-MS, and 3-NT and 15(S)-iso-PGF(2alpha) by GC-MS/MS. Mean creatinine-corrected urinary excretion rates of nitrite (1.1 versus 0.19 micromol/mmol, P = 0.00012) and 3-NT (1.2 versus 0.39 nmol/mmol, P = 0.01629), but not of nitrate (105 versus 106 micromol/mmol), were significantly elevated in rheumatism as compared to health. Urinary excretion rate of 15(S)-iso-PGF(2alpha) did not differ between patients and healthy subjects (65 versus 69 pmol/mmol creatinine, P = 0.48). In rheumatism, urinary 3-NT correlated closely with nitrite (R = 0.788, P < 0.0001) and moderately with nitrate (R = 0.45, P < 0.016), but did not correlate with 15(S)-iso-PGF(2alpha) (R = -0.083, P = 0.68). In healthy persons there was no correlation between urinary 3-NT and nitrite or nitrate. Our study suggests that urinary nitrite may represent a novel specific biomarker of nitrative stress in chronic inflammatory rheumatic disease. In another eight patients with chronic inflammatory rheumatic diseases we found higher nitrite concentrations in synovial fluid as compared to serum (1.30 versus 0.35 microM). We hypothesize that in chronic inflammatory rheumatic diseases nitrite concentration is elevated in the inflamed joint and contributes to the inactivation of myeloperoxidase-catalyzed production of hypochloric acid by forming nitryl chloride which eventually nitrates tyrosine to form 3-NT.

[Diagnostics of glomerulonephritis]. / Diagnostik der Glomerulonephritiden.

Glomerulonephritis occurs frequently in patients with multisystemic rheumatic disease, especially in collagen vascular disorders and vasculitides. From a clinical point of view nephrotic syndrome has to be distinguished from nephritic syndrome. Rapid deterioration of renal function is referred to as rapid progressive glomerulonephritis. The differential diagnosis of glomerulonephritis can be narrowed by the findings on urine sediment, amount of proteinuria, degree of renal insufficiency and serological findings. In particular, the presence of urine acanthocytes and cellular casts are diagnostic for glomerulonephritis or vasculitis. Renal biopsy is necessary to establish the final diagnosis in most cases; however, some histological pattern such as membranous glomerulonephritis may occur in several different etiopathogenetic diseases and one disease process may lead to different histomorphologic pictures. Rapid progressive glomerulonephritis is a nephrological emergency and should be diagnosed and treated early to prevent dialysis-dependent renal insufficiency.

Direct measurements of xanthine in 2000-fold diluted xanthinuric urine with a nanoporous carbon fiber sensor.

High selectivity and sensitivity is reported in the measurements of xanthine in urine by fast scan cyclic voltammetry (FSV) with a nanostructured carbon fiber sensor of 3.5 +/- 0.4 mum radius. Fabrication of the sensors for the measurements is described. Fabrication of the nanostructure at the carbon fiber sensor surface exposes surface pores. SEM images confirm the formation of the nanostructure. The results indicate that the nanostructure improves the sensitivity and limit of detection (LOD) in the measurements of xanthine and uric acid. The sensors allow rapid direct measurements of xanthine in 2000-fold diluted xanthinuric urine and of uric acid in 2000-fold diluted normal urine. The sensitivity and the LOD of xanthine is 0.40 +/- 0.02 nA microM(-1) (0.995) and 1 microM, respectively, and 0.99 +/- 0.01 nA microM(-1) (0.998) and 500 nM for uric acid. The concentration of xanthine in 2000-fold diluted xanthinuric urine is 1.6 +/- 0.2 muM from FSV and from HPLC. The concentration of xanthine and uric acid in urine can be determined by pre- or post-calibration of the sensor in buffer or by the method of standard addition.

Detection of WT1 mRNA in urine from patients with kidney diseases.

Detachment of glomerular epithelial cells (GEC) from glomerular basement membrane (GBM) could account for a part of the pathogenic mechanism of proteinuria seen in primary and secondary renal diseases. The Wilms' tumour suppresser gene (WT1) is strictly expressed in GEC in the adult kidney. Mutations of WT1 gene have been implicated in progressive renal damage. Utilizing nested RT-PCR we detected mRNA of WT1 in the urine of patients with renal diseases. Seven of 20 (35%) chronic glomerulonephritis (CGN), eight of 20 (40%) diabetes mellitus (DM) with proteinuria, and two of 24 (8.3%) rheumatic diseases were WT1 positive. Interestingly, only one of 51 (2%) DM without proteinuria was WT1 positive. None of the healthy volunteers or cystitis patients were WT1 positive. This is the first report describing the detection of endogenous WT1 mRNA, an important gene in progressive renal failure, from patients' urine. This technique could be a powerful tool in the search for information about glomerular damage in clinical settings as well as for WT1 mutations or isoform imbalance at the research level without renal biopsy.

Subclinical renal toxicity in rheumatic patients receiving longterm treatment with nonsteroidal antiinflammatory drugs.

OBJECTIVE: To study the possible renal toxicity of longterm treatment with nonsteroidal antiinflammatory drugs (NSAID), in a population of patients with rheumatic diseases. METHODS: Comparative study of 104 patients treated for more than 2 years with NSAID and 123 healthy controls, nonusers of these drugs. After fasting during 12 h the following tests were performed in both groups: urinalysis, creatinine clearance, osmolar clearance, negative free water clearance, and urinary excretion of sodium. RESULTS: In the patient group the urinary pH was higher than in the controls (5.9 +/- 0.7 versus 5.2 +/- 0.6 p < 0.05) and in addition, they had an impaired renal concentration capacity, as it is shown by a significant decreased urinary density (1018.6 +/- 4.7 vs 1026.3 +/- 5.4 in the controls p < 0.05), a decreased urinary osmolality (502.1 +/- 150.7 vs 661.6 +/- 157.6 mOsm/ml p < 0.001), a lower osmolar clearance (1.26 +/- 0.25 ml/min vs 1.83 +/- 0.4 ml/min p < 0.001) and an increased free water clearance (-0.21 +/- 0.40 ml/min vs -0.98 +/- 0.41 ml/min, p < 0.001). This renal impairment was related to the cumulative intake of NSAID: CONCLUSION: The longterm treatment with NSAID is able to produce a subclinical renal dysfunction, consistent with the early stages of analgesic nephropathy.

Urinary glycosaminoglycan excretion in rheumatic diseases.

We used Alcian Blue (AB) and dimethylmethylene blue (DMB) methods to measure glycosaminoglycan (GAG) excretion in the first morning urine specimens of patients with osteoarthritis (OA), ankylosing spondylitis (AS), and rheumatoid arthritis (RA) in different stages of disease. By the AB method, urinary GAG excretion in patients with RA was not different from healthy control subjects. However, the DMB method showed significant differences (in milligrams of GAG per gram of creatinine) for OA (median 25.4, range 14.3-44.0, P less than 0.01, n = 23) and RA patients (median 33.0; range 10.0-147.6; P less than 0.001, n = 63) in comparison with unaffected individuals (median 20.2; range 8.9-41.4, n = 38). We noted a significant difference in urinary GAG excretion between RA and OA patients (P less than 0.01) and between RA and AS (P less than 0.01) patients. The DMB method was further investigated by clinical decision analysis. The DMB method is simple and rapid and may be useful in diagnosing RA by distinguishing between RA and OA or AS.

Individual variability in concentrations of urinary sulindac sulfide.

Among 70 patients with arthritis who were receiving satisfactory maintenance therapy with sulindac (300 to 400 mg daily), 64% had no detectable sulindac sulfide (active metabolite) in one to four random urine specimens. However, 36% had 1.0 to 7.8 (mean, 2.2 +/- 1.4) micrograms/ml sulindac sulfide in urine, similar to the therapeutically effective concentrations found in 24 concurrent plasma specimens (1.4 to 9.0 micrograms/ml). Ten patients had sulindac sulfide in only one or two of two to four urine specimens. Thus, 36% of the patients had pharmacodynamically significant concentrations of sulindac sulfide in urine, presumably capable of suppressing the cyclooxygenase pathway responsible for prostaglandin synthesis in the kidney and elsewhere. The findings suggest individual variability in the capacity for renal oxidation of sulindac sulfide to inactive metabolites, perhaps related to genetic or environmental factors or both. These findings may help to explain conflicting reports on the effects of sulindac on urinary prostaglandins and renal function.

[Pathologic urine findings related to medication]. / Patologiske urinfunn relatert til medikamentbruk.

We examined urine specimens from 144 consecutive patients attending a rheumatological department. Transient abnormal findings were frequent, but most urine samples normalized spontaneously. We found no association with use of non-steroidal anti-inflammatory drugs, but there was an association between pathological urine findings and the combined use of such drugs and systemic steroids.

[The diagnostic importance of determining minimal amounts of the Bence-Jones protein in the urine of patients with morphologically nondemonstrable lymphatic tumors]. / Diagnosticheskoe znachenie opredeleniia minimal'nykh kolichestv belka Bens-Dzhonsa v moche bol'nykh s morfologicheski nedokazuemymi limfaticheskimi opukholiami.

Urinalysis by the IITP method in 115 patients with lymphatic tumors has shown that in half of them, BJ protein can be identified. The authors' and reported data evidence the lack of BJ proteinuria in normal people and in patients afflicted with other diseases. Since BJ proteinuria was demonstrable with the minimal tumorous mass in successfully treated patients with CLL and LC, the IITP method was used for excluding a morphologically undemonstrable lymphatic tumor in 23 patients with rheumatic diseases, AIHA, and splenomegaly of obscure genesis. Based on the identified BJ protein secretion in the urine, the diagnoses of CLL (I), LC (2), and LS (I) were proved in 4 cases. Later on these diagnoses were supported by the cytologic and histologic findings.

Screening for proteinuria in a rheumatology clinic: comparison of dipstick testing, 24 hour urine quantitative protein, and protein/creatinine ratio in random urine samples.

Measurements of protein/creatinine ratio in 'spot' urine samples were compared with measurements of 24 hour quantitative proteinuria and side room 'dipstick' testing in 104 samples from 90 patients presenting consecutively to a rheumatology unit. Linear regression analysis showed a highly significant correlation between the random urinary protein/creatinine ratio and total protein excretion in 24 hour urine samples (r = 0.92, p less than 0.001, y = 6.55x + 0.04). Although an approximation of 24 hour urinary protein excretion could have been made from the regression line: 24 hour urine protein = 6.55 x protein/creatinine ratio + 0.04 (g/l), there was a wide scatter of values, particularly in patients with greater than 1 g/24 h urinary protein excretion. Nevertheless, significant proteinuria (greater than 300 mg/24 h) could have been confirmed or excluded with a sensitivity and specificity of 97% by adopting random protein/creatinine values of less than 0.04 as 'normal'. Specificity and sensitivity could have been increased to 100%, however, by excluding patients with values lying between 0.01 and 0.10 as all the false negatives (n = 3) and false positives (n = 3) lay within this range. In comparison, dipstick testing, although 100% sensitive, had a poor specificity due to the high false positive rate (40/83 (48%] in patients with 1+ to 3+ readings. Assessment of random urinary protein/creatinine ratio may obviate the need for 24 hour urine collections in the initial assessment of suspected proteinuria. A wider application of this technique seems indicated in view of the obvious advantages in terms of cost, time, and patient convenience.

Renal biochemistry in rheumatic disease.

In patients with osteo-arthritis, renal disease will almost invariably be the consequence of unrelated coincidental renal pathology. In polyarthritic rheumatoid arthritis and ankylosing spondylitis, renal disease can arise as part of the pathology of a systemic disease, or more likely its treatment. As a rule amyloidosis is the most important complication in terms of progressive irreversible loss of renal function. By contrast, SLE, polyarteritis and Sjögren's disease carry a much higher risk of renal involvement. The regular evaluation of renal function in such patients can enable the kidney damage to be assessed at an early stage and allow treatment to be instituted early.

Serum and urinary aminoterminal type III procollagen peptide in progressive systemic sclerosis: relationship to sclerodermal involvement, serum hyaluronan and urinary collagen metabolites.

Increased serum values of aminoterminal type III procollagen peptide and hyaluronan (hyaluronate) and enhanced urinary content of hydroxyproline and hydroxylsine containing polypeptides were demonstrated in patients with progressive systemic sclerosis (PSS). The serum propeptide level and the relative urinary excretion of hydroxyproline as polypeptides were related to the extent of cutaneous involvement. Elevated serum propeptide and hyaluronan values were seen in patients who progressed within the following 6 months. Patients with CREST syndrome had normal propeptide values. Reduced renal propeptide clearance is a likely cause of high serum levels of propeptide degradation products demonstrated in PSS. Serum propeptide seems to be a useful novel marker for disease activity and progression in PSS because of its linkage to the actual connective tissue metabolism.

Radioimmunoassay for urinary amyloid P component.

A sensitive double-antibody radioimmunoassay for the measurement of amyloid P component (AP) in urine is described. The method is linear with AP concentrations in the range 5 to 2500 micrograms/L, the lower limit of the assay being 5 micrograms/L. Intra-assay and interassay coefficients of variation ranged from 2.2% to 10.3% and from 3.0% to 9.8%, respectively. The mean urinary excretion of AP in 20 normal subjects was 37 micrograms/24 hr, range 5 to 102 micrograms/24 hr. Compared with normal subjects, patients with rheumatic disease had an increased urinary output of AP (mean 98 micrograms/24 hr, range 5 to 218 micrograms/24 hr; P less than 0.005). In patients with reactive (secondary) amyloidosis the diurnal excretion of AP was markedly increased (mean 615 micrograms/24 hr), but the urinary AP/albumin ratio did not significantly differ from that in patients with nonamyloid kidney disease who were matched with the amyloid group with respect to the degree of proteinuria and impairment of renal glomerular filtration rate.