BackgroundChronic kidney disease is common in HIV positive patients and renal tubular dysfunction has been reported in those receiving combination antiretroviral therapy (cART). Tenofovir (TFV) in particular has been linked to severe renal tubular disease as well as proximal tubular dysfunction. Markedly elevated urinary concentrations of retinal-binding protein (RBP) have been reported in patients with severe renal tubular disease, and low-molecular-weight proteins (LMWP) such as RBP may be useful in clinical practice to assess renal tubular function in patients receiving TFV. We analysed 3 LMWP as well as protein and albumin in the urine of a sample of HIV positive patients.MethodsIn a cross-sectional fashion, total protein, albumin, RBP, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) were quantified in random urine samples of 317 HIV positive outpatients and expressed as the ratio-to-creatinine (RBPCR, CCR and NGALCR). Exposure to cART was categorised as none, cART without TFV, and cART containing TFV and a non-nucleoside reverse-transcriptase-inhibitor (TFV/NNRTI) or TFV and a protease-inhibitor (TFV/PI).ResultsProteinuria was present in 10.4 % and microalbuminuria in 16.7 % of patients. Albumin accounted for approximately 10 % of total urinary protein. RBPCR was within the reference range in 95 % of patients while NGALCR was elevated in 67 % of patients. No overall differences in urine protein, albumin, and LMWP levels were observed among patients stratified by cART exposure, although a greater proportion of patients exposed to TFV/PI had RBPCR >38.8 μg/mmol (343 μg/g) (p = 0.003). In multivariate analyses, black ethnicity (OR 0.43, 95 % CI 0.24, 0.77) and eGFR <75 mL/min/1.73 m2 (OR 3.54, 95 % CI 1.61, 7.80) were independently associated with upper quartile (UQ) RBPCR. RBPCR correlated well to CCR (r2 = 0.71), but not to NGALCR, PCR or ACR.ConclusionsIn HIV positive patients, proteinuria was predominantly of tubular origin and microalbuminuria was common. RBPCR in patients without overt renal tubular disease was generally within the reference range, including those receiving TFV. RBP therefore appears a promising biomarker for monitoring renal tubular function in patients receiving TFV and for distinguishing patients with normal tubular function or mild tubular dysfunction from those with severe renal tubular disease or Fanconi syndrome.
The case of a neonate is presented who had early onset seizure associated with hypocalcemia, hyperphosphatemia, and raised parathyroid hormone. The infant did not have any stigmata of pseudohypoparathyroidism. The hypocalcemia was initially resistant to calcium therapy, but responded to vitamin D analog therapy. The diagnosis of 'neonatal pseudohypoparathyroidism' was entertained; the infant remained stable and seizure-free with normal serum biochemistry during 3 months of follow-up.
The most commonly used techniques to measure vitamin D are automated immunoassays which are known to be affected by interferences, especially from immunoglobulins present in the patient's serum. We present a case of a patient with myeloma in whom interference with the vitamin D assay was identified. An 83-year-old female, known to have IgG myeloma, was found to have a high concentration of 25-OH vitamin D on a routine test without any signs of vitamin D toxicity. She was not taking vitamin D supplements or any other multivitamin preparation and had minimal sun exposure. The initial and subsequent samples run by the ARCHITECT 25-OH vitamin D assay (chemiluminescent microparticle immunoassay technology, Abbott Laboratories, Abbott Park, IL) showed a high concentration of 25-OH vitamin D of 281 nmol/L and 327 nmol/L, respectively. Further fresh samples taken for 25-OH vitamin D and analysed by liquid chromatography-mass spectrometry (LC-MS/MS) and ARCHITECT analysis showed results of 49 nmol/L and 289 nmol/L, respectively. Our patient had high concentrations of circulating IgG paraproteins and had a long history of rheumatoid arthritis; paraproteins and rheumatoid factor may interfere in the assay. In conclusion, we report a case of a patient with IgG myeloma and rheumatoid arthritis with high concentrations of 25-OH vitamin D detected by the Abbott ARCHITECT, but not by a reference method (LC-MS/MS). The most likely cause of the discordant results is interference in the immunoassay by the paraprotein but interference from rheumatoid factor remains a possibility.
Background and Aims Serum zinc, copper and selenium are measured in patients prior to commencing on parenteral nutrition; however, their interpretation can be difficult due to acute phase reactions. We assessed (i) the relationship of raised C-reactive protein with trace elements and albumin (ii) benefits of measuring trace elements when C-reactive protein is raised in patients requiring short-term parenteral nutrition. Methods Samples were collected for zinc, copper, selenium and albumin at baseline and then every two weeks and correlated with C-reactive protein results in patients on parenteral nutrition. Results were categorized into four groups based on the C-reactive protein concentrations: (i) <20 mg/L, (ii) 20-39 mg/L, (iii) 40-79 mg/L and (iv) ≥80 mg/L. Results In 166 patients, zinc, selenium and albumin correlated (Spearman's) negatively with C-reactive protein; r = -0.26, P < 0.001 (95% CI -0.40 to -0.11), r = -0.44, P < 0.001 (-0.56 to -0.29) and r = -0.22 P = 0.005 (-0.36 to -0.07), respectively. Copper did not correlate with C-reactive protein (r = 0.09, P = 0.25 [-0.07 to 0.25]). Comparison of trace elements between the four groups showed no difference in zinc and copper (both P > 0.05), whereas selenium and albumin were lower in the group with C-reactive protein > 40 mg/L ( P < 0.05). Conclusion In patients on short-term parenteral nutrition, measurement of C-reactive protein is essential when interpreting zinc and selenium but not copper results. Routine measurement of trace elements prior to commencing parenteral nutrition has to be considered on an individual basis in patients with inflammation.
Renal risk stratification in systemic immunoglobulin light-chain (AL) amyloidosis is according to estimated glomerular filtration rate (eGFR) and urinary protein creatinine ratio (uPCR), the latter attributed to glomerular dysfunction, with proximal tubular dysfunction (PTD) little studied. Urinary retinol binding protein 4 (uRBP), a low molecular weight tubular protein and highly sensitive marker of PTD, was prospectively measured in 285 newly diagnosed, untreated patients with systemic AL amyloidosis between August 2017 to August 2018. At diagnosis, the uRBP/creatinine ratio (uRBPCR) correlated with serum creatinine (r = 0Á618, P < 0Á0001), uPCR (r = 0Á422, P < 0Á0001) as well as both fractional excretion of phosphate and urate (r = 0Á563, P < 0Á0001). Log uRBPCR at diagnosis was a strong independent predictor of end-stage renal disease {hazard ratio [HR] 2Á65, [95% confidence interval (CI) 1Á06-6Á64]; P = 0Á038}, particularly in patients with an eGFR >30 ml/min/1.73 m 2 [HR 4Á11, (95% CI 1Á45-11Á65); P = 0Á008] and those who failed to achieve a deep haematological response to chemotherapy within 3 months of diagnosis [HR 6Á72, (95% CI 1Á83-24Á74); P = 0Á004], and also predicted renal progression [HR 1Á91, (95% CI 1Á18-3Á07); P = 0Á008]. Elevated uRBPCR indicates PTD and predicts renal outcomes independently of eGFR, uPCR and clonal response in systemic AL amyloidosis. The role of uRBPCR as a novel prognostic biomarker merits further study, particularly in monoclonal gammopathies of renal significance.
Background- Retinol-binding protein4 (RBP) assays using polyclonal antibodies (pRBP) have major problems of non-linearity of dilution and a very small useable dynamic range. Our objective was to develop a specific assay with a wider dynamic range to detect tubular proteinuria. Methods: mRBP (monoclonal capture and second antibody with colorimetric detection) and fRBP, (polyclonal capture and monoclonal second antibody with fluorescence detection) were developed and compared with pRBP. 488 patient samples were collected- 290 samples were analysed by mRBP and 198 samples with fRBP and compared with pRBP. Results: mRBP assay has the advantages of better linearity on dilution and wider analytical range over pRBP. It is limited by poor signal in the patients with albuminuria and glomerular proteinuria and inferior discrimination between patient groups. fRBP had an intra-assay and inter-assay CV of <6% and <8% respectively; and analytical range was 2.3-599 µg/L. fRBP was linear on dilution within the analytical range. Correlation (r) was 0.8722(95% CI 0.7621 to 0.9333, p< 0.0001), Mann-Whitney test revealed no significant difference (U= 18877, n=198, p = 0.5244) asserting that the medians of the two samples were identical. Bland-Altman test between pRBP and fRBP showed a mean negative bias of 16.43(CI -994 to 1027) μg/mmol Conclusion: The combination assay with fluorescence detection (fRBP) proved more discriminatory than a purely monoclonal system especially in patients with significant proteinuria and has advantages of better linearity on dilution and wider analytical range than the existing pRBP assay and compared extremely well with pRBP.
Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease. When fully expressed, it is characterized by inflammatory soft tissue changes, exophthalmos, ocular dysmotility causing diplopia, and, rarely, sight-threatening dysthyroid optic neuropathy (DON). The prevalence of GO among Graves' patients seems lately declining, probably due to early diagnosis, early intervention on risk factors associated with its occurrence or progression (smoking, uncontrolled thyroid dysfunction), early correction of hyper and hypothyroidism. Only about 25-30% of newly diagnosed Graves' hyperthyroids are affected with GO, which is usually mild and rarely progressive. Assessment of activity and severity of GO according to standardized criteria is fundamental to plan management. The European Thyroid Association and the European Group on Graves' Orbitopathy (EUGOGO) have recently published the first guideline on management of GO. Mild GO usually requires only a watchful strategy, in addition to local measures (eye drops, ointments) and removal of risk factors. Intravenous glucocorticoids (ivGCs) are the first-line treatment for moderate-to-severe and active GO, as demonstrated by randomized clinical trials. When ivGCs fail or GO recurs after treatment withdrawal, options include a second course of ivGCs, oral GCs combined with orbital radiotherapy or cyclosporine, rituximab. Evidence that the any of the above treatment be effective in the context of a poor response to a first course of ivGCs is limited and should be investigated in larger studies. In addition to rituximab, ongoing investigations are exploring the role of other biologics targeting, e.g., the IGF-1 receptor or the IL-6 receptor, and results will probably available in 1-2 years. When GO has been treated medically and is inactive, rehabilitative surgery (orbital decompression, squint surgery, eyelid surgery) is often needed. S2Role of T3 and TRH in the hypothalamic regulation of energy metabolism Eric Fliers (e.fliers@amc.uva.nl) Department of Endocrinology and Metabolism at the Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands Thyroid Research 2017, 10(Suppl 1):S2The relation between thyrotoxicosis, the clinical syndrome resulting from exposure to excessive thyroid hormone, and the autonomic nervous system remains enigmatic. Recent experiments from our lab and others have shown that T3 may act within several hypothalamic nuclei to modulate hepatic glucose metabolism and brown adipose tissue (BAT) activity. These effects are mediated via pre-autonomic neurons connecting the paraventricular and ventromedial nuclei (PVN and VMH) with these peripheral organs via neural pathways. Intrahypothalamic effects of T3 on glucose metabolism in the liver could be modulated by selective hepatic sympathetic and parasympathetic denervation. Thyroid hormone appeared to stimulate hepatic glucose production via a sympathetic pathway, representing a novel central route for thyroid hormone action. As most of the experiments were performed in a ...
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