EFSUMB 2020 Proposal for a Contrast-Enhanced Ultrasound-Adapted Bosniak Cyst Categorization - Position Statement.

The well-established Bosniak renal cyst classification is based on contrast-enhanced computed tomography determining the malignant potential of cystic renal lesions. Ultrasound has not been incorporated into this pathway. However, the development of ultrasound contrast agents coupled with the superior resolution of ultrasound makes it possible to redefine the imaging of cystic renal lesions. In this position statement, an EFSUMB Expert Task Force reviews, analyzes, and describes the accumulated knowledge and limitations and presents the current position on the use of ultrasound contrast agents in the evaluation of cystic renal lesions.

Autosomal dominant polycystic kidney disease: Disrupted pathways and potential therapeutic interventions.

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic inherited renal cystic disease that occurs in different races worldwide. It is characterized by the development of a multitude of renal cysts, which leads to massive enlargement of the kidney and often to renal failure in adulthood. ADPKD is caused by a mutation in PKD1 or PKD2 genes encoding the proteins polycystin-1 and polycystin-2, respectively. Recent studies showed that cyst formation and growth result from deregulation of multiple cellular pathways like proliferation, apoptosis, metabolic processes, cell polarity, and immune defense. In ADPKD, intracellular cyclic adenosine monophosphate (cAMP) promotes cyst enlargement by stimulating cell proliferation and transepithelial fluid secretion. Several interventions affecting many of these defective signaling pathways have been effective in animal models and some are currently being tested in clinical trials. Moreover, the stem cell therapy can improve nephropathies and according to studies were done in this field, can be considered as a hopeful therapeutic approach in future for PKD. This study provides an in-depth review of the relevant molecular pathways associated with the pathogenesis of ADPKD and their implications in development of potential therapeutic strategies.

Two in One: Epithelioid angiomyolipoma within a classic kidney angiomyolipoma - a case report.

BACKGROUND: Epithelioid angiomyolipoma is defined as potentially malignant mesenchymal neoplasm, characterized by proliferating epithelioid cells, whereas classic angiomyolipoma, composed of fat, smooth muscle cells and dysmorphic vessels, is defined as a potentially benign. The usual or classic angiomyolipoma is often found incidentally on imaging studies, relatively easily identified due to the presence of fat, in contrast to the epithelioid angiomyolipoma that can pose diagnostic challenges. CASE PRESENTATION: We report a 51-year-old female patient in which an ultrasonography examination showed a solid mass close to the right renal pelvis with hypoechoic and hyperechoic areas. A differential diagnosis of atypical sinus lipomatosis, lipoma and a transitional cell carcinoma was postulated whereas in a subsequent computed tomography a classic angiomyolipoma was postulated. A re-examination by contrast enhanced ultrasound revealed a striking perfusion difference of the hypoechoic and hyperechoic areas. The hypoechoic area showed homogenous and prolonged enhancement whereas the hypoechoic area displayed a marked slower contrast material flooding and a relatively rapid wash out. The histological analysis from the biopsy of the hyperechoic area showed a classic angiomyolipoma, whereas the sample of the hypoechoic central portion revealed an epithelioid angiomyolipoma. A nephrectomy was performed because of the malignant potential of the epithelioid variant of the angiomyolipoma. CONCLUSIONS: A solid kidney mass with two sharply defined parts, one-part compatible with a classical angiomyolipoma and the other being suspected of carcinoma, is rare, but also illustrative and instructive. The combination of different imaging modalities in the work up of a solid renal mass facilitated to discriminate benign from malignant areas.

Allogeneic islet cells implant on poly-l-lactide matrix to reduce hyperglycaemia in streptozotocin-induced diabetic rat.

OBJECTIVE: To demonstrate the effects of allogeneic islet cell matrix implants for glycaemic control in rats with induced diabetes. METHOD: Sprague-Dawley rats were used as allogeneic donors of islet cells. Cells were seeded on three-dimensional proprietary poly-(l-lactide) matrices. Animals were rendered diabetic and a week later a matrix seeded with islet cells (IMI group) or a control matrix (placebo group) was implanted in the small bowel mesentery. Blood glucose levels were measured weekly for 12 weeks. After sacrifice, implant sections were Gomori stained for beta-cells and immuno-stained for insulin 3, 4, 5, and 6 months post implantation. RESULTS: 82% of seeded islet cells attached to the matrices. In the IMI group blood glucose levels were significantly reduced after implantation compared with before implantation across several time points. In the IMI group beta-cells and insulin-positive cells were identified at the implant site. CONCLUSION: The islet cell matrix implant reduced the blood glucose levels although complete normo-glycaemia was not established. The islet cell matrix implant may serve as an additional option for islet cell transplantation using 3D scaffold platforms for better survival and function of the islet cells.

25-Hydroxyvitamin-D3 serum modulation after use of sunbeds compliant with European Union standards: A randomized open observational controlled trial.

BACKGROUND: Regular use of sunbed exposure has been reported to increase 25-hydroxyvitamin-D3 [25(OH)D] serum levels. However, the influence of sunbeds compliant with the recent European Union standard EN-60335-2-27 on 25(OH)D serum levels is unknown. OBJECTIVE: We investigated the impact of standard sunbed use compliant with the European Union standard on 25(OH)D serum modulation and well-being. METHODS: In a randomized controlled study, 25(OH)D serum levels were measured at enrollment, after 1 week, and after completion of the 12-week period of sunbed use with twice weekly exposure and compared with the control group without any sunbed exposure. RESULTS: In the sunbed intervention group (N = 31), a 27% increase of mean 25(OH)D levels was noted 1 week after starting sunbed use (P < .01). However, after 12 weeks, mean 25(OH)D levels had declined and were no longer different from baseline (P = .06). After 12 weeks, 25(OH)D levels did not differ between the intervention and control group (P = .36). Also the 5-item World Health Organization Well-Being Index score did not differ between the sunbed and control groups (P = .19). LIMITATIONS: For ethical reasons recruitment was limited to persons actively seeking sunbed exposure. CONCLUSIONS: Standard use of sunbeds compliant with the European Union standard induced a transient increase of 25(OH)D levels, whereas no change in well-being was observed.

Temporal and geographical external validation study and extension of the Mayo Clinic prediction model to predict eGFR in the younger population of Swiss ADPKD patients.

BACKGROUND: Prediction models in autosomal dominant polycystic kidney disease (ADPKD) are useful in clinical settings to identify patients with greater risk of a rapid disease progression in whom a treatment may have more benefits than harms. Mayo Clinic investigators developed a risk prediction tool for ADPKD patients using a single kidney value. Our aim was to perform an independent geographical and temporal external validation as well as evaluate the potential for improving the predictive performance by including additional information on total kidney volume. METHODS: We used data from the on-going Swiss ADPKD study from 2006 to 2016. The main analysis included a sample size of 214 patients with Typical ADPKD (Class 1). We evaluated the Mayo Clinic model performance calibration and discrimination in our external sample and assessed whether predictive performance could be improved through the addition of subsequent kidney volume measurements beyond the baseline assessment. RESULTS: The calibration of both versions of the Mayo Clinic prediction model using continuous Height adjusted total kidney volume (HtTKV) and using risk subclasses was good, with R2 of 78% and 70%, respectively. Accuracy was also good with 91.5% and 88.7% of the predicted within 30% of the observed, respectively. Additional information regarding kidney volume did not substantially improve the model performance. CONCLUSION: The Mayo Clinic prediction models are generalizable to other clinical settings and provide an accurate tool based on available predictors to identify patients at high risk for rapid disease progression.

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides.

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

Sirolimus and secondary skin-cancer prevention in kidney transplantation.

BACKGROUND: Transplant recipients in whom cutaneous squamous-cell carcinomas develop are at high risk for multiple subsequent skin cancers. Whether sirolimus is useful in the prevention of secondary skin cancer has not been assessed. METHODS: In this multicenter trial, we randomly assigned transplant recipients who were taking calcineurin inhibitors and had at least one cutaneous squamous-cell carcinoma either to receive sirolimus as a substitute for calcineurin inhibitors (in 64 patients) or to maintain their initial treatment (in 56). The primary end point was survival free of squamous-cell carcinoma at 2 years. Secondary end points included the time until the onset of new squamous-cell carcinomas, occurrence of other skin tumors, graft function, and problems with sirolimus. RESULTS: Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median time until onset, 15 vs. 7 months; P=0.02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98). There were 60 serious adverse events in the sirolimus group, as compared with 14 such events in the calcineurin-inhibitor group (average, 0.938 vs. 0.250). There were twice as many serious adverse events in patients who had been converted to sirolimus with rapid protocols as in those with progressive protocols. In the sirolimus group, 23% of patients discontinued the drug because of adverse events. Graft function remained stable in the two study groups. CONCLUSIONS: Switching from calcineurin inhibitors to sirolimus had an antitumoral effect among kidney-transplant recipients with previous squamous-cell carcinoma. These observations may have implications concerning immunosuppressive treatment of patients with cutaneous squamous-cell carcinomas. (Funded by Hospices Civils de Lyon and others; TUMORAPA ClinicalTrials.gov number, NCT00133887.).

Impaired expression of key molecules of ammoniagenesis underlies renal acidosis in a rat model of chronic kidney disease.

BACKGROUND: Advanced chronic kidney disease (CKD) is associated with the development of renal metabolic acidosis. Metabolic acidosis per se may represent a trigger for progression of CKD. Renal acidosis of CKD is characterized by low urinary ammonium excretion with preserved urinary acidification indicating a defect in renal ammoniagenesis, ammonia excretion or both. The underlying molecular mechanisms, however, have not been addressed to date. METHODS: We examined the Han:SPRD rat model and used a combination of metabolic studies, mRNA and protein analysis of renal molecules involved in acid-base handling. RESULTS: We demonstrate that rats with reduced kidney function as evident from lower creatinine clearance, lower haematocrit, higher plasma blood urea nitrogen, creatinine, phosphate and potassium had metabolic acidosis that could be aggravated by HCl acid loading. Urinary ammonium excretion was highly reduced whereas urinary pH was more acidic in CKD compared with control animals. The abundance of key enzymes and transporters of proximal tubular ammoniagenesis (phosphate-dependent glutaminase, PEPCK and SNAT3) and bicarbonate transport (NBCe1) was reduced in CKD compared with control animals. In the collecting duct, normal expression of the B1 H(+)-ATPase subunit is in agreement with low urinary pH. In contrast, the RhCG ammonia transporter, critical for the final secretion of ammonia into urine was strongly down-regulated in CKD animals. CONCLUSION: In the Han:SPRD rat model for CKD, key molecules required for renal ammoniagenesis and ammonia excretion are highly down-regulated providing a possible molecular explanation for the development and maintenance of renal acidosis in CKD patients.

Sclerostin quo vadis? - is this a useful long-term mortality parameter in prevalent hemodialysis patients?

BACKGROUND/AIMS: Cardiovascular calcification contributes to the increased mortality in hemodialysis patients. Sclerostin was identified as an antianabolic bone factor causing soft tissue calcification. Data on prospective large-scale studies associating sclerostin with mortality in hemodialysis patients are so far inconsistent. METHODS: In our multicenter prospective longitudinal study following hemodialysis patients, we assessed the associations of sclerostin and bone remodeling markers with long-term mortality. We evaluated the relationship between circulating sclerostin, Fibroblast growth factor 23 (FGF23) and traditional bone remodeling markers. Sclerostin levels in hemodialysis patients were compared with healthy controls. RESULTS: We enrolled 239 hemodialysis patients with a median follow up of 1461 days. In Cox regression analysis, FGF23 (HR 1.40;95%CI 1.11-1.76), parathyroid hormone (PTH) (HR 1.80;95%CI 1.44-2.26) and alkaline phosphatase (AP) (HR 1.50;95%CI 1.10-2.04) per SD, 25(OH)vitamin D (HR 0.42;95%CI 0.23-0.76) per natural log but not sclerostin (HR 1.02;95%CI 0.75-1.38) per SD increase were associated with mortality. FGF23, PTH and AP were negatively associated with sclerostin. Among control and hemodialysis females, sclerostin levels were lower than in men. CONCLUSION: Higher FGF23, PTH, AP and lower 25(OH)vitamin D but not sclerostin predict long-term mortality. Sclerostin was negatively associated with FGF23, PTH and AP and lower in females than in males.

Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease.

Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is linked to cardiovascular disease and all-cause mortality in chronic kidney disease. FGF23 rises in patients with CKD stages 2-3, but in patients with autosomal dominant polycystic kidney disease, the increase of FGF23 precedes the first measurable decline in renal function. The mechanisms governing FGF23 production and effects in kidney disease are largely unknown. Here we studied the relation between FGF23 and mineral homeostasis in two animal models of PKD. Plasma FGF23 levels were increased 10-fold in 4-week-old cy/+ Han:SPRD rats, whereas plasma urea and creatinine concentrations were similar to controls. Plasma calcium and phosphate levels as well as TmP/GFR were similar in PKD and control rats at all time points examined. Expression and activity of renal phosphate transporters, the vitamin D3-metabolizing enzymes, and the FGF23 co-ligand Klotho in the kidney were similar in PKD and control rats through 8 weeks of age, indicating resistance to FGF23, although phosphorylation of the FGF receptor substrate 2α protein was enhanced. In the kidneys of rats with PKD, FGF23 mRNA was highly expressed and FGF23 protein was detected in cells lining renal cysts. FGF23 expression in bone and spleen was similar in control rats and rats with PKD. Similarly, in an inducible Pkd1 knockout mouse model, plasma FGF23 levels were elevated, FGF23 was expressed in kidneys, but renal phosphate excretion was normal. Thus, the polycystic kidney produces FGF23 but is resistant to its action.

Building a network of ADPKD reference centres across Europe: the EuroCYST initiative.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic inherited kidney disease, affecting an estimated 600 000 individuals in Europe. The disease is characterized by age-dependent development of a multiple cysts in the kidneys, ultimately leading to end-stage renal failure and the need of renal replacement therapy in the majority of patients, typically by the fifth or sixth decade of life. The variable disease course, even within the same family, remains largely unexplained. Similarly, assessing disease severity and prognosis in an individual with ADPKD remains difficult. Epidemiological studies are limited due to the fragmentation of ADPKD research in Europe. METHODS: The EuroCYST initiative aims: (i) to harmonize and develop common standards for ADPKD research by starting a collaborative effort to build a network of ADPKD reference centres across Europe and (ii) to establish a multicentric observational cohort of ADPKD patients. This cohort will be used to study factors influencing the rate of disease progression, disease modifiers, disease stage-specific morbidity and mortality, health economic issues and to identify predictive disease progression markers. Overall, 1100 patients will be enrolled in 14 study sites across Europe. Patients will be prospectively followed for at least 3 years. Eligible patients will not have participated in a pharmaceutical clinical trial 1 year before enrollment, have clinically proven ADPKD, an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m(2) and above, and be able to provide written informed consent. The baseline visit will include a physical examination and collection of blood, urine and DNA for biomarker and genetic studies. In addition, all participants will be asked to complete questionnaires detailing self-reported health status, quality of life, socioeconomic status, health-care use and reproductive planning. All subjects will undergo annual follow-up. A magnetic resonance imaging (MRI) scan will be carried out at baseline, and patients are encouraged to undergo a second MRI at 3-year follow-up for qualitative and quantitative kidney and liver assessments. CONCLUSIONS: The ADPKD reference centre network across Europe and the observational cohort study will enable European ADPKD researchers to gain insights into the natural history, heterogeneity and associated complications of the disease as well as how it affects the lives of patients across Europe.

Multicentre prospective validation of a urinary peptidome-based classifier for the diagnosis of type 2 diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is one of the major late complications of diabetes. Treatment aimed at slowing down the progression of DN is available but methods for early and definitive detection of DN progression are currently lacking. The 'Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria trial' (PRIORITY) aims to evaluate the early detection of DN in patients with type 2 diabetes (T2D) using a urinary proteome-based classifier (CKD273). METHODS: In this ancillary study of the recently initiated PRIORITY trial we aimed to validate for the first time the CKD273 classifier in a multicentre (9 different institutions providing samples from 165 T2D patients) prospective setting. In addition we also investigated the influence of sample containers, age and gender on the CKD273 classifier. RESULTS: We observed a high consistency of the CKD273 classification scores across the different centres with areas under the curves ranging from 0.95 to 1.00. The classifier was independent of age (range tested 16-89 years) and gender. Furthermore, the use of different urine storage containers did not affect the classification scores. Analysis of the distribution of the individual peptides of the classifier over the nine different centres showed that fragments of blood-derived and extracellular matrix proteins were the most consistently found. CONCLUSION: We provide for the first time validation of this urinary proteome-based classifier in a multicentre prospective setting and show the suitability of the CKD273 classifier to be used in the PRIORITY trial.

[Significance of phosphate in internal medicine]. / Phosphat in der Inneren Medizin.

Phosphate is essential for bone metabolism and for energy provision. Phosphate homeostasis is achieved by hormonal feedback mechanisms, predominantly parathyroid hormone, fibroblast growth factor 23 and calcitriol, with renal phosphate absorption taking on a special role. Although even large deviations from the serum normal range are rarely symptomatic, the health consequences can be significant. Essentially, the clinically relevant disturbances in phosphate balance can be attributed to three mechanisms: 1. shifts of phosphate between the extracellular space and the cytosol; 2. inadequate phosphate reabsorption in the kidney; 3. decreased intestinal phosphate absorption. Knowledge of physiology enables diagnosis and therapy of phosphate disorders.

Enriched human embryonic stem cells-derived CD133+, CD24+ renal progenitors engraft and restore function in a gentamicin-induced kidney injury in mice.

Introduction: Acute kidney injury (AKI) is a common health problem that leads to high morbidity and potential mortality. The failure of conventional treatments to improve forms of this condition highlights the need for innovative and effective treatment approaches. Regenerative therapies with Renal Progenitor Cells (RPCs) have been proposed as a promising new strategy. A growing body of evidence suggests that progenitor cells differentiated from different sources, including human embryonic stem cells (hESCs), can effectively treat AKI. Methods: Here, we describe a method for generating RPCs and directed human Embryoid Bodies (EBs) towards CD133+CD24+ renal progenitor cells and evaluate their functional activity in alleviating AKI. Results: The obtained results show that hESCs-derived CD133+CD24+ RPCs can engraft into damaged renal tubules and restore renal function and structure in mice with gentamicin-induced kidney injury, and significantly decrease blood urea nitrogen levels, suppress oxidative stress and inflammation, and attenuate histopathological disturbances, including tubular necrosis, tubular dilation, urinary casts, and interstitial fibrosis. Conclusion: The results suggest that RPCs have a promising regenerative potential in improving renal disease and can lay the foundation for future cell therapy and disease modeling.

Targeting of sodium-glucose cotransporters with phlorizin inhibits polycystic kidney disease progression in Han:SPRD rats.

Renal tubular epithelial cell proliferation and transepithelial cyst fluid secretion are key features in the progression of polycystic kidney disease (PKD). As the role of the apical renal sodium-glucose cotransporters in these processes is not known, we tested whether phlorizin inhibits cyst growth and delays renal disease progression in a rat model of PKD. Glycosuria was induced by subcutaneous injection of phlorizin in male heterozygous (Cy/+) and wild-type Han:SPRD rats. Phlorizin induced immediate and sustained glycosuria and osmotic diuresis in these rats. Cy/+ rats treated with phlorizin for 5 weeks showed a significant increase in creatinine clearance, a lower 2-kidneys/body weight ratio, a lower renal cyst index, and reduced urinary albumin excretion as compared with vehicle-treated Cy/+ rats. Measurement of Ki67 staining found significantly lower cell proliferation in dilated tubules and cysts of Cy/+ rats treated with phlorizin, as well as a marked inhibition of the activated MAP kinase pathway. In contrast, the mTOR pathway remained unaltered. Phlorizin dose dependently inhibited MAP kinase in cultured tubular epithelial cells from Cy/+ rats. Thus, long-term treatment with phlorizin significantly inhibits cystic disease progression in a rat model of PKD. Hence, induction of glycosuria and osmotic diuresis (glycuresis) by renal sodium-glucose cotransporters inhibition could have a therapeutic effect in polycystic kidney disease.

Sirolimus and kidney growth in autosomal dominant polycystic kidney disease.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), aberrant activation of the mammalian target of rapamycin (mTOR) pathway is associated with progressive kidney enlargement. The drug sirolimus suppresses mTOR signaling. METHODS: In this 18-month, open-label, randomized, controlled trial, we sought to determine whether sirolimus halts the growth in kidney volume among patients with ADPKD. We randomly assigned 100 patients between the ages of 18 and 40 years to receive either sirolimus (target dose, 2 mg daily) or standard care. All patients had an estimated creatinine clearance of at least 70 ml per minute. Serial magnetic resonance imaging was performed to measure the volume of polycystic kidneys. The primary outcome was total kidney volume at 18 months on blinded assessment. Secondary outcomes were the glomerular filtration rate and urinary albumin excretion rate at 18 months. RESULTS: At randomization, the median total kidney volume was 907 cm3 (interquartile range, 577 to 1330) in the sirolimus group and 1003 cm3 (interquartile range, 574 to 1422) in the control group. The median increase over the 18-month period was 99 cm3 (interquartile range, 43 to 173) in the sirolimus group and 97 cm3 (interquartile range, 37 to 181) in the control group. At 18 months, the median total kidney volume in the sirolimus group was 102% of that in the control group (95% confidence interval, 99 to 105; P=0.26). The glomerular filtration rate did not differ significantly between the two groups; however, the urinary albumin excretion rate was higher in the sirolimus group. CONCLUSIONS: In adults with ADPKD and early chronic kidney disease, 18 months of treatment with sirolimus did not halt polycystic kidney growth. (Funded by Wyeth and others; ClinicalTrials.gov number, NCT00346918.)

Secreted Klotho and FGF23 in chronic kidney disease Stage 1 to 5: a sequence suggested from a cross-sectional study.

BACKGROUND: Klotho and fibroblast growth factor 23 (FGF23) are key regulators of mineral metabolism in renal insufficiency. FGF23 levels have been shown to increase early in chronic kidney disease (CKD); however, the corresponding soluble Klotho levels at the different CKD stages are not known. METHODS: Soluble Klotho, FGF23, parathyroid hormone (PTH), 1,25-dihydroxy vitamin D(3) (1,25D) and other parameters of mineral metabolism were measured in an observational cross-sectional study in 87 patients. Locally weighted scatter plot smoothing function of these parameters were plotted versus estimated glomerular filtration rate (eGFR) to illustrate the pattern of the relationship. Linear and non-linear regression analyses were performed to estimate changes in mineral metabolism parameters per 1mL/min/1.73 m(2) decline. RESULTS: In CKD 1-5, Klotho and 1,25D linearly decreased, whereas both FGF23 and PTH showed a baseline at early CKD stages and then a curvilinear increase. Crude mean Klotho level declined by 4.8 pg/mL (95% CI 3.5-6.2 pg/mL, P < 0.0001) and 1,25D levels by 0.30 ng/L (95% CI 0.18-0.41 ng/L, P < 0.0001) as GFR declined by 1 mL/min/1.73 m(2). After adjustment for age, gender, serum 25-hydroxyvitamin D levels and concomitant medications (calcium, supplemental vitamin D and calcitriol), we estimated that the mean Klotho change was 3.2 pg/mL (95% CI 1.2-5.2 pg/mL, P = 0.0019) for each 1 mL/min/1.73 m(2) GFR change. FGF23 departed from the baseline at an eGFR of 47 mL/min/1.73 m(2) (95% CI 39-56 mL/min/1.73 m(2)), whereas PTH departed at an eGFR of 34 mL/min/1.73 m(2) (95% CI 19-50 mL/min/1.73 m(2)). CONCLUSIONS: Soluble Klotho and 1,25D levels decrease and FGF23 levels increase at early CKD stages, whereas PTH levels increase at more advanced CKD stages.

Quantitative BOLD response of the renal medulla to hyperoxic challenge at 1.5 T and 3.0 T.

The aim of this study was to gage the magnitude of changes of the apparent renal medullary transverse relaxation time (ΔT(2)) induced by inhalation of pure oxygen (O(2) ) or carbogen (95% O(2) , 5% CO(2) ) versus baseline breathing of room air. Eight healthy volunteers underwent 2D multi-gradient echo MR imaging at 1.5 T and 3.0 T. Parametrical T(2) relaxation time maps were computed and average T(2) was measured in regions of interest placed in the renal medulla and cortex. The largest T(2) changes were measured in the renal medulla, with a relative ∆T(2) of 33.8 ± 22.0% (right medulla) and 34.7 ± 17.6% (left medulla) as compared to room air for oxygen breathing (p > 0.01), and 53.8 ± 23.9% and 53.5 ± 33.9% (p < 0.01) for carbogen breathing, respectively at 3 T. At 1.5 T, the corresponding values were 13.7 ± 18.5% and 24.1 ± 17.1% (p < 0.01) for oxygen breathing and 23.9 ± 17.2% and 38.9 ± 37.6% (p < 0.01) for carbogen breathing. As a result, we showed that renal medullary T(2) times responded strongly to inhalation of hyperoxic gases, which may be attributed to the hypoxic condition of the medulla and subsequent reduction in deoxyhemoglobin.

Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation.

BACKGROUND: The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. METHODS: Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. RESULTS: Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m(2)/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m(2)/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m(2)/year). CONCLUSIONS: Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.