Mass Spectrometry-Based Adrenal and Peripheral Venous Steroid Profiling for Subtyping Primary Aldosteronism.

BACKGROUND: Differentiating patients with primary aldosteronism caused by aldosterone-producing adenomas (APAs) from those with bilateral adrenal hyperplasia (BAH), which is essential for choice of therapeutic intervention, relies on adrenal venous sampling (AVS)-based measurements of aldosterone and cortisol. We assessed the utility of LC-MS/MS-based steroid profiling to stratify patients with primary aldosteronism. METHODS: Fifteen adrenal steroids were measured by LC-MS/MS in peripheral and adrenal venous plasma from AVS studies for 216 patients with primary aldosteronism at 3 tertiary referral centers. Ninety patients were diagnosed with BAH and 126 with APAs on the basis of immunoassay-derived adrenal venous aldosterone lateralization ratios. RESULTS: Among 119 patients confirmed to have APAs at follow-up, LC-MS/MS-derived lateralization ratios of aldosterone normalized to cortisol, dehydroepiandrosterone, and androstenedione were all higher (P < 0.0001) than immunoassay-derived ratios. The hybrid steroids, 18-oxocortisol and 18-hydroxycortisol, also showed lateralized secretion in 76% and 35% of patients with APAs. Adrenal venous concentrations of glucocorticoids and androgens were bilaterally higher in patients with BAH than in those with APAs. Consequently, peripheral plasma concentrations of 18-oxocortisol were 8.5-fold higher, whereas concentrations of cortisol, corticosterone, and dehydroepiandrosterone were lower in patients with APAs than in those with BAH. Correct classification of 80% of cases of APAs vs BAH was thereby possible by use of a combination of steroids in peripheral plasma. CONCLUSIONS: LC-MS/MS-based steroid profiling during AVS achieves higher aldosterone lateralization ratios in patients with APAs than immunoassay. LC-MS/MS also enables multiple measures for discriminating unilateral from bilateral aldosterone excess, with potential use of peripheral plasma for subtype classification.

[Renal replacement therapy in the intensive care unit]. / Nierenersatztherapie auf der Intensivstation.

BACKGROUND: Acute kidney injury is still one of the most common serious complications in critical ill patients and is associated with high mortality. Even small changes in renal function significantly influence survival and long-term prognosis. MATERIAL AND METHODS: Selective literature research and analysis of intensive care population with renal failure. CONCLUSION: Prophylactic measures as well as early diagnosis and therapy must be the goal of a modern intensive care treatment. Various treatment modalities for renal replacement therapy allow individualized treatment of each patient. The review summarizes the main aspects on prophylaxis and early diagnosis of acute kidney injury as well as the different treatment modalities for an individualized renal replacement therapy.

Assay characteristics influence the aldosterone to renin ratio as a screening tool for primary aldosteronism: results of the German Conn's registry.

Primary aldosteronism (PA) is the most frequent cause of secondary arterial hypertension. The aldosterone to renin ratio (ARR) is the gold standard for screening, but variability between biochemical methods used remains of concern. The aim of the study was to analyze center-specific features of biochemical diagnostic strategies prior to the 2008 consensus within the German Conn's Registry. The study was designed as a retrospective study in 5 tertiary care hospitals. Patients analyzed for PA between 1990 and 2006 were studied. Characteristics of the assays used to determine ARR during establishing the diagnosis of PA were analyzed in the retrospective part of the German Conn's Registry. Eighty-six out of 484 documented ARR values had to be excluded from further evaluations because the laboratory or the assays were unknown. In the remaining 398 patients ARR was determined using 10 different assay combinations in the centers (aldosterone plus plasma renin activity or concentration). Considerable differences were seen between the mean concentrations for aldosterone (p<0.0001), renin concentration (p<0.001), and renin activity (p=0.009) for the different assays. The differences between the absolute concentrations measured by the different assays also had significant impact upon the resulting mean ratios. If published cutoff values are applied, the use of different commercial assays to determine the ARR in clinical routine results in major differences in positive screening rates. This heterogeneity affects sensitivity and specificity of screening for PA. Our data emphasize the importance of standardized screening procedures, which must include standardization of biochemical methods.

Comparison of the saline infusion test and the fludrocortisone suppression test for the diagnosis of primary aldosteronism.

For the diagnosis of primary aldosteronism (PA), confirmatory testing is mandatory and different function tests can be employed. There are, however, sparse data comparing the fludrocortisone suppression test (FST) and the saline infusion test (SIT). Patients with PA (n=90) or essential hypertension (n=65) were studied. They underwent one or the other test or both of them. Using the DPC Siemens aldosterone radioimmunoassay, we found that the SIT led to a stronger suppression of aldosterone than the FST. Post-test aldosterone-to-renin ratios (ARRs) and the percentage of suppression of aldosterone serum concentrations performed worse. The same results were observed in patients who underwent both FST and SIT. Some patients had divergent results in both tests. For the SIT, a lower cutoff value should be used than for the FST for the adequate identification of patients with unilateral PA. Long-term prospective studies are needed to address the question at what cutoff values patients benefit from subtype differentiation of PA. We discuss here possible explanations for divergent results obtained with both tests.

Renal artery revascularization after unsuccessful percutaneous therapy: a single centre experience.

PURPOSE: This retrospective review describes the long time effect of surgical revascularization after unsuccessful early or mid-term failure of percutaneous transluminal renal angioplasty (PTRA). METHODS: From January 1995 to January 2005, 60 out of 696 patients operated due to renal artery occlusive disease (17 fibromuscular dyplasia (FMD): mean age, 33.4 years; 43 atherosclerotic disease (ASD): mean age, 62.46 years) after unsuccessful PTRA underwent surgical revascularization for renal artery stenosis at our institution. The mean duration from failed PTRA to operation was 1.74 years. Out of the 68 renal arteries, 44 were pretreated with angioplasty alone (19, FMD; 25, ASD), and 24 were treated with PTRA and stent (all ASD). Operative management, response of renal function and hypertension as well as survival were compared to the literature. RESULTS: Fifty-nine per cent (n = 40) of the renal arteries were treated by transaortic thrombendarterectomy, 37% (n = 25) by bypass. Thirty-day and in-hospital mortality was 0% in all pretreated patients; after a mean of 4.16 years, it was 16.6% (only atherosclerotic). There was a significant decrease in systolic blood pressure values for all patients early after surgery as well as in follow-up. Creatinine remained stable in the patients with FMD, and there was an insignificant increase in creatinine level in the atherosclerotic patients. Hypertension was improved or healed in 32.5% of all pretreated patients, in cases with FMD in 54%, in atherosclerotic cases in 22.2%. Re-stenoses occurred in 26% of cases with FMD and in 18% of patients with atherosclerotic RAS. CONCLUSION: Surgical renal artery revascularization after failed PTRA is feasible and safe and systolic blood pressure can be lowered. The higher rate in re-stenoses in both the literature as well as in our own experience may be explained by the alterations in the renal artery after interventional treatment.

[Renal insufficiency and cardiovascular diseases]. / Niereninsuffizienz und kardiovaskuläre Erkrankungen.

Chronic kidney disease (CKD) is a strong cardiovascular risk factor. Microalbuminuria is an early indicator of renal and cardiac damage. Optimal blood pressure therapy and reduction of proteinuria are important measures in order to reduce increased cardiovascular morbidity and mortality in this cohort. Secondary prevention by optimal medical as well as interventional therapy is employed in an inadequate number of CKD patients. In addition, CKD patients should be screened for sleep-related disorders and, if required, adequate therapy should be provided in order to improve cardiovascular outcome. Prospective data in advanced CKD patients concerning new therapeutical approaches such as oral factor Xa- or thrombin-inhibitor therapy are lacking. Optimal treatment of atrial fibrillation in dialysis patients with vitamin K antagonists is also unclear. Prospective studies of transcatheter aortic valve implantation for severe aortic stenosis in patients with advanced stages of renal insufficiency or dialysis therapy are still missing.

[Medicinal or instrumental (corrected) therapy of renal artery stenosis?]. / Medikamentöse oder instrumentelle Therapie der Nierenarterienstenose?

Arteriosclerotic renal artery stenosis (RAS) has an increased incidence in patients with cardiovascular risk factors. Clinically RAS presents in some patients as secondary, sometimes resistant arterial hypertension and in others as chronic renal insufficiency, sometimes with acute renal failure and in a third group both symptoms are observed. Doppler ultrasound plays a central role in the diagnosis of RAS. Therapeutically, it is important to identify hemodynamically relevant RAS before interventional therapy is initiated. The therapy of RAS has been under intensive debate since the publication of randomized controlled trials (RCT) which showed that only a subset of RAS can be successfully treated by interventional therapy. Since then the medicinal therapy of RAS has gained more and more impact. The following questions are raised: which forms of RAS can be treated by which therapy? What is the best medicinal therapy to treat RAS? What substances are recommended?

[Treatment resistant hypertension. Value of a new treatment concept]. / Therapierefraktäre Hypertonie. Stellenwert neuer Therapiekonzepte.

Sympathetic overexpression can be found in a majority of hypertensive patients. Resistant arterial hypertension requires a targeted diagnostic procedure in order to exclude secondary causes of hypertension which can be treated specifically with established therapies. If secondary reasons are not identified, the antihypertensive medication is already optimal and lifestyle changes have been realized, but still the goal of antihypertensive therapy cannot be achieved, alternative invasive therapy strategies such as renal sympathetic denervation and baroreflex activation have been developed to achieve blood pressure control. These therapies are restricted to specialized centers which treat well-defined patients with therapy-resistant hypertension. Little long-term data concerning safety and efficacy are available for the two strategies. However, they should preferably be used as an ultima-ratio and add-on pathway to conservative procedures when established medication fails to achieve blood pressure control. To date, the effectiveness of the interventional antihypertensive therapies has only been shown on patients with systolic blood pressure over 160 mmHg and a mean oral medication of five drugs.

Feasibility of renal perfusion quantification by Fourier decomposition MRI.

PURPOSE: To evaluate the feasibility of perfusion measurements in the human kidney by Fourier decomposition MRI (FD-MRI). METHODS: Renal perfusion measurements by FD-MRI and arterial spin labeling (ASL) were performed using a 1.5 T whole-body MR-scanner (Magnetom Avanto, Siemens Healthineers AG, Germany) in 15 healthy volunteers (mean age 33.0 ± 13.6 years). Five healthy volunteers were measured twice to evaluate the reproducibility. Besides, five patients with renal artery stenosis (RAS) (mean age 58.4 ± 16.2 years) were included in the study to evaluate potential clinical use of the FD-MRI for evaluating renal perfusion. For renal FD-MRI, coronal 2D-TrueFisp sequence (1 section; section thickness: 10 mm; FOV: 400 × 400 mm 2; TR/TE: 2.06/0.89 ms; 250 images; 0,36 s/image), for renal ASL, coronal FAIR-TrueFisp sequence (1 section; section thickness: 10 mm; FOV: 400 × 400 mm2; TR/TE 4.0/2.0 ms, TI 1200 ms, 30 averages; 8,32 s/average) were acquired without any triggering. Perfusion parameter maps of the kidneys were calculated for both methods. After manual segmentation, ROI-based analysis (whole kidney, cortex and medulla, respectively) was performed and the results were subsequently compared using the Student t-test. RESULTS: The acquisition times were 1.30 min and 4.16 min, for renal FD-MRI and ASL, respectively. No significant difference in global renal perfusion (RBF) between both methods was detected (mean RBF in the right kidney: 308.4 ± 31.5 mL/100 mL/min for FD-MRI; 315.2 ± 41.1 for ASL; in the left kidney: 315.6 ± 32.8 mL/100 mL/min for FD-MRI; 310.2 ± 39.1 mL/100 mL/min for ASL, respectively). The results indicated good reproducibility of both considered methods. However, cortico-medullar differentiation was not possible by FD-MRI, probably due to lower SNR compared to ASL. Significant difference in the side-separated RBF were measured by FD-MRI as well as by ASL (p < 0.05) in patients with RAS. CONCLUSIONS: FD-MRI is a novel, rapid approach for contrast-free perfusion quantification in the human kidney. Main advantage of this new method compared to ASL perfusion is the significant shorter acquisition time and lower dependency on patient's compliance. However, lower SNR of FD-MRI needs further improvement to make FD-MRI a competitive alternative to ASL.

[Pregnancy and kidney diseases]. / Schwangerschaft und Nierenerkrankungen.

The prevalence of chronic kidney disease in women of childbearing age reaches approximately 0.2%. Under physiological conditions pregnancy results in important hemodynamic changes on the maternal organism. In the case of chronic kidney disease these adaptations often are only partial. Physiological changes of immune response during pregnancy may contribute to the progress of renal disease. Regardless of the underlying kidney disease, one can assume that the better the glomerular filtration rate and blood pressure are the more favorable the course of pregnancy will be with the chance for a healthy child and stable renal function. To achieve this goal, a close interaction is required between gynecologist, nephrologist, and other specialists in a center with appropriate experience.

Determinants of urinary albumin excretion within the normal range in patients with type 2 diabetes: the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study.

AIMS/HYPOTHESIS: In contrast to microalbuminuric type 2 diabetic patients, the factors correlated with urinary albumin excretion are less well known in normoalbuminuric patients. This may be important because even within the normoalbuminuric range, higher rates of albuminuria are known to be associated with higher renal and cardiovascular risk. METHODS: At the time of screening for the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) Study, the urinary albumin/creatinine ratio (UACR) was 0.44 mg/mmol in 4,449 type 2 diabetic patients. The independent correlates of UACR were analysed. RESULTS: Independent correlates of UACR during baseline were (in descending order): night-time systolic BP (r(s) = 0.19); HbA(1c) (r(s) = 0.18); mean 24 h systolic BP (r(s) = 0.16); fasting blood glucose (r(s) = 0.16); night-time diastolic BP (r(s) = 0.12); office systolic BP, sitting (r(s) = 0.11), standing (r(s) = 0.10); estimated GFR (r(s) = 0.10); heart rate, sitting (r(s) = 0.10); haemoglobin (r(s) = -0.10); triacylglycerol (r(s) = 0.09); and uric acid (r(s) = -0.08; all p

Familial hyperaldosteronism I-III.

Primary aldosteronism is the most frequent cause of secondary hypertension. Three variants of familial hyperaldosteronism are known today. Early onset hypertension and severe target organ damage are hallmarks of the heritable forms. The underlying gene defect has already been identified in familial hyperaldosteronism type I. In type II and III research is ongoing. A highly variable phenotype often precludes the discovery of the familial appearance of these syndromes. Taking a sound family history is extremely important to discover the Mendelian pattern of inheritance. The identification of affected families is highly rewarding because all variants can potentially be cured or at least specifically treated. Testing the relatives of an index patient sometimes even allows preemptive treatment. However, the availability of specific treatment options necessitates a solid differentiation between the three syndromes to avoid unnecessary medical therapy or surgery.

Clinical relevance of dietary salt intake on aldosterone and the aldosterone-to-renin ratio as screening parameters for primary aldosteronism.

AIMS: The recommendations for screening for primary aldosteronism (PA) are determination and interpretation of both plasma aldosterone and the aldosterone-renin ratio (ARR). Although it is known that oral sodium chloride intake has an important impact on plasma aldosterone and ARR, more detailed data of this impact are sparse. We evaluated the relevance of natriuresis as a parameter of oral sodium intake, as well as patient age and antihypertensive medication on the PA screening parameters in our hypertensive patient population. METHOD: Our cross-sectional, single-center study investigated the impact of natriuresis, patient age, body mass index, Ca-antagonists, beta-blockers, ACE inhibitors and/or AT1 blockers on aldosterone and ARR in 777 hypertensive patients (393 men, 384 women) with a mean age (± SD) of 49.5 ± 15.7 years and an endogenous creatinine clearance of at least 80 ml/min. A total of 401 patients (51.6%) were on antihypertensive therapy. The mean natriuresis of the total population was 206.7 ± 97.0 mmol/day. The potential impact factors on plasma aldosterone and ARR were analyzed in two separate univariate, bivariate, and multiple regression analyses, respectively, with natriuresis as the main impact factor. RESULTS: Natriuresis as well as patient age had a significant impact on both plasma aldosterone and ARR. In addition, beta-blockers, ACE inhibitors and/or AT1 blockers had a significant impact on ARR (p < 0.05). CONCLUSIONS: In addition to antihypertensive medication, natriuresis as well as patient age seem to need further consideration in the process of PA screening and interpretation of its results. Additional experimental studies are warranted to confirm and generalize our results.

B-type natriuretic peptide and severe heart failure at baseline predict overall mortality in incident dialysis patients.

AIMS: The B-type natriuretic peptide (BNP) has become increasingly important as a diagnostic and prognostic method for cardiovascular disease or death. To our knowledge no prospective studies exist to evaluate the value of baseline BNP and baseline heart failure as predictors of overall death in incident rather than prevalent hemodialysis patients with end-stage renal disease (ESRD). METHODS: 255 ESRD patients were included in our observational study with a median observation period of 1.11 years. A Kaplan-Meier survival curve was stratified by BNP concentration (< 340 pg/ml and > or = 340 pg/ml) to estimate the impact on the overall mortality rate. Univariate and multiple Cox regression models were fitted for a variety of covariables including severe heart failure (graded according to the New York Heart Association) to evaluate the independent predictors of death. Association between BNP and four explanatory variables was described in a multiple linear regression model. RESULTS: Survival analysis demonstrated a significantly higher mortality rate in patients with higher BNP values at baseline. The independent predictive value of high BNP concentration at baseline could be statistically confirmed by multiple Cox regression analysis. However, when including the covariates hemoglobin and severe heart failure, significantly associated with BNP, in the same model, severe heart failure rather than BNP becomes a significant predictor of overall death. CONCLUSIONS: A higher BNP level at baseline may be confirmed as an independent predictor of death in the incident dialysis population. However, severe heart failure may affect the impact of BNP on the overall survival rate and thus be a stronger predictor of death than BNP.

The German registry for nephrogenic systemic fibrosis: findings from 23 patients.

BACKGROUND AND AIM: Nephrogenic systemic fibrosis (NSF) is a highly debilitating disorder primarily affecting the skin, but also other organ compartments. So far, it has only occurred in patients suffering from acute or chronic renal failure, with almost all of them having been exposed to gadolinium-based contrast agents (GBCA). The NSF registry was initiated on behalf of the German Society of Nephrology. The aim was to analyze the development, risk factors and clinical course of patients suffering from NSF. PATIENTS AND METHODS: Between July 2007 and July 2009, 23 patients were registered (12/23 (52,2%) male and 11/23 (47,8%) female). Onset of NSF symptoms was between 2002 and 2008, with a maximum of 8 cases in 2005. Since January 2008 no patient with a new onset of NSF has been reported. On all patients nuclear magnetic resonance procedures were performed between 1 day and 3 years (median 30 days) before the onset of symptoms ("index procedure"). At the time of the index procedure 21/23 (91,3%) patients required dialysis, 15/22 patients (68,2%) showed signs and symptoms of atherosclerosis and 17/20 (76,5%) of inflammation. 22/23 patients remained in chronic kidney disease stage 5D. Upper and lower extremities were affected in 18/23 (78,3%) patients; 20/23 (87%) developed joint contractures. RESULTS: Our data confirm previous observations that NSF is associated with impaired renal function and the application of GBCA. In individual cases the interval between the index procedure and the onset of symptoms lasted years. CONCLUSION: The incidence of NSF has decreased rapidly within the past 4 years. This could be due to general awareness within the medical community and the application of macrocyclic chelates.

Fulminant staphylococcus lugdunensis septicaemia following a pelvic varicella-zoster virus infection in an immune-deficient patient: a case report.

INTRODUCTION: the deadly threat of systemic infections with coagulase negative Staphylococcus lugdunensis despite an appropriate antibiotic therapy has only recently been recognized. The predominant infectious focus observed so far is left-sided native heart valve endocarditis, but bone and soft tissue infections, septicaemia and vascular catheter-related bloodstream infections have also been reported. We present a patient with a fatal Staphylococcus lugdunensis septicaemia following zoster bacterial superinfection of the pelvic region. case presentation: a 71-year old male diagnosed with IgG kappa plasmocytoma presented with a conspicuous weight loss, a hypercalcaemic crisis and acute renal failure. After initiation of haemodialysis treatment his condition improved rapidly. However, he developed a varicella-zoster virus infection of the twelfth thoracic dermatome requiring intravenous acyclovir treatment. Four days later the patient presented with a fulminant septicaemia. Despite an early intravenous antibiotic therapy with ciprofloxacin, piperacillin/combactam and vancomycin the patient died within 48 hours, shortly before the infective isolate was identified as Staphylococcus lugdunensis by polymerase chain reaction. CONCLUSION: despite S. lugdunensis belonging to the family of coagulase-negative staphylococci with an usually low virulence, infections with S. lugdunensis may be associated with an aggressive course and high mortality. This is the first report on a Staphylococcus lugdunensis septicaemia following a zoster bacterial superinfection of the pelvic region.

[Kidney and hypertension]. / Niere und Hypertonie.

In patients with chronic kidney disease elevated blood pressure is a common finding, but primary hypertension can also damage healthy kidneys. Renal outcome is strictly dependent on blood pressure, no matter whether the kidneys are cause or consequence of hypertension. Furthermore, hypertension and kidney disease are strong cardiovascular risk factors. In every patient diagnosed with hypertension glomerular filtration rate has to be checked. Proteinuria and structural abnormalities of the kidneys should be ruled out. Patients with a decreased glomerular filtration rate, proteinuria or pathologic ultrasound should be seen by a nephrologist. A strict antihypertensive therapy (blood pressure <130/80 mmHg) can substantially improve the prognosis of hypertensive renal patients. In patients with kidney damage, inhibitors of the renin-angiotensin-system are preferred. To avoid adverse events a close monitoring of antihypertensive therapy is warranted.

[Hypertension in patients with renal artery stenosis]. / Hypertonie bei Patienten mit Nierenarterienstenosen.

Renal artery stenosis (RAS) is often present in patients with severe hypertension and atherosclerotic vascular disease. In this setting it is important to screen patients for renovascular disease, e.g. with Duplex-ultrasound, CT- or MR-angiography. The challenge of treating these patients is to find the evidence proving that the RAS is responsible for hypertension and/or renal dysfunction. Measurement of the intra-arterial pressure gradient is necessary in order to determine hemodynamic relevance. On the other side, in these patients hypertension is often of primary and/or renoparenchymatous origin and is aggravated by a renovascular disease. This explains why hypertension cannot be cured even if a high grade stenosis has been removed. In addition, thromb- and cholesterol-embolic material is often mobilized during an invasive procedure and leads to renaparenchymatous ischemia which sustains hypertension after intervention. An individual evaluation of profit versus risk is important for the decision for or against an invasive procedure, especially since there is no sufficient evidence for a decrease of mortality after interventions of RAS. The optimal conservative treatment, including the treatment of atherosclerotic risk factors is recommended.

Oncogenic osteomalacia, a rare paraneoplastic syndrome due to phosphate wasting--a case report and review of the literature.

An appropriate phosphate homeostasis is absolutely required for correct bone mineralization and remodeling, for diverse signaling pathways as well as cell membrane formation. Its disequilibrium results in serious complications like hypophosphatemia and excessively reduced fractional tubule phosphate reabsorption (TRP). A rare cause of such a disturbed phosphate balance is tumor-induced osteomalacia (TIO)--a phosphate wasting disorder sometimes associated with certain mesenchymal tumors. These primitive tumors secrete so-called phosphatonins--recently identified factors involved in the regulation of phosphate homeostasis such as the secreted frizzled related protein 4 (sFRP-4), the fibroblast growth factors 7 and 23 (FGF-7/-23), or the matrix extracellular phosphoglycoprotein (MEPE). Progressive muscular weakness and spontaneous bone fractures caused by inadequate osteoid mineralization are the characteristic clinical symptoms, which completely resolve after tumor resection. Here we report a new case of TIO caused by tumor secreted FGF-23 and review the literature to facilitate the correct diagnosis of this rare disorder.