Sodium chloride, a vital mineral resource, should be consumed not too much. The DEGS-Study (German Adult Health Survey), which focuses on documenting the salt intake of the German population, shows that the median salt intake of 70% of the participating women and 80% of the men lies above the DGE's (German Society for Nutrition) recommended daily dose of 6 g. The WHO similarly recommends a salt consumption of no more than 5 g per day (approximately a teaspoon of salt) as a target value in its guidelines. Salt plays an important role in regulating the renin angiotensin pathway (also known as the RAA pathway), which, in turn, maintains volume, sodium chloride and blood pressure homeostasis within the body. Understanding this process becomes increasingly important, as arterial hypertension is still a significant cause of death worldwide. The data of numerous large, randomized, controlled studies is evidence for the harmful effects of a high sodium chloride consumption on the human body. Current research is focused on further understanding the regulation of salt depots in the skin as well as the effect of sodium chloride on the microbiome of the intestinal tract.

Zusammenfassung Natrium ist ein essenzieller Mineralstoff, der jedoch nur in begrenzter Menge zugeführt werden sollte. So zeigt die DEGS-Studie (DEGS: Deutsches Erwachsenen Gesundheitssurvey), die sich mit der Salzzufuhr der deutschen Bevölkerung beschäftigt, dass die mediane Speisesalzaufnahme bei 70% der Frauen und 80% der Männer deutlich über der Empfehlung der DGE (Deutsche Gesellschaft für Ernährung) von 6 g pro Tag liegt. Auch die Weltgesundheitsorganisation (WHO) empfiehlt in ihren Leitlinien einen Orientierungswert zur Salzaufnahme von 5 g pro Tag, was etwa einem Teelöffel entspricht. Kochsalz stellt einen wesentlichen Einflussfaktor der Blutdruckregulation und des Renin-Angiotensin-Aldosteron-Systems (RAAS) dar. Das Verständnis dieser Regelkreise gewinnt zunehmend an Bedeutung, da die arterielle Hypertonie noch immer eine der wesentlichen Todesursachen weltweit darstellt. Hier kann bereits auf eine evidenzbasierte Datenlage zurückgegriffen werden, die eine schädliche Wirkung einer erhöhten Kochsalzzufuhr belegt. Gegenstand aktueller Forschung sind die Regulation der Salzspeicher in der Haut sowie die Beeinflussung des Mikrobioms im Darm durch Kochsalz.

BACKGROUND: Insulin-like growth factor (IGF) system components are important regulators of bone formation. Alterations of individual IGF system components have been described in osteoporosis (OP) patients; however, no study has addressed changes in free IGF-I and in all six IGF binding proteins (IGFBPs). METHODS: A cross-sectional study was performed in 45 OP patients and 100 healthy matched controls. Serum levels of free and total insulin-like growth factor I (IGF-I), IGFBP-1 through -6, intact parathyroid hormone (PTH), 25-OH-vitamin D(3) (25OHD(3)), 1,25-(OH)(2)-vitamin D(3) (1,25-(OH)(2)D(3)), osteocalcin (OSC), bone alkaline phosphatase (B-ALP), and carboxyterminal propeptide of type-I procollagen (PICP) were measured with specific assays. Bone mineral density (BMD) of the lumbar spine was determined by dual-energy X-ray absorptiometry (DEXA). RESULTS: Compared with age- and sex-matched control subjects, OP patients showed a 73% decrease in free IGF-I, a 29% decrease in total IGF-I, a 10% decrease in IGFBP-3, and a 52% decrease in IGFBP-5 levels; they had higher levels of IGFBP-1 (4.1-fold), IGFBP-2 (1.8-fold), IGFBP-4 (1.3-fold), and IGFBP-6 (2.1-fold). Alterations in IGF system components were most evident in 13 OP patients with vertebral fractures in the past 4 years compared to patients without fractures. In OP patients with fractures, the ratio between IGFBP-4 and IGFBP-5 was increased whereas levels of OSC were decreased. CONCLUSIONS: Our data provide strong indirect evidence for a functional connection between circulating IGF system components and bone metabolism and the susceptibility to fractures in OP patients.

Glucagon-like peptide-1-(7---36) amide (GLP-1) is a potent incretin hormone secreted from distal gut. It stimulates basal and glucose-induced insulin secretion and proinsulin gene expression. The present study tested the hypothesis that GLP-1 may modulate insulin receptor binding. RINm5F rat insulinoma cells were incubated with GLP-1 (0.01-100 nM) for different periods (1 min-24 h). Insulin receptor binding was assessed by competitive ligand binding studies. In addition, we investigated the effect of GLP-1 on insulin receptor binding on monocytes isolated from type 1 and type 2 diabetes patients and healthy volunteers. In RINm5F cells, GLP-1 increased the capacity and affinity of insulin binding in a time- and concentration-dependent manner. The GLP-1 receptor agonist exendin-4 showed similar effects, whereas the receptor antagonist exendin-(9---39) amide inhibited the GLP-1-induced increase in insulin receptor binding. The GLP-1 effect was potentiated by the adenylyl cyclase activator forskolin and the stable cAMP analog Sp-5, 6-dichloro-1-beta-D-ribofuranosyl-benzimidazole-3', 5'-monophosphorothioate but was antagonized by the intracellular Ca(2+) chelator 1,2-bis(0-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM. Glucagon, gastric inhibitory peptide (GIP), and GIP-(1---30) did not affect insulin binding. In isolated monocytes, 24 h incubation with 100 nM GLP-1 significantly (P<0.05) increased the diminished number of high-capacity/low-affinity insulin binding sites per cell in type 1 diabetics (9,000+/-3,200 vs. 18,500+/-3,600) and in type 2 diabetics (15,700+/-2,100 vs. 28,900+/-1,800) compared with nondiabetic control subjects (25,100+/-2,700 vs. 26,200+/-4,200). Based on our previous experiments in IEC-6 cells and IM-9 lymphoblasts indicating that the low-affinity/high-capacity insulin binding sites may be more specific for proinsulin (Jehle, PM, Fussgaenger RD, Angelus NK, Jungwirth RJ, Saile B, and Lutz MP. Am J Physiol Endocrinol Metab 276: E262-E268, 1999 and Jehle, PM, Lutz MP, and Fussgaenger RD. Diabetologia 39: 421-432, 1996), we further investigated the effect of GLP-1 on proinsulin binding in RINm5F cells and monocytes. In both cell types, GLP-1 induced a significant increase in proinsulin binding. We conclude that, in RINm5F cells and in isolated human monocytes, GLP-1 specifically increases the number of high-capacity insulin binding sites that may be functional proinsulin receptors.

blast function. This is also true for chronic renal failure Clinical significance of corticosteroid-induced (CRF) patients who therefore should be regarded as osteoporosis high-risk patients. In such patients vitamin D deficiency, metabolic acidosis, dialysis-associated amyloidosis, alu- Although recognized for almost 60 years, corticosteroid-minium accumulation, and malnutrition are further induced osteoporosis (COP) is a major problem.

BACKGROUND:The insulin-like growth factor (IGF) system plays a key role in regulation of bone formation. In patients with renal osteodystrophy, an elevation of some IGF binding proteins (IGFBPs) has been described, but there is no study measuring serum levels of both IGF-I and IGF-II as well as IGFBP-1 to -6 in different forms of renal osteodystrophy and hyperparathyroidism.METHODS:In a cross-sectional study, we investigated 319 patients with mild (N = 29), moderate (N = 48), preuremic (N = 37), and end-stage renal failure (ESRF; N = 205). The ESRF group was treated by hemodialysis (HD; N = 148), peritoneal dialysis (PD; N = 27), or renal transplantation (RTX; N = 30). As controls without renal failure, we recruited age-matched healthy subjects (N = 87) and patients with primary hyperparathyroidism (pHPT; N = 25). Serum levels of total and free IGF-I, IGF-II, IGFBP-1 to -6, and biochemical bone markers including intact parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), and osteocalcin (OSC) were measured by specific immunometric assays. IGF system components and bone markers were correlated with clinical and bone histologic findings. Mean values +/- SEM are given.RESULTS:With declining renal function a significant increase was measured for IGFBP-1 (range 7- to 14-fold), IGFBP-2 (3- to 8-fold), IGFBP-3 (1.5- to 3-fold), IGFBP-4 (3- to 19-fold), and IGFBP-6 (8- to 25-fold), whereas IGFBP-5 levels tended to decrease (1.3- to 1. 6-fold). In contrast, serum levels of IGF-I, free IGF-I, and IGF-II remained constant in most patients. Compared with renal failure patients, pHPT patients showed a similar decline in IGFBP-5 levels and less elevated levels of IGFBP-1 (3.5-fold), IGFBP-2 (2-fold), IGFBP-3 (1.2-fold), and IGFBP-6 (4-fold) but no elevation of IGFBP-4 levels. In all subjects, free and total IGF-I levels showed significant negative correlations with IGFBP-1, IGFBP-2, and IGFBP-4 (that is, inhibitory IGF system components) and significant positive correlations with IGFBP-3 and IGFBP-5 (that is, stimulatory IGF system components). A positive correlation was observed between IGF-II and IGFBP-6. ESRF patients with mixed uremic bone disease and histologic evidence for osteopenia revealed significantly (P < 0.05) higher levels of IGFBP-2 and IGFBP-4 but lower IGFBP-5 levels. Histologic parameters of bone formation showed significant positive correlations with serum levels of IGF-I, IGF-II, and IGFBP-5. In contrast, IGFBP-2 and IGFBP-4 correlated positively with indices of bone loss. Moreover, dialysis patients with low bone turnover (N = 24) showed significantly (P < 0.05) lower levels of IGFBP-5, PTH, B-ALP, and OSC than patients with high bone turnover.CONCLUSION:Patients with primary and secondary hyperparathyroidism showed lower levels of the putative stimulatory IGFBP-5 but higher levels of IGFBP-1, -2, -3, and -6, whereas total IGF-I and IGF-II levels were not or only moderately increased. The marked increase in serum levels of IGFBP-4 appeared to be characteristic for chronic renal failure. IGFBP-5 correlated with biochemical markers and histologic indices of bone formation in renal osteodystrophy patients and was not influenced by renal function. Therefore, IGFBP-5 may gain significance as a serological marker for osteopenia and low bone turnover in long-term dialysis patients.

During vitamin-D therapy drug accumulation and intoxication should be considered. In the present study we report on five patients with renal insufficiency during therapy with dihydrotachysterol or calcitriol. Four patients received dihydrotachysterol for 29 (7-44) years and one patient received calcitriol for 4 years to treat hypoparathyroidism after thyroid surgery. As confirmed by renal biopsy impairment of renal function was due to calcifications as a consequence of prolonged hypercalcemia. The effective duration of dihydrotachysterol is ten days as compared with five days for calcitriol. Severe hypercalcemic episodes with dihydrotachysterol are longer-lasting than those with the shorter acting vitamin-D derivatives. Further, they occur with higher incidence as was shown by our own observations and previously published data by other workers. Hence, impairment of renal function during therapy with dihydrotachysterol should be considered as being due to hypercalcemia and hypercalciuria.

Background Neutral protamine Hagedorn (NPH) insulin is one of the most commonly used insulins in insulin pens. NPH in pen cartridges is in a two-phase solution with either a solvent or a short-acting insulin, and needs adequate mixing for complete resuspension. We assessed whether NPH insulin is accurately resuspended by patients and the association of suspension errors with diabetes control.Methods 109 patients (39 with type 1 diabetes) who had received conventional diabetic education had the NPH content of their cartridges measured by an optical system; a control cartridge was designated as 100%. A questionnaire was used to assess clinical details and insulin suspension habits. After the information about residual insulin error was known, all 109 patients were instructed to resuspend their insulin by rolling and tipping the pen 20 times. 52 patients were randomly selected to have cartridges reanalysed 3 months or 6 months later and to complete another questionnaire.Findings Only 10 (9%) of 109 patients tipped and rolled their pen more than ten times. NPH insulin content ranged from 5% to 214% and varied by more than 20% in 71 (65%) of 109 cartridges. There was no relation between inadequate suspension and the frequency of hypoglycaemic episodes (r=0.2, p=0.08). For all patients, there was a correlation between the absolute error of NPH suspension and cycles of rolling and tipping the pen (r=-0.23, p<0.05). After education on resuspending the pen's contents, data were available from 44 of 52 patients; suspension errors decreased in 35 (80%), were unchanged in three (7%), and increased in six (13%). The 35 patients with improved NPH insulin suspension had fewer mean hypoglycaemic episodes per month compared with the previous period (0.4 [SD 0.1] vs 1.0 [0.3], p<0.05). Mean HbA(1c) values in patients with improved suspension quality did not differ from baseline (8.4% [0.3] vs 8.9% [0.4], p=0.07). Mixing of NPH insulin by a mechanical device showed that at least 20 cycles were necessary before complete resuspension was obtained.Interpretation Inadequate NPH insulin suspension is common. We recommended that patients tip pens that contain NPH insulin at least 20 times, since inadequate mixing may impair diabetes control.

Hepatocyte growth factor (HGF) accelerates renal tubule cell regeneration and induces tubulogenic differentiation via the intracellular tyrosine kinase (TK) domain of its receptor, the proto-oncogene c-Met. We tested whether different signaling pathways may be involved by examining HGF binding and effects on cell proliferation, migration, scattering, and tubulogenic differentiation in the bipolar differentiating rabbit proximal tubule cell line PT-1 under serum-free conditions in the presence or absence of the protein TK inhibitors (PTKIs) herbimycin-A, genistein, methyl-2,5-dihydroxycinnamate, and geldanamycin. These PTKIs inhibit pp60(c-src), a nonreceptor TK involved in cell-growth control. HGF bound to a single high-affinity receptor class, increased microvilli numbers 1.5-fold, enhanced cell proliferation and migration 1.8-fold, and stimulated formation of tubule structures 2.2-fold. PTKI inhibited the mitogenic and motogenic effects of HGF with different potencies and comparable maximal effects but had no specific influence on HGF-induced tubulogenic cell differentiation. These data underline the importance of pp60(c-src) in mediating mitogenic and motogenic effects of HGF, whereas stimulation of tubulogenic cell differentiation may be transduced by a pp60(c-src)-independent pathway.

Background: Although in the last decades great progress has been made concerning renal replacement therapy, secondary hyper parathyroidism (sHPT) is still of major clinical importance in patients with chronic renal failure. sHPT demineralizes bone via enhanced osteoclastic activity and leads to osteofibrosis. On the other hand, defective kidneys are not able to synthesize enough active metabolites of vitamin Dg, leading to osteoidosis and osteomalacia. Recently, there is a change in the spectrum of renal osteodystrophy in favor of low turnover lesions. However, changes of parathyroid gland function can be observed in sHPT and adynamic bone disease, emphasizing its central role.

BACKGROUND: As a renotropic cytokine, hepatocyte growth factor (HGF) prevents acute renal failure and accelerates renal regeneration. HGF initiates its biological effects by interaction with specific transmembrane receptors, the c-Met proto-oncogene, possessing an intracellular tyrosine kinase domain. We tested the hypothesis of whether the complex biological effects of HGF in renal proximal tubular cells are mediated by different intracellular signalling cascades and/or different receptors. METHODS: PT-1 cells, a proximal tubular cell line derived from rabbit kidney, were cultured under defined serum-free conditions to examine the biological effects of exogenously added HGF. By specific assays, we determined HGF binding and its effects on cell proliferation, migration, scattering and tubulogenic differentiation. To investigate whether HGF action could be inhibited by protein tyrosine kinase inhibitors (PTKIs), cells were incubated with HGF and different concentrations of herbimycin A, genestein, methyl-2,5-dihydroxycinnamate (MDC) and geldanamycin. All PTKIs are known inhibitors of pp60(c-src), a non-receptor tyrosine kinase involved in cell growth control. RESULTS: HGF bound with high affinity to cell membrane receptors and displayed multiple biological effects. Compared with serum-free controls, HGF increased the number of microvilli 1.5-fold, enhanced cell proliferation and migration 1.8-fold, and stimulated the formation of tubular structures 2.3-fold. Consistent with the known tyrosine kinase activity of the c-Met receptor, the mitogenic and motogenic effects of HGF were inhibited by PTKIs in a dose-dependent manner with the following order of potency: geldanamycin > herbimycin A > genestein > MDC. In contrast, however, the HGF-induced tubulogenic cell differentiation was not inhibited specifically by PTKIs. CONCLUSIONS: The finding that PTKIs inhibited the mitogenic response but not the tubulogenic differentiation induced by HGF indicates different intracellular signal transduction pathways. We suggest that pp60(c-src) plays a key role in mediating the mitogenic and motogenic action of HGF, whereas tubulogenic cell differentiation induced by HGF is transduced by a pp60(c-src)-independent signalling pathway.

Long before parathyroid hormone could be measured, soft tissue calcifications were observed in patients with renal disorders as early as in 1877. The increased bone turnover seen due to secondary hyperparathyroidism in patients with renal osteodystrophy leads to osteofibrosis. On the other hand, defective kidneys are not able to synthesize enough active metabolites of vitamin D3, leading to osteoidosis and osteomalacia. To lower elevated serum PTH levels, aluminum-containing phosphate binders have been used for a long time. Vitamin D metabolites such as 5,6-trans-25-hydroxycholecalciferol, alfacalcidol or calcitriol were introduced to restore bone calcification. After it had been recognized that aluminum causes a special type of bone disease, the aluminum-osteopathy, reversed osmosis was introduced and aluminum-free phosphate binders were prescribed. Later on, histology revealed a complication of long-term renal replacement therapy: a bony manifestation of dialysis-related amyloidosis caused by ß2-microglobulin. Furthermore, it was recognized that persisting metabolic acidosis leads to the consumption of bone buffers and contributes to low calcitriol levels. To ameliorate this variety of osteopathy oral bicarbonate has been used to correct acidosis. Calciphylaxis, a severe complication with high mortality, was seen in some patients, even after kidney transplantation and only total parathyroidectomy could rescue them. However, PTH is also the best known factor that stimulates bone formation. Recent studies also indicate that diminished PTH levels may contribute to a low bone turnover, a condition called adynamic bone disease which occurs in the absence of aluminum. In studies on the molecular mechanisms which contribute to changes in bone formation seen in patients with chronic renal failure, studies have been focused on the role of circulating and locally produced cytokines and growth factors. These studies suggest a potential role for growth factors in the pathogenesis of renal osteodystrophy. Of the various bone growth factors, insulin-like growth factors may gain a future role in the diagnosis and therapy of renal osteodystrophy, especially for malnourished, aged, diabetic and immobile patients.