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Guidelines for Parenteral Nutrition were prepared by the German Society for Nutritional Medicine (http://www.dgem.de/), in collaboration with other medical associations to provide guidance for quality assurance for parenteral nutrition (PN) practice, and to promoting health and quality of life of patients concerned. A coordination team proposed topics, working group leaders who along with working group members performed systematic literatur searches and drafted recommendations in a nominal group process. Recommendations were discussed and agreed upon in a structured consensus conference process, followed by a Delphi consensus. The current English version of the guidelines was written and updated during the period between the last quarter of 2007 and the first quarter of 2009. The recommendations of the guidelines should be reviewed, and if necessary updated five years after publication.

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Guidelines for Parenteral Nutrition were prepared by the German Society for Nutritional Medicine (http://www.dgem.de/), in collaboration with other medical associations to provide guidance for quality assurance for parenteral nutrition (PN) practice, and to promoting health and quality of life of patients concerned. A coordination team proposed topics, working group leaders who along with working group members performed systematic literatur searches and drafted recommendations in a nominal group process. Recommendations were discussed and agreed upon in a structured consensus conference process, followed by a Delphi consensus. The current English version of the guidelines was written and updated during the period between the last quarter of 2007 and the first quarter of 2009. The recommendations of the guidelines should be reviewed, and if necessary updated five years after publication.

Primary and secondary forms of focal segmental glomerulosclerosis (FSGS) are characterized by depletion of podocytes and constitute a central manifestation of chronic progressive glomerular diseases. Here we report that podocytes undergo apoptosis at early stages in the course of progressive glomerulosclerosis in TGF-beta1 transgenic mice. Apoptosis is associated with progressive depletion of podocytes and precedes mesangial expansion. Smad7 protein expression is strongly induced specifically in damaged podocytes of transgenic mice and in cultured murine podocytes treated with TGF-beta. TGF-beta1 and Smad7 each induce apoptosis in podocytes, and their coexpression has an additive effect. Activation of p38 MAP kinase and caspase-3 is required for TGF-beta-mediated apoptosis, but not for apoptosis induced by Smad7. Unlike TGF-beta, Smad7 inhibits nuclear translocation and transcriptional activity of the cell survival factor NF-kappaB. Our results suggest a novel functional role for Smad7 as amplifier of TGF-beta-induced apoptosis in podocytes and a new pathomechanism for podocyte depletion in progressive glomerulosclerosis.

Background: Human immunodeficiency virus (HIV)-associated nephropathy is characterized by focal segmental glomerulosclerosis and microcystic tubular dilation. We have previously described a mouse transgenic for a Deltagag-pol HIV-1 genome, which develops glomerulosclerosis, cutaneous papillomas, and cataracts., Methods: We developed mice transgenic for a Deltagag-pol-nef HIV genome in order to investigate the role of the nef gene in these phenotypes., Results: One transgenic line, X5, expressed HIV mRNA in kidney and consistently manifested focal segmental glomerulosclerosis and tubular dilation by six weeks of age. Northern analysis indicated that renal transgene expression was higher in the Deltagag-pol-nef mice compared with the Deltagag-pol mice. In situ hybridization and immunostaining demonstrated HIV RNA and protein expression within the glomerular epithelial cells and tubular epithelial cells. These cell types showed histologic evidence of toxicity, including vacuolation and detachment from basement membrane, and exhibited increased rates of apoptosis. These data suggest that the renal disease seen in the Deltagag-pol-nef transgenic mouse may be caused by the expression of HIV genes within renal epithelial cells, that this expression may induce cellular toxicity, including apoptosis, and that nef is not required for the induction of renal disease. We have previously described mice bearing the nef gene, which do not manifest renal disease. In further experiments, Deltagag-pol-nef mice were bred with nef mice; these dual-transgenic mice developed renal disease that generally resembled that seen in Deltagag-pol-nef mice, but with somewhat more severe glomerulosclerosis and less severe tubulointerstitial injury., Results: The results of these transgenic studies suggest that the role of nef is complex and may act both to reduce transgene expression and to potentiate glomerular injury induced by other HIV-1 gene products.

Oxygen sensing is essential for homeostasis in all aerobic organisms, but its mechanism is poorly understood. Data suggest that a phagocytic-like NAD(P)H oxidase producing reactive oxygen species serves as a primary sensor for oxygen. We have characterized a source of superoxide anions in the kidney that we refer to as a renal NAD(P)H oxidase or Renox. Renox is homologous to gp91(phox) (91-kDa subunit of the phagocyte oxidase), the electron-transporting subunit of phagocytic NADPH oxidase, and contains all of the structural motifs considered essential for binding of heme, flavin, and nucleotide. In situ RNA hybridization revealed that renox is highly expressed at the site of erythropoietin production in the renal cortex, showing the greatest accumulation of renox mRNA in proximal convoluted tubule epithelial cells. NIH 3T3 fibroblasts overexpressing transfected Renox show increased production of superoxide and develop signs of cellular senescence. Our data suggest that Renox, as a renal source of reactive oxygen species, is a likely candidate for the oxygen sensor function regulating oxygen-dependent gene expression and may also have a role in the development of inflammatory processes in the kidney.

Objectives: To determine the frequency of crystalluria in patients treated with the human immunodeficiency virus protease inhibitor indinavir and to compare methods of detecting crystalluria., Methods: A total of 308 freshly voided urine specimens from 168 patients treated with indinavir were evaluated by manual microscopy of sediment and microscopy with an automated workstation and by dipstick analysis., Results: Crystals were detected in 22%, 31%, or 32% of specimens using, respectively, an automated workstation, manual microscopy, or both methods. Proteinuria or hemoglobinuria occurred significantly more often in specimens with (28%) than without (18%) crystals. Frequency of crystalluria was unrelated to specific gravity, but it increased at higher pH. Crystals were detected in 21% of specimens with pH less than 6 and 42% of specimens with pH of 6 or higher., Conclusions: Crystalluria occurs in more than 30% of urine specimens from patients treated with indinavir, but detection rates vary substantially with method of analysis. Manual microscopy detected crystalluria 41% more often than did an automated workstation.

Background: Chronic renal allograft rejection is the leading cause of late graft failure. However, its pathogenesis has not been defined., Methods: To explore the pathogenesis of chronic rejection, we studied a mouse model of kidney transplantation and examined the effects of altering the expression of donor major histocompatibility complex (MHC) antigens on the development of chronic rejection., Results: We found that long-surviving mouse kidney allografts develop pathological abnormalities that resemble chronic rejection in humans. Furthermore, the absence of MHC class I or class II antigens did not prevent the loss of graft function nor alter the pathological characteristics of chronic rejection. Expression of transforming growth factor-beta (TGF-beta), a pleiotropic cytokine suggested to play a role in chronic rejection, was markedly enhanced in control allografts compared with isografts. However, TGF-beta up-regulation was significantly blunted in MHC-deficient grafts. Nonetheless, these differences in TGF-beta expression did not affect the character of chronic rejection, including intrarenal accumulation of collagens., Conclusions: Reduced expression of either class I or II direct allorecognition pathways is insufficient to prevent the development of chronic rejection, despite a reduction in the levels of TGF-beta expressed in the allograft. This suggests that the severity of chronic rejection is independent of the level of MHC disparity between donor and recipient and the level of TGF-beta expression within the allograft.

The HIV-1 virion-associated accessory protein Vpr affects both viral replication and cellular transcription, proliferation, and differentiation. We report that Vpr enhances the activity of glucocorticoids in lymphoid and muscle-derived cell lines by interacting directly with the glucocorticoid receptor and general transcription factors, acting as a coactivator. Vpr contains the signature motif LXXLL also present in cellular nuclear receptor coactivators, such as steroid receptor coactivator 1 and p300/CREB-binding protein, which mediates their interaction with the glucocorticoid and other nuclear hormone receptors. A mutant Vpr molecule with disruption of this coactivator signature motif lost its ability to influence transcription of glucocorticoid-responsive genes and became a dominant-negative inhibitor of Vpr, possibly by retaining its general transcription factor-binding activities. The glucocorticoid coactivator activity of Vpr may contribute to increased tissue glucocorticoid sensitivity in the absence of hypercortisolism and to the pathogenesis of AIDS.

The expression of the inducible isoform of nitric oxide synthase (NOS2, iNOS) is increased in patients undergoing sepsis as well as in animal models in which septic shock is induced by injection of bacterial lipopolysaccharide (LPS). Transforming growth factor-beta1 (TGF-beta1) potently suppresses NO production both in vitro and in vivo. After intraperitoneal injection of LPS, mice over-expressing a cDNA coding for active TGF-beta1 in the liver (Alb/ TGF-beta1) exhibited reduced serum levels of the NO reaction products NO2(-) + NO3(-) compared with controls. Paradoxically, while endotoxemic Alb/ TGF-beta1 mice expressed much less NOS2 protein in peritoneal exudate cells than did endotoxemic wild-type mice, Alb/TGF-beta1 mice expressed more NOS2 mRNA and protein in both liver and kidney. Alb/ TGF-beta1 mice treated with LPS had eightfold higher serum tumor necrosis factor alpha (TNF-alpha) levels and experienced increased mortality compared with wild-type mice, which was associated with renal insufficiency. These results suggest that renal dysfunction, decreased production of NO, and/or increased production of TNF-alpha are associated with increased mortality of endotoxemic Alb/TGF-beta1 mice.

Schistosomiasis mansoni, a major cause of hepatic fibrosis in many developing countries, triggers a granulomatous inflammatory reaction in response to its eggs that lodge in the liver. The egg antigens are eliminated slowly, and the persistent granulomatous response leads to prolonged matrix synthesis and hepatic fibrosis. In mice, soluble egg antigens (SEA) induce interleukin 4 synthesis, promoting a dominant T helper type 2 lymphocyte accumulation with the release of additional cytokines (IL-5, IL-10), which not only suppress Th1 lymphocyte subset cytokines, but mediate the characteristic pathophysiology. Manipulation of the cytokine profile with antagonists or exogenous cytokine delivery alters the course of the hepatic inflammation and fibrosis. In the evolution of the granulomatous response to the S. mansoni eggs, transforming growth factor beta (TGF-beta) is also produced that may modulate inflammation and regulate fibrogenesis. In TGF-beta 1-gene targeted mutant mice that over-express TGF-beta 1 (TGF-beta 1 transgenics) or in which TGF-beta 1 has been inactivated (TGF-beta 1-/-; null mutation) or partially inactivated (TGF-beta 1+/-; null mutation heterozygotes), the altered production of TGF-beta 1 impacts on S. mansoni granuloma and hepatic fibrosis. In addition to the Th1/Th2 cytokine balance, modulation of TGF-beta 1 may change the outcome of chronic inflammatory fibrotic disease.

Human immunodeficiency virus (HIV)-1 infection may be complicated by progressive renal glomerular disease, including focal segmental glomerulosclerosis (FSGS) and proliferative glomerulonephritis. We examined renal tissue from 71 patients, including biopsies and autopsies from patients in the presence and absence of HIV-1 infection. We assessed the extent of TGF-beta, interstitial fibrosis, and interstitial CD45-positive cellular infiltrate using immunohistochemistry. Extracellular TGF-beta 1/beta 3 was largely confined to the renal interstitium, with the highest scores in HIV-seropositive renal disease and crescentic nephritis. Among all biopsies, the TGF-beta 1/beta 3 score correlated with the fibrosis score (r = 0.79, P < 0.0001) and with the CD45 score (r = 0.60, P < 0.0001). Biopsies from HIV-infected patients, taken together, showed marginally more TGF-beta 1/beta 3 compared to biopsies from HIV-uninfected patients (P = 0.05); similarly, HIV-associated FSGS showed marginally more TGF-beta 1/beta 3 compared to FSGS biopsies obtained from HIV-uninfected patients (P = 0.05). Intracellular TGF-beta 1 and TGF-beta 3 were both expressed by renal tubular epithelial cells and in extraglomerular crescents, whereas TGF-beta 3 was also present within interstitial mononuclear cells and eosinophils, and, exclusively in HIV-infected patients, within glomerular cells. In conclusion, TGF-beta expression was increased in several progressive glomerular diseases, and was particularly but not uniquely elevated in HIV-associated renal diseases.

Unilateral ureteral obstruction (UUO) leads to fibrosis of the obstructed kidney. We tested the hypothesis that interstitial fibrosis in UUO results, at least in part, from enhanced expression of transforming growth factor-beta (TGF-beta) which in turn is regulated by local angiotensin II (Ang II) generation. (The generic name TGF-beta is used to discuss properties shared by all isoforms, but special reference to other isoforms is made when specifically needed.) Using Northern blot and immunohistochemical analysis, we examined the expression of TGF-beta in rat kidneys after 24 hours (aUUO) and one week (cUUO) of obstruction. Obstructed kidneys from both periods had increased interstitial and perivascular TGF-beta immunoreactivity compared to contralateral and sham kidneys, in which immunostaining was confined to the inner medulla. Relative abundance of all TGF-beta mRNA isoforms were higher in the obstructed than in contralateral and sham kidneys in both aUUO and cUUO. Expression of TGF-beta isoforms varied according to site (cortex vs. medulla), segment of the nephron, type of cells and duration of the obstruction. The increase in TGF-beta immunoreactivity and mRNA levels in aUUO and cUUO was almost totally abolished by pretreatment with losartan. We conclude that in UUO: (a) TGF-beta gene expression is increased and differentially regulated; (b) Ang II, at least partially, mediates the overexpression of TGF-beta gene; and (c) Ang II may play a central role in fibrogenesis in this and other models of tubulointerstitial disease.

Skin from mice transgenic (Tg) for part of the human immunodeficiency virus type 1 (HIV-1) genome was transplanted onto normal mice of the same strain. All Tg grafts were rejected within 29 days. In contrast, skin from normal mice that was transplanted to HIV-1-Tg recipients remained viable for > 67 days. Histologic examination of Tg grafts on normal mice showed evidence of monocytic infiltrates. Monocytic infiltrates were not observed, however, when either normal or Tg skin was transplanted onto Tg mice. Immunohistologic staining verified the presence of gp120 protein expression in the Tg-transplanted skin but not in adjacent normal skin. It is concluded that the Tg mice are immunologically tolerant to the HIV-1 gene products they express.

The systemic administration of phosphorothioated antisense oligonucleotides has been demonstrated to be an effective strategy for the control of gene expression. Because previous studies have suggested both hepatic and renal accumulation of systemically administered oligonucleotides, we explored whether the kidney might be a site of free DNA transport. [32P]-phosphorothioate oligonucleotides (20 mers) were excreted in urine but cleared at only 30% of glomerular filtration rate. Plasma clearance of the label was very rapid (t1/2 approximately 5 min) but the half life of labeled S-deoxynucleotide excreted in urine was much slower (28 min). Infused oligonucleotide appeared in urine with little degradation. By autoradiography of renal tissue, labeled antisense oligonucleotides appeared within Bowman's capsule and the proximal tubule lumen. DNA was detected in association with brush border membrane and within tubular epithelial cells. Brush border membrane preparations from rat kidney contained oligonucleotide binding proteins as determined by gel mobility shift and UV cross linking assays. Because renal epithelial cells efficiently take up phosphorothioate oligonucleotides without apparent degradation, the kidney appears to be an excellent target for site-directed antisense therapy, but may be a site of antisense toxicity as well.

HIV-associated nephropathy is characterized by extensive tubulointerstitial disease with epithelial cell injury, microcystic proliferation, and tubular regeneration with glomerulosclerosis. To explore the role of bFGF as a mediator of HIV-induced interstitial disease, we utilized an HIV transgenic mouse model that manifests clinical and histological features observed in patients. In transgenic mice, simultaneous renal epithelial cell proliferation and injury were detected in vivo. In areas of microcystic proliferation, immunoreactive bFGF colocalized with extracellular matrix. Kidneys from transgenic mice had increased bFGF low affinity binding sites, particularly in the renal interstitium. In vitro, transgenic renal tubular epithelial cells proliferated more rapidly and generated tubular structures spontaneously, in marked contrast to nontransgenic renal cells where these pathologic features could be mimicked by exogenous bFGF. These studies suggest that renal bFGF and its receptors play an important role in the pathogenesis of HIV-associated nephropathy.

Recently, we have found that transforming growth factor (TGF)-beta 2 and renin are abundantly expressed in the juxtaglomerular apparatus (JGA) of dehydrated mice. Since potassium (K+) depletion also stimulates renin and induces hypertrophy of the JGA, we examined the ability of this maneuver to stimulate TGF-beta isoforms and renin in renovascular tissue and the JGA of young rats. Sprague-Dawley rats (50 +/- 5 g) were fed either a control diet or a potassium-deficient diet (< 0.05% K+) for 7, 16, or 21 days. As a control for TGF-beta and renin stimulation, an additional group of animals was fed a normal diet but was water deprived for three days. Potassium-depleted animals experienced severe growth retardation but kidney weight increased significantly. Potassium depletion induced both TGF-beta 2 and renin immunoreactivity in renal arterioles and the JGA but had no effect on TGF-beta 1 and TGF-beta 3 isoforms. To determine the role of circulating angiotensin II in the stimulation of TGF-beta 2 by potassium depletion, a group of potassium-depleted rats received enalapril (100 mg/liter) in the drinking water. The addition of converting enzyme inhibitor increased both the intensity of TGF-beta 2 and renin staining as well as the number of cells positively stained. Our results demonstrate that K+ depletion induces TGF-beta 2 and renin in renal arterioles and in the JGA. Furthermore, circulating angiotensin II is not responsible for the increase in the local expression of TGF-beta 2. These findings suggest that TGF-beta 2 may be an important mediator of JGA hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Osteonectin (SPARC, culture shock protein, BM-40) is a widely distributed glycoprotein which binds calcium and several extracellular matrix proteins, including interstitial collagens and thrombospondin, but whose physiologic role remains undefined. In the present studies, we have demonstrated that immunoreactive osteonectin is present in the distal cortical tubule and medullary tubules of murine kidney. We surveyed the renal epithelial cell lines LLC-PK1, MDCK, and OK for the expression of mRNA encoding osteonectin. We found that osteonectin mRNA is expressed by LLC-PK1 and OK cells but not by MDCK cells, as well as by adult kidney from several species. Calcitonin and vasopressin, agents which increase cAMP in these cells, were found to decrease steady-state osteonectin mRNA concentrations. We found that LLC-PK1 cells produced osteonectin protein, that the protein was localized to intracellular granules, and that the protein bound hydroxyapatite in vitro. Pulse-chase analysis revealed that osteonectin was secreted from the cell layer to the medium after a lag time of four to six hours and was secreted preferentially from the basolateral domain of the cell. The preferential secretion of the calcium-binding protein osteonectin from the renal epithelial cell is consistent with several possible functions, including a structural extracellular matrix protein, a participant in transepithelial ion transport, and an inhibitor of extracellular calcification.

Accumulating evidence suggests that angiotensin II (Ang II) may play an important role in renal growth and glomerular development. During nephrogenesis, a complex relationship between the capillary and renal mesangium develops. Since the mesangial cell is a centrally-located pericyte with contractile, endocrine, and immune modulating functions, it may play a unique role in maintaining normal glomerular function. Therefore, we examined whether Ang II affects proliferation of human fetal mesangial cells in vitro and compared these findings to mesangial cells isolated from adult kidney. In these primary isolates, we studied the relationship between Ang II receptors and the mitogenic activity of angiotensin. Scatchard analysis of the binding of 125I[Sar1,Ile8]Ang II to subconfluent cultured human fetal mesangial cells revealed the presence of one class of binding sites with a Kd of 1.25 nM and a Bmax of 70 fmol/1 x 10(5) cells. Ang II receptors on adult mesangial cells had similar binding kinetics with a Kd of 1.6 nM and Bmax of 65 fmol/10(5) cells in subconfluent culture. In subconfluent culture of fetal mesangial cells, Ang II increased [3H]thymidine incorporation by 130% (P less than 0.005). In subconfluent culture of adult mesangial cells, Ang II increased [3H]thymidine incorporation by only 35% (P less than 0.05). In confluent culture of fetal mesangial cells, Ang II receptor number and mitogenic response were reduced. The Ang II antagonist [Sar1,Ile8]Ang II (1 microM) inhibited the mitogenic response of fetal mesangial cells to Ang II. Ang II increased fetal mesangial cell number by 25% (after 4 days) in serum-free medium supplemented with insulin or supplemented with insulin and 1% Nutridoma (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

The noncollagenous proteins osteonectin, bone sialoprotein, osteocalcin, the small proteoglycan decorin (PG II), and alpha 2-HS glycoprotein (which is synthesized in the liver but highly concentrated in bone) were measured in extracts of cortical bone from 3 type I, 2 type II, 8 type III and 13 type IV patients with osteogenesis imperfecta (OI) and from 7 control subjects. Osteonectin was found to be reduced in the bone of all OI patients. The bone from severely affected type III OI patients contained the lowest levels of osteonectin. In contrast, bone sialoprotein was found to be elevated in the bones of OI patients. The highest levels were found in individuals classified as type IV patients. Osteocalcin and alpha 2-HS glycoprotein concentrations were increased in all OI patients. Decorin levels were not significantly altered in OI bones compared to controls. These changes in the concentrations of the noncollagenous proteins may contribute to the fragility of the OI bone by interfering with complete mineralization and/or normal tissue architecture.

Sodium fluoride has been shown to be effective therapy for some patients with vertebral osteoporosis. Data from histomorphometric studies in patients and animals suggest that at least part of this effect may be a consequence of a proliferative effect of fluoride, either direct or indirect, on the osteoblast or on an osteoblastic precursor cell. Experiments with osteoblastic cells derived from embryonic chick calvaria have demonstrated a mitogenic effect of fluoride. The present study examined whether fluoride affects in a similar way fetal human bone cells derived from femur or calvaria. Under a variety of culture conditions, including medium supplemented with serum and in serum-free medium, fluoride did not alter the proliferative rate of human bone cells as measured by thymidine incorporation and direct cell counting.

Bone formation in uremia is considered to be regulated in part by parathyroid hormone (PTH). However, while low levels of immunoreactive PTH are usually associated with low rates of bone formation in uremia, elevated PTH levels do not always correlate with increased bone formation. In an attempt to identify other factors that may regulate bone formation in uremic patients, we measured plasma immunoreactive insulin-like growth factors (IGF-I and IGF-II) in 15 patients who did not have aluminum-associated reductions in bone formation. Plasma levels of IGF-I but not PTH, were significantly higher in patients with high rates of bone formation when compared to patients with low or normal bone formation (P less than 0.02). While the bone formation rate at the tissue level correlated significantly with plasma PTH (r = 0.53, P less than 0.05) and IGF-I (r = 0.67, P less than 0.01), only for plasma IGF-I were there significant correlations with bone apposition (r = 0.57, P less than 0.05) and bone formation rate at the BMU level (r = 0.62, P less than 0.02), parameters which reflect mineralization activity at the cellular level. Among the static histologic parameters, osteoblastic osteoid correlated only with plasma PTH (r = 0.76, P less than 0.001), while osteoclast number correlated with both PTH (r = 0.56, P less than 0.05) and IGF-I (r = 0.67, P less than 0.01). There were no correlations between IGF-II levels and bone histology. From these data we suggest that IGF-I may promote bone formation in uremic patients with hyperparathyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone biopsies and plasma parathyroid hormone (PTH) from 27 diabetic dialysis patients were compared to biopsies and PTH levels from matched patients without diabetes to determine if PTH has a role in preserving bone mass in diabetic renal osteodystrophy. Significantly lower values were present in the diabetic group for mineralized bone area (p less than 0.003), osteoblastic osteoid (p less than 0.01), resorptive surface (p less than 0.001), fibrosis (p less than 0.005), bone apposition rate (p less than 0.01), bone formation rate (BMU level) (p less than 0.04), and plasma PTH (p less than 0.05). Bone-surface aluminum was higher in the diabetic group (44 +/- 5% vs. 20 +/- 5%, p less than 0.005). Linear regression analysis revealed significant positive correlations of mineralized bone area with time on dialysis, bone formation rate, bone resorption, and PTH only in the group without diabetes. While both groups had significant positive correlations of PTH with osteoblastic osteoid and bone resorption, only in the nondiabetic group was there a positive correlation of PTH with bone apposition and bone formation rate (BMU level), observations suggesting that the lower bone formation in the diabetic patients may have arisen in part from a failure of PTH to promote bone mineralization. We conclude that relatively low PTH levels and high bone aluminum in diabetic patients with chronic renal failure may be responsible in part for low bone mass when compared to uremic patients without diabetes.