Mediators of inflammatory and ischemic renal damage: the role of neoangiogenesis

Neoangiogenesis is at the forefront of research in a number of fields that are of interest to the nephrologist, ranging from the development of the kidney and glomerulus to microvascular injury and its repair. The molecular mechanisms have recently been elucidated to a considerable extent. They are relevant for understanding the link between endothelial cells and podocytes, which underlie the glomerular barrier function. For reasons poorly understood capillarogenesis is defective in renal failure.     

The clinical management of hyperphosphatemia

As renal function declines in patients with end-stage renal disease (ESRD), excess dietary phosphorus accumulates in the bloodstream. Routine dialysis removes up to 70% of absorbed phosphorus; therefore, hyperphosphatemia is found in the majority of patients with ESRD. The consequences of this imbalance include secondary hyperparathyroidism and osteodystrophy. Recent studies have also documented that hyperphosphatemia can lead to soft-tissue and vascular calcification; the latter is strongly associated with cardiovascular disease and, thus, increased mortality and morbidity. The reduction of phosphorus levels is, therefore, an important therapeutic target in this patient group. Management of hyperphosphatemia using conventional phosphate binders is not always successful. However, emerging therapies aim to reduce the incidence of hyperparathyroidism, bone disease, and calcification in this patient population. In this article, the consequences of hyperphosphatemia are reviewed, and recent developments in the treatment of the condition are discussed.     

Detection of consciousness by electroencephalogram and auditory evoked potentials

BACKGROUND: A set of electroencephalographic and auditory evoked potential (AEP) parameters should be identified that allows separation of consciousness from unconsciousness (reflected by responsiveness/unresponsiveness to command). METHODS: Forty unpremedicated patients received anesthesia with remifentanil and either sevoflurane or propofol. With remifentanil infusion (0.2 microg . kg . min), patients were asked every 30 s to squeeze the investigator's hand. Sevoflurane or propofol was given until loss of consciousness. After intubation, propofol or sevoflurane was stopped until patients followed the command (return of consciousness). Thereafter, propofol or sevoflurane was started again (loss of consciousness), and surgery was performed. Return of consciousness was observed after surgery. The electroencephalogram and AEP from immediately before and after the transitions were selected. Logistic regression was calculated to identify models for the separation between consciousness and unconsciousness. For the top 10 models, 1,000-fold cross-validation was performed. Backward variable selection was applied to identify a minimal model. Prediction probability was calculated. The digitized electroencephalogram was replayed, and the Bispectral Index was measured and accordingly analyzed. RESULTS: The best full model (prediction probability 0.89) contained 15 AEP and 4 electroencephalographic parameters. The best minimal model (prediction probability 0.87) contained 2 AEP and 2 electroencephalographic parameters (median frequency of the amplitude spectrum from 8-30 Hz and approximate entropy). The prediction probability of the Bispectral Index was 0.737. CONCLUSIONS: A combination of electroencephalographic and AEP parameters can be used to differentiate between consciousness and unconsciousness even in a very challenging data set. The minimal model contains a combination of AEP and electroencephalographic parameters and has a higher prediction probability than Bispectral Index for the separation between consciousness and unconsciousness.     

Die Genomsonderung während der durch Buttergelb induzierten Cancerogenese der Rattenleber

Zusammenfassung In buttergelbbehandelten Rattenlebern wurden Mitosen mit Genomsonderungen (Gläss) festgestellt und deren Häufigkeit, Chromosomenkombination und Verhalten während der Cancerogenese bis ins ausgebildete Hepatom verfolgt. Je höher die Ploidiestufe, desto höher der Prozentsatz an Zellen mit Genomsonderung. Mit steigender Buttergelbkonzentration steigt die Zahl der eu- und aneuploiden Zellen mit Genomsonderung an. Im Hepatom wird die Zellenzahl mit Genomsonderung wieder kleiner. In aneuploiden Kernen findet sich in den meisten Fällen eine Trennung nach ganzen Genomen plus einer Restchromosomengruppe. Mit steigender Buttergelbdosis erhöht sich die Zahl der Sonderfälle der Genomsonderung, d. h. der aneuploiden Sonderungen stark. Durch bisher nicht vorkommende Chromosomenzahlkombinationen können — in Abhängigkeit von der Buttergelbdosis — auch neue Aneuploidzahlen entstehen. Zwischen den aneuploiden Sonderungsgruppen der Genomsonderung und den späteren Aneuploidzahlen besteht ein enger Zusammenhang: Aneuploidzahlen, die durch Genomsonderung besonders häufig abgegliedert werden, treten auch im Mitosemuster gehäuft auf. Unter 51 verschiedenen Aneuploidzahlen in insgesamt 1903 Mitosen zeichnen sich 14 durch ihre besondere Häufigkeit aus (insgesamt 84% aller Aneuploiden). Sie enthalten Funktionsgruppen von je sechs Chromosomen, die, zu einem kompletten Genom hinzugefügt, funktionstüchtige aneuploide Zellen gewährleisten. Die Genomsonderung läuft der Bildung von Aneuploiden voraus.

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Summary Mitoses with genome segregation (Gläss) were detected in the livers of rats which had been given butter yellow; the frequencies of the genome segregations, their chromosomal combinations, and their behavior during the cancerogenesis were followed to and including the development of hepatomas. The higher the degree of ploidy, the more frequent were the cells with genomic segregation. With increasing concentrations of butter yellow the number of the euploid and aneuploid cells with genomic segregation rose. In hepatomas the number of cells with genome segregation fell. Diploid nuclei separated into single genomes, whereas in polyploid nuclei the separation occurred in groups with diploid chromosomal numbers. In aneuploid nuclei, in most instances, there was a separation into whole genomes plus an additional chromosomal group.With increasing dosage of butter yellow the number of unusual i. e. aneuploid genome segregations rose. Depending on the dosage of butter yellow new combinations of chromosomal numbers occurred that were not seen previously, and new aneuploid numbers thus developed (e. g., 18, 24, 48). Those aneuploid chromosome numbers, prefered in genome segregation can be demonstrated with equal frequency in metaphases of mitosis. Among 51 various aneuploid numbers in a total of 1903 mitoses, 14 were characterized by their marked frequency (a total of 84% of all aneuploidy). These 14 aneuploid numbers contained functional groups of 6 chromosomes each, which when added to a complete genome, guaranteed functionally competent aneuploid nuclei.

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Herrn Prof. Dr. A. Butenandt zum 60. Geburtstag gewidmet.     

Calcimimetics—fooling the calcium receptor

The cloning and characterization of a calcium-sensing receptor from bovine parathyroid cells has opened up the possibility of modulating the activity of this receptor protein by organic small molecules, either increasing the sensitivity for calcium (calcimimetics) or decreasing the sensitivity (calciolytics), thus suppressing or stimulating parathyroid hormone (PTH) secretion and synthesis, respectively. In primary and secondary hyperparathyroidism, calcimimetics have proven to effectively lower the PTH concentration with minimal side effects. In secondary hyperparathyroidism, a specific advantage is the concomitant lowering of serum calcium and phosphate concentrations.     

Role of calcium-phosphorous disorders in the progression of renal failure

Among factors related to disturbed calcium-phosphate metabolism in chronic kidney disease, the following must be mainly considered as potential culprits in the progression of renal dysfunction: hyperphosphatemia, hyperparathyroidism, lack of active vitamin D, and possibly excess of the phosphaturic hormone FGF 23. Early experimental work suggested a parathyroid hormone (PTH)-independent beneficial role of phosphate restriction on progression in rats (animals with physiologic hyperphosphatemia), so that the generalization of the data is uncertain. Recent observational studies also found a correlation between S-phosphate and progression, but it remains uncertain whether the relationship is causal. There is very little direct experimental or clinical evidence for a role of PTH in accelerating progression, although the PTH1 receptor is expressed in podocytes and PTH affects podocyte function (i.e., Kf). It is undoubtedly a candidate that requires more sophisticated investigation. Recently, it has been shown that progression is significantly attenuated by calcimimetics (and equally by parathyroidectomy), but it is currently impossible to exclude a confounding effect of lower blood pressure values. The most solid evidence for an impact on progression exists for active vitamin D. In the past, it was widely assumed that vitamin D was "nephrotoxic." In retrospect, nephrotoxicity was the result of hypercalcemia. Recent evidence is overwhelming that 1,25(OH)2D3 and its analogues attenuate progression in noninflammatory and inflammatory models of chronic kidney disease. The main target cells identified so far are podocytes and mesangial cells. It is currently unknown whether the novel phosphaturic hormones have an impact on progression.     

High-grade trichoblastic carcinoma arising in trichoblastoma: a rare adnexal neoplasm often showing metastatic spread

It has been debated whether malignant transformation of trichoblastoma occurs. The concept was recently forwarded that basal cell carcinoma is as a malignant neoplasm of follicular germinative cells and should be named trichoblastic carcinoma to show its relationship to trichoblastoma. Almost all basal cell carcinomas are low-grade malignant neoplasms and develop metastases only very rarely, and if so, only after very long duration and untreated growth. Only rare basal cell carcinomas arise in trichoblastomas. Up to now there have only been two reports of high-grade trichoblastic carcinoma arising in trichoblastoma, showing systemic metastatic spread and death. We add two further cases of trichoblastic carcinoma with anaplastic nuclei, arising in trichoblastoma. One of the tumors arose in a small nodular trichoblastoma on the right forearm of an 84-year-old male patient. The other one was a trichoblastic carcinoma at the base of a trichoepithelioma on the right thigh of an 87-year-old woman with Brooke-Spiegler syndrome. Our cases emphasize that high-grade trichoblastic carcinoma develops via malignant transformation of trichoblastoma, and is very rare.     

The role of the kidney in cardiovascular medicine

The relationship between the kidney and hypertension is complex. The kidney is both culprit and victim. Renal disease and even renal structural abnormalities (nephron underdosing) lead to hypertension. On the other hand, blood pressure (even blood pressure values in the range of normotension) accelerates a progressive loss of renal function in patients with primary renal disease. This review discusses some recent work in this field, emphasizing that multiple mechanisms are operative in renal hypertension, particularly a shift in the natriuresis-blood pressure relationship (blood pressure natriuresis), inappropriate activation of the renin-angiotensin system, sympathetic overactivity, and impaired endothelial cell-dependent vasodilatation. It also emphasizes the substantial revision of past recommendations concerning blood pressure targets. In renal patients, blood pressure should be reduced to levels below 125/75 mm Hg. In addition to blood pressure, a reduction in proteinuria is widely considered an additional treatment target.     

Uptake, tissue distribution and accumulation of microcystin-RR in Corydoras paleatus, Jenynsia multidentata and Odontesthes bonariensis. A field and laboratory study

The uptake and accumulation of microcystin-RR (MC-RR) in fish was investigated under laboratory conditions and in wild fish. Jenynsia multidentata and Corydoras paleatus were exposed for 24h to 50mug/L MC-RR dissolved in water. After exposure, liver, gill, brain, intestine, gall bladder, blood and muscle were analyzed for MC-RR by HPLC and analysis confirmed by LC-ESI-TOF-MS spectrometry. Furthermore, wild individuals of Odontesthes bonariensis were sampled from the eutrophic, cyanobacteria-containing San Roque reservoir, and analyzed for the presence of MC-RR in liver, gill, intestine, and muscle. MC-RR was found in liver, gills, and muscle of all exposed and wild fish, while in C. paleatus MC-RR was also present in the intestine. Moreover, we found presence of MC-RR in brain of J. multidentata. Results indicate that MC-RR uptake might occur at two different organs: intestine and gills, through either feeding (including drinking) or respiratory activities. This suggests that MC-RR is taken into the blood stream after absorption, and distributed to different tissues. The liver showed the major bioaccumulation of MC-RR in both experimentally exposed and wild individuals, with muscle of wild fish showing relative high amounts of this toxin in comparison with those exposed in the laboratory; though MC-RR was present in muscle of fish exposed for 24h. The amount of MC-RR in muscle of O. bonariensis exceeded the value suggested by WHO to be safe, thus causing a health risk to persons consuming fish as a result of chronic exposure to microcystin. Gills also showed bioaccumulation of MC-RR, raising questions on the mechanism involved in the possible uptake of MC-RR through gills as well as on its accumulation in this organ. Although MC-LR has been reported in brain of fish, this is the first report confirming the presence of MC-RR in this organ, which means that both toxins are able to cross the blood-brain barrier. These findings also raise questions on the probable neurotoxicity of microcystins.