Pelvic urine composition as a determinant of inner medullary solute concentration and urine osmolarity

Summary To clarify the question whether solute and water fluxes between pelvic urine and the renal papilla contribute to the medullary accumulation of osmotically active substances and thus to final urine concentration, we measured the osmolarity of urine samples from the papillary tip of rat kidneys during superfusion of the exposed papillae with solutions of widely varying osmotic concentrations. When the osmolarity of the superfusion fluid consisted half of urea and half of sodium chloride, urine osmolarity was observed to change parallel to the bath solution over a certain concentration range (800–2000 mosm/l). The changes of urine concentration occurred within 90 min after the start of the papillary superfusion. Similar results were obtained when the sodium chloride concentration was kept constant at 300 mosm/l and the urea concentration varied to yield bath concentrations up to 3000 mosm/l. A rise of urine concentration by papillary superfusion above 2000 mosm/l was achieved when exogenous arginine-vasopressin was infused intravenously suggesting that the failure of urine concentration to equilibrate with the bath concentration was due to a limited water permeability of the collecting ducts. These results suggest that solute and water fluxes between pelvic urine and the renal papilla are a necessary prerequisite to achieve maximal osmotic urine concentrations. In addition, such fluxes may explain the variability of medullary tissue concentrations under various diuretic states.This work was supported by the Deutsche Forschungsgemeinschaft     

Role and regulation of glycerophosphorylcholine in rat renal papilla

Glycerophosphorylcholine (GPC) — an organic solute which is considered to be involved in cellular osmoregulation in the renal medulla — was determined by means of an enzymatic assay in various zones of the rat kidney and in papillary tubule suspensions. In antidiuresis, GPC content in cortex, outer medulla and papillary tip was 0.64, 14.6, and 108.9 mmol/kg fresh weight, respectively. Significant concentrations of GPC could not be detected in the urine or in the peripheral plasma. The sharp increase in GPC concentration from cortex to papillary tip was partially abolished by the induction of diuresis by either waterloading or furosemide. These manoeuvres, however, did not change cortical GPC content. Papillary tubule suspensions prepared from hydrogenic rats contained only slightly less GPC per g protein than whole, papillae from antidiuretic animals. Incubation of tubules over 120 min did not lead to a singnificant loss of GPC which is in accordance with the low activity of GPC degrading enzymes in papillary tissue. The results confirm the intracellular localization of GPC and provide further evidence that this substance plays a substantial role in the osmoregulation of renal papillary cells.     

Effect of papillary exposure on intrarenal distribution of glomerular filtration rate and of plasma flow

Removal of the renal pelvis in order to expose the renal papilla has been shown to cause impairment of the renal concentrating ability by an unknown mechanism. To study this phenomenon, urine osmolality (Uosm), single-nephron glomerular filtration rate (SNGFR) in outer and inner cortical nephrons and the inner and outer medullary plasma flow were determined. Measurements were performed on groups of rats before (control) and 15, 45 and 90 min after exposure of the left renal papilla. Rats with an intact ureter were studied in parallel to see whether the variables varied within the 90-min period of the study. In all groups of animals with an exposed papilla, Uosm was lower than in non-exposed animals. Outer cortical SNGFR in rats with exposed papillae, regardless of time, was not different from that in control rats. Inner cortical SNGFR after 45 and 90 min of exposure did not differ from that in controls, but after 15 min of exposure it was lower than in control animals. Outer and inner medullary plasma flow did not differ between rats with exposed papillae and controls, irrespective of exposure time. In conclusion, papillary exposure results in a permanent decrease in urine osmolality. This impairment of the concentrating ability cannot be attributed to prolonged changes in renal haemodynamics.     

A study on renal papillary necrosis experimentally produced by the Shwartzman mechanism in rabbits

To produce renal papillary necrosis experimentally by means of the Shwartzman mechanism in rabbits, E. coli endotoxin was injected into the renal pelvis unilaterally through the ureter as a preparative procedure after pretreatment by local administration of alcohol, and the same endotoxin was given again 24 hours later, but intravenously this time via the ear vein, as a provocation. Marked necrosis was produced in the renal papillae, where many intravascular fibrin thrombi were found histologically. Such papillary necrosis was largely prevented by heparin administration, and this lesion was considered to be the univisceral Shwartzman reaction occurring in the renal papillae. The lesion produced in the new experimental system of renal papillary necrosis described here has a good similarity to that of human cases in etiology, pathogenesis and morphology. The present system may therefore be a good model of human renal papillary necrosis, and should be useful for future studies.     

The Altered Structure of Renal Papillary Outflow Tracts in Obesity

Weight gain is associated with an expanded renal medullary interstitium in humans and in animal models of obesity. In this study, the consequence of obesity and this expanded matrix on renal papillary structure was examined in 15 obese rabbits fed a high fat diet for 8-12 weeks compared to 21 rabbits fed a standard diet. When examined under a dissecting microscope, the tips of the renal papillae from formalin-fixed, methylene blue-stained kidneys showed patent ducts of Bellini in 5 of 5 instances from 2 lean rabbits, but in only 2 out of 12 ducts from 3 obese rabbits. The ostia of the remaining ducts were significantly distended (205+/- 42 mum versus 56+/- 8 mum) and occupied by lightly staining granular material. When examined with scanning electron microscopy, all ducts were patent in lean rabbits (6 ducts in 4 rabbits, averaging 104+/- 12 mum across), whereas only 6 of 11 ducts were patent in papillae from 4 obese rabbits. Renal medullary parenchymal tissue appeared at the openings of the remaining 5 ducts of Bellini in the 4 rabbits. Not only were these 5 ducts significantly distended by the interstitial material (with openings averaging 248+/- 56 mum across), but the associated collecting ducts were dilated relative to control (100+/- 15 mum versus 75 +/- 7 mum). Since the ducts of Bellini are the only renal openings that are not corsetted by a fibrous capsule, the authors speculate that the expanded medullary interstitium and increased renal sinus lipid partially obstruct renal outflow and elevate renal interstitial hydrostatic pressure in obesity, causing a prolapse of parenchymal contents, further obstructing urine outflow and leading to distention of the collecting ducts and ducts of Bellini.     

The altered structure of renal papillary outflow tracts in obesity

Weight gain is associated with an expanded renal medullary interstitium in humans and in animal models of obesity. In this study, the consequence of obesity and this expanded matrix on renal papillary structure was examined in 15 obese rabbits fed a high fat diet for 8-12 weeks compared to 21 rabbits fed a standard diet. When examined under a dissecting microscope, the tips of the renal papillae from formalin-fixed, methylene blue-stained kidneys showed patent ducts of Bellini in 5 of 5 instances from 2 lean rabbits, but in only 2 out of 12 ducts from 3 obese rabbits. The ostia of the remaining ducts were significantly distended (205+/- 42 mum versus 56+/- 8 mum) and occupied by lightly staining granular material. When examined with scanning electron microscopy, all ducts were patent in lean rabbits (6 ducts in 4 rabbits, averaging 104+/- 12 mum across), whereas only 6 of 11 ducts were patent in papillae from 4 obese rabbits. Renal medullary parenchymal tissue appeared at the openings of the remaining 5 ducts of Bellini in the 4 rabbits. Not only were these 5 ducts significantly distended by the interstitial material (with openings averaging 248+/- 56 mum across), but the associated collecting ducts were dilated relative to control (100+/- 15 mum versus 75 +/- 7 mum). Since the ducts of Bellini are the only renal openings that are not corsetted by a fibrous capsule, the authors speculate that the expanded medullary interstitium and increased renal sinus lipid partially obstruct renal outflow and elevate renal interstitial hydrostatic pressure in obesity, causing a prolapse of parenchymal contents, further obstructing urine outflow and leading to distention of the collecting ducts and ducts of Bellini.     

Vascular anatomy and tissue osmolality in the filiform and fungiform papillae of the cat's tongue.

The vascular anatomy of the filiform and fungiform papillae of the feline tongue was studied by i.a. injection of India ink. Vascular loops of various appearances were found in the types of papillae studied, i.e. the large and the small filiform papillae and the fungiform ones. Such hairpin loops may function as countercurrent exchangers and to test this hypothesis tissue osmolality was determined in the papillae, while exposing them to various isotonic electrolyte solutions. The large filiform papillae with a vascular arrangement similar to that of intestinal villi exhibited a marked osmolar gradient from tip to base when exposed to a solution containing both glucose and sodium. If sodium and/or glucose was excluded from the solution, tissue osmolality was significantly decreased. This was also the case when the chloride ions of the solution was substituted with sulphate. The small filiform papillae are only provided with one or a few capillary loops. They exhibited a less marked osmolar gradient than the large ones and one of the different electrolyte solutions decreased the gradient. In the fungiform papillae a tissue hyperosmolality at the tip was also demonstrated. It is proposed that the papillary epithelium is provided with active transport mechanism(s) and that the papillary vessels function as countercurrent multipliers. The functional importance of these mechanisms are tentatively discussed.     

Solid papillary renal cell carcinoma: clinicopathologic,morphologic, and immunohistochemical analysis of 10 cases and review of the literature

Solid papillary renal cell carcinoma is rarely reported in the literature, and its tumor characteristics are not entirely compatible with the concept of 2 histological subtypes of papillary renal cell carcinoma (PRCC). Tumor is composed mostly of small compressed tubules and short abortive papillae giving solid appearance of monomorphic epithelial cells with scanty cytoplasm and small nuclei, sometimes mimicking spindle cells, without or with sparse true papillae. It shows immunohistochemical (+ CK7, + EMA, + AMACR) and genetic hallmarks (polysomy/trisomy 7/17, loss of Y) of conventional PRCC. About 53 cases have been described in the literature, with male predominance and age ranging from 17 to 82 years. By available follow-up data, solid PRCC has a favorable clinical course. We describe 10 cases compatible with the diagnosis of solid PRCC. All patients were males age range was from 34 to 70 years, and all but one were pT1 according to TNM 2009. On follow-up, 9 patients were without evidence of disease, and 1 had recurrent tumor. Size of the tumor ranged from 1.4 to 5.5 cm (mean, 3.32 cm). Tumors were well-circumscribed whitish to yellow masses with granular surface. Although solid architecture was a prominent morphologic feature, detailed analysis revealed that the tumors were composed of compressed short abortive papillae and compressed tubules admixed with true solid areas. Well-formed papillae were exceptionally present. All 10 cases were strongly and diffusely positive for CK7 and negative for WT-1. In conclusion, solid PRCC is a rare tumor with an incidence of less than 1% of all renal tumors. In majority of the cases, tumors were composed of tightly compressed tubular structures and short abortive papillae that render a solid morphologic appearance. Immunohistochemical and molecular features do not differ from conventional PRCC. Metanephric adenoma; epithelioid nephroblastoma; and, rarely, mucinous tubular and spindle cell carcinoma and oncocytic variant of PRCC should be considered in the differential diagnosis.     

Vascular anatomy and tissue osmolality in the filiform and fungiform papillae of the cat's tongue

The vascular anatomy of the filiform and fungiform papillae of the feline tongue was studied by i.a. injection of India ink. Vascular loops of various appearances were found in the types of papillae studied, i.e. the large and the small filiform papillae and the fungiform ones. Such hairpin loops may function as counter-current exchangers and to test this hypothesis tissue osmolality was determined in the papillae, while exposing them to various isotonic electrolyte solutions. The large filiform papillae with a vascular arrangement similar to that of intestinal villi exhibited a marked osmolar gradient from tip to base when exposed to a solution containing both glucose and sodium. If sodium and/or glucose was excluded from the solution, tissue osmolality was significantly decreased. This was also the case when the chloride ions of the solution was substituted with sulphate. The small filiform papillae are only provided with one or a few capillary loops. They exhibited a less marked osmolar gradient than the large ones and none of the different electrolyte solutions decreased the gradient. In the fungiform papillae a tissue hyperosmolality at the tip was also demonstrated. It is proposed that the papillary epithelium is provided with active transport mechanism(s) and that the papillary vessels function as countercurrent multipliers. The functional importance of these mechanisms are tentatively discussed.     

Back-leak of pelvic urine to the bloodstream

The aim of the present investigation was to measure the back-leak of pelvic urine to the blood circulation. In normopenic hydronephrotic, dehydrated hydronephrotic and dehydrated control kidneys the back-leak was estimated from a servocontrolled machine which regulated infused saline to keep a present pelvic pressure constant. The disappearance of fluid from the renal pelvis could be measured at different pressure levels, and a pressure-dependent outflow of fluid was found. From these measurements a back-leak conductance could be calculated which proved to be independent of pressure. In the lower pressure range (15-20 mmHg) there was a significantly lower conductance in the dehydrated controls compared with the dyhydrated hydronephrotic kidneys, while in the higher pressure range (25-30 mmHg) no difference was found. From electron microscopical studies the pyelorenal back-leak of fluid in both hydronephrotic and control animals seemed to be most pronounced in the fornix region, as documented by a heavy presence of horseradish peroxidase in the intracellular spaces there. Other experiments with radioactively labelled inulin, which was injected into the pelvic cavity, indicated that most of the back-leak occurred via the renal blood vessels and not through the lymphatic system. The importance of this back-leak was evident from the measurements of the total kidney glomerular filtration rate (GFR) at a slightly increased pelvic pressure, where some of the urine with radioactive tracer flows back to circulation. The back-leak of pelvic urine could also affect the concentration mechanism by removing diluted urine which had flowed over the renal papilla, and through water and urea diffusion increased papillary interstitial osmolarity.     

Influence of prehydration on the changes in renal tissue composition induced by water diuresis in the rat

1. The composition of renal tissue was determined in rats before and immediately after intravenous infusion of dextrose (2.5 g/100 ml.) in amounts sufficient to administer a positive fluid load of 4% body weight over 2 hr. The rats were classified into three groups, according to the preinfusion urine osmolality: hydropaenia, normal and moderately diuretic (over 2400, 800-1500 and below 800 mu-osmoles/g H(2)O, respectively).2. In non-infused rats, the steepness of the corticomedullary osmolal gradient varied, due to differences in both water and solute (sodium and urea) contents, and was related to urinary osmolality. Whereas differences in medullary and papillary solute contents occurred between all three groups, papillary water content was significantly higher only in the moderately diuretic animals.3. Dextrose infusion caused the induction of water diuresis, the lowest urinary osmolalities being produced in the previously moderately diuretic animals.4. Dextrose infusion caused a considerable reduction in the steepness of the corticomedullary osmolal gradient in all rats, particularly in the previously hydropaenic animals, due to changes in both solute (sodium and urea) and water contents. Whereas reductions in medullary and papillary solute contents occurred in all three groups, there was no further increase in papillary water content from the already high values seen in the noninfused diuretic animals.5. Thus, dextrose infusion largely abolished any previous differences in tissue water content, whereas significant, though small, differences in osmolal (particularly urea) content persisted.6. These data are discussed in terms of changes and differences in endogenous antidiuretic hormone (A.D.H.) release.7. Changes in the magnitude and direction of the urinary-papillary urea concentration difference are discussed in terms of passive transport, with probable A.D.H.-induced changes in nephron urea permeability.     

Unilateral papillary necrosis complicating renal artery stenosis—evidence of activation of the intrarenal renin–angiotensin system?

We report an association between renal artery stenosis and papillary necrosis. We studied three kidneys with renal artery stenosis, two of which showed ipsilateral acute papillary necrosis. In all three cases there had been a sudden fall in perfusion of the ischaemic kidney. In the case with intact papillae, immunostainable renin was normal in amount and distribution, whereas both kidneys with papillary necrosis showed hyperplasia of renin-containing cells, and these were mainly in the JGAs of the juxtamedullary cortex. Since the contralateral kidneys were spared, we suggest that in an ischaemic kidney with hyperplasia of renin-secreting cells in the deep cortex, local activation of the renin-angiotensin system could cause acute papillary necrosis due to vasoconstriction.     

Natriuresis obtained by intracerebroventricular infusion of hypertonic NaCI in rats with papillary necrosis.

Raising the sodium concentration in the third cerebral ventricle increases renal sodium, potassium and water excretion. The identification and characterization of the factor(s) mediating the centrally evoked natriuresis would be greatly facilitated if the exact intrarenal effector site were known. We have assessed the importance of inner medullary structures for the effects of CNS stimulation by examining its ability to alter renal excretion in rats with papillary necrosis, induced 2 d earlier with 2-bromoethylamine hydrobromide (BEA), 250 mg kg^-1 body wt i. v. Male Lewis x DA rats were divided into a BEA-treated group (n = 6) and a control group receiving vehicle alone (n = 6). In contrast to the white papillae normally seen, the papillae of BEA-treated animals were bright red and showed a clear line of demarcation at their base. The rats were anaesthetized i. p. with Inactin (120 mg kg^-l body wt). Artificial cerebrospinal fluid (CSF) was infused (520 nL min^-1) via a cannula into the left lateral ventricle. After 45 min CSF containing 1 M NaCl was used. Stimulation of the control rats with hypertonic CSF increased urine flow rate five-fold (5.4± 0.8 to 27.1±6.1 μL min^-1), Na excretion 23-fold (0.4±0.1 to 7.6±1.8 μmol min^-1) and K excretion fourfold (0.6±0.18 to 3.8±O.5 pmol min^-1). When the concentration mechanisms were damaged with BEA, the basal excretion rates of water and Na increased. The natriuretic response to ICV stimulation was severely impaired in these rats, but the kaliuretic effect was sustained. In conclusion, the natriuretic effect of ICV stimulation with hypertonic CSF is dependent on an intact renal inner medulla, which is not the case for the less pronounced kaliuretic response. Thus, either the juxtamedullary nephrons possess marked natriuretic responsiveness, not present in the cortical ones, or the responsiveness lies mainly in the papillary collecting ducts. However, it cannot be excluded that a disturbance of salt balance contributes to the observations.     

Mechanism of Formation of Human Calcium Oxalate Renal Stones on Randall's Plaque

Although calcium oxalate (CaOx) renal stones are known to grow attached to renal papillae, and specifically to regions of papillae that contain Randall's plaque (interstitial apatite deposits), the mechanisms of stone overgrowth on plaque are not known. To investigate the problem, we have obtained biopsy specimens from two stone patients that included an attached stone along with its tissue base and have studied the ultrastructural features of the attachment point using light and transmission electron microscopy, Fourier transform infrared spectroscopy (μ‐FTIR), and immunohistochemical analysis. The epithelium is disrupted at the attachment site. The denuded plaque that borders on the urinary space attracts an envelope of ribbon‐like laminates of crystal and organic matrix arising from urine ions and molecules. Into the matrix of this ribbon grow amorphous apatite crystals that merge with and give way to the usual small apatite crystals imbedded in stone matrix; eventually CaOx crystals admix with apatite and become the predominant solid phase. Over time, urine calcium and oxalate ions gradually overgrow on the large crystals forming the attached stone. Anat Rec, 290:1315‐1323, 2007. © 2007 Wiley‐Liss, Inc.     

The time course of changes in renal tissue composition during water diuresis in the rat

1. The time course and extent of changes in the composition of renal tissue slices in water diuresis were determined by sacrificing groups of rats before and during the intravenous infusion of dextrose (2.5 g/100 ml.) in amounts sufficient to administer over 2 hr, and subsequently to maintain for up to 7(1/2) hr, a positive fluid load of 4% body weight.2. The corticomedullary osmolal gradient characteristic of the nondiuretic rats was progressively dissipated until, at 7(1/2) hr, only papillary tip concentrations were higher than those of other segments.3. The changes in individual constituents followed different time courses: (i) an increase in water content in all segments, particularly the papilla, was almost complete by 1 hr, preceding the maximal increases in urine flow; (ii) a marked decrease in papillary and medullary urea content in the first hour was followed by a slower, progressive decrease leading to an almost complete dissipation of the urea gradient by 7(1/2) hr; (iii) small, non-significant decreases in sodium content occurred in all segments in the first hr, followed by a further small, progressive decrease in papillary sodium content; (iv) changes in ammonium and potassium concentrations were mainly related to those in water content, since the contents of these solutes showed only small changes.4. By 2 hr, differences in the rates of decline of osmolal and urea concentrations in urine and papilla led to urinary concentrations significantly lower than papillary values. The steep papilla-urine urea concentration difference became smaller, but remained significant even at 7(1/2) hr.5. The findings are discussed in terms of changes in countercurrent mechanisms, particularly as influenced by anti-diuretic hormone.6. The development of papilla/urine urea concentration ratio greater than unity is also considered in terms of passive transport with changes in membrane permeability.     

Haloalkylamine-induced renal papillary necrosis: a histopathological study of structure-activity relationships.

The haloalkylamine 2-bromoethanamine (BEA) causes necrosis of renal papillae of rats within 24 h of a single intraperitoneal dose greater than or equal to 100 mg/kg. Nine structural analogues of BEA, differing by halide substitution, alkyl chain elongation or amine substitution, were tested for their ability to induce renal papillary lesions in rats. Three compounds (2-chloroethanamine, 3-bromopropanamine and 2-chloro-N,N-dimethylethanamine) induced lesions which were morphologically indistinguishable from those of BEA. All the molecular structural variations investigated reduced papillotoxicity compared with BEA, the parent compound. A variety of non-renal lesions including hepatic, adrenal, testicular and lymphoid necroses were also encountered. The most toxic compound was 2-fluorethanamine, a 5 mg/kg dose of which was lethal and induced renal corticomedullary mineralization and centrilobular hepatic necrosis. One analogue, 3-bromo-2-hydroxypropanamine, caused rapid and extensive necrosis of the adrenal pars fasciculata and reticularis, simulating human Waterhouse Friderichsen syndrome. The three newly identified renal papillotoxins are all theoretically capable of generating direct-acting alkylating species in solution and their activity as direct-acting mutagens in the Ames bacterial mutagenicity test with TA100 (indicating base pair substitution) closely correlated with their potency as papillotoxins. We therefore hypothesize that non-enzymically formed direct-acting alkylating species mediate these papillary lesions, and that the target selectivity of haloalkylamine toxicity most probably results from the accumulation of these alkylating species in papillary tissue.     

Immunoassay of urinary retinol binding protein as a putative renal marker in cats

The presence of low molecular weight retinol binding protein (RBP) in urine reflects tubular damage. Therefore, RBP has been used as a renal marker in humans and dogs. Using an anti-human RBP antibody (Ab), this study first demonstrates feline urinary RBP by Western blot analysis and then evaluates its potential as a renal marker in cats by enzyme-linked immunosorbent assay (ELISA). Urine was taken by cystocentesis, centrifuged and stored at -80 degrees C until analysis. Urinary RBP levels were compared in clinically healthy cats (H), chronic renal failure patients (CRF) and cats with hyperthyroidism (HT). The detection of a band at the same position as the human RBP standard with Western blot analysis, indicated that RBP was present in the urine of CRF and HT patients but minimally present in H cats. The data obtained with ELISA were in accordance with these observations. RBP levels were expressed as RBP:creatinine (RBP:c) ratios following normalisation with urinary creatinine. The functional assay sensitivity was 1.37 microg/l RBP. Parallelism between the trend lines of the human RBP standard curve and the curves obtained from sequentially diluted urine samples indicated that feline RBP was recovered. The mean intra-assay coefficient of variance was 7% and the standardised agreement index revealed satisfactory day-to-day repeatability. The RBP:c ratio in all H cats (n=10) was below the assay sensitivity. The groups of CRF and HT patients had increased mean RBP:c ratios of 1.6+/-0.5x10(-2) microg/mg (mean+/-SEM, n=10) and 1.4+/-0.4x10(-2) microg/mg (n=13), respectively. Both groups showed a large variation in the relative RBP concentrations of individual cats. In conclusion, RBP is demonstrated for the first time in urine from most CRF and HT patients and the validated ELISA allows its evaluation as a putative renal marker in cats.     

Urine cytology of micropapillary carcinoma of the urinary bladder

A case of micropapillary carcinoma (MPC) of urinary bladder is presented, in which the urine smear was studied in detail in an attempt to better characterize the cytologic findings of MPC. When the voided urine was examined in low power, cancer cells were scattered in the specimens as compact papillary/spheroidal clusters composed of pleomorphic cancer cells. Solitary carcinoma cells were occasionally observed. High power view of the smear revealed that the papillae/spheroids consisted of high-grade urothelial carcinoma cells. The cancer cells had pleomorphic nuclei with coarsely granular chromatin and thickened, irregular nuclear membrane, and thick cytoplasm. Histologically, the tumor in the resected bladder appeared as small nests with surrounding hallo both in the luminal surface and in the site of wall involvement. These tightly bound papillary/spheroidal clusters comprised of highly atypical cancer cells were the most specific cytologic finding in the urine of MPC, which were considered as a key diagnostic clue of MPC. The background of the urine smear showed numerous granulocytes and bacilli compatible with cystitis, which is a previously known complication of MPC. Differential diagnoses of MPC from those with pertinent cytologic findings such as conventional UC (including glandular differentiation), and primary/secondary adenocarcinoma of urinary bladder are discussed with a brief review of literature.     

Papillary carcinoma of the thyroid: evidence for a role for hepatocyte growth factor (HGF) in promoting tumour angiogenesis

The pattern of vascularization of papillary carcinoma was investigated in tumour sections from 31 cases and in primary cultures from 12 cases. Tumour sections were immunostained for von Willebrand Factor (vWF) to visualize blood vessels; for endothelial-specific nitric-oxide-synthase (EC-NOS), as a marker of endothelial cell activation; and for Ki-67 to evaluate endothelial cell proliferation. It was found that endothelial cells lining venous vessels located in peritumoural fibrous tissue were intensely EC-NOS-positive and occasionally Ki-67-positive. Capillary vessels of tumour papillae were not stained for Ki-67 and were weakly EC-NOS-positive. Primary cultures of papillary carcinoma cells were used as a potential source of factors active on endothelial cells. It was found that thyroid tumour cells contain RNAs for angiopoietin, vascular endothelial growth factor (VEGF), and VEGF-C; moreover, they release large amounts of VEGF into culture supernatants and exert chemotactic activity in vitro for the endothelial cell line SIEC. The ability of papillary carcinoma cells to release angiogenic factors could be stimulated in vitro. Hepatocyte growth factor (HGF; 25 ng/ml) induced a 1.2- to 5-fold increase in the amount of VEGF released by tumour cells and a 1.2- to 4.2-fold increase in the amount of chemotactic activity present in culture supernatants. Met protein, the high affinity HGF-receptor, is overexpressed in a large proportion of cases of papillary carcinoma. These findings are consistent with the possibility that HGF-Met protein interaction is one of the molecular mechanisms promoting the vascularization of papillary carcinoma of the thyroid.