Retrograde venous invasion in renal cell carcinoma: a complication of sinus vein and main renal vein invasion.

Renal cell carcinoma, especially clear cell, gains access to the venous system as the initial route of extrarenal spread. Intravenous growth can involve extrarenal veins or renal veins in other portions of the kidney, referred to herein as retrograde venous invasion. This study investigates the incidence and defines the pathological features of retrograde venous invasion. Retrograde venous invasion is defined as rounded nodules of tumor separated from the primary tumor and in a location that conforms to the venous outflow. Nine cases of retrograde venous invasion were identified in a series of 115 renal cell carcinomas (8%). Two blocks from each case were stained with elastic van Gieson, Masson trichrome, CD31 and desmin to evaluate intravenous involvement. All cases were staged using the 2010 TNM staging schema. The tumors ranged in size from 4.2 to 17 cm. All cases showed sinus vein and main renal vein invasion (pT3a); three cases involved the vena cava (pT3b). Direct continuity between the primary tumor and tumor in the main renal vein was grossly evident in every case. Involved sinus veins could be followed retrograde to the cortex between renal pyramids with tumor nodules arrayed along the pyramid-cortex interface. Histologically, the involved parenchymal veins lacked a smooth muscle media and elastica. CD31 demonstrated an endothelial cell lining around many nodules. As intravenous nodules enlarged endothelium was lost, extra-venous invasion occurred and nodules coalesced and merged with the primary tumor. In conclusion, retrograde venous invasion occurred only with main renal vein involvement. Gross evaluation allowed detection in every case. Histological confirmation of intravenous nature is challenging due to the absence of smooth muscle in parenchymal veins. As retrograde growth becomes extensive nodules coalesce and merge with the primary tumor and may be included in measurement of primary tumor size if this process is unrecognized.

Renal veins and venous extension in clear cell renal cell carcinoma.

The 2002 TNM formulation defines a pT3b tumor as one that 'extends into the renal vein or its segmental (muscle containing) branches.' This definition elicits uncertainty when veins with little muscle are involved or the relationship to the main renal vein is unknown. The diameter and medial thickness of 10 normal renal venous systems were studied and compared to sinus veins involved in 54 pT3b clear cell renal cell carcinomas (CC). All tumors were grossly examined and sampled for histology by the author. An immunoperoxidase cocktail containing CD 31 and actin, Masson trichrome and elastic stains were employed to aid identification of intravenous tumor. The venous dissections showed variable numbers of primary and secondary divisions with substantial overlap in diameter and medial thickness. The medial thickness decreased with each proximal division and ranged from being nonexistent to being thick. Study of the 54 pT3b CC revealed that the initial phase of extrarenal extension involved large caliber veins draining the primary tumor. With extensive venous involvement, tumor invaded through the vein wall into sinus fat or demonstrated retrograde venous extension into adjacent cortex. Correlation between gross and histology revealed that most nodules of tumor within the sinus fat contained evidence of pre-existing veins. The following observations were made: (1) the diameter of a sinus vein or the quantity of muscle is a poor indicator of vein segment or relationship to the main renal vein; therefore, the wording used to define pT3b should be clarified; (2) extrarenal spread in CC begins with intravenous extension whereas sinus fat invasion is usually secondary; (3) retrograde venous extension occurs in cases with massive renal vein involvement; and (4) nodules within the sinus fat usually represent venous involvement.

Intravenous Tamm-Horsfall protein polyps: report of a case in association with a hematoma that mimicked a renal neoplasm.

Tamm-Horsfall protein (THP) is a glycoprotein produced only in the thick ascending limb of the loop of Henle. Its primary physiological function is unknown, but it may have a role in host defense against infectious organisms. THP is the primary scaffolding protein in all varieties of tubular casts. Under certain conditions, THP may be extruded from tubular lumens into the interstitium and lymphatic channels. It even may be found within lymph nodes sampled for staging of neoplastic conditions. THP deposits were described in lumens of large veins. The pathogenetic basis of this finding is not known, but obstruction of renal outflow was suggested, and several cases were associated with macroscopic hematuria. We report a case of intravenous THP polyposis in which, in addition to abundant hemorrhage, there was formation of a hematoma. This measured 12 cm in diameter and caused clinical concern for the possibility of renal cell carcinoma. Although the cause of the hematoma was not apparent, the association with striking intravenous polyps of THP is noteworthy because this represents the first association of intravenous THP polyps with a large intraparenchymal hematoma.

Asymmetry of renal blood flow in patients with moderate to severe hypertension.

It is generally assumed that renal blood flow is symmetric in the absence of renal artery stenosis. The aim of the present study was to evaluate whether this is really the case. From a group of consecutive hypertensive patients who had undergone renal angiography, we selected those with patent renal arteries. In all of them selective renal blood flow (RBF) measurements (133Xenon washout technique) had been performed with blood sampling from aorta and both renal veins (n=148). Asymmetry of RBF, defined as > or =25% difference in RBF between left and right kidney, was present in 51% of the patients. Subjects with and without asymmetry did not differ in age, body mass index, blood pressure, creatinine clearance, renal volume, or activity of the renin-angiotensin system. The presence of asymmetry coincided with an increased rate of false-positive results on renal scintigraphy. Preliminary data suggest that there may be a relation between asymmetry and renal sympathetic nerve activity. This study demonstrates that asymmetry of RBF is a frequent finding in essential hypertension, which may confound the results of diagnostic tests for renal artery stenosis. Furthermore, the present results underscore the importance of studying the function of both kidneys separately, because it cannot be assumed that they are functionally equal.

What is critical renal artery stenosis? Implications for treatment.

Renovascular disease due to progressive atherosclerotic renal artery stenosis is being diagnosed with increasing frequency in the elderly. At what degree of renal artery stenosis should intervention be recommended is not clear. To answer this question, unilateral or bilateral activation of the renin-angiotensin system or its absence were detected by captopril-stimulated renal vein renin measurements in 49 hypertensive patients, aged 63 years, with normal or near-normal renal function (serum creatinine concentration < or =2.0 mg/dL), and the information was matched against radiographic measurements of the extent of renal artery stenosis. With few exceptions, unilateral or bilateral hypersecretion of renin was associated with 80% or greater reduction of renal artery lumen diameter. In contrast, normal secretion or suppression of renin production in a kidney contralateral to an ischemic one was associated with either normal caliber renal artery or renal artery stenosis less than 80%. These findings suggest that renal artery stenosis less than 80% should be monitored rather than treated because improvement of renal function and amelioration of hypertension are not expected unless the renin-angiotensin system has been activated in the affected kidney. Renoprotection by early intervention is uncertain because progression of renal artery stenosis is unpredictable. Normal captopril-stimulated renal vein renin measurements in hypertensive patients obviate the need for further work-up or interventional therapy of renovascular disease.

Increased renal production of transforming growth factor-beta1 in patients with type II diabetes.

Diabetic nephropathy is a common complication in patients with either type I or type II diabetes. The pathogenesis of diabetic nephropathy is thought to involve both metabolic and vascular factors leading to chronic accumulation of glomerular mesangial matrix. In this context, both transforming growth factor-beta (TGF-beta) and endothelin may contribute to these processes. To determine if diabetic patients demonstrate increased renal production of TGF-beta and endothelin, aortic, renal vein, and urinary levels of these factors were measured in 14 type II diabetic patients and 11 nondiabetic patients who were undergoing elective cardiac catheterization. Renal blood flow was measured in all patients to calculate net mass balance across the kidney. Diabetic patients demonstrated net renal production of immunoreactive TGF-beta1 (830 +/- 429 ng/min [mean +/- SE]), whereas nondiabetic patients demonstrated net renal extraction of circulating TGF-beta1 (-3479 +/- 1010 ng/min, P < 0.001). Urinary levels of bioassayable TGF-beta were also significantly increased in diabetic patients compared with nondiabetic patients (2.435 +/- 0.385 vs. 0.569 +/- 0.190 ng/mg creatinine, respectively; P < 0.001). Renal production of immunoreactive endothelin was not significantly increased in diabetic patients. In summary, type II diabetes is associated with enhanced net renal production of TGF-beta1, whereas nondiabetic patients exhibit net renal extraction of circulating TGF-beta1. Increased renal TGF-beta production may be an important manifestation of diabetic kidney disease.

Increased immunoreactivity of transforming growth factor-beta in human kidney transplants.

Transforming growth factor-beta (TGF-beta) has been known to be involved in the pathogenesis of various kidney diseases. TGF-beta is also a potent immunosuppressor that has been shown to be induced after allogeneic transplantation. We have studied the distribution of immunoreactive TGF-beta proteins in different compartments of 21 allogeneic transplanted kidneys that had been rejected through acute (eight interstitial or six vascular) and chronic (seven vascular) processes. This distribution was compared with that in seven non-rejected transplanted and five non-transplanted kidneys with intact morphology. There were no obvious differences between the three groups of rejected grafts and the transplanted non-rejected group for the expression of TGF-beta s. A major difference was seen between transplanted kidneys, which exhibited clearly positive TGF-beta and LTBP1 (latent TGF-beta binding protein) immunoreactivities, and the non-transplanted kidneys. The non-transplanted kidneys showed only very weak or no immunoreactivity for these proteins. The morphologically intact non-rejected grafts showed a significantly increased immunoreactivity compared with the non-transplanted kidneys. When the transplanted kidneys were classified into two groups (i.e. with or without diabetes mellitus) and compared with regard to the expression of all TGF-beta s, no difference was found. Thus, transplantation was the most important predictor for expression of TGF-beta s and LTBP1, and the largest expression increase in the allografts occurred in the interstitium, followed by the glomeruli and blood vessels. Tubuli and lymphocyte aggregates stained only faintly. The results imply that TGF-beta is induced rapidly after kidney transplantation. This induction can suppress immunoreactivation, but concomitantly promotes changes such as arteriosclerosis and fibrosis associated with rejection.

Mesenteric organ production, hepatic metabolism, and renal elimination of norepinephrine and its metabolites in humans.

This study used regional differences in plasma concentrations of norepinephrine and its metabolites to examine how production of the transmitter by sympathetic nerves, in particular, those innervating mesenteric organs, is integrated with metabolism by the liver and elimination by the kidneys. Higher concentrations of norepinephrine, its glycol metabolites 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol and their sulfate conjugates in portal venous than arterial plasma indicate substantial production of norepinephrine by mesenteric organs (15.5 nmol/min). Much lower concentrations of norepinephrine and its glycol metabolites in plasma leaving than entering the liver indicate their efficient hepatic removal (20 nmol/min). Higher concentrations of vanillylmandelic acid in the hepatic outflow than inflow indicate that this metabolic end product is produced largely from the norepinephrine and glycol metabolites removed by the liver. Renal elimination of vanillylmandelic acid (18-20 nmol/min), produced mainly by the liver (17 nmol/min), and of 3-methoxy-4-hydroxyphenylglycol sulfate (7-9 nmol/min), produced largely by mesenteric organs (7 nmol/min), compromised 86-91% of the total renal elimination of norepinephrine metabolites. The results show that mesenteric organs produce about one-half of the norepinephrine formed in the body. The liver removes substantial amounts of circulating norepinephrine and its glycol metabolites and converts these compounds to vanillylmandelic acid, which is then eliminated from the body by the kidneys. The sulfate conjugates are also metabolic end products eliminated by the kidneys. However, these metabolites are produced by extrahepatic tissues, in particular, mesenteric organs, which represent a significant source of sulfate-conjugated norepinephrine and 3,4-dihydroxyphenylglycol, and the main source of sulfate-conjugated 3-methoxy-4-hydroxyphenylglycol.

Autoradiographic localization of NK1 and NK3 tachykinin receptors in rat kidney.

The distribution of neurokinin receptors in rat kidney, renal artery, renal vein, and proximal ureter was evaluated by autoradiography after in vitro labeling of NK1 sites with [125I]Bolton-Hunter substance P (BHSP) or NK3 sites with [125I][MePhe7]neurokinin B ([MePhe7]NKB). Film autoradiography using [125I][MePhe7]NKB revealed specific binding sites associated with the renal vein and its large branches, the renal pelvis, the inner strip of outer renal medulla, and the proximal ureter. High-resolution autoradiograms demonstrated that these sites were localized to the smooth muscle layer in the veins, pelvis, and ureter. Neither the renal arterial system nor the renal cortex contained specific [125I][MePhe7]NKB binding sites although a high level of nonspecific binding was associated with the renal artery. Specific binding of [125I]BHSP was associated with the renal artery and renal pelvis but not the renal veins. Arterial NK1 receptors appeared to be localized to the adventitia. The results indicate that at least two types of tachykinin receptor are present in the rat kidney. The distinct localization observed for most of the NK1 and NK3 receptors suggests that they have different functions.

The role of the renal nerves in renin synthesis.

1. Renin synthesis and secretion were studied in Balb/c mice with a denervated left kidney. 2. Denervation inhibited renin secretion. 3. Denervation reduced the renal renin content. 4. Denervation reduced renal renin mRNA. 5. Renal denervation inhibits renin secretion by blocking the synthetic system prior to mRNA formation.

Renal vein oxygen saturation in renal artery stenosis.

Renal vein oxygen-saturation was measured in 56 patients with arterial hypertension and unilateral stenosis or occlusion of the renal artery. Oxygen-saturation in blood from the ischaemic kidney (84.4%, range 73-93%) was significantly higher than that from the 'normal' contralateral kidney (81.2%, range 70-90%, P less than 0.001). In only six patients, the ischaemic kidney revealed a venous oxygen-saturation below the contralateral value (mean difference ischaemic-normal kidney 3.2%, range -6 to 15%). The results indicate that the oxygen uptake in the chronic ischaemic kidney is more decreased than its blood flow. This is probably due to decreased filtration fraction and filtered sodium with subsequent reduction in absolute tubular re-absorption of sodium ions.

The effect of caffeine on renal vein renin concentration in patients with renal arterial disease.

The aim of this study was to investigate whether caffeine stimulates selectively renal vein renin levels at the side of unilateral stenosis in patients with renovascular hypertension. In this study seven of the involved patients had renal arterial stenosis and four had no stenosis. Four of the seven patients with a stenosis had retrospectively-proven renovascular hypertension. Renal vein renin sampling was performed before and after intravenous administration of caffeine. Caffeine did not induce any consistent effect on plasma renin activity in the renal veins, either on the stenotic side or on the contralateral side in patients with renovascular hypertension. There were no consistent caffeine mediated changes in systemic plasma renin activity.

Bilateral renal artery stenosis and renovascular hypertension.

Experience with the diagnostic evaluation and operative management of 38 hypertensive patients having bilateral renal revascularization is presented. Twenty-four patients had atherosclerotic occlusions and 14 had fibromuscular dysplasia. Renal vein renin assays (RVRA) and/or split renal function studies (SRFS) were performed in 37 of the 38 patients before operation. Although RVRA was negative in 29 percent and SRFS negative in 31 percent, 24 of 26 patients (92 percent) having both tests done had at least one positive study. Twenty-one patients had simultaneous bilateral repairs and 12 had staged bilateral reconstructions. The incidence of technical failures in these two groups was 21 and 9 percent, respectively. Excluding three uncorrected technical failures and two patients with recurrent branch renal artery lesions, 90 percent of patients with atherosclerosis and all patients with fibromuscular dysplasia had a favorable blood pressure response to operation. This study supports the use of both RVRA and SRFS in the diagnostic evaluation of hypertensive patients with renal artery stenosis. If these functional tests lateralize to one side, repair of that side only is recommended. If the functional studies do not lateralize, operation is suggested only when hypertension is severe and is not controlled readily with medications. In this circumstance reconstruction of the side that appears to be diseased most severely is recommended. Contralateral repair is undertaken only when hypertension persists and when repeat functional studies lateralize to the unoperated side.