Total tumour volume as a prognostic factor in patients with resectable colorectal cancer liver metastases.

BACKGROUND: Although total tumour volume (TTV) may have prognostic value for hepatic resection in certain solid cancers, its importance in colorectal liver metastases (CRLM) remains unexplored. This study investigated its prognostic value in patients with resectable CRLM. METHOD: This was a retrospective review of patients who underwent hepatic resection for CRLM between 2008 and 2017 in a single institution. TTV was measured from CT images using three-dimensional construction software; cut-off values were determined using receiver operating characteristic (ROC) curve analyses. Potential prognostic factors, overall survival (OS) and recurrence-free survival (RFS) were determined using multivariable and Kaplan-Meier analyses. RESULTS: Some 94 patients were included. TTV cut-off values for OS and RFS were 100 and 10 ml respectively. Right colonic primary tumours, primary lymph node metastasis and bilobar liver metastasis were included in the multivariable analysis of OS; a TTV of 100 ml or above was independently associated with poorer OS (hazard ratio (HR) 6·34, 95 per cent c.i. 2·08 to 17·90; P = 0·002). Right colonic primary tumours and primary lymph node metastasis were included in the RFS analysis; a TTV of 10 ml or more independently predicted poorer RFS (HR 1·90, 1·12 to 3·57; P = 0·017). The 5-year OS rate for a TTV of 100 ml or more was 41 per cent, compared with 67 per cent for a TTV below 100 ml (P = 0·006). Corresponding RFS rates with TTV of 10 ml or more, or less than 10 ml, were 14 and 58 per cent respectively (P = 0·009). A TTV of at least 100 ml conferred a higher rate of unresectable initial recurrences (12 of 15, 80 per cent) after initial hepatic resection. CONCLUSION: TTV was associated with RFS and OS after initial hepatic resection for CRLM; TTV of 100 ml or above was associated with a higher rate of unresectable recurrence.

ANTECEDENTES: Aunque el volumen total del tumor (total tumour volume, TTV) puede tener valor pronóstico tras la resección hepática (hepatic resection, HR) en algunas neoplasias sólidas, no se conoce su importancia en las metástasis hepáticas de cáncer colorrectal (colorectal liver metastases, CRLMs). Este estudio analizó el valor pronóstico del TTV en pacientes con CRLMs resecables. MÉTODOS: Revisión retrospectiva de pacientes a los que se realizó una HR por CRLMs entre 2008 y 2017 en un solo centro. El TTV se estimó a partir de imágenes de tomografía computarizada utilizando un programa de reconstrucción 3D; se determinaron los valores de corte mediante un análisis de las características operativas del receptor. Se identificaron los posibles factores pronósticos y se calcularon la supervivencia global (overall survival, OS) y la supervivencia libre de recidiva (recurence-free survival, RFS) mediante análisis multivariados y de Kaplan-Meier. RESULTADOS: Se incluyeron 94 pacientes. Los valores de corte del TTV para la OS y la RFS fueron de 100 mL y 10 mL, respectivamente. En el análisis multivariable para la OS, se incluyeron los tumores del colon derecho, las metástasis linfáticas primarias y la metástasis hepática bilobar; un TTV ≥ 100 mL se asoció de forma independiente con una peor OS (cociente de riesgos instantáneos, hazard ratio, HR, 6,34, i.c. del 95% 2,08-17,9; P = 0,002). En el anáisis para la RFS, se incluyeron tumores primarios de colon derecho y las metástasis linfáticas primarias; un TTV ≥ 10 mL predijo de forma independiente una peor RFS (HR 1,90, i.c. del 95% 1,12-3,57; P = 0,017). Las tasas de OS a los 5 años con TTVs ≥ 100 mL versus < 100 mL fueron del 41% versus 67% (P = 0,006); las tasas de RFS respecto a TTVs ≥ 10 mL versus < 10 mL fueron del 14% versus 58% (P = 0,009). Un TTV ≥ 100 mL conllevó una tasa más elevada (80%) de recidivas no resecables después de la HR inicial. CONCLUSIÓN: El TTV se asoció con la RFS y la OS tras la HR por CRLMs; unos valores ≥ 100 mL conllevan una tasa más elevada de recidiva irresecable.

Activated extracellular signal-regulated kinase correlates with cyst formation and transforming growth factor-beta expression in fetal obstructive uropathy.

Human renal dysplasia is frequently associated with urinary tract obstruction and the abnormal expression of mitogen-activated protein kinase (MAPK). Here, we determined the renal responses and MAPK expression in developing kidneys that were obstructed in fetal lambs. Kidneys were harvested at various times after obstruction (gestation day 60) through normal term (day 145). Dilation of Bowman's capsule and proximal tubules was seen 2 days after obstruction and involved the whole cortex 18 days later, with numerous cysts present throughout the kidney at term. The proliferation marker Ki-67 and transforming growth factor-beta (TGF-beta) were detected 2 days after obstruction and progressively increased in tubules, cysts, and the interstitium. In control kidneys, p38 was expressed in tubules only during the fetal stage, whereas phosphorylated extracellular signal-regulated kinase (P-ERK) was limited to ureteric buds and collecting ducts at all stages examined. However, Jun-N-terminal kinase (JNK) was absent in the fetal kidney but present in tubules at term. In obstructed kidneys, cyst epithelia were positive for p38 and P-ERK but negative for JNK throughout all stages. These studies show that P-ERK correlated spatially and temporally with Ki-67 and TGF-beta expression, which suggests that ERK may contribute to cyst formation and fibrosis in the obstructed fetal kidney.

Poststreptococcal acute glomerulonephritis superimposed on bilateral renal hypoplasia.

An 8-year-old girl with preexisting chronic renal failure (CRF) due to bilateral renal hypoplasia presented with edema, gross hematuria and acute deterioration of renal function. The diagnosis of poststreptococcal acute glomerulonephritis (PSAGN) was made based on clinical presentation, red blood cell casts, low level of C3 and elevated antistreptolysin 0 titer. Her course was prolonged with serum creatinine increased from the baseline level of 1.1 mg/dl to 2.2 mg/dl, returning toward the baseline level (1.2 mg/dl) after one month. Serum creatinine then started to increase again. The slope of creatinine clearance over time became steeper after the episode of PSAGN. A severe course of PSAGN and subsequent deterioration of renal function have previously been reported in patients with diabetic nephropathy or focal glomerulosclerosis. The present case along with a literature review suggests that individuals with fewer nephrons are at higher risk of severe course and outcome of PSAGN. Conversely, patients with severe PSAGN may be born with fewer nephrons due to low birth weight, unrecognized renal hypoplasia or other unknown causes.

Trapidil inhibits platelet-derived growth factor-stimulated mitogen-activated protein kinase cascade.

Trapidil, an antiplatelet drug, has been shown to reduce restenosis after angioplasty. It exerts its action, at least in part, by inhibiting vascular smooth muscle cell proliferation, antagonizing platelet-derived growth factor (PDGF). We examined its site of action on PDGF cellular signaling. Exposure of cultured rat vascular smooth muscle cells to increasing concentrations of trapidil for 18 hours resulted in a dose-dependent reduction in PDGF-BB-stimulated [3H] thymidine incorporation. Trapidil (400 microg/mL) increased PDGF beta-receptor protein by 28+/-8%, whereas PDGF-induced tyrosine phosphorylation of PDGF beta-receptor remained unchanged. PDGF-induced tyrosine phosphorylation of phospholipase Cgamma, the p85 regulatory subunit of phosphatidyl-inositol 3 kinase, Ras GTPase-activating protein, and an adaptor molecule Shc were also not altered. On the other hand, trapidil inhibited PDGF-stimulated mitogen-activated protein kinase (MAP kinase) activity by 35+/-7% at 10 minutes and by 32+/-10% at 6 hours. Activation of Raf-1, an upstream activator of MAP kinase, by PDGF was also attenuated by trapidil. Moreover, protein content of MAP kinase phosphatase-1, which inactivates MAP kinase, was elevated in trapidil-treated cells. These actions of trapidil may be mediated by cAMP. Thus, there was a 1.9-fold increase in cellular cAMP generation in trapidil-treated cells. The present results demonstrate that trapidil antagonizes PDGF-induced mitogenesis and MAP kinase activation in vascular smooth muscle cells, probably through cAMP.

Blunted pressure natriuresis in the Brattleboro diabetes insipidus rat.

Antidiuretic hormone is known to stimulate the renal synthesis of prostaglandins. These autacoids, in turn, modulate the pressure natriuresis phenomenon. Accordingly, the present study was done to test the hypothesis that, in the absence of antidiuretic hormone and antidiuretic hormone-dependent prostaglandin synthesis, the pressure natriuresis response is blunted. Experiments were performed on Brattleboro diabetes insipidus rats (n = 7) and Long Evans control rats (n = 14). A change in perfusion pressure in the Long Evans rats from 89.3 +/- 1.0 to 108.7 +/- 1.1 mm Hg (p less than 0.05) was associated with significant increases in the fractional excretion of sodium (1.1 +/- 0.2 to 2.3 +/- 0.3%) and the urinary prostaglandin excretion (32.6 +/- 6.8 to 56.6 +/- 10.0 pg/min). In contrast, a similar change in perfusion pressure in the diabetes insipidus rat from 88.6 +/- 1.4 to 106.2 +/- 1.5 mm Hg (p less than 0.05) resulted in no significant increases in either sodium or prostaglandin excretions. Treatment of a third group of diabetes insipidus rats (n = 9) with 1-desamino-8-D-arginine vasopressin (1 microgram/day) restored the natriuretic response to increases in renal perfusion pressure. Treated diabetes insipidus and Long Evans control rats had comparable natriuretic responses to increases in renal perfusion pressure. Untreated diabetes insipidus rats, on the other hand, had blunted responses. In summary, the pressure natriuresis response in diabetes insipidus rats is blunted compared with Long Evans control rats. We conclude that antidiuretic hormone is necessary for the complete expression of the pressure natriuresis response.

Hepatic dysfunction in two sibs with Alström syndrome: case report and review of the literature.

Alström syndrome is an autosomal recessive disorder (MIM No. *203800) characterized by retinal degeneration, obesity, deafness, noninsulin-dependent diabetes mellitus, and nephropathy. We report two sibs with Alström syndrome and hepatic dysfunction. The first sib developed elevations in liver enzymes at 29 years of age. Liver biopsy showed fatty liver, lymphocytic infiltration, and piecemeal necrosis. The second sib had had elevated gamma-glutamyltransferase levels since she was 10 years old. She developed ascites, esophageal varices, and splenomegaly in her twenties. Cirrhosis was confirmed by autopsy; the patient was 26 years of age at death. Three Alström syndrome patients with hepatic dysfunction have been documented previously. No specific cause was identified for liver disease in any of the patients, including ours. Hepatic dysfunction appears to be a manifestation of Alström syndrome.

Alterations in renal function in experimental congestive heart failure.

The delicate interplay between vasoconstrictors and vasodilators preserves glomerular filtration in CHF despite marked hypoperfusion. Activation of vasoconstrictive systems seems to depend on the severity and the chronicity of the disease. The importance of renin-angiotensin, sympathetic nerves, vasopressin and counterregulatory ANP, and prostaglandins in CHF has been elucidated. Possible roles of newly identified substances, such as endothelin and EDRF, deserve investigation.

Molecular and clinical studies of Dent's disease in Japan: biochemical examination and renal ultrasonography do not predict carrier state.

BACKGROUND: Dent's disease is an X-linked renal tubular disorder characterized by low-molecular-weight-proteinuria, hypercalciuria, nephrolithiasis and renal failure. The disease is due to inactivation of a renal chloride channel gene, CLCN5. We have investigated 3 unrelated Japanese families for CLCN5 mutations and assessed the carrier mothers biochemically and ultrasonogaraphically to ascertain whether these clinical examinations can predict the carrier state of the disease. MATERIAL AND METHODS: Twelve members from these families were studied biochemically and ultrasonographically. Leukocyte DNA from probands was used with CLCN5-specific primers for PCR amplification of the coding region and exon-intron boundaries, and the DNA sequences of the products determined to identify abnormalities in the gene. RESULTS: Three novel CLCN5 mutations consisting of a single base "A" insertion between nucleotides 590 and 591, a nonsense mutation (R28X) and a missense mutation (G506R) were exhibited. Hypophosphatemia was detected in 2 patients, beta2-microglobulinuria, alpha1-microglobulinuria, and hyperretinol binding proteinuria in 6 patients, hypercalciuria in 5 patients, decreased urine osmolality in 3 patients, and nephrocalcinosis or nephrolithiasis in 4 patients. Biochemical analysis of the urine and the renal ultrasonography in each carrier mother were completely normal. CONCLUSIONS: Neither urinary low-molecular-weight-proteins, urinary calcium to creatinine ratio, nor renal ultrasonography was predictive of carrier state in the 3 families with this disease, although each carrier mother had CLCN5 mutation. Hypophosphatemia and decreased urine osmolality might be a hint to suspect the carrier state of Dent's disease, although these findings are not found frequently.

[Standard versus long-term prednisolone with sairei-to for initial therapy in childhood steroid-responsive nephrotic syndrome: a prospective controlled study].

The most appropriate initial treatment for children with steroid-responsive nephrotic syndrome is controversial. Initial treatment with 18-week prednisolone and the Chinese herbal medicine. Sairei-to, may prevent subsequent relapse. To determine whether similar results can be obtained with a combination of just initial 8-week prednisolone and Sairei-to, we compared the effects of such treatment with those of treatment with 18-week prednisolone and Sairei-to in 196 children with steroid-responsive nephrotic syndrome. The patients were randomly assigned to receive 8-week (group 1) or 18-week (group 2) prednisolone for the initial therapy. All patients received Sairei-to for 2 years in addition to prednisolone. Eighty-eight of the 98 patients in group 1 and 83 of the 98 patients in group 2 completed their trial. At entry, the two groups of patients did not differ in their clinical and laboratory findings. During the 2-year trial, 62 group 1 patients (70%) and 54 group 2 patients (65%) had relapses, and 19 group 1 patients (21%) and 20 group 2 patients (24%) had frequent relapses. The present study demonstrates that a combination of initial 8-week prednisolone and 2-year Sairei-to is effective in children with steroid-responsive nephrotic syndrome.

[A prospective controlled study of sairei-to in childhood IgA nephropathy with focal/minimal mesangial proliferation. Japanese Pediatric IgA Nephropathy Treatment Study Group].

To determine the effect of the Chinese herbal medicine, Sairei-to (TJ-114) in children with newly diagnosed IgA nephropathy showing focal/minimal mesangial proliferation, we undertook a prospective controlled study. One hundred and one patients were randomly assigned to receive Sairei-to for 2 years (group 1) or no drug for 2 years (group 2). Forty-six of the 50 patients in group 1 and 48 of the 51 patients in group 2 completed their trial. At entry, the two groups of patients did not differ in the clinical, laboratory and pathologic findings. At the end of the trial, urinary protein excretion and hematuria were significantly reduced in group 1, but were unchanged in group 2. Twenty-one group 1 patients (46%) had normal urine, but only 5 group 2 patients (10%) had normal urine at the end of the trial (p < 0.001). Blood pressure and creatinine clearance were normal at the end of the trial in all but one group 2 patient, who developed chronic renal failure. The present study demonstrates that 2-year Sairei-to treatment early in the course of disease is effective in children with IgA nephropathy showing focal/minimal mesangial proliferation.

Inhibition of platelet-derived growth factor receptor tyrosine kinase by atrial natriuretic peptide.

Atrial natriuretic peptide (ANP) is known to suppress platelet-derived growth factor (PDGF)-stimulated proliferation of rat cultured vascular smooth muscle cells. The present study examined whether ANP inhibits the PDGF receptor (PDGFR) tyrosine kinase activation, an initial event for PDGF cellular signaling. ANP reduced the in vivo tyrosine phosphorylation of PDGFR stimulated by PDGF in a dose-dependent manner. This effect was not due to the reduction in PDGFR protein as detected by immunoblot analysis. 8-Bromo-cyclic GMP, a membrane-permeable 3',5'-cyclic monophosphate (cGMP) derivative, mimicked the action of ANP. HS-142-1, an antagonist for guanylate cyclase A (GC-A) and B, co-incubated with ANP, restored the PDGF-induced PDGFR autophosphorylation. The effect of ANP was also observed in the presence of a protein tyrosine phosphatase inhibitor, sodium orthovanadate. To confirm that ANP exerts its action by inhibiting protein tyrosine kinase (PTK), an in vitro kinase assay was performed. Cyclic GMP inhibited PTK activity of PDGFR partially purified by lectin affinity chromatography. In contrast, PTK activity in immobilized PDGFR immunocomplexes was not inhibited by cGMP. However, exogenous cGMP dependent protein kinase (PKG) reduced the PTK activity in the presence of cGMP. These results demonstrate that ANP suppresses PDGFR PTK through GC-A probably by activating PKG. This may be an important mechanism by which ANP exerts its anti-proliferative action antagonizing PDGF.

Biological significance of atrial natriuretic peptide in the kidney.

In summary, ANP exerts its action in the kidney directly and indirectly. Its qualitative importance in body fluid regulation remains unsettled. It appears that its role is more important in pathophysiological conditions such as CHF in which plasma ANP is elevated. Paradoxically, kidneys in heart failure, nephrosis and diabetes are characterized by diminished responsiveness to exogenous ANP. Further studies are needed to ascertain whether this involves an alteration at the receptor or postreceptor site. The cellular mechanisms for receptor regulation and postreceptor signalling in physiology and pathophysiology need further investigation. Finally, a paracrine mode for the action of ANP and other natriuretic peptides has been proposed. Whether they act locally to facilitate sodium excretion and how much importance they have compared to circulating ANP remain to be clarified. The potential role of ANP as a growth inhibitor is also intriguing.

Endothelin and cyclosporine nephrotoxicity.

Although some humoral and neural factors have been implicated in the persistent vasoconstriction characterizing many forms of acute renal failure, the mechanisms for this abnormal vascular function have remained largely unresolved. Several factors previously postulated to have a role in acute renal failure have been shown to enhance endothelin (Et) production or gene expression. We studied the potential pathophysiologic role for Et in several models of acute renal failure, including postischemia, endotoxin, and cyclosporine (Cy) nephrotoxicity. We have found that, in vivo, Cy (and also endotoxin) elevates circulating Et. We further showed that antagonizing Et's action with Et antibody ameliorates renal vasoconstriction following renal ischemia, Cy, and endotoxin administration. Additionally, our studies showed that even after circulating levels of Et decrease (following Cy), there is upregulation in Et receptors in the kidneys. Overall, endothelin appears to feature prominently in the pathophysiologic processes occurring during several forms of acute renal failure.

Tubulointerstitial nephritis and uveitis syndrome with autoantibody directed to renal tubular cells.

The pathogenesis of tubulointerstitial nephritis and uveitis (TINU) syndrome remains unknown, but T cell-mediated immune response has been postulated to play a role. On the other hand, TINU syndrome is characterized by hypergammaglobulinemia and high serum immunoglobulin G (IgG) levels, suggesting an involvement of humoral immunity. We describe a case of TINU syndrome in a 13-year-old girl with multiple tubular dysfunctions including renal glucosuria, tubular proteinuria, phosphaturia, uricosuria, and concentrating and acidifying defect. IgG antibody from her serum was reactive against 125-kDa human kidney protein. Immunofluorescence study using mouse kidney revealed that the antibody was against cortical renal tubular cells. The antibody disappeared as the renal symptoms resolved. We suggest that IgG antibody may contribute to tubular dysfunction in some patients with TINU syndrome.

Effect of phosphate infusion on proximal tubule phosphate reabsorption in phosphate-deprived and respiratory alkalotic rats.

Phosphate deprivation and acute respiratory alkalosis both stimulate phosphate conservation by the kidney. To evaluate the response of the superficial proximal tubule to increases in the filtered load of phosphate (Pi), micropuncture studies were performed in these two models of Pi conservation, rats fed a low-phosphate diet (0.07% Pi), and rats with acute respiratory alkalosis (RA). All animals were acutely thyroparathyroidectomized. After basal collections, the animals were infused with Pi at a rate of 4 microM/min and then the samples recollected 30 min after the initiation of the Pi infusion. Infusion of phosphate increased the filtered load of phosphate (FLPi) of single nephrons from 112 +/- 13 to 266 +/- 44 pmol/min in phosphate-derived rats and from 123 +/- 21 to 217 +/- 44 pmol/min in respiratory alkalotic rats. However, absolute reabsorption of phosphate (ARPi) increased only in phosphate deprivation (94 +/- 16 to 126 +/- 25 pmol/min). These results indicate that the superficial proximal convoluted tubule responds to phosphate infusion by increasing reabsorption in the phosphate-deprived model, but not in the respiratory alkalotic model, of phosphate conservation.

Natriuretic effect of atrial natriuretic peptide in diabetes insipidus rats.

Washout of the solute concentration gradient in the renal medullary interstitium has been suggested to play a role in mediating the natriuretic response to atrial natriuretic peptide (ANP). The purpose of this study was to determine the effects of ANP 8-33 on sodium excretion in Brattleboro diabetes insipidus (DI) rats, in which medullary tonicity is known to be decreased as compared to Long-Evans (LE) control rats. Basal urine osmolality (Uosm) was significantly lower in DI rats as compared to LE rats (123 +/- 6 vs 673 +/- 38 mOsm/kg). Infusion of ANP 8-33 at a rate of 4 micrograms/kg/hr for 60 min resulted in a significantly greater increase in UnaV (delta 6.1 +/- 1.2 vs delta 2.9 +/- 0.7 microEq/min) and urine flow (delta 40 +/- 12 vs delta 8 +/- 7 microliter/min) in the LE rats than in the DI rats. The greater natriuresis occurred in the LE rats despite no significant change in Uosm. Fractional lithium reabsorption (an indicator of proximal sodium reabsorption) decreased similarly in both groups. Infusion of ANP had no effect on mean arterial pressure in LE and DI groups. In summary, infusion of ANP in the DI rat resulted in a significant natriuresis, albeit less than in LE rats. The natriuresis in the LE rats occurred despite no significant change in Uosm. These data suggest that mechanisms other than medullary washout are responsible for the natriuretic effects of ANP.

Mechanisms of mitogen-activated protein kinase activation in experimental diabetes.

Various growth factors and vasoactive substances are implicated in the pathogenesis of renal growth seen in early diabetes mellitus (DM). Mitogen-activated protein kinase (MAPK) is an important mediator of these extracellular stimuli. Protein kinase C (PKC), an enzyme known to be stimulated in DM, also activates MAPK. Thus, MAPK activity was examined in glomeruli from streptozotocin-induced DM rats. MAPK activity, measured as myelin basic protein kinase, was elevated by approximately 50% in DM versus controls (CON). Increased protein contents of p42mapk and p44mapk, as well as increased tyrosine phosphorylation and mobility shift of p42mapk, were also observed in DM. Tyrosine dephosphorylation of pp42mapk, on the other hand, assessed by incubating glomerular membrane with or without sodium orthovanadate (vanadate), was significantly diminished in DM. Protein expression of MAPK phosphatase-1 (MKP-1), a dual specificity phosphatase that inactivates MAPK, was approximately 60% of CON. Reduction in MKP-1 was reproduced in cultured mesangial cells grown under high glucose (30 mM; HG). The suppression of MKP-1 was PKC-dependent since incubation of HG cells with phorbol 12-myristate 13-acetate for 24 h abolished it. Furthermore, calcium ionophore A23187 reversed the suppression, suggesting that blunted Ca2+ signalling, characteristic of HG cells secondary to PKC stimulation, may be the cause. These results demonstrate that glomerular MAPK is activated in DM by multiple mechanisms i.e., increases in protein contents, increased phosphorylation, and decreased dephosphorylation of the enzyme due to suppression of MKP-1. These alterations may have an implication in the pathogenesis of diabetic nephropathy.