Evaluation of exercise-induced acute renal failure in renal hypouricemia using Tc-99m DTPA renography

We present a case of a thirty-eight-year-old man who had exercise-induced acute renal failure (exercise-induced ARF). He experienced oliguria, general fatigue, and vague discomfort in the lower abdomen after he exercised. As he had suffered from hypouricemia before, he was diagnosed as having exercise-induced ARF associated with hypouricemia. Enhanced computed tomography (CT) images showed patchy wedge-shaped contrast enhancement on his bilateral kidneys, consistent with characteristic observations for exercise-induced ARF. Tc-99m diethylene triamine pentaacetic acid (DPTA) renography revealed decreases in both the renal blood flow (RBF) and glomerular filtration rate (GFR), and revealed parenchymal dysfunction of the bilateral kidneys. Renogram revealed a hypofunctional pattern on the bilateral kidneys. CT images and Tc-99m DTPA renography also had improved when the symptoms of exercised-induced ARF indicated improvement. It has been hypothesized that one cause of exercise-induced ARF may be renal vasocontraction. Although CT images are useful in evaluating exercise-induced ARF, Tc-99m DTPA renography can more easily and safely evaluate renal function. We also show that Tc-99m DTPA renography is useful in precisely evaluating the degree of improvement of exercise-induced ARF.     

Assessment of therapeutic effect in acute myocardial infarction using early/delayed images of 123I-BMIPP myocardial scintigraphy

This study was aimed at analyzing the discordance between the initial and late scintigraphic images in patients with acute myocardial infarction (AMI), and utilizing the data obtained for the treatment of AMI patients. Ninety-one patients with a history of the first episode of AMI were enrolled as subjects for this study. Emergency coronary angiography was performed in all the patients and left ventriculography (LVG) was carried out subsequently. 123I-BMIPP myocardial scintigraphy was performed to obtain initial images (BMi) and delayed images at 4 hours (BMd). Scintigraphy was performed a mean of 6 days after the onset of AMI in the patients. The subjects were classified into three groups according to the scintigraphic data. Quantitative gated single photon emission computed tomography (SPECT) with 99mTc-sestamibi (MIBI) was also conducted one month and 6 months later in all the patients. Discordance was observed in 51% of the patients. Left ventricular volume based on the quantitative gated SPECT (QGS) data at one month and 6 months after myocardial scintigraphy was significantly smaller in the washout group than in the other two groups. There was no significant change in LV volume measured at 6 months as compared to that measured at one month in the washout group. Significant increases in LVEDVI and LVESVI were observed over time in the no discordance group. In the fill-in group, the LV volume at one month was significantly higher than that in the washout group, but no significant change with time was observed. During the subacute stage of myocardial infarction, discordance is often seen between initial and late BMIPP-myocardial-scintigraphic images. The presence of such discordance, and analysis of its pattern, may be useful in predicting the cardiac function in these patients during the chronic phase of this disease.     

The pathobiology of pig‐to‐primate xenotransplantation: a historical review

The immunologic barriers to successful xenotransplantation are related to the presence of natural anti‐pig antibodies in humans and non‐human primates that bind to antigens expressed on the transplanted pig organ (the most important of which is galactose‐α1,3‐galactose [Gal]), and activate the complement cascade, which results in rapid destruction of the graft, a process known as hyperacute rejection. High levels of elicited anti‐pig IgG may develop if the adaptive immune response is not prevented by adequate immunosuppressive therapy, resulting in activation and injury of the vascular endothelium. The transplantation of organs and cells from pigs that do not express the important Gal antigen (α1,3‐galactosyltransferase gene‐knockout [GTKO] pigs) and express one or more human complement‐regulatory proteins (hCRP, e.g., CD46, CD55), when combined with an effective costimulation blockade‐based immunosuppressive regimen, prevents early antibody‐mediated and cellular rejection. However, low levels of anti‐non‐Gal antibody and innate immune cells and/or platelets may initiate the development of a thrombotic microangiopathy in the graft that may be associated with a consumptive coagulopathy in the recipient. This pathogenic process is accentuated by the dysregulation of the coagulation‐anticoagulation systems between pigs and primates. The expression in GTKO/hCRP pigs of a human coagulation‐regulatory protein, for example, thrombomodulin, is increasingly being associated with prolonged pig graft survival in non‐human primates. Initial clinical trials of islet and corneal xenotransplantation are already underway, and trials of pig kidney or heart transplantation are anticipated within the next few years.     

Platelet aggregation in humans and nonhuman primates: relevance to xenotransplantation

Iwase H, Ekser B, Zhou H, Dons EM, Cooper DKC, Ezzelarab MB. Platelet aggregation in humans and nonhuman primates: relevance to xenotransplantation. Xenotransplantation 2012; 19: 233–243.. © 2012 John Wiley & Sons A/S. Abstract: Introduction: Platelet activation/aggregation plays a key role in the dysregulation of coagulation and the development of thrombotic microangiopathy in nonhuman primate recipients of pig xenografts. As a preliminary to the study of anti‐platelet therapy in vitro and in vivo, the present study aimed to compare platelet aggregation in whole blood from humans, baboons, and cynomolgus monkeys. Methods: Using “Chrono‐log” technology (two‐sample four‐channel Chrono‐log Whole Blood Aggregometer), we studied aggregation of platelets in healthy humans (n = 8), baboons (n = 5), and monkeys (n = 8). Whole blood (WB) samples were collected, and platelet aggregation was assessed using three different volumes of blood (1, 0.5, and 0.25 ml). Platelet activation was induced using collagen (at 3 and 5 μg/ml), ristocetin (at 0.5 and 1.0 mg/ml), adenosine diphosphate (ADP; at 10, 20, and 40 μm ), or thrombin (at 1 and 5 IU/ml). Inhibition of agonist‐induced platelet aggregation by heparin and low molecular weight heparin (LMWH) (at 1, 10, and 100 IU/ml) was evaluated. Results: Mean platelet counts were 222.1, 263.2, and 276.1 (×10³/μl) in humans, baboons, and monkeys, respectively. In all three species, platelet aggregation was induced by collagen, ristocetin, ADP, or thrombin in a dose‐dependent manner. A blood volume of 0.5 ml provided the most consistent results with all agonists in all three species. Dilution studies indicated that there was a significant positive correlation between platelet count and percent aggregation of platelets (P < 0.05). Collagen (3 and 5 μg/ml), ADP (10, 20, and 40 μm ), and thrombin (1 and 5 IU/ml) induced significantly greater platelet aggregation in humans than in baboons. ADP (20 and 40 μm ) and thrombin (1 and 5 IU/ml) induced significantly greater platelet aggregation in monkeys than in baboons. There was no species difference with ristocetin (0.5 or 1.0 mg/ml). In all species, thrombin (1 or 5 IU) induced greater platelet aggregation than any of the other reagents. Heparin at 1 IU/ml and LMWH at 10 IU/ml in all species almost completely abrogated thrombin‐induced platelet aggregation. Heparin at 100 IU/ml effectively inhibited platelet aggregation induced by collagen, but only partially inhibited aggregation induced by ADP or ristocetin. LMWH only partially inhibited aggregation induced by collagen, ristocetin, and ADP. Conclusions: The “Chrono‐log” technology proved to be a reliable method of evaluating platelet activation and aggregation in vitro in primates. Species differences may play a role in platelet aggregation, with the monkey being more comparable to the human than the baboon, although overall trends were similar. In all species, thrombin induced greater platelet aggregation than other agonists. Even a concentration of heparin of 1 IU/ml, which is probably the maximal concentration that is clinically‐applicable, prevented platelet aggregation induced by thrombin, but was less effective in preventing aggregation induced by collagen, ADP, or, particularly, ristocetin.     

Sarcoidosis of the ureter

We report a rare case of sarcoidosis of the ureter in a 65-year-old Japanese man. Left nephroureterectomy and regional lymph node dissection were performed under the clinical diagnosis of transitional cell carcinoma of the left ureter with lymph node metastasis. Microscopically, noncaseous epithelioid granuloma with large Langerhans cells was noted in the ureter and dissected lymph nodes. Pulmonary lesions were not found on computed tomography. The final diagnosis was sarcoidosis of the ureter. Although sarcoidosis is rare in the genitourinary tract, it should be considered in the differential diagnosis of urologic conditions.     

Expression of matrix metalloproteinases 2 and 9 and tissue inhibitors of matrix metalloproteinases 2 and 1 in the glomeruli of human glomerular diseases: the results of studies using immunofluorescence, in situ hybridization, and immunoelectron microscopy

Background

It has been reported matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), play important roles in the decomposition of the extracellular matrices of the glomerulus during the pathological processes in various glomerular diseases. Although the activity of these enzymes in cases of experimental glomerulonephritis has been described, the expression sites in the glomeruli of human renal diseases have been identified in only a few articles and remain controversial.

Methods

The expression of the gelatinase group of MMPs (MMP-2 and MMP-9) and their inhibitors (TIMP-2 and TIMP-1) were evaluated in 19 renal biopsies of several types of glomerular diseases by immunofluorescence (IF) labeling. In addition, several samples of immunoglobulin A nephropathy (IgAN) were also investigated by in situ hybridization (ISH) and immunoelectron microscopy (IEM).

Results

The expression of MMP-2 was observed in all the cases examined by IF and ISH. TIMP-2 expression varied from negative to positive among 11 cases of IgAN, but was negative in the cases with lupus nephritis (LN) (n?=?3), membranoproliferative glomerulonephritis (MPGN) (n?=?2), and post-streptococcal glomerulonephritis (n?=?1). However, it was weakly positive in the cases of diabetic nephropathy (DMN) (n?=?2). MMP-2 was mainly observed along glomerular capillary loops (GCLs) and Bowman??s capsules, whereas TIMP-2 was found in the mesangial area. The expression of MMP-9 in cases of IgAN varied, and was local, not diffuse, if it was present. MMP-9 expression in cases of LN, MPGN, and DMN was diffuse, but the intensity of staining varied. MMP-9 was primarily expressed in the mesangium. TIMP-1 expression was negative in all cases except for those with IgAN. The localization of MMP-2 in patients with IgAN, which was investigated by IEM, was revealed to be mainly on the endothelial cell membranes of GCLs, podocyte membranes, the parietal cell membranes of Bowman??s capsules, and some on the membranes of mesangial cells.

Conclusion

The study results suggest that the expression levels and patterns of MMPs and TIMPs are generally similar in several types of glomerular diseases, even though each case has a somewhat different distribution and intensity of expression. When these enzymes were present, their main sites were as follows: MMP-2 was found along glomerular basement membrane, TIMP-2 was located in the acellular mesangial area, MMP-9 was seen in the mesangium, and TIMP-1 was hardly detected. MMP-2 expression is clearly demonstrated to exist at the above-described sites by IEM in patients with IgAN.     

Subgroup analysis of Japanese patients in a phase 3 study of lenvatinib in radioiodine‐refractory differentiated thyroid cancer

Lenvatinib significantly prolonged progression‐free survival (PFS) versus placebo in patients with radioiodine‐refractory differentiated thyroid cancer (RR‐DTC) in the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. This subanalysis evaluated the efficacy and safety of lenvatinib in Japanese patients who participated in SELECT. Outcomes for Japanese patients (lenvatinib, n = 30; placebo, n = 10) were assessed in relationship to the SELECT population (lenvatinib, n = 261; placebo, n = 131). The primary endpoint was PFS; secondary endpoints included overall survival, overall response rate, and safety. Lenvatinib PFS benefit was shown in Japanese patients (median PFS: lenvatinib, 16.5 months; placebo, 3.7 months), although significance was not reached, presumably due to sample size (hazard ratio, 0.39; 95% confidence interval, 0.10–1.57; P = 0.067). Overall response rates were 63.3% and 0% for lenvatinib and placebo, respectively. No significant difference was found in overall survival. The lenvatinib safety profile was similar between the Japanese and overall SELECT population, except for higher incidences of hypertension (any grade: Japanese, 87%; overall, 68%; grade ≥3: Japanese, 80%; overall, 42%), palmar–plantar erythrodysesthesia syndrome (any grade: Japanese, 70%; overall, 32%; grade ≥3: Japanese, 3%; overall, 3%), and proteinuria (any grade: Japanese, 63%; overall, 31%; grade ≥3: Japanese, 20%; overall, 10%). Japanese patients had more dose reductions (Japanese, 90%; overall, 67.8%), but fewer discontinuations due to adverse events (Japanese, 3.3%; overall, 14.2%). There was no difference in lenvatinib exposure between the Japanese and overall SELECT populations after adjusting for body weight. In Japanese patients with radioiodine‐refractory differentiated thyroid cancer, lenvatinib showed similar clinical outcomes to the overall SELECT population. Some differences in adverse event frequencies and dose modifications were observed. Clinical trial registration no.: NCT01321554.     

Angiotensin II Dose-Dependently Stimulates Human Renal Proximal Tubule Transport by the Nitric Oxide/Guanosine 3′,5′-Cyclic Monophosphate Pathway

Stimulation of renal proximal tubule (PT) transport by angiotensin II (Ang II) is critical for regulation of BP. Notably, in rats, mice, and rabbits, the regulation of PT sodium transport by Ang II is biphasic: transport is stimulated by picomolar to nanomolar concentrations of Ang II but inhibited by nanomolar to micromolar concentrations of Ang II. However, little is known about the effects of Ang II on human PT transport. By functional analysis with isolated PTs obtained from nephrectomy surgery, we found that Ang II induces a dose-dependent profound stimulation of human PT transport by type 1 Ang II receptor (AT₁)-dependent phosphorylation of extracellular signal-regulated kinase (ERK). In PTs of wild-type mice, the nitric oxide (NO) /cGMP/cGMP-dependent kinase II (cGKII) pathway mediated the inhibitory effect of Ang II. In PTs of cGKII-deficient mice, the inhibitory effect of Ang II was lost, but activation of the NO/cGMP pathway failed to phosphorylate ERK. Conversely, in human PTs, the NO/cGMP pathway mediated the stimulatory effect of Ang II by phosphorylating ERK independently of cGKII. These contrasting responses to the NO/cGMP pathway may largely explain the different modes of PT transport regulation by Ang II, and the unopposed marked stimulation of PT transport by high intrarenal concentrations of Ang II may be an important factor in the pathogenesis of human hypertension. Additionally, the previously unrecognized stimulatory effect of the NO/cGMP pathway on PT transport may represent a human-specific therapeutic target in hypertension.Among the several regulatory systems for BP, the renin-angiotensin system (RAS) plays a key role. Angiotensin II (Ang II) can regulate BP by type 1 (AT₁) Ang II receptors in either the kidney or the extrarenal tissues. Using a kidney cross-transplantation strategy, Crowley et al.¹ revealed that AT_1A in the kidney is critical for the pathogenesis of Ang II-mediated hypertension and its cardiovascular complications. Crowley et al.¹ also showed that genetic abrogation AT_1A in renal proximal tubules (PTs) alone is sufficient to reduce BP and provide substantial protection against Ang II–induced hypertension in mice, suggesting that the stimulation of PT sodium transport by Ang II has a major impact on BP regulation.²Paradoxically, however, the regulation of PT sodium transport by Ang II is biphasic: transport is stimulated by low (picomolar to nanomolar) concentrations of Ang II, whereas it is inhibited by high (nanomolar to micromolar) concentrations of Ang II.^3,4 Notably, the concentrations of Ang II within the kidney are known to be much higher than the concentrations in plasma, although the measurement of urinary Ang II may be less valuable.^5,6 Therefore, the inhibitory effect of high concentrations of Ang II could also have some physiologic relevance to the regulation of in vivo PT transport.⁵ Ang II regulates the major PT sodium transporters the apical Na⁺/H⁺ exchanger isoform 3 (NHE3), the basolateral Na⁺-HCO₃⁻ cotransporter (NBCe1), and the basolateral Na⁺/K⁺ ATPase in the biphasic manner.^7–12 Although controversial results had been reported of the receptor subtype(s) mediating the biphasic effects of Ang II,^13,14 the studies using isolated PTs obtained from AT_1A knockout (KO) mice have established that AT_1A mediates both the stimulatory and inhibitory effects of Ang II.^11,15 The stimulation by Ang II has been attributed to the activation of protein kinase C and/or the decrease in the intracellular cAMP concentration, resulting in the activation of extracellular signal-regulated kinase (ERK) pathway.^16–18 However, the inhibition by Ang II has been attributed to the activation of the phospholipase A₂/arachidonic acid/5,6-epoxyeicosatrienoic acid (EET) pathway and/or the nitric oxide (NO)/guanosine 3′,5′-cyclic monophosphate (cGMP) pathway.^7,12,17,19 Although the biphasic regulation of PT transport by Ang II has been reported in several species, such as rats, mice, and rabbits,^3,4,15 whether Ang II has similar biphasic effects on human PT transport remains unknown. Moreover, the signaling mechanisms mediating the Ang II actions on human kidney have not been clarified at all.To clarify these issues, we examined the effects of Ang II on isolated human PTs obtained from nephrectomy surgery. Unexpectedly, our findings revealed that Ang II, unlike in the other species, dose-dependently stimulates human PT transport. The different modes of transport regulation by Ang II can be largely explained by the contrasting roles of the NO/cGMP pathway, which as a downstream mediator of Ang II signaling in PTs, is stimulatory in human subjects but inhibitory in the other species. The unopposed marked stimulation of PT transport by the high local concentrations of Ang II may be an important factor in the pathogenesis of human hypertension. Furthermore, the stimulatory effect of the NO/cGMP pathway on human PT transport may represent a previously unrecognized therapeutic target of hypertension.     

Recurrent,Spontaneous Esophageal Ruptures Associated With Antiphospholipid Antibody Syndrome: Report of a Case

A 52-year-old man was admitted to our hospital with a spontaneous esophageal rupture (Boerhaave syndrome) and was successfully treated. Eight years after the first incident, he was readmitted with a recurrent rupture. Recurrence of Boerhaave syndrome is extremely rare, with only 7 cases reported in the English literature. During treatment, the patient was also diagnosed with antiphospholipid syndrome (APS). Although APS is known to cause a variety of symptoms due to vascular thrombosis, recurrence of Boerhaave syndrome, coincident with APS, has never been reported. The pathogenesis of Boerhaave syndrome has not been clearly determined. This report serves to increase awareness of the risk of APS, which results in an increased risk of spontaneous rupture of the esophagus.Key words: Boerhaave syndrome, Esophageal rupture, Antiphospholipid syndromeSpontaneous rupture of the esophagus (Boerhaave syndrome) is a relatively rare entity among digestive tract emergencies.¹ Because Boerhaave syndrome has a high rate of mortality, few reports describe the late complications of the syndrome. Further, recurrence of the syndrome is extremely rare, with only 7 cases having been reported in the English literature.^2–7 In addition, the pathophysiologic mechanisms responsible for Boerhaave syndrome have not been clearly determined.Antiphospholipid syndrome (APS) is a type of autoimmune syndrome and is known to cause a variety of complications, which are primarily caused by vascular disorders. In the present report we describe a case of recurrent Boerhaave syndrome associated with APS, and we discuss the pathogenesis of spontaneous esophageal ruptures.     

Intrahepatic Biliary Dilatation Caused by a Small Simple Hepatic Cyst: Report of a Case

Biliary obstruction caused by small simple cysts is very rare. We present a case of biliary dilatation caused by a simple cyst with a 4-cm diameter. The patient was a 75-year-old woman referred to our hospital for evaluation of a cystic tumor associated with peripheral biliary duct dilatation in the left segment of the liver. Computed tomography and magnetic resonance imaging showed that the cyst probably communicated with the intrahepatic bile duct. Malignant tumors, including intrahepatic papillary neoplasms of the bile duct, could not be ruled out; therefore, we performed surgery with the patient''s consent. Histopathologic examination of the resected liver showed that the cystic lesion was a simple cyst. The finding that even small simple cysts can obstruct the biliary tract is important for the management of cystic lesions of the liver.Key words: Hepatic cyst, Biliary obstruction, Biliary dilatationSimple cysts of the liver are usually asymptomatic. However, if the cyst is large, patients may experience abdominal bloating or a dull pain in the upper quadrant of the abdomen. Biliary obstruction caused by a simple cyst is very rare,^1–4 and dilatation of the intrahepatic bile duct in association with tumor lesions usually indicates malignancy.^4–6 With the development of computed tomography and magnetic resonance imaging, it is now possible to accurately differentiate between benign cysts and malignant neoplasms, including intraductal papillary neoplasms of the bile duct. However, it remains difficult to correctly establish the diagnosis preoperatively for all patients with cystic lesions of the liver. In this report, we present a case of intrahepatic bile duct dilatation caused by a small simple cyst and discuss the management of cystic lesions of the liver.