Naobumi Mise

Diverse Effects of Increasing Lisinopril Doses on Lipid Abnormalities in Chronic Nephropathies

Background—Dyslipidemia frequently complicates chronic nephropathies and increases the risk of renal and cardiovascular events. This might be ameliorated by drugs, such as angiotensin-converting enzyme inhibitors, which effectively reduce proteinuria. Methods and Results—In this longitudinal study, we evaluated the extent to which uptitration of the ACE inhibitor lisinopril to maximum tolerated doses (median [range]: 30 [10 to 40] mg/d) ameliorated proteinuria and dyslipidemia in 28 patients with nondiabetic chronic nephropathies. Maximum lisinopril doses significantly and safely reduced proteinuria, serum total, LDL cholesterol, and triglycerides without substantially affecting serum HDL and renal hemodynamics. Proteinuria already decreased at 10 mg/d. Serum lipids progressively and dose-dependently decreased during uptitration to maximum doses. Reduction in total and LDL cholesterol correlated with increases in serum albumin/total protein concentration and oncotic pressure, peaked at lisinopril maximum doses, and persisted after treatment withdrawal. Despite less proteinuria reduction, hypercholesterolemia decreased more (and reflected the increase in serum albumin) in hypoalbuminemic than in normoalbuminemic patients who, despite more proteinuria reduction, had less decrease in cholesterol and no changes in serum albumin. Changes in serum triglycerides were independent of changes in serum proteins, were strongly correlated with lisinopril doses (r =−0.89, P =0.003) and recovered promptly after treatment withdrawal. Lisinopril was well tolerated, did not affect renal hemodynamics, and caused symptomatic, reversible hypotension in only two patients. Conclusions—In chronic nephropathies, angiotensin converting enzyme inhibitor uptitration to maximum tolerated doses safely ameliorated hypertriglyceridemia by a direct, dose-dependent effect, and hypercholesterolemia through amelioration of the nephrotic syndrome, particularly in patients with more severe hypoalbuminemia.

Mesangial expression of a nonmuscle myosin heavy chain, SMemb, is associated with glomerular sclerosis and renal prognosis in IgA nephropathy

To characterize the phenotypic alteration in mesangial cells in human glomerulonephritis, we investigated the expression of nonmuscle-type myosin heavy chain, SMemb, and α-smooth muscle actin (α-SM actin) in IgA nephropathy. The expression of SMemb and α-SM actin was examined by immunohistochemistry in biopsy specimens from 45 patients with IgA nephropathy. We examined a total of 489 glomeruli representing all patients enrolled, and found that mesangial expression of SMemb and α-SM actin was associated with mesangial proliferation. Only mesangial expression of SMemb showed a significant relationship with mesangial matrix accumulation. Semiquantitative evaluation using composite expression scores showed that the expression of SMemb was elevated in the patients with poor renal prognosis. The expression of α-SM actin showed no significant relationship with renal prognosis. These results suggest that mesangial expression of SMemb is an important factor in the progression of IgA nephropathy, and that SMemb and α-SM actin are associated with the activation of mesangial cells by different mechanisms.

EFFECTS OF AMLODIPINE, A CALCIUM CHANNEL BLOCKER, ON RAT RENAL ARTERIOLES

The objective of this study was to investigate the effects of amlodipine, a dihydropyridine calcium channel blocker, on renal microvasculature in hypertensive rats. Hydronephrosis was induced by permanent ligation of the left ureter in 8-week-old spontaneously hypertensive rats. After the hydronephrotic left kidney was split longitudinally and spread out as a thin sheet, the renal microvasculature was observed directly under a light microscope. Administration of amlodipine 200 μg/kg caused a gradual fall in systolic blood pressure (39 mm Hg). The afferent arterioles were dilated and maintained the same level of dilation after 60 minutes (19% at 5 minutes and 21% at 60 minutes at the diameter). The efferent arterioles were similarly dilated (14% at 5 minutes and 18% at 60 minutes). The glomerular blood flow was significantly increased (28% at 5 minutes and 46% at 60 minutes). We concluded that amlodipine dilated both the afferent and efferent arterioles and increased the glomerular blood flow.

EFFECTS OF BARNIDIPINE HYDROCHLORIDE, A CALCIUM CHANNEL BLOCKER, ON RENAL MICROCIRCULATION IN RATS: A PILOT STUDY

Abstract Barnidipine hydrochloride, a dihydropyridine calcium channel blocker, increases both renal blood flow and glomerular filtration while effectively reducing blood pressure. The goal of the present study was to determine the effects of barnidipine on renal microcirculation. We used the rat in vivo split hydronephrotic kidney model to directly observe renal arterioles by light microscopy. When administered into the organ bath (ie, administered from outside of the blood vessels), 10 −7 M of barnidipine significantly dilated both afferent and efferent arterioles and increased glomerular blood flow in both normotensive and hypertensive rats. Systolic blood pressure remained unchanged. Intravenous injection of barnidipine 600 μg/kg body weight dilated afferent arterioles and increased glomerular blood flow in normotensive rats. In contrast, the same treatment in hypertensive rats caused significant sustained dilatation of both afferent and afferent arterioles and gradually reduced systolic blood pressure. Future studies are needed to determine the clinical relevance of these effects of barnidipine

Arteriovenous access closure in hemodialysis patients with refractory heart failure: a single center experience.

Arteriovenous dialysis access may impose a burden on the cardiac system. The objective of this study is to examine the usefulness of access closure in hemodialysis patients with refractory heart failure and to identify possible factors associated with symptomatic improvements. The study population comprised 33 hemodialysis patients with symptomatic heart failure (New York Heart Association [NYHA] class ≥II), who underwent arteriovenous access closure (30 fistulas and three grafts) between 1991 and 2008. In all patients, heart failure was refractory to all possible medical and surgical treatments, and persisted after optimal dry weight control. First, short‐term changes in hemodynamics, clinical symptoms and echocardiographic morphology were examined. Second, clinical and echocardiographic parameters were compared between responders (N = 23), who demonstrated NYHA class improvement after access closure, and non‐responders (N = 10). After access closure, systolic blood pressure rose and the heart rate decreased significantly. Body weight and echocardiographic parameters did not change significantly. Twenty‐three patients (70%) demonstrated NYHA class improvement and were designated as responders. In responders, the duration from access creation to closure was significantly shorter and fewer had ischemic heart disease, compared with non‐responders. Access flow, cardiac output and ejection fraction were comparable between the two groups. Although the five‐year survival was 20.2% in all patients, responders showed better early survival than non‐responders. Arteriovenous access closure improved clinical symptoms in 70% of patients with refractory heart failure. This improvement was especially likely to be achieved in patients without ischemic heart disease and those who developed heart failure within a relatively short time after access creation.

Left ventricular geometry and cardiovascular mortality based on haemodialysis patient autopsy analyses

Aim:  In end‐stage renal disease (ESRD) patients, left ventricular hypertrophy (LVH) is common and a risk for cardiovascular events. LVH is geometrically classified into two major groups, concentric and eccentric, and accumulating evidence suggests eccentric LVH has a more negative effect than concentric LVH on ESRD outcome. However, there have been very few studies on the cardiac findings from ESRD patient autopsy in which the relationship between LVH geometry and mortality was analyzed.

AA amyloid nephropathy with predominant vascular deposition in Crohns disease

A 44-year-old man with a 17-year history of Crohns disease (CD) was referred to our nephrology department on suspicion of drug-induced nephrotoxicity. Over the preceding 18 months, he had slowly progressive renal insufficiency with slight urinary abnormalities. His disease activity had been well controlled up to that point with 5-aminosalicylic acid and azathiopurine. Laboratory examination revealed slight proteinuria without hematuria and an elevated serum creatinine level of 1.4 mg/dl. Pathological examination revealed amyloid A (AA) deposition in the kidney, predominantly in the arterial and arteriolar walls with little to none in the glomerular capillaries. AA amyloidosis is typically accompanied by glomerular amyloid deposition and massive proteinuria. In the present case, however, vascular amyloid deposition was predominant, and the renal function was deteriorated with slight urinary abnormalities. The present case confirmed the importance of conducting a definitive pathological diagnosis of renal insufficiency in CD patients.

Effects of the beta-adrenoceptor blocker nipradilol on renal microcirculation in a rat model: A comparative study with propranolol

Abstract The objective of the present study was to compare the effects of the vasodilating nonselective beta-adrenoceptor blocker nipradilol on renal microvasculature with those occurring with propranolol, a typical nonselective beta-adrenoceptor blocker. Hydronephrosis was induced by ligation of the left ureter in seventeen 8-week-old stroke-prone, spontaneously hypertensive rats. The experiment was performed 2 months after the surgery. The hydronephrotic kidney was split longitudinally and spread out as a thin sheet, and the renal microvasculature was observed directly under a light microscope. Intravenous administration of nipradilol 200 μg/kg as a bolus caused a significant decrease in the systolic blood pressure (−36 mm Hg) at 5 minutes. The afferent arteriole was significantly dilated transiently (+13% in diameter) at 10 minutes. The changes in the efferent arteriole were not statistically significant. The glomerular blood flow was statistically significantly increased (+22%) at 10 minutes. Intravenous administration of propranolol 600 μg/kg did not cause statistically significant changes in the systolic blood pressure, the afferent arteriolar diameter, or the glomerular blood flow. The efferent arteriole showed a statistically significant constriction (−16% in diameter) at 20 minutes. In summary, nipradilol dilated the afferent arteriole and increased the glomerular blood flow despite a significant decrease in the systolic blood pressure. This vasodilating effect on the afferent arteriole was not observed with propranolol.

Differential Effects of the Calcium Channel Blocker Nifedipine on Renal Microcirculation: A Comparative Study Using Hydronephrotic Rats

Abstract Objective Using a rat in vivo hydronephrotic model we studied the acute and chronic effects of the short-acting calcium channel blocker nifedipine on renal microcirculation. Background Antihypertensive drugs such as angiotensin-converting enzyme (ACE) inhibitors that dilate both preglomerular afferent and postglomerular efferent arterioles are thought to have a renal protective effect; calcium channel blockers, in contrast, are thought to elevate glomerular pressure and aggravate glomerular damage. Because slow-release nifedipine has been shown to have beneficial effects on the course of glomerular disease, we hypothesized that nifedipine has differential effects on renal microcirculation, depending on its mode of action. Methods Hydronephrosis was induced by permanent ligation of the left ureter in spontaneously hypertensive rats. Under a light microscope, renal microcirculation was observed directly by spreading out the hydronephrotic kidney as a thin sheet. The effects of nifedipine or imidapril on renal microcirculation were analyzed by importing the microscopic images into a computer. Results Intravenous injection of nifedipine 10 μg/kg transiently decreased blood pressure and dilated afferent arterioles (from 14% to 19% in diameter at 10 minutes after injection). In contrast, nifedipine did not affect efferent arteriolar diameter. The ACE inhibitor imidapril 50 μg/kg was administered in the same manner for reference; it dilated both afferent and efferent arterioles in this experimental model (17% increase at 20 minutes and 12% at 10 minutes, respectively). When administered into an organ bath, nifedipine dilated both afferent (from 15% to 20% at both 10 −8 M and 10 −6 M) and efferent arterioles (15% at 10 −10 M and 20% at 10 −6 M). Conclusions These results show that when nifedipine is administered to the renal microvasculature in a stable manner, it acts on the renal microcirculation in the same fashion as do ACE inhibitors.

Warfarin-related nephropathy in a patient with renal pelvic cancer

An 83-year-old Japanese man had a history of chronic heart failure due to bradycardia-tachycardia syndrome. He was admitted to our hospital because of macrohematuria and acute kidney injury (AKI), which were detected by an urologist at an outpatient visit. He had a history of recurrent macrohematuria and transurethral resection of bladder tumors twice in the preceding 2 years. He had been on warfarin for 12 years, with a stable international normalized ratio (INR) that was usually less than 2.1. Urinalysis revealed numerous red blood cells (RBCs) and mild proteinuria without RBC casts. His serum creatinine level was elevated to 2.41 mg/dL from 0.96 mg/dL at 3 weeks before admission. INR was 1.44. Hydronephrosis was not observed. Ureteroscopy detected invasive urothelial carcinoma of the renal pelvis, and right laparoscopic nephroureterectomy was performed at 41 days after diagnosis of AKI. The background renal parenchyma displayed tubular obstruction by red blood cell casts and acute tubular injury, which were changes compatible with warfarin-related nephropathy (WRN). Warfarin was discontinued, and the serum creatinine level recovered to 1.66 mg/dL after 3 months. In the present patient with nephrosclerosis, WRN occurred at a therapeutic INR level after 12 years of uneventful warfarin therapy, and the coexisting urothelial malignancy was a unique feature.