The renoprotective effect and safety of a DPP-4 inhibitor, sitagliptin, at a small dose in type 2 diabetic patients with a renal dysfunction when changed from other DPP-4 inhibitors: REAL trial.

BACKGROUND: We conducted the multicenter, prospective, open-label study in type 2 diabetic (T2DM) patients with renal dysfunction, to clarify the efficacy and the safety in relation to renal function and glycemic control, and the economic effect when other dipeptidyl peptidase-4 (DPP-4) inhibitors were switched to a small dose of sitagliptin depending on their renal function. METHODS: Vildagliptin, alogliptin, or linagliptin received for more than 2 months were changed to sitagliptin at 25 or 12.5 mg/day depending on their renal function in 49 T2DMs. Renal function and glycemic control, and the drug cost were assessed during 6 months. RESULTS: Estimated glomerular filtration rate was not changed in patients not on hemodialysis (n = 29). The HbA1c levels were not altered in all of the patients including those on hemodialysis (n = 20). The active glucagon-like peptide-1 levels or other renal parameters were not altered significantly. There were no adverse events to be related to the drugs. The daily drug expense was reduced by 88.1 yen per patient. CONCLUSION: Switching to a small dose of sitagliptin according to the renal function in T2DM patients with renal dysfunction demonstrated the same efficacy and safety as those with other full-dose DPP-4 inhibitors, indicating a therapeutic option with a high cost performance.

Decline of renal function is associated with proteinuria and systolic blood pressure in the morning in diabetic nephropathy.

The aim of this study was to investigate a significance of increased proteinuria in the morning and the effects of antihypertensive treatment on proteinuria and arterial blood pressure in the progression of chronic renal insufficiency in type 2 diabetic patients with hypertension and nephropathy. In three 24-hr urine samples and blood pressure monitoring, separated into a night-and daytime and spot urine in the morning, variation in protein-creatinine ratio (g/g) and blood pressure were assessed in 24 (58 +/- 3 years old; M/F: 17/7) diabetic patients with hypertension and nephropathy. Furthermore, the effects of antihypertensive therapy of combinations of angiotensin converting enzyme (ACE) inhibitor, calcium antagonists, diuretics, and alpha1 blocker were evaluated in 3 years. Home blood pressure measurement was carried out every month and 24-hr urine was collected every 2 months. The baseline urine excretion of protein-creatinine ratio and blood pressure were (1.22 +/- 0.13 g/g creatinine: 154/96 +/- 6/5 mmHg) in daytime and (1.39 +/- 0.13: 168/88 +/- 15/7) in the morning. At the end of the study, significant associations among a decline of 24-hr creatinine clearance and both of the urine excretion of protein-creatinine ratio (r = 0.47, p < .01) and the levels of systolic blood pressure (r = 0.46, p < .01) and between the levels of systolic blood pressure and the urine excretion of protein-creatinine ratio in the morning (r = 0.57, p < .001) were demonstrated. However, there were no significant associations among other variables. Analysis of patients who had systolic blood pressure in the morning less than 140 mmHg revealed that 65% of these patients received doxazosin-averaged doses of 4.8 +/- 1.5 mg daily. The levels of both blood pressure and proteinuria-creatinine ratio in the morning mainly associate with progression of renal function in diabetic patients with hypertension and nephropathy.

An unusual form of crystal-forming chronic interstitial nephritis following long-term exposure to tosufloxacin tosilate.

Fluoroquinolones are known to cause acute renal failure because of interstitial nephritis with or without epithelioid granulomas. We report the first case of slowly progressive renal failure caused by crystal-forming chronic interstitial nephritis with non-Langerhans' cell histiocytosis after long-term exposure to a fluoroquinolone, tosufloxacin tosilate. Lesions consisted of spindle- to cuboidal-shaped histiocytes with minimal collagenous matrix and low-level lymphocyte infiltration replacing normal tubulointerstitial structure of the kidney. Histiocytes were positive for CD68, but negative for S-100, suggesting they were derived from macrophages. There were numerous rhomboid- to needle-shaped crystal deposits in the cytoplasm of histiocytes, which showed bright birefringence under polarized light. No immunoglobulin deposits were seen in the kidney, and no evidence of paraproteinemia/lymphoproliferative diseases was identified in this patient. Despite a negative drug lymphocyte-stimulating test result using tosufloxacin tosilate, withdrawal of the drug and treatment with steroids gradually improved renal function. In this report, we describe the clinical course and histopathologic findings of this patient and discuss the possible pathogenesis.

Early start on continuous hemodialysis therapy improves survival rate in patients with acute renal failure following coronary bypass surgery.

Acute renal failure requiring dialysis therapy after cardiac surgery occurs in 1% to 5% of patients; however, the optimal timing for initiation of dialysis therapy still remains undetermined. To assess the validity of early start of dialysis therapy, we studied the comparative survival between 14 patients who started to receive dialysis therapy when urine volume decreased to less than 30 mL/hr and another group of 14 patients who waited to begin dialysis therapy until the level of urine volume was less than 20 mL/hr for 14 days following coronary bypass graft surgery. Twelve of 14 patients who received early intervention survived. In contrast, only 2 of 14 patients in the late-dialysis group survived. There was a significant difference in survival between the two groups (p < 0.01). There were no significant differences between the two groups with respect to age, sex ratio, the APACHE (Acute Physiologic and Chronic Health Evaluation) II score, and the levels of serum creatinine at the start of dialysis therapy (2.9 +/- 0.2 mg/dL vs. 3.1 +/- 0.2 mg/dL), as well as the levels of serum creatinine at admission. We propose that the timing of the start for treatment of acute renal failure following cardiac surgery should be determined by the decrease of urine volume and not the levels of serum creatinine. Early start of dialysis therapy may help improve the survival of patients with acute renal failure following cardiac surgery.

Selection of the dose of angiotensin converting enzyme inhibitor for patients with diabetic nephropathy depends on the presence or absence of left ventricular hypertrophy.

The coexistence of hypertension increases cardiovascular risks and the rate of deterioration of renal function for diabetic patients. For patients with left ventricular hypertrophy (LVH), the use of an angiotensin converting enzyme (ACE) inhibitor is known to be effective and well tolerated and to be protective against chronic renal insufficiency (CRI). However, serious adverse reactions to ACE inhibitors, such as the rapid deterioration of renal function, have been reported, making physicians hesitant to use these agents. To resolve this dilemma, we compared changes in renal function and left ventricular function and the safety and effectiveness of benazepril, an ACE inhibitor, in patients with diabetic nephropathy, with or without LVH. The age, sex, duration of diabetes, levels of blood pressure and blood glucose and rates of creatinine clearance (CrCl) were compared between 36 diabetic patients with LVH and 36 matched diabetic patients without LVH. The rates of CrCl in all patients were between 14 and 35 ml/min, and all patients received an ACE inhibitor before enrollment. The group comprised 43 men and 29 women, with a mean age of 56 +/- 4 years. These patients were divided into three groups, each of which was subdivided into a group with and a group without LVH. Group I (without LVH) or I-L (with LVH) received a half dose of benazepril (2.5 mg daily), Group II (without LVH) or II-L (with LVH) received a normal daily dose of 5 mg benazepril, and Group III (without LVH) or III-L (with LVH) discontinued the administration of the ACE inhibitor. The follow-up period was 1 year and, during the study, blood pressure was maintained at less than 140/90 mmHg. If the blood pressure control was not satisfactory, benidipine, a calcium antagonist, and/or furosemide, a loop diuretic, and/or guanabenz, a central acting antihypertensive agent, were administered. In the diabetic patients with LVH, the administration of a normal dose of benazepril inhibited the decline of renal function and cardiac function (CrCl: 24.2 +/- 1.5 to 22.0 +/- 2.5 ml/min; EF (ejection fraction): 56 +/- 3 to 54 +/- 6%) compared to the other two groups. In patients without LVH, a half dose of benazepril preserved renal function (23.4 +/- 2.6 to 22.0 +/- 3.1 ml/min; EF: 54 +/- 3 to 56 +/- 3%). Discontinuation of the administration of ACE inhibitor led to the further progression of renal dysfunction and decreases in EF in patients with or without LVH. Our results provide some indications for the use of ACE inhibitors in diabetic patients when renal dysfunction and/or cardiac hypertrophy are present.

An atypical pattern of Epstein-Barr virus infection in a case with idiopathic tubulointerstitial nephritis.

Recently, Epstein-Barr virus (EBV) received attention because a latent form of its infection in renal proximal tubular epithelial cells was found to cause idiopathic, chronic tubulointerstitial nephritis. In this report, we describe the case of a patient with a replicative form of EBV infection, chronic active EBV infection (CAEBV), who developed acute tubulointerstitial nephritis and minimal change nephrotic syndrome. A renal biopsy revealed papillary infoldings of atypical tubular epithelium and adjacent dense infiltration of lymphocytes. Using in situ polymerase chain reaction methods, we detected the EBV genome in some of the infiltrating lymphocytes, but not in the tubular epithelial cells. EBV-infected T cells are thought to activate other educated T cells, as well as secrete an unrestricted variety of cytokines, thus playing a pivotal role in CAEBV and its end organ disease. Therefore, in our case, the CAEBV activated, educated T cells may have followed the EBV-infected lymphocytes as they infiltrated into the peritubular interstitium, and promoted focal tubular epithelial atypia and minimal change nephrotic syndrome. The long-term observation of such patients is important because CAEBV may progress into lymphoproliferative diseases.

Intensive blood pressure reduction is beneficial in patients with impaired cardiac function coexisting with chronic renal insufficiency.

Both in CHF (congestive heart failure) and CRI (chronic renal insufficiency), blood pressure reduction is beneficial for preservation of cardiac and renal function. However, it is uncertain how much blood pressure reduction is appropriate in patients with both CHF and coexisting CRI. In the present study, we examined whether intensive blood pressure reduction is more beneficial in these patients than the usually accepted level of reduction. Thirty-five men and 21 women of average age 63+/-5 years suffering from both CHF and CRI were selected from 316 patients attending the Kidney Disease Center of Saitama Medical School Hospital. All participants had an ejection fraction (EF) of less than 55% as determined by echocardiography. Renal function was evaluated by 24-h creatinine clearance (GFR), and a GFR of less than 50 ml/min was regarded as indicating renal insufficiency. Patients were divided into 2 groups according to the target blood pressure: in group I, blood pressure (BP) was lowered to less than 120/75 mmHg and in group II, blood pressure was lowered to less than 130/80 but more than 121/76 mmHg. The daily doses of basic antihypertensive agents were amlodipine 5 to 20 mg, benazepril 2.5 to 5 mg, guanabenz 2 to 8 mg and furosemide 20 to 60 mg. At the end of a 2-year follow-up period, the BP in group I was controlled at the level of 118+/-4/73+/-3 mmHg with good maintenance of EF (46+/-4 to 60+/-4%) and GFR (44+/-4 to 40+/-3 ml/min). In group II, BP was maintained at 128+/-4/81+/-2 mmHg, accompanied by a reduction of EF (46+/-4 to 42+/-3%) and a significant reduction of GFR (44+/-3 to 35+/-3 ml/min). These results suggest that intensive blood pressure reduction might be beneficial in cases complicated by cardiorenal failure.