Improvement of Renal Function in Type 2 Diabetic Nephropathy

Background. Therapeutic failure in preventing renal disease progression in type 2 diabetic nephropathy (DN) is due to a failure in the early detection of DN by microalbuminuria and the inappropriate correction of renal hemodynamic maladjustment secondary to glomerular endothelial dysfunction. Methods. Thirty patients associated with normoalbuminuric type 2 DN were subject to the following studies: tubular function by means of fractional excretion of magnesium (FE Mg), vascular function by means of determining the circulating endothelial cell, VEGF, VEGF/TGF B ratio, and intrarenal hemodynamic studies. Results. FE Mg, circulating endothelial cells, and TGF B were abnormally elevated, and VEGF/TGF B ratio was decreased in these normoalbuminuric patients. The intrarenal hemodynamic study revealed a hemodynamic maladjustment characterized by a preferential constriction at the efferent arteriole and a reduction in peritubular capillary flow. Following treatment with vasodilators, a decrease in efferent arteriolar resistance and increase in peritubular capillary flow as well as glomerular clearance were observed. Conclusion. FE Mg appears to be a more sensitive marker than microalbuminuria for the early detection of DN. Increased endothelial cell injury is reflected by enhanced circulating endothelial cell loss in conjunction with the increased TGF B and the decreased ratio between VEGF and TGF B. This is further supported by the dysfunctioning glomerular endothelium, which is characterized by hemodynamic maladjustment and a reduction in the peritubular capillary flow. A correction of such hemodynamic maladjustment by multidrug vasodilators effectively improves renal perfusion and restores renal function in type 2 DN.     

Hypotension,renal failure,and pulmonary complications in leptospirosis

During a recent outbreak of leptospirosis in northeastern Thailand, 148 patients with serologically diagnosed leptospirosis were seen in Loei hospital. The common serotypes were L. pyrogenes, and L. sejroe. Hypotension with a mean arterial pressure less than 70 mmHg upon admission or within 24 h after admission was observed in 94 patients or 64%. 30 patients had normal renal function; 30 patients had prerenal azotemia with mild pulmonary complication in 2; and 34 patients had acute renal failure. 29 patients with acute renal failure had pulmonary complications including pulmonary hemorrhage in 8, pulmonary edema in 3, acute respiratory distress syndrome (ARDS) in 14 and interstitial pneumonitis in 4. 54 patients had normal blood pressure. In this group 5 patients had acute renal failure; 16 had prerenal azotemia and 33 had normal renal function. Interstitial pneumonitis was noted in one patient with prerenal azotemia. Less renal complication and minimal pulmonary complication were seen in leptospirosis patients with normal blood pressure. The patients with normal renal function had no pulmonary complication. Good association existed between hypotension, renal failure and pulmonary complications.     

Rabies control in South and Southeast Asia

We have the knowledge and tools to eliminate the threat of canine rabies but this disease, nevertheless, remains a public health threat in many parts of the world. Lack of motivation by governments, cultural issues and inadequate funding remain barriers. This is amazing since the number of human rabies deaths worldwide is greater than that from polio, meningococcal meningitis, Japanese encephalitis, yellow fever, SARS, bird flue and other scourges that attract more attention. Safe and effective vaccines are now widely available. Reduced dose effective and less expensive post-exposure vaccination regimens have helped eliminate nerve tissue vaccines in Thailand, Philippines and Sri Lanka. India and Pakistan, the major users of dangerous nerve tissue derived Semple type vaccine, are now considering following suite. Immediate wound care and prompt use of a potent vaccine will save a majority of infected persons. Rabies immunoglobulin, injected into and around bite wounds, provides added safety for the severely exposed. The high cost of rabies immunoglobulin and tissue culture vaccines are remaining barriers, but new manufacturers and the use of intradermal vaccination schedules can reduce costs. Ultimately, it is the need to control rabies in dogs that must occupy most of our attention. The tools are available, but attitudes must change before they can be applied. There have been many new developments since publication of the last WHO rabies expert committee report in 1992 (new version in print)] and we will address those that have practical applicability.     

A lyophilized formulation to extend the shelf-life of tuberculin PPD

This study was aimed to develop a dry purified protein devirative (PPD) preparation to extend the shelf-life of tuberculin PPD. Five percent sucrose (S), 6.5% mannitol (M), 2.5% trehalose (T) or 0.3% Hemaccel (H) was added to each formulation. In vivo and in vitro analyses were carried out to determine the efficacy of the lyophilized products. In the in vivo test, the delayed type hypersensitivity (DTH) responses of the lyophilized preparations were compared to the liquid preparation (CL) after injection into BCG vaccinated guinea pigs. The preparations of H, M, T, and S generated DTH responses of 100, 90, 89, and 60%, as compared to the response of CL, respectively. There was no loss of tuberculin activity in the H formula. A statistically significant difference in activity was found between S and CL (p < 0.05). The cellular test for IFN-gamma secretions was performed using the whole blood of human subjects screened for DTH response to tuberculin PPD Mantoux tests. The detection of IFN-gamma secretions was done using ELISA and the efficacy was expressed in terms of percentage of IFN-gamma responses to the tuberculin antigens. The results of CL, H, M, T and S were 3.28, 10.40, 0.84, 1.52 and 1.29%, compared to mitogen stimulation, respectively. The lyophilized H, M and T formulations and the liquid CL were studied for their shelf-life stabiliy. Accelerated degradation was done by storing the samples at higher temperatures of 37 degrees C and 56 degrees C for 3, 6, 9 and 12 months. All the tuberculin PPD solutions were injected into BCG vaccinated guinea pigs at the end of each storage period and the activity of each solution was evaluated. The formulation with the Hemaccel as excipient gave a superior response than the others at the normal storage temperature of 40 micro C for 12 months. Therefore, Hemaccel provides protection for PPD activity. This supports the potential for the development of lyophilized tuberculin PPD with the addition of 0.3% Hemaccel to extend shelf life.     

Proteomics in nephrology: current status and future directions

Proteomics is one among various 'OMICS' fields that have been growing rapidly in the postgenomic era. During the past few years, proteomics has been extensively applied to several fields of medicine to better understand normal physiology, to define the pathophysiology of diseases, and to identify novel biomarkers and new therapeutic targets. This review focuses on current status and future directions of proteomics in the nephrology field. Recent studies of renal proteome, proteomes of individual intrarenal structures (i.e., glomerular, vascular, tubular, brush border membrane, mesangial, and podocyte proteomes), urinary proteome, and protein profiles in dialysate or ultrafiltrate removed by renal replacement therapy are summarized.     

Alterations in the renal elastin-elastase system in type 1 diabetic nephropathy identified by proteomic analysis

Diabetes now accounts for >40% of patients with ESRD. Despite significant progress in understanding diabetic nephropathy, the cellular mechanisms that lead to diabetes-induced renal damage are incompletely defined. For defining changes in protein expression that accompany diabetic nephropathy, the renal proteome of 120-d-old OVE26 transgenic mice with hypoinsulinemia, hyperglycemia, hyperlipidemia, and proteinuria were compared with those of background FVB nondiabetic mice (n = 5). Proteins derived from whole-kidney lysate were separated by two-dimensional PAGE and identified by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. Forty-one proteins from 300 visualized protein spots were differentially expressed in diabetic kidneys. Among these altered proteins, expression of monocyte/neutrophil elastase inhibitor was increased, whereas elastase IIIB was decreased, leading to the hypothesis that elastin expression would be increased in diabetic kidneys. Renal immunohistochemistry for elastin of 325-d-old FVB and OVE26 mice demonstrated marked accumulation of elastin in the macula densa, collecting ducts, and pelvicalyceal epithelia of diabetic kidneys. Elastin immunohistochemistry of human renal biopsies from patients with type 1 diabetes (n = 3) showed increased elastin expression in renal tubular cells and the interstitium but not glomeruli. These results suggest that coordinated changes in elastase inhibitor and elastase expression result in increased tubulointerstitial deposition of elastin in diabetic nephropathy. The identification of these coordinated changes in protein expression in diabetic nephropathy indicates the potential value of proteomic analysis in defining pathophysiology.