Regression Of Diabetic Nephropathy Research Articles

Regression of diabetic nephropathy by treatment with empagliflozin in BTBR ob/ob mice.

The sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin lowers blood glucose via reduced tubular reabsorption of filtered glucose and is an important new therapy for diabetic nephropathy (DN). This study tested whether treatment with empagliflozin would ameliorate proteinuria and the pathologic alterations of DN including podocyte number and integrity in the leptin-deficient BTBR ob/ob mouse model of DN. Study cohorts included wild-type (WT) BTBR mice, untreated diabetic BTBR ob/ob mice and mice treated with empagliflozin for 6 weeks after development of established DN at 18 weeks of age. Hyperglycemia, proteinuria, serum creatinine, accumulation of mesangial matrix and the extent of mesangiolysis were reversed with empagliflozin treatment. Treatment with empagliflozin resulted in an increased podocyte number and podocyte density, improvement in the degree of podocyte foot process effacement and parietal epithelial cell activation. SGLT2 inhibition reduced renal oxidative stress, measured by urinary excretion of markers of RNA/DNA damage and in situ demonstration of decreased carbonyl oxidation. There was no discernable difference in accumulations of advanced glycation end-products by immunohistochemistry. The structural improvements seen in BTBR ob/ob mice treated with empagliflozin provide insights into potential long-term benefits for humans with DN, for whom there is no comparable biopsy information to identify structural changes effected by SGLT2 inhibition. The findings suggest SGLT2 inhibition may ameliorate DN through glucose lowering-dependent and -independent mechanisms that lead to podocyte restoration and delay or reversal of disease progress.

Clinical impact of albuminuria in diabetic nephropathy

Patients suffering from diabetic nephropathy, resulting in end-stage renal failure, are increasing in number. The pathophysiology of diabetic nephropathy remains to be fully investigated. In the clinical setting, the presence of albuminuria/overt proteinuria and a low glomerular filtration rate may predict poor renal prognosis, but the prognosis of the normoalbuminuric renally insufficient diabetic patient remains controversial. In addition to the measurement of urinary albumin excretion, biomarker studies to detect diabetic nephropathy more specifically at the early stage have been performed worldwide. There is a growing body of evidence for remission and/or regression of diabetic nephropathy, which may be an indicator for cardiovascular and renal risk reduction. Deeper insights into the pathological characteristics as well as the clinical impact of albuminuria on renal and cardiovascular outcome are required.

Bone Marrow Transplantation Induces Normoglycemia in a Type 2 Diabetes Mellitus Murine Model

To study the cellular mechanisms involved in the regression of diabetic nephropathy, bone marrow-derived cells must be identified. The aim of this study was to obtain a diabetic chimeric model with bone marrow cells expressing enhanced green fluorecence protein (EGFP), without modifying the course of diabetic nephropathy. Bone marrow transplantation (BMT) was performed in an obese type 2 diabetic murine model (db/db) owing to a mutation in the leptin receptor gene. Whole bone marrow from female donor C57BL/6 EGFP+ mice was transplanted into 8-week-old C57BL/6 mice and into 8- and 24-week-old female C57BLKS (db/db) EGFP- mice. Recipient mice received total body irradiation (TBI) followed by bone marrow (BM) cell infusion. We tested various irradiation doses (Gy) and numbers of BM cells. When a low TBI dose and a small number of BM cells were administered, only syngeneic C57BL/6 mice became chimeric, whereas allogeneic db/db mice showed rejection. When Gy dose and BM cells were increased, db/db mice became chimeric. However, 8-week-old db/db mice lost the obese phenotype and became normoglycemic, probably due to peripheral BM cell infiltration. Conversely, 24-week-old db/db mice remained obese showing similar blood glucose values, body weights, albuminuria, and glomerular lesions at nontransplanted db/db mice. Recipient age greatly influenced the peripheral repopulation after BMT in db/db mice. Only the adult chimeric db/db mice seemed to be a good model to study the cellular mechanisms involved in the regression of diabetic nephropathy.

New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology

Although debated for many years whether haemodynamic or structural changes are more important in the development of diabetic nephropathy, it is now clear that these processes are interwoven and present two sides of one coin. On a molecular level, hyperglycaemia and proteins altered by high blood glucose such as Amadori products and advanced glycation end-products (AGEs) are key players in the development of diabetic nephropathy. Recent evidence suggests that an increase in reactive oxygen species (ROS) formation induced by high glucose-mediated activation of the mitochondrial electron-transport chain is an early event in the development of diabetic complications. A variety of growth factors and cytokines are then induced through complex signal transduction pathways involving protein kinase C, mitogen-activated protein kinases, and the transcription factor NF-kappaB. High glucose, AGEs, and ROS act in concert to induce growth factors and cytokines. Particularly, TGF-beta is important in the development of renal hypertrophy and accumulation of extracellular matrix components. Activation of the renin-angiotensin system by high glucose, mechanical stress, and proteinuria with an increase in local formation of angiotensin II (ANG II) causes many of the pathophysiological changes associated with diabetic nephropathy. In fact, it has been shown that angiotensin II is involved in almost every pathophysiological process implicated in the development of diabetic nephropathy (haemodynamic changes, hypertrophy, extracellular matrix accumulation, growth factor/cytokine induction, ROS formation, podocyte damage, proteinuria, interstitial inflammation). Consequently, blocking these deleterious effects of ANG II is an essential part of every therapeutic regiment to prevent and treat diabetic nephropathy. Recent evidence suggests that regression of diabetic nephropathy could be achieved under certain circumstances.

Prevention and reversal of renal injury by leptin in a new mouse model of diabetic nephropathy

Diabetic nephropathy is the leading cause of end-stage renal disease, for which effective therapy to prevent the progression at advanced stages remains to be established. There is also a long debate whether diabetic glomerular injury is reversible or not. Lipoatrophic diabetes, a syndrome caused by paucity of adipose tissue, is characterized by severe insulin resistance, dyslipidemia, and fatty liver. Here, we show that a genetic model of lipoatrophic diabetes (A-ZIP/F-1 mice) manifests a typical renal injury observed in human diabetic nephropathy that is associated with glomerular hypertrophy, diffuse and pronounced mesangial widening, accumulation of extracellular matrix proteins, podocyte damage, and overt proteinuria. By crossing A-ZIP/F-1 mice with transgenic mice overexpressing an adipocyte-derived hormone leptin, we also reveal that leptin completely prevents the development of hyperglycemia and nephropathy in A-ZIP/F-1 mice. Furthermore, continuous leptin administration to A-ZIP/F-1 mice by minipump beginning at 40 weeks of age significantly alleviates the glomerular injury and proteinuria. These findings demonstrate the therapeutic usefulness of leptin at least for a certain type of diabetic nephropathy. The model presented here will serve as a novel tool to analyze the molecular mechanism underlying not only the progression but also the regression of diabetic nephropathy.

Remission and regression of diabetic nephropathy.

Diabetic kidney disease is considered to be an irreversible and inexorable progressive disease. Therefore, prevention of development of ESRD is extremely important. Animal studies have demonstrated that regression of existing renal morphologic lesions is feasible. In a sizable fraction of type 1 diabetic patients with overt nephropathy, remission (decrease in albuminuria to <300 mg/24 h) was obtained (31%), and regression of diabetic nephropathy (rate of decline in GFR < or = 1 mL/min/y), achieved (22%) by aggressive antihypertensive treatment. Furthermore, remission of nephrotic-range albuminuria (from >2500 mg/24 h to <600 mg/24 h) have been demonstrated to be achievable in one fifth of patients with nephrotic-range albuminuria. Remission of nephrotic-range albuminuria was associated with a reduction in decline in GFR and improved survival free of ESRD. However, to prevent development of ESRD in diabetic patients, an aggressive multifactorial approach, aiming at lowering blood pressure and albuminuria, and improving glycemic control, must be applied.

Remission and regression of diabetic nephropathy.

Diabetic nephropathy has become the single largest cause of end-stage renal disease (ESRD) worldwide. Until recently, it was thought that once a patient developed overt proteinuria, diabetic nephropathy was irreversible and inevitably progressed to ESRD. However, the reversal of lesions caused by diabetic nephropathy (e.g., glomerular basement membrane thickening and mesangial matrix increase) has been demonstrated in a series of patients who underwent a pancreas transplantation 10 years prior to the reversal. Remission of nephrotic range proteinuria has also been reported in some patients with type 1 diabetes from the Collaborative Study Group during a median follow-up of 3 years of angiotensin-converting enzyme (ACE) inhibitor administration; no deterioration of renal function was observed in these patients. Remission and regression in nephropathy of type 1 diabetes patients have also been reported when blood pressure was controlled aggressively. Recent clinical trials have demonstrated that angiotensin II receptor blocker (ARB) preserved renal function and slowed the progression of nephropathy to ESRD in patients with type 2 diabetes. Since many patients with type 2 diabetes manifest with a metabolic syndrome, multifactorial intensive treatment is necessary; such treatment includes behavior modifications, dietary intervention, exercise, and smoking cessation. In this population, pharmacological therapy targeting hyperglycemia, hypertension (including ARB/ACE inhibitor), and hyperlipidemia in cases of type 2 diabetes is also necessary.

Recent progress in the treatment of diabetic nephropathy: Importance of strict glycemic control on the regression of diabetic nephropathy

Recent progress in the treatment of diabetic nephropathy: Importance of strict glycemic control on the regression of diabetic nephropathy

One hundred pancreas transplants at a single institution.

Clinical pancreas transplantation at the University of Minnesota began in 1966. An initial series of 14 whole pancreas grafts was reported in part to the American Surgical Association in 1970. Only one patient survived for more than 1 year with a functioning graft. Twenty attempts at islet allotransplantation in the mid-1970s were unsuccessful. In 1978 we resumed performing pancreas transplants by the segmental technique, allowing the use of related donors. The current series (July 25, 1978 to December 20, 1983) includes 86 pancreas transplants (51 cadaver, 35 related) in 75 patients (41 with and 34 without previous kidney grafts). Variations in management of the pancreatic duct include three ligated, 15 duct-open, 39 duct-injected, and 29 pancreaticojejunostomies. The latter technique is currently preferred. Currently (April 1984) 61 patients are alive (81%), 24 have functioning grafts (32%), and 21 are insulin-independent (28%), three with open-duct grafts for 4.4 to 5.7 years, seven with silicone-injected grafts from 10 to 39 months, and 14 with pancreaticojejunostomies for 3 to 31 months; 15 of the grafts have functioned for greater than 1 year. Twenty-two of the grafts (25%) failed for technical reasons (thrombosis, infection, or ascites); 35 grafts functioned for 1 to 13 months before totally failing from either rejection, fibrosis, or recurrent disease; five patients died with functioning grafts. The graft survival rate has been higher for pancreases from related (15/35, 43% functioning) than from cadaver (9/51, 18% functioning) donors. The success rate has increased, e.g., 11/22 recipients of pancreas transplants in 1983 currently have functioning grafts (50%). Metabolic studies show most patients with functioning grafts to be euglycemic; however, three of 24 have chronic hyperglycemia unless supplemented with insulin, but they are no longer ketosis-prone. Glucose tolerance test results are normal or nearly normal in 12 and abnormal in 12 of the recipients with currently functioning grafts. Regression of diabetic nephropathy has been documented in two long-term recipients. Pancreas transplantation is currently applicable as treatment for selected diabetics who have demonstrated their propensity to develop serious secondary complications.