Reversal Of Diabetic Nephropathy Research Articles

Reversal of Diabetic Nephropathy with Intensive Lifestyle Intervention: A Case Report

Background: Diabetic nephropathy is a leading cause of chronic kidney disease, and early intervention is very important to prevent the progression of the disease .Case Presentation: A 45-year-old male patient who is a known case of type 2 diabetes mellitus from 10 years and nephropathy from 1 year underwent intensive lifestyle modification, including caloric restriction, high-intensity interval training, and stress management, alongside medication. Results: After 6 months of following the advice , significant improvements were observed:HbA1c decreased from 10.5% to 6.5%, eGFR increased from 45 to 60 ml/min/1.73m, proteinuria reduced from 2.5 to 0.5 g/day, and blood pressure normalized. Conclusion: This case demonstrates the potential for intensive lifestyle intervention to reverse diabetic nephropathy, highlighting the importance of a multidisciplinary approach in managing diabetes and preventing renal complications.

β2-Adrenergic receptor agonists as a treatment for diabetic kidney disease.

We have previously shown that the long-acting β2-adrenergic receptor (β2-AR) agonist formoterol induced recovery from acute kidney injury in mice. To determine whether formoterol protected against diabetic nephropathy, the most common cause of end-stage kidney disease (ESKD), we used a high-fat diet (HFD), a murine type 2 diabetes model, and streptozotocin, a murine type 1 diabetes model. Following formoterol treatment, there was a marked recovery from and reversal of diabetic nephropathy in HFD mice compared with those treated with vehicle alone at the ultrastructural, histological, and functional levels. Similar results were seen after formoterol treatment in mice receiving streptozotocin. To investigate effects in humans, we performed a competing risk regression analysis with death as a competing risk to examine the association between Veterans with chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), who use β2-AR agonists, and Veterans with CKD but no COPD, and progression to ESKD in a large national cohort of Veterans with stage 4 CKD between 2011 and 2013. Veterans were followed until 2016 or death. ESKD was defined as the initiation of dialysis and/or receipt of kidney transplant. We found that COPD was associated with a 25.6% reduction in progression from stage 4 CKD to ESKD compared with no COPD after adjusting for age, diabetes, sex, race-ethnicity, comorbidities, and medication use. Sensitivity analysis showed a 33.2% reduction in ESKD in Veterans with COPD taking long-acting formoterol and a 20.8% reduction in ESKD in Veterans taking other β2-AR agonists compared with those with no COPD. These data indicate that β2-AR agonists, especially formoterol, could be a treatment for diabetic nephropathy and perhaps other forms of CKD.NEW & NOTEWORTHY Diabetic nephropathy is the most common cause of ESKD. Formoterol, a long-acting β2-adrenergic receptor (β2-AR) agonist, reversed diabetic nephropathy in murine models of type 1 and 2 diabetes. In humans, there was an association with protection from progression of CKD in patients with COPD, by means of β2-AR agonist intake, compared with those without COPD. These data indicate that β2-AR agonists, especially formoterol, could be a new treatment for diabetic nephropathy and other forms of CKD.

480-P: Reversal of Diabetic Nephropathy in T2D db/db Mouse Model by Systemic Pyruvate Kinase M2 (PKM2) Activation

Mitochondrial abnormalities induced by diabetes have been postulated to cause several complications including nephropathy. Elevated expressions of enzymes for glycolysis and mitochondrial functions in the glomeruli have been associated with protection against the development of diabetic nephropathy of chronic duration. Activation of a glycolytic enzyme, pyruvate kinase M2 (PKM2), by a small molecule selective activator (TEPP-46) or its targeted overexpression to the podocytes in mice reversed glomerular mitochondrial dysfunction and pathology in insulin deficient diabetic mice. However, the effects of PKM2 activation to stop glomerular dysfunction and pathology have not been studied in animal models of type 2 diabetes (T2D). Thus, we studied the effect of activating glycolysis and mitochondrial metabolism with PKM2 activator, TEPP-46, in db/db mice (with obesity and hyperglycemia) and BLKS mice on regular diet (RD) or high fat diet (HFD). HFD feeding induced obesity in BLKS but did not cause changes in glomerular PKM activities or functions as measured by urinary albumin to creatinine ratio (ACR). Oral feeding with TEPP-46 did not affect body weight (BW), glucose tolerance, lipids, ACR, glomerular pathology in BLKS mice on RD or HFD. In contrast, db/db mice on RD had elevated BW and hyperglycemia that were significantly increased by HFD, which also induced loss of glomerular PKM2 protein expression and activities, elevations of gene expression for fibrosis (fibronectin, TGF-b), mesangial expansion and ACR after 3 months. Intervention with oral TEPP-46 treatment for 3 months, but not 1 month, after 3 months of diabetes and HFD, (total of 6 months of diabetes), improved significantly both glomerular PK activities and ACR, without lowering hyperglycemia and hyperlipidemia of the db/db mice. These findings support the idea that systemic activation of PKM2 can improve renal functions in both T1D and T2D. Disclosure R. St-Louis: None. J. Fu: None. K. Park: None. T. Shinjo: None. J. Ludeke: None. H. Yokomizo: None. Q. Li: None. E. Wolfson: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.

Effect of the Diabetic State on Islet Engraftment and Function in a Large Animal Model of Islet–Kidney Transplantation

In islet transplantation, in addition to immunologic and ischemic factors, the diabetic/hyperglycemic state of the recipient has been proposed, although not yet validated, as a possible cause of islet toxicity, contributing to islet loss during the engraftment period. Using a miniature swine model of islet transplantation, we have now assessed the effect of a persistent state of hyperglycemia on islet engraftment and subsequent function. An islet–kidney (IK) model previously described by our laboratory was utilized. Three experimental donor animals underwent total pancreatectomy and autologous islet transplantation underneath the renal capsule to prepare an IK at a load of ≤1,000 islet equivalents (IE)/kg donor weight, leading to a chronic diabetic state during the engraftment period (fasting blood glucose >250 mg/dL). Three control donor animals underwent partial pancreatectomy (sufficient to maintain normoglycemia during islet engraftment period) and IK preparation. As in vivo functional readout for islet engraftment, the IKs were transplanted across an immunologic minor or class I mismatch barrier into diabetic, nephrectomized recipients at an islet load of ∼4,500 IE/kg recipient weight. A 12-d course of cyclosporine was administered for tolerance induction. All experimental donors became diabetic and showed signs of end organ injury, while control donors maintained normoglycemia. All recipients of IK from both experimental and control donors achieved glycemic control over long-term follow-up, with reversal of diabetic nephropathy and with similar glucose tolerance tests. In this preclinical, large animal model, neither islet engraftment nor subsequent long-term islet function after transplantation appear to be affected by the diabetic state.

The phenotypes of podocytes and parietal epithelial cells may overlap in diabetic nephropathy

Reversal of diabetic nephropathy (DN) has been achieved in humans and mice, but only rarely and under special circumstances. Since progression of DN is related to podocyte loss, reversal of DN requires restoration of podocytes. Here we identified and quantified potential glomerular progenitor cells that could be a source for restored podocytes. DN was identified in 31 human renal biopsy cases and separated into morphologically early or advanced lesions. Markers of podocytes (WT-1, p57), parietal epithelial cells (claudin-1) and cell proliferation (Ki-67) were identified by immunohistochemistry. Podocyte density was progressively reduced with DN. Cells marking as podocytes (p57) were present infrequently on Bowman's capsule in controls, but significantly increased in histologically early DN. Ki-67 expressing cells were identified on the glomerular tuft and Bowman's capsule in DN, but rarely in controls. Cells marking as PECs were present on the glomerular tuft, particularly in morphologically advanced DN. These findings show evidence of phenotypic plasticity in podocyte and PEC populations and are consistent with studies in the BTBR ob/ob murine model in which reversibility of DN occurs with podocytes potentially regenerating from PEC precursors. Thus, our findings support, but do not prove, that podocytes may regenerate from PEC progenitors in human DN. If so, progression of DN may represent a modifiable net balance between podocyte loss and regeneration.

Reversibility of diabetic nephropathy in a mouse model

Reversibility of diabetic nephropathy in a mouse model

Renal function in recipients of pancreas transplant alone

Pancreas transplant alone (PTA) has become an accepted therapy for selected nonuremic patients with type 1 diabetes mellitus. We report a literature review, as well as data from the McGill University pancreas transplant program. The published literature suggests that there is reversibility of diabetic nephropathy when normoglycemia is maintained for 5-10 years after successful PTA. There is also evidence of development and progression of histological lesions compatible with calcineurin inhibitor nephrotoxicity, as well as a decline in renal function overtime, with an increased risk of end-stage renal disease (ESRD). We studied 43 patients with PTA. Nine patients had a pretransplant estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m, and 34 patients had an eGFR greater than 60 ml/min/1.73 m. The actuarial incidence of ESRD at 1, 3 and 5 years was 0, 28.57 and 61.9% in patients with pretransplant eGFR less than 60 ml/min/1.73 m, and 0, 8.2 and 12.5% in patients with pretransplant eGFR greater than 60 ml/min/1.73 m, respectively (P=0.006). Multivariate analysis confirmed that age, sex, duration of diabetes prior to PTA and eGFR pretransplant were significant predictors of ESRD. The ideal management of candidates for PTA with eGFR less than 60 ml/min/1.73 m remains to be determined. Future studies should focus on determining potentially reversible predictive factors of progression to ESRD after PTA, as well as the outcomes of these patients on chronic dialysis.

Reversal of diabetic nephropathy: lessons from pancreas transplantation

Pancreas transplantation is the only therapeutic intervention able to achieve and maintain long-term euglycemia, without risks of hypoglycemia; this makes it possible to test the impact of normoglycemia in the different stages of diabetic nephropathy. Pancreas and islet transplantation in animal models prevent the development of diabetic nephropathy lesions and ameliorate or reverse established glomerular lesions. In type 1 diabetic patients, pancreas transplantation, performed simultaneously or after kidney transplantation, has been shown to prevent the recurrence of diabetic glomerulopathy lesions. The established lesions of diabetic nephropathy have been considered to be irreversible; pancreas transplantation alone allows us to test whether this is true. To this end, we studied renal structure before and 5 and 10 years after pancreas transplantation in 8 nonuremic type 1 diabetic patients. These patients, with a long diabetes duration, had established diabetic nephropathy lesions at the time of transplantation. We report that diabetic glomerulopathy lesions, unchanged at 5 years post pancreas transplantation, significantly improved after 10 years, with complete normalization of glomerular structure in most patients. Thus this study demonstrates that the lesions of diabetic nephropathy are reversed by long-term normoglycemia and that the human kidney has the potential in humans to obtain a substantial architectural remodeling of the glomerular and tubular structures toward healing.

Reversal of Diabetic Nephropathy by a Ketogenic Diet

Intensive insulin therapy and protein restriction delay the development of nephropathy in a variety of conditions, but few interventions are known to reverse nephropathy. Having recently observed that the ketone 3-beta-hydroxybutyric acid (3-OHB) reduces molecular responses to glucose, we hypothesized that a ketogenic diet, which produces prolonged elevation of 3-OHB, may reverse pathological processes caused by diabetes. To address this hypothesis, we assessed if prolonged maintenance on a ketogenic diet would reverse nephropathy produced by diabetes. In mouse models for both Type 1 (Akita) and Type 2 (db/db) diabetes, diabetic nephropathy (as indicated by albuminuria) was allowed to develop, then half the mice were switched to a ketogenic diet. After 8 weeks on the diet, mice were sacrificed to assess gene expression and histology. Diabetic nephropathy, as indicated by albumin/creatinine ratios as well as expression of stress-induced genes, was completely reversed by 2 months maintenance on a ketogenic diet. However, histological evidence of nephropathy was only partly reversed. These studies demonstrate that diabetic nephropathy can be reversed by a relatively simple dietary intervention. Whether reduced glucose metabolism mediates the protective effects of the ketogenic diet remains to be determined.

The effects of the aqueous extract of Pterocarpus santalinus heartwood and vitamin E supplementation in streptozotocin-induced diabetic rats

Diabetic Nephropathy (DN) is a major complication of Diabetes Mellitus (MD) resulting in end-stage renal disease. Prevention or reversal of diabetic nephropathy is a major challenge in the current management of diabetes. The aim of the present study is to evaluate the hypoglycemic, antioxidant, hypolipidemic and nephroprotective effects of the aqueous extract of the Pterocarpus santalinus L (red sandalwood) alone, and in combination with vitamin E (α-tocopherol) supplementation in streptozotocin-induced diabetic rats. Twenty five healthy adult male Wistar rats were made diabetic by STZ-induction. At the end of 16 weeks of therapy, there were significant reductions in blood glucose (p<0.001), and improvements in glucose tolerance (p<0.001) as compared to untreated diabetic rats. Significant changes were also observed in lipid peroxidation (free radical activity), tissue and organ mass and cholesterol levels. The treatment caused significant lowering of blood sugar and improvement in glucose tolerance tests (p<0.001). The treatment also resulted in a significant reduction in serum lipids and body weight (p<0.001). A decrease was observed in HbA1c (p<0.01) on regular long-term control over blood glucose levels. The antioxidant effect of the red sandal wood extract was also evident, as it caused a reduction in Malondialdehyde (MDA) in the brain, liver and muscle tissues. The extract also caused a decrease in the formation of lipid peroxidase, estimated by Thiobarbituric Acid Reactive Substance (TBARS) and increased antioxidants, Superoxide Dismutase (SOD), Catalase (CAT), glutathione peroxidase and gluthathione transferase in erythrocytes with p<0.001. Serum creatinine and urine albumin showed decreased levels after treatment and returned to control values (p<0.05). The kidneys were examined histologically for diabetic nephropathy and showed regression following treatment. Sixteen weeks combination therapy also resulted in decreases in LDL-C/ HDL-C, TC (p<0.001), TG (p<0.001) and an increase in HDL-C (p<0.001) of treated diabetic rats. The use of the aqueous extract of P. santalinus caused improvements in glycemia, lipid peroxidation and brain, liver and heart tissue masses. Key words: Pterocarpus santalinus L, red sandal wood, antioxidant, diabetic nephropathy, vitamin E, Malondialdehyde, lipid peroxidation, Catalase, Thiobarbituric Acid Reactive Substance (TBARS), streptozotocin induction.

Quantitative proteomic profiling identifies new renal targets of copper(II)‐selective chelation in the reversal of diabetic nephropathy in rats

This study aimed to identify new diabetic nephropathy (DN)-related proteins and renal targets of the copper(II)-selective chelator, triethylenetetramine (TETA) in streptozotocin-diabetic rats. We used the recently developed iTRAQ technology to compare renal protein profiles among non-diabetic, diabetic, and TETA-treated diabetic rats. In diabetic kidneys, tubulointerstitial nephritis antigen (TINag), voltage-dependent anion-selective channel (VDAC) 1, and VDAC2 were up-regulated in parallel with alterations in expression of proteins with functions in oxidative stress and oxidative phosphorylation (OxPhos) pathways. By contrast, mitochondrial HSP 60, Cu/Zn-superoxide dismutase, glutathione S-transferase alpha3 and aquaporin-1 were down-regulated in diabetic kidneys. Following TETA treatment, levels of D-amino acid oxidase-1, epoxide hydrolase-1, aquaporin-1, and a number of mitochondrial proteins were normalized, with concomitant amelioration of albuminuria. Changes in levels of TINag, collagen VIalpha1, actinin 4alpha, apoptosis-inducing factor 1, cytochrome C, histone H3, VDAC1, and aquaporin-1 were confirmed by Western blotting or immunohistochemistry. Changes in expression of proteins related to tubulointerstitial function, podocyte structure, and mitochondrial apoptosis are implicated in the mechanism of DN and their reversal by TETA. These findings are consistent with the hypothesis that this new experimental therapy may be useful for treatment of DN.

Prevention and Reversal of Diabetic Nephropathy in db/db Mice Treated with Alagebrium (ALT-711)

Background: Alagebrium (ALT-711) has been shown to improve renal dysfunction in animal models of diabetes. Methods: To test its effects in diabetic nephropathy (DN), ALT-711 was administered (1 mg/kg daily i.p.) to 9-week-old female db/db mice (n = 15, group A1) for 3 weeks and to 3-month-old (n = 15, group A2), 7-month-old (n = 7, group A3), and 12-month-old (n = 5, group A4) female db/db mice for 12 weeks, while a similar number of diabetic and nondiabetic mice were used as controls. The ΕN-carboxymethyllysine (CML) levels in serum, urine, skin, and kidney tissue were measured by enzyme-linked immunosorbent assay. The renal morphometric parameters were assessed by electron and light microscopy. Results: By the 3rd week of treatment, the serum CML level decreased by 41%, and the urinary CML concentration increased by 138% from baseline, while the urinary albumin/creatinine ratio was lower (p < 0.05) in diabetic and nondiabetic group A1 mice. After 3 months of treatment, serum, skin, and kidney CML levels and urinary albumin/creatinine ratio were lower (p < 0.05) and the urinary CML levels higher (p < 0.05) in treated group A2, A3, and A4 animals compared with groups which received phosphate-buffered saline, with a similar pattern observed in nondiabetic mice. The renal morphological parameters characteristic of DN decreased in treated compared with untreated mice. Conclusion: Alagebrium may prevent, delay, and/or reverse established DN in db/db mice by reducing the systemic advanced glycation end product pools and facilitating the urinary excretion of advanced glycation end products.

Genes and diabetic nephropathy: what have we learnt so far?

Genes and diabetic nephropathy: what have we learnt so far?