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1.  Near Normalization of Metabolic and Functional Features of the Central Nervous System in Type 1 Diabetic Patients With End-Stage Renal Disease After Kidney-Pancreas Transplantation 
Diabetes Care  2012;35(2):367-374.
The pathogenesis of brain disorders in type 1 diabetes (T1D) is multifactorial and involves the adverse effects of chronic hyperglycemia and of recurrent hypoglycemia. Kidney-pancreas (KP), but not kidney alone (KD), transplantation is associated with sustained normoglycemia, improvement in quality of life, and reduction of morbidity/mortality in diabetic patients with end-stage renal disease (ESRD).
The aim of our study was to evaluate with magnetic resonance imaging and nuclear magnetic resonance spectroscopy (1H MRS) the cerebral morphology and metabolism of 15 ESRD plus T1D patients, 23 patients with ESRD plus T1D after KD (n = 9) and KP (n = 14) transplantation, and 8 age-matched control subjects.
Magnetic resonance imaging showed a higher prevalence of cerebrovascular disease in ESRD plus T1D patients (53% [95% CI 36–69]) compared with healthy subjects (25% [3–6], P = 0.04). Brain 1H MRS showed lower levels of N-acetyl aspartate (NAA)-to-choline ratio in ESRD plus T1D, KD, and KP patients compared with control subjects (control subjects vs. all, P < 0.05) and of NAA-to-creatine ratio in ESRD plus T1D compared with KP and control subjects (ESRD plus T1D vs. control and KP subjects, P ≤ 0.01). The evaluation of the most common scores of psychological and neuropsychological function showed a generally better intellectual profile in control and KP subjects compared with ESRD plus T1D and KD patients.
Diabetes and ESRD are associated with a precocious form of brain impairment, chronic cerebrovascular disease, and cognitive decline. In KP-transplanted patients, most of these features appeared to be near normalized after a 5-year follow-up period of sustained normoglycemia.
PMCID: PMC3263904  PMID: 22190674
2.  Beta cell mass and growth after syngeneic islet cell transplantation in normal and streptozocin diabetic C57BL/6 mice. 
Journal of Clinical Investigation  1993;91(3):780-787.
In islet transplantation, nonimmunological factors such as limited growth capacity or increased death rate could reduce the beta cell mass in the graft and lead to failure of the transplant. We studied the evolution of beta cell replication and mass after transplantation of insufficient, minimally sufficient, or excessive islet tissue. Streptozocin diabetic C57BL/6 mice received 150 or 300 syngeneic islets under the kidney capsule and normal mice received 300 islets. In streptozocin diabetic mice 300 islets restored normoglycemia; beta cell replication in transplanted islets was similar to replication in normal pancreas and beta cell mass in the graft remained constant. In contrast, 150 islets were insufficient to achieve normoglycemia; beta cell replication was increased initially but not by 18 or 30 d despite persistent hyperglycemia, and beta cell mass fell progressively. When islets were transplanted into normal recipients, beta cell replication remained normal but beta cells underwent atrophy and mass in the graft was substantially reduced. Therefore, with a successful islet transplant, in diabetic mice beta cell replication and mass remain constant. In contrast, when insufficient islet tissue is transplanted an initial increase in beta cell replication can not compensate for a decline in beta cell mass. When excessive islet tissue is transplanted, beta cell mass is reduced despite normal beta cell replication.
PMCID: PMC288028  PMID: 8450059
3.  Evolving Pandemic Diabetic Nephropathy 
The expanding impact of chronic kidney disease (CKD) due to pandemic diabetes mellitus is recounted emphasizing its epidemiology that has induced global socioeconomic stress on health care systems in industrialized nations now attempting to proffer optimal therapy for end stage renal disease (ESRD). Strategies to delay and perhaps prevent progression of diabetic nephropathy from minimal proteinuria through nephrotic range proteinuria and azotemia to ESRD appear to have decreased the rate of persons with diabetes who develop ESRD. For those with ESRD attributed to diabetes, kidney transplantation affords better survival and rehabilitation than either hemodialysis or peritoneal dialysis. It is likely that advances in genetics and molecular biology will suggest early interventions that will preempt diabetic complications including renal failure.
PMCID: PMC3721652  PMID: 23908777
diabetic nephropathy; chronic kidney disease; glycation; renal failure; renoprotection
4.  MicroRNA Circuits in Transforming Growth Factor-β actions and Diabetic Nephropathy 
Seminars in nephrology  2012;32(3):253-260.
Diabetes is associated with significantly increased rates of kidney disease or diabetic nephropathy (DN), a severe microvascular complication that can lead to End-stage renal disease (ESRD). ESRD needs to be treated by dialysis or kidney transplantation and is also associated with cardiovascular disease and macrovascular complications. Therefore, effective renal protection is critical to reduce the rates of mortality associated with diabetes. Although key signal transduction and gene regulation mechanisms have been identified and several drugs are currently in clinical use, the rates of DN are still escalating, suggesting the imperative need to identify new biomarkers and drug targets. The recent discovery of microRNAs (miRNAs) and their cellular functions provide an opportunity to fill these critical gaps. Since miRNAs can modulate the actions of key factors involved in DN such as transforming growth factor-beta (TGF-β), they could be novel targets for the treatment of DN. This review covers the recent studies on the roles of miRNAs and miRNA circuits in TGF-β actions and in DN.
PMCID: PMC3407375  PMID: 22835456
microRNAs; TGF-β; Diabetic Nephropathy; Fibrosis; Hypertrophy
5.  Successful Kidney Transplantation for End-Stage Renal Disease in Marfan's Syndrome 
Marfan's syndrome is a systemic disorder of the connective tissue caused by mutations in the extracellular matrix protein fibrillin-1, with aortic dissection and aneurysm being its most life-threatening manifestations. Kidney transplantation for end-stage renal disease (ESRD) in patients with Marfan's syndrome has not been reported in the literature, and the rate of the incidence of dissection or aneurysm in the iliac artery is unknown. Here, we present a patient with Marfan's syndrome with ESRD due to severe renal ischemia caused by massive bleeding from thoracoabdominal aortic dissection leading to transplant surgery of a living kidney procured from the patient's mother. After kidney transplantation, the renal function normalized without vascular complications, and stable graft function along with negative results for both microhematuria and proteinuria continued for two years. Also, vascular complication such as aneurysm or dissection of the iliac artery was not observed using ultrasonography during the follow-up period. ESRD patients with Marfan's syndrome might be suitable for kidney transplantation, but long-term and careful observations are needed.
PMCID: PMC3777197  PMID: 24093072
6.  Coronary microvascular dysfunction in diabetes mellitus: A review 
World Journal of Cardiology  2010;2(11):377-390.
The exploration of coronary microcirculatory dysfunction in diabetes has accelerated in recent years. Cardiac function is compromised in diabetes. Diabetic patients manifest accelerated atherosclerosis in coronary arteries. These data are confirmed in diabetic animal models, where lesions of small coronary arteries have been described. These concepts are epitomized in the classic microvascular complications of diabetes, i.e. blindness, kidney failure and distal dry gangrene. Most importantly, accumulating data indicate that insights gained from the link between inflammation and diabetes can yield predictive and prognostic information of considerable clinical utility. This review summarizes the evidence for the predisposing factors and the mechanisms involved in diabetes, and assesses the current state of knowledge regarding the triggers for inflammation in this disease. We evaluate the roles of hyperglycemia, oxidative stress, polyol pathway, protein kinase C, advanced glycation end products, insulin resistance, peroxisome proliferator-activated receptor-γ, inflammation, and diabetic cardiomyopathy as a “stem cell disease”. Furthermore, we discuss the mechanisms responsible for impaired coronary arteriole function. Finally, we consider how new insights in diabetes may provide innovative therapeutic strategies.
PMCID: PMC3006474  PMID: 21179305
Coronary artery; Diabetes; Endothelial dysfunction; Hyperglycemia; Inflammation; Insulin; Microcirculation; Nitric oxide; Oxidative stress
7.  Sodium-Glucose Cotransporter Inhibition Prevents Oxidative Stress in the Kidney of Diabetic Rats 
The hyperglycemia triggers several chronic diabetic complications mediated by increased oxidative stress that eventually causes diabetic nephropathy. The aim of this study was to examine if the sodium-glucose cotransporter (SGLT2) inhibition prevents the oxidative stress in the kidney of diabetic rats. Methods. The diabetic rat model was established by intraperitoneal injection of streptozotocin (50 mg/kg). The inhibition of SGLT2 was induced by daily subcutaneous administration of phlorizin (0.4 g/kg). Oxidative stress was assessed by catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities and by immunohistochemical analysis of 3-nitrotyrosine (3-NT). Results. Streptozotocin-induced diabetes caused hyperglycemia and lower body weight. The CAT activity decreased in cortex and medulla from diabetic rats; in contrast, the GPx activity increased. Furthermore the 3-NT staining of kidney from diabetic rats increased compared to control rats. The inhibition of SGLT2 decreased hyperglycemia. However, significant diuresis and glucosuria remain in diabetic rats. The phlorizin treatment restores the CAT and GPX activities and decreases 3-NT staining. Conclusion. The inhibition of SGLT2 by phlorizin prevents the hyperglycemia and oxidative stress in kidney of diabetic rats, suggesting a prooxidative mechanism related to SGLT2 activity.
PMCID: PMC3512343  PMID: 23227274
8.  The Continuum of Diabetic Vascular Disease: From Macro- to Micro- 
Hyperglycemia can promote vascular complications by multiple mechanisms, with formation of advanced glycation endproducts (AGEs) and increased oxidative stress proposed to contribute to both macrovascular and microvascular complications. Many of the earliest pathologic responses to hyperglycemia are manifest in the vascular cells that directly encounter elevated blood glucose levels. In the macrovasculature, these include endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). In the microvasculature, these include ECs, pericytes (in retinopathy), and podocytes (in renal disease). Additionally, neovascularization arising from the vasa vasorum may promote atherosclerotic plaque progression and contribute to plaque rupture, thereby interconnecting macro- and microangiopathy.
PMCID: PMC2663393  PMID: 19179216
glucose; atherosclerosis; advanced glycation endproducts; oxidative stress; inflammation
9.  Role of Nitrosative Stress and Peroxynitrite in the Pathogenesis of Diabetic Complications. Emerging New Therapeutical Strategies 
Current medicinal chemistry  2005;12(3):267-275.
Macro- and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus. Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction. Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications. Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition of PARP.
PMCID: PMC2225483  PMID: 15723618
peroxynitrite; nitric oxide; superoxide; nitrotyrosine; diabetes; vascular; cardiomyopathy; nephropathy; neuropathy; retinopathy
10.  The Case for Control in Diabetes Mellitus 
Western Journal of Medicine  1978;129(3):193-200.
In all diabetic animal models studied to date, microangiopathic complications develop which can be prevented by tight control and reversed by either islet cell transplantation or transplanting the diabetic kidney into a nondiabetic environment. In humans the prevalence of these complications in secondary diabetes mellitus is similar to the prevalence in genetic diabetes. Furthermore, mesangial basement membrane thickness is normal at the onset of the disease and increases shortly thereafter. These two facts strongly suggest that the microangiopathic complications are not an independent genetic component but rather are secondary to the metabolic derangements of uncontrolled diabetes. Normal kidneys transplanted into diabetic recipients developed the vascular lesions of diabetes. Conversely, two diabetic kidneys inadvertently transplanted into nondiabetic recipients showed clearing of the vascular lesions.
Most retrospective studies support the conclusion that control is associated with lessened complications. The three prospective studies published to date also support this hypothesis. Because glucose concentrations cannot be brought to normal levels by present methods, the critical question is whether a major emphasis on restoring metabolism to as nearly normal as possible will help ameliorate the microangiopathic complications in our patients. The accumulated evidence would strongly favor an affirmative answer. Two daily injections of intermediate-acting insulin supplemented with small amounts of short-acting insulin as needed is one method to approach this goal.
PMCID: PMC1238311  PMID: 360622
11.  The Role of Kidney-Pancreas Transplantation in Diabetic Kidney Disease 
Current Diabetes Reports  2010;10(5):385-391.
For patients with type 1 diabetes, innovations in insulin formulations and delivery have improved the ability to achieve excellent blood glucose control. However, it is uncommon to achieve euglycemia, particularly while avoiding complications arising from hypoglycemia. Pancreas transplantation remains the only broadly applied treatment strategy that can result in normalization of blood glucose, but this must be weighed against the risks of a surgical procedure and subsequent immunosuppression. To improve this risk/benefit ratio, pancreas transplantation is typically performed in patients with kidney failure who are to undergo kidney transplantation and immunosuppression (simultaneous pancreas-kidney transplant) or who have undergone kidney transplant and are obligated to the use of immunosuppressive medications (pancreas after kidney transplant). The purpose of this review is to clarify the benefit of an added pancreas transplant in these clinical settings and formulate an approach to the patient with type 1 diabetes as they approach kidney failure.
PMCID: PMC2922623  PMID: 20661671
Pancreas transplantation; Type 1 diabetes; Chronic kidney disease
12.  Pancreatic transplantation 
A pancreas transplant is a surgical procedure to place a healthy pancreas from a donor into a patient whose pancreas no longer functions properly. Exocrine pancreas transplantation remains the standard treatment of choice for patients with diabetes mellitus complicated by end-stage renal disease. The use of pancreas transplantation for type 2 diabetes mellitus is an emerging concept. A pancreas transplant is often done in conjunction with a kidney transplant. Even if pancreas transplantation provides the best glycemic control option for diabetes mellitus, it is associated with significant morbidities related to infectious disease. The present article provides with a review of pancreatic transplantation.
PMCID: PMC3338212  PMID: 22558557
Graft survival; pancreas transplantation; histopathology; diabetes; pancreas-kidney; infectious disease
13.  Impact of Exercise and Metabolic Disorders on Heat Shock Proteins and Vascular Inflammation 
Autoimmune Diseases  2012;2012:836519.
Heat shock proteins (Hsp) play critical roles in the body's self-defense under a variety of stresses, including heat shock, oxidative stress, radiation, and wounds, through the regulation of folding and functions of relevant cellular proteins. Exercise increases the levels of Hsp through elevated temperature, hormones, calcium fluxes, reactive oxygen species (ROS), or mechanical deformation of tissues. Isotonic contractions and endurance- type activities tend to increase Hsp60 and Hsp70. Eccentric muscle contractions lead to phosphorylation and translocation of Hsp25/27. Exercise-induced transient increases of Hsp inhibit the generation of inflammatory mediators and vascular inflammation. Metabolic disorders (hyperglycemia and dyslipidemia) are associated with type 1 diabetes (an autoimmune disease), type 2 diabetes (the common type of diabetes usually associated with obesity), and atherosclerotic cardiovascular disease. Metabolic disorders activate HSF/Hsp pathway, which was associated with oxidative stress, increased generation of inflammatory mediators, vascular inflammation, and cell injury. Knock down of heat shock factor-1 (HSF1) reduced the activation of key inflammatory mediators in vascular cells. Accumulating lines of evidence suggest that the activation of HSF/Hsp induced by exercise or metabolic disorders may play a dual role in inflammation. The benefits of exercise on inflammation and metabolism depend on the type, intensity, and duration of physical activity.
PMCID: PMC3533452  PMID: 23304460
14.  Race and kidney disease: role of social and environmental factors. 
Numerous studies have documented the presence of racial disparities among Americans in health outcomes with respect to cardiovascular disease, infant mortality, cancer, and kidney disease. With regard to kidney diseases, these disparities are more dramatic. African, Hispanic, and Native Americans have the highest risks of end-stage renal disease (ESRD). The incidence of ESRD is four times higher in African Americans than in whites. Diseases causing chronic kidney failure, such as diabetes mellitus, hypertension, systemic lupus erythematosus, and human immunodeficiency virus-associated nephropathy, are particularly prevalent among African-American patients. In addition to the higher prevalence, the morbidity associated with kidney complications of these diseases appears worse in African-American patients. African Americans also have worse outcomes and a relatively reduced access to kidney transplantation--the best therapy for ESRD. It is highly likely that social and environmental factors play a very significant role in the persistence of these disparities. A detailed understanding of these socioeconomic and environmental factors will be critical in formulating rational public health strategies to redress these disparities. This paper reviews the social, economic and environmental factors that impact on the incidence of ESRD in minority groups.
PMCID: PMC2594163  PMID: 12152910
15.  Management of small bowel volvulus in a patient with simultaneous pancreas-kidney transplantation (SPKT): a case report 
There are several surgical complications which can occur following simultaneous pancreas-kidney transplantation (SPKT). Although intestinal obstruction is known to be a common complication after any type of abdominal surgery, the occurrence of small bowel volvulus, which is one of the rare causes of intestinal obstruction, following SPKT has not been published before. A 24-year-old woman suffering from type I diabetes mellitus with complications of nephropathy resulting in end stage renal disease (ESRD), neuropathy and retinopathy underwent SPKT. On the postoperative month 5, she was brought to the emergency service due to abdominal distention with mild abdominal pain. After laboratory research and diagnostic radiological tests had been carried out, she underwent exploratory laparotomy to determine the pathology for acute abdominal symptoms. Intra-operative observation revealed the presence of an almost totally ischemic small bowel which had occurred due to clockwise rotation of the mesentery. Initially, simple derotation was performed to avoid intestinal resection because of her risky condition, particularly for short bowel syndrome, and subsequent intestinal response was favorable. Thus, surgical treatment was successfully employed to solve the problem without any resection procedure. The patient's postoperative follow-up was uneventful and she was discharged from hospital on postoperative day 7. According to our clinical viewpoint, this study emphasizes that if there is even just a suspicion of acute abdominal problem in a patient with SPKT, surgical intervention should be promptly performed to avoid any irreversible result and to achieve a positive outcome.
PMCID: PMC2117004  PMID: 17903265
16.  Reasons for the lack of salutary effects of cholesterol lowering interventions in ESRD populations 
Blood purification  2013;35(1-3):31-36.
Cardiovascular disease (CVD) is the main cause of premature death in patients with chronic kidney disease (CKD). The underlying mechanisms of CVD in patients with mild to moderate CKD are different from those with end-stage renal disease (ESRD). While serum cholesterol is frequently elevated and contributes to atherosclerosis in many CKD patients particularly those with nephrotic proteinuria, it is usually normal, even subnormal in most ESRD patients receiving hemodialysis. CVD in the ESRD population is primarily driven by oxidative stress, inflammation, accumulation of the oxidation-prone intermediate density lipoproteins (IDL), chylomicron remnants and small dense LDL particles as well as HDL deficiency and dysfunction, hypertension, vascular calcification, and arrhythmias. Only a minority of hemodialysis patients have hypercholesterolemia which is most likely due to genetic or unrelated factors. In addition due to peritoneal losses of proteins which simulate nephrotic syndrome, peritoneal dialysis patients often exhibit hypercholesterolemia. Clearly when present, hypercholesterolemia contributes to CVD in CKD and ESRD population and justifies cholesterol lowering therapy. However the majority of ESRD patients and a subpopulation of CKD patients with minimal proteinuria have normal or subnormal serum cholesterol levels and do not benefit from and can be potentially harmed by statin therapy. In fact the lack of efficacy of statins in hemodialysis patients has been demonstrated in several randomized clinical trials. This review is intended to provide an overview of the mechanisms responsible for the failure of statins to reduce cardiovascular morbidity and mortality in most ESRD patients and to advocate the adoption of individualized care principal in the management of dyslipidemia in this population.
PMCID: PMC3595172  PMID: 23343544
Statins; lipid disorders; cardiovascular disease; progression of kidney disease; hemodialysis; nephrotic syndrome
17.  New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes 
Sandholm, Niina | Salem, Rany M. | McKnight, Amy Jayne | Brennan, Eoin P. | Forsblom, Carol | Isakova, Tamara | McKay, Gareth J. | Williams, Winfred W. | Sadlier, Denise M. | Mäkinen, Ville-Petteri | Swan, Elizabeth J. | Palmer, Cameron | Boright, Andrew P. | Ahlqvist, Emma | Deshmukh, Harshal A. | Keller, Benjamin J. | Huang, Huateng | Ahola, Aila J. | Fagerholm, Emma | Gordin, Daniel | Harjutsalo, Valma | He, Bing | Heikkilä, Outi | Hietala, Kustaa | Kytö, Janne | Lahermo, Päivi | Lehto, Markku | Lithovius, Raija | Österholm, Anne-May | Parkkonen, Maija | Pitkäniemi, Janne | Rosengård-Bärlund, Milla | Saraheimo, Markku | Sarti, Cinzia | Söderlund, Jenny | Soro-Paavonen, Aino | Syreeni, Anna | Thorn, Lena M. | Tikkanen, Heikki | Tolonen, Nina | Tryggvason, Karl | Tuomilehto, Jaakko | Wadén, Johan | Gill, Geoffrey V. | Prior, Sarah | Guiducci, Candace | Mirel, Daniel B. | Taylor, Andrew | Hosseini, S. Mohsen | Parving, Hans-Henrik | Rossing, Peter | Tarnow, Lise | Ladenvall, Claes | Alhenc-Gelas, François | Lefebvre, Pierre | Rigalleau, Vincent | Roussel, Ronan | Tregouet, David-Alexandre | Maestroni, Anna | Maestroni, Silvia | Falhammar, Henrik | Gu, Tianwei | Möllsten, Anna | Cimponeriu, Danut | Ioana, Mihai | Mota, Maria | Mota, Eugen | Serafinceanu, Cristian | Stavarachi, Monica | Hanson, Robert L. | Nelson, Robert G. | Kretzler, Matthias | Colhoun, Helen M. | Panduru, Nicolae Mircea | Gu, Harvest F. | Brismar, Kerstin | Zerbini, Gianpaolo | Hadjadj, Samy | Marre, Michel | Groop, Leif | Lajer, Maria | Bull, Shelley B. | Waggott, Daryl | Paterson, Andrew D. | Savage, David A. | Bain, Stephen C. | Martin, Finian | Hirschhorn, Joel N. | Godson, Catherine | Florez, Jose C. | Groop, Per-Henrik | Maxwell, Alexander P. | Böger, Carsten A.
PLoS Genetics  2012;8(9):e1002921.
Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
Author Summary
The global prevalence of diabetes has reached epidemic proportions, constituting a major health care problem worldwide. Diabetic kidney disease, or diabetic nephropathy (DN)—the major long term microvascular complication of diabetes—is associated with excess mortality among patients with type 1 diabetes. Even though DN has been shown to cluster in families, the underlying genetic and molecular pathways remain poorly defined. We have undertaken the largest genome-wide association study and meta-analysis to date on DN and on its most severe form of kidney disease, end-stage renal disease (ESRD). We identified new loci significantly associated with diabetic ESRD: AFF3 and an intergenic locus on chromosome 15q26 residing between RGMA and MCTP2. Our functional analyses suggest that AFF3 influences renal tubule fibrosis, a pathological hallmark of severe DN. Another locus in ERBB4 was suggestively associated with DN and resides in the same intronic region as a variant affecting the expression of ERBB4. Subsequent pathway analysis of the genes co-expressed with ERBB4 indicated involvement of fibrosis.
PMCID: PMC3447939  PMID: 23028342
18.  Partial Characterization of the Molecular Nature of Collagen-Linked Fluorescence: Role of Diabetes and End-Stage Renal Disease 
Collagen-linked fluorescence at excitation/emission 370/440 nm has widely been used as a marker for advanced glycation in studies of aging, diabetic complications and end-stage renal disease (ESRD). Diagnostic devices measuring skin autofluorescence at this wavelength revealed an association between fluorescence and cardiovascular morbidity and mortality. We now report the presence of a major fluorophore (LW-1) in human skin collagen which increases with age, diabetes and ESRD. It has a molecular weight of 623.2 Da, a UV maximum at 348 nm, and involves a lysine residue in an aromatic ring. LW-1 could not be synthesized using traditional glycation chemistry suggesting a complex mechanism of formation, perhaps related to hypoxia since elevated levels were also found in nondiabetic individuals with chronic lung disease.
PMCID: PMC2812593  PMID: 19879855
aging; glycation; skin; structure; marker
19.  Defining human diabetic nephropathy on the molecular level 
Diabetic nephropathy (DN) is the most common cause for end stage renal disease (ESRD). Next to environmental factors, genetic predispositions determine the susceptibility for DN and its rate of progression to ESRD. With the availability of genome wide expression profiling we have the opportunity to define relevant pathways activated in the individual diabetic patient, integrating both environmental exposure and genetic background. In this review we summarize current understanding of how to link comprehensive gene expression data sets with biomedical knowledge and present strategies to build a transcriptional network of DN. Information about the individual disease processes of DN might allow the implementation of a personalized molecular medicine approach with mechanism-based patient management. Web based search engines like Nephromine are essential tools to facilitate access to molecular data of genomics, proteomics and metabolomics of DN.
PMCID: PMC2597685  PMID: 18704688
Diabetic nephropathy; personalized molecular medicine; patient tailored medicine; gene expression; transcription regulatory networks
20.  Sex Differences in the Development of Kidney Disease in Individuals With Type 1 Diabetes Mellitus: A Contemporary Analysis 
Kidney disease in type 1 diabetes has been historically thought to be more prevalent in men. As recent data do not reflect this pattern, we evaluated whether a sex difference persists.
Study design
Prospective cohort study.
Setting and participants
We used 18-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications study (n=788; baseline mean age 27 and diabetes duration 19 years).
Predictor or factor
Sex and diagnosis interval (1950–64 or 1965–80).
The cumulative incidences of macroalbuminuria (albumin excretion rate >200 μg/min) and end-stage renal disease (ESRD, kidney failure, dialysis or transplant) were evaluated at 20, 25, and 30 years of diabetes duration. To address potential survival bias, death certificate information was included in determining ESRD for those who died before baseline (n=145). Analyses were stratified by diagnosis year (1950–64 or 1965–80).
Other measurements
Kidney disease risk factor information was available.
A significant interaction was noted between sex and diagnosis cohort for ESRD incidence by 25 (p=0.002) and 30 (p<0.001) years’ duration. Thus, within the 1950–64 cohort (210 men, 180 women), ESRD was higher in men compared to women by 25 (30.6% vs. 18.0%, respectively) and 30 (43.4% vs. 24.6%, respectively) years duration. However, within the 1965–80 cohort (260 men, 283 women), incidence was higher in women (7.6% vs. 13.8% by 25 yrs [p=0.04] and 13.7% vs. 21.0% by 30 yrs [p=0.09] in men vs. women, respectively). Results were similar for macroalbuminuria.
Study participants were not followed from the onset of diabetes and thus, risk factor data from that period are lacking.
Our data suggest that the male excess of type 1 diabetic kidney disease cases observed in the earlier cohort has been eliminated in the younger cohort. The reason for this dramatic change is currently unclear but should be addressed in subsequent studies.
PMCID: PMC3183221  PMID: 21840097
21.  Evidence That Hyperglycemia After Recovery From Hypoglycemia Worsens Endothelial Function and Increases Oxidative Stress and Inflammation in Healthy Control Subjects and Subjects With Type 1 Diabetes 
Diabetes  2012;61(11):2993-2997.
Currently there is debate on whether hypoglycemia is an independent risk factor for atherosclerosis, but little attention has been paid to the effects of recovery from hypoglycemia. In normal control individuals and in people with type 1 diabetes, recovery from a 2-h induced hypoglycemia was obtained by reaching normoglycemia or hyperglycemia for another 2 h and then maintaining normal glycemia for the following 6 h. Hyperglycemia after hypoglycemia was also repeated with the concomitant infusion of vitamin C. Recovery with normoglycemia is accompanied by a significant improvement in endothelial dysfunction, oxidative stress, and inflammation, which are affected by hypoglycemia; however, a period of hyperglycemia after hypoglycemia worsens all of these parameters, an effect that persists even after the additional 6 h of normoglycemia. This effect is partially counterbalanced when hyperglycemia after hypoglycemia is accompanied by the simultaneous infusion of vitamin C, suggesting that when hyperglycemia follows hypoglycemia, an ischemia–reperfusion-like effect is produced. This study shows that the way in which recovery from hypoglycemia takes place in people with type 1 diabetes could play an important role in favoring the appearance of endothelial dysfunction, oxidative stress, and inflammation, widely recognized cardiovascular risk factors.
PMCID: PMC3478543  PMID: 22891214
22.  Mechanisms of Homocysteine-Induced Glomerular Injury and Sclerosis 
American Journal of Nephrology  2007;28(2):254-264.
Hyperhomocysteinemia (hHcys) has been recognized as a critical risk or pathogenic factor in the progression of end-stage renal disease (ESRD) and in the development of cardiovascular complications related to ESRD. Recently, evidence is accumulating that hHcys may directly act on glomerular cells to induce glomerular dysfunction and consequent glomerular sclerosis, leading to ESRD. In this review, we summarize recent findings that reveal the contribution of homocysteine as a pathogenic factor to the development of glomerular sclerosis or ESRD. In addition, we discuss several important mechanisms mediating the pathogenic action of homocysteine in the glomeruli or in the kidney, such as lo- cal oxidative stress, endoplasmic reticulum stress, homocysteinylation, and hypomethylation. Understanding these mechanisms may help design new approaches to develop therapeutic strategies for treatment of hHcys-associated end-organ damage and for prevention of deterioration of kidney function and ultimate ESRD in patients with hypertension and diabetes mellitus or even in aged people with hHcys.
PMCID: PMC2820346  PMID: 17989498
Hyperhomocysteinemia; Glomerulus; Sulfur amino acids; Oxidative stress; Mesangial cells; Podocytes; Proteinuria
23.  Human Evaluation of the Glu298Asp Polymorphism in NOS3 Gene and its Relationship with Onset age of ESRD in Iranian Patients Suffering from ADPKD 
One of the most striking features in autosomal dominant polycystic kidney disease (ADPKD) is the difference at onset age of end-stage renal disease (ESRD). Modifier genes may play a role in this phenotypic variability. The mutated nitric oxide synthase 3 gene (NOS3), have a modifier effect on the severity of ADPKD by impairment of NOS3 activity and decreasing of renal vascular nitric oxide production and, subsequently, reduced kidney function. In order to test this hypothesis, we investigated the relationship between Glu298Asp polymorphism in exon 7 of this gene and ESRD in ADPKD patients refered from Shahid Labbafi Nedjad Hospital in Tehran. The polymorphism was examined by PCR, followed by RFLP (with MboI) in three groups of ADPKD with ESRD; ADPKD without ESRD patients and normal individual as the cases, case-controls and controls, respectively. The frequencies of GG, GT, and TT genotypes in cases were 66.7%, 33.3% and 0%, in case-controls were 78.6%, 19%, 2.4%, and in controls were 64.3%, 35.7% and 0%, respectively. Our findings revealed that there was no significant difference in the genotype frequency of NOS3 gene in ADPKD patients (p=0.311).The age of onset of ESRD in ADPKD patients, harbouring the T allele of this polymorphism, was two years lower than G/G patients, but this difference was not significant (p =0.641). In conclusion, our results suggest that there is no evidence of relationship between Glu298Asp polymorphism and onset age of ESRD in Iranian ADPKD patients.
PMCID: PMC3920495  PMID: 24551766
ADPKD; ESRD; NOS3; Glu298Asp polymorphism
24.  Allograft outcomes after simultaneous pancreas kidney transplantation comparing T1DM with Type 2 DM (detectable C-peptide and absence of glutamic acid decarboxylase 65 antibody) 
Transplantation proceedings  2010;42(7):2650-2652.
Prior studies reporting outcomes after pancreas transplant have included a combination of C-peptide cutoffs and clinical criteria to classify type 2 diabetes mellitus (T2DM). However, since the kidney is the major site for C-peptide catabolism, C-peptide is unreliable to discriminate type of diabetes in patients with kidney disease.
To improve the discriminating power and better classify type of diabetes we used a composite definition to identify T2DM: Presence of C-peptide, negative GAD65 antibody, absence of diabetic ketoacidosis and use of oral hypoglycemics. Additionally, BMI <30 kg/m2 and use of < than 1 unit/kg of insulin/day are selection criteria among T2DM patients with ESRD deemed suitable for SPKTx. We compared graft and patient survival between T1DM and T2DM after SPKTx.
Our study cohort consisted of 80 patients, 10 of whom were assigned as T2DM based on our study criteria. Approximately 15% of patients with T1DM had detectable C-peptide. Cox regression survival analyses found no significant differences in allograft (pancreas and kidney) and patient survival in the 2 groups. The mean creatinine clearance at 1 year by MDRD equation was not significantly different between the 2 groups. Among those with 1 year follow up, all patients with T2DM had HbA1C < 6.0 at 1 year vs. 92% of those with T1DM.
SPKTx needs to be considered in the therapeutic armamentarium for renal replacement in selected patients with T2DM and ESRD. Utilization of C-peptide in patients with ESRD as sole criteria to phenotype type of diabetes can be misleading.
PMCID: PMC3060052  PMID: 20832562
25.  Kidney Transplant in a 26-Year-Old Nigerian Patient with Sickle Cell Nephropathy 
Case reports in nephrology  2012;2012:406406.
Sickle cell nephropathy (SCN) is a common complication of sickle cell disease (SCD). It has variable presentation, ranging from hyposthenuria to end-stage renal disease (ESRD). Management of ESRD in SCD patients is froth with multiple challenges which has potential to impact negatively the outcome of the patient. Kidney transplant is the preferred renal replacement therapy in these patients. The objective of this case study is to report kidney transplant in a Nigerian young man with sickle cell nephropathy and to highlight the outcome and the challenges to kidney transplant in this patient. The index case is a 26-years-old sickle cell disease patient with ESRD complicated with cardiovascular, pulmonary, immunological, and infective challenges. These conditions were controlled, and the patient had a successful live-related kidney transplant. Kidney transplant is a viable option for sickle cell disease patients with ESRD.
PMCID: PMC3914253  PMID: 24555134

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