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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.  Embryonic Pig Pancreatic Tissue Transplantation for the Treatment of Diabetes 
PLoS Medicine  2006;3(7):e215.
Transplantation of embryonic pig pancreatic tissue as a source of insulin has been suggested for the cure of diabetes. However, previous limited clinical trials failed in their attempts to treat diabetic patients by transplantation of advanced gestational age porcine embryonic pancreas. In the present study we examined growth potential, functionality, and immunogenicity of pig embryonic pancreatic tissue harvested at different gestational ages.
Methods and Findings
Implantation of embryonic pig pancreatic tissues of different gestational ages in SCID mice reveals that embryonic day 42 (E42) pig pancreas can enable a massive growth of pig islets for prolonged periods and restore normoglycemia in diabetic mice. Furthermore, both direct and indirect T cell rejection responses to the xenogeneic tissue demonstrated that E42 tissue, in comparison to E56 or later embryonic tissues, exhibits markedly reduced immunogenicity. Finally, fully immunocompetent diabetic mice grafted with the E42 pig pancreatic tissue and treated with an immunosuppression protocol comprising CTLA4-Ig and anti–CD40 ligand (anti-CD40L) attained normal blood glucose levels, eliminating the need for insulin.
These results emphasize the importance of selecting embryonic tissue of the correct gestational age for optimal growth and function and for reduced immunogenicity, and provide a proof of principle for the therapeutic potential of E42 embryonic pig pancreatic tissue transplantation in diabetes.
Editors' Summary
Diabetes is a growing global health problem. By 2030, more than 300 million people around the world will have this chronic, incurable disorder, double the current number. In non-diabetic people, cells in the pancreas called beta cells release insulin, a hormone that controls the level of sugar (glucose) in the blood. In diabetics, blood-sugar levels become dangerously high either because the beta cells have been destroyed so no insulin is made (type 1 diabetes, 5%–10% of all cases) or because the cells that normally remove sugar from the blood have become insensitive to insulin (type 2 diabetes). In particularly severe cases of type 2 diabetes, the beta cells also stop releasing insulin. People with type 2 diabetes can usually control their blood-sugar levels through diet and exercise and by taking oral anti-diabetic drugs; people with type 1 diabetes or severe type 2 diabetes have to replace the missing insulin by injections. It is very important that diabetics keep their blood-sugar levels as normal as possible to minimize the disorder's serious long-term complications. These include kidney failure, blindness, nerve damage, and an increased risk of heart disease and strokes.
Why Was This Study Done?
While individuals with type 1 diabetes can control their blood-sugar levels pretty well by carefully monitoring their life style and injecting insulin, potentially better control and fewer long-term complications can be achieved by providing a new source of insulin-producing cells through transplantation of pancreatic tissue from a dead human donor. However, because there is not enough human pancreatic tissue to treat all the diabetics who could benefit from such transplants, researchers are investigating other sources of insulin-producing cells. One possibility is pig pancreatic tissue. Glucose control is very similar in pigs and humans, pig insulin injections have been used for years to control diabetes, and pigs are in plentiful supply. However, besides general concerns about xenotransplantation (that is, transplantation from a foreign species such as pigs into humans), early attempts to treat human diabetes by transplantation of pancreatic tissue taken from pig embryos at late stages of gestation were not successful. The researchers involved in this study had done earlier experiments that suggested that the age of the pig donor tissue influences how well transplantation into other species works. They therefore wanted to test whether pancreatic tissue from younger pig embryos might work better for pancreas transplants: they hoped that younger tissue would grow and integrate better with the surrounding host tissue. Additionally, a major concern with all transplantations is whether the transplanted cells or tissue will be recognized as foreign and as such destroyed by the host's immune system. Because tissue from younger embryos is generally less likely to trigger an immune reaction, the researchers hoped that pancreatic tissue from younger pig embryos would be less readily recognized as foreign by the human immune system.
What Did the Researchers Do and Find?
They started by transplanting pancreatic tissue from pig embryos of different ages into mice with defective immune systems. Tissue taken about a third of the way through gestation (that is, from embryos 42 or 56 days old) grew better than tissue taken earlier or later, secreted more pig insulin over extended periods of time, and was better at maintaining normal blood-sugar levels when the beta cells of the host mice were destroyed. The researchers then examined whether embryonic pig pancreatic tissue of different ages triggered an immune reaction by seeing how well it survived when human immune system cells were also transplanted into the mice. Tissue from 42-day-old embryos came out best in this test too, suggesting that there is little or no “direct” immune reaction by circulating immune cells against pancreatic tissue from this stage. Finally, the researchers transplanted pancreatic tissue of this age into diabetic mice with an intact immune system. These mice rejected the transplants (presumably through an “indirect” immune reaction), but that rejection could be overcome when the recipient mice were treated with drugs that suppressed the part of their immune system that is responsible for these indirect immune reactions. (Human patients who receive a transplant are usually treated with drugs that suppress direct and indirect immune reactions.) When the mice were kept on the drugs, the grafts survived in the long term, and the mice had normal blood-sugar levels once the graft was well established.
What Do These Findings Mean?
These results suggest that the exact age of embryonic pig pancreatic tissue influences how well the transplanted tissue grows and integrates into a host from a different species (in this case, the mouse) and how strong an immune reaction it triggers. Overall, these results support the notion that pig embryonic pancreas tissue could potentially be a source of tissue for transplantation into human patients with diabetes. The next steps in exploring this possibility are likely to involve experiments in monkeys to find out how much tissue should be implanted and where, and to check that the transplanted tissue remains functional in these animals. The ability of the 42-day-old embryonic tissue to avoid direct immune rejection also needs to be confirmed. And, ideally, the goal remains to find ways to avoid an immune reaction altogether, so that recipients of transplants do not need to be continually treated with drugs that suppress their immune system (which makes them more susceptible to infections and can have other side effects). Xenotransplantation has potential benefits and risks and remains controversial. Studies like this one and others that seek to better understand the risks and benefits are necessary to allow reasonable decisions to be made.
Additional Information.
Please access these Web sites via the online version of this summary at
• MedlinePlus pages on diabetes and on pancreas transplantation
• Information from the Juvenile Diabetes Research Foundation International Description
• Wikipedia pages on diabetes, xenotransplantation, and pancreas transplantation (note: Wikipedia is a free online encyclopedia that anyone can edit)
Pancreatic tissue from embryonic pigs co-transplanted with or without human immune cells into immune-deficient mice suggests that the embryonic stage of the pig donor affects the immunogenicity of the graft.
PMCID: PMC1479387  PMID: 16768546
3.  Time to Renal Disease and End-Stage Renal Disease in PROFILE: A Multiethnic Lupus Cohort 
PLoS Medicine  2006;3(10):e396.
Renal involvement is a serious manifestation of systemic lupus erythematosus (SLE); it may portend a poor prognosis as it may lead to end-stage renal disease (ESRD). The purpose of this study was to determine the factors predicting the development of renal involvement and its progression to ESRD in a multi-ethnic SLE cohort (PROFILE).
Methods and Findings
PROFILE includes SLE patients from five different United States institutions. We examined at baseline the socioeconomic–demographic, clinical, and genetic variables associated with the development of renal involvement and its progression to ESRD by univariable and multivariable Cox proportional hazards regression analyses. Analyses of onset of renal involvement included only patients with renal involvement after SLE diagnosis (n = 229). Analyses of ESRD included all patients, regardless of whether renal involvement occurred before, at, or after SLE diagnosis (34 of 438 patients). In addition, we performed a multivariable logistic regression analysis of the variables associated with the development of renal involvement at any time during the course of SLE.
In the time-dependent multivariable analysis, patients developing renal involvement were more likely to have more American College of Rheumatology criteria for SLE, and to be younger, hypertensive, and of African-American or Hispanic (from Texas) ethnicity. Alternative regression models were consistent with these results. In addition to greater accrued disease damage (renal damage excluded), younger age, and Hispanic ethnicity (from Texas), homozygosity for the valine allele of FcγRIIIa (FCGR3A*GG) was a significant predictor of ESRD. Results from the multivariable logistic regression model that included all cases of renal involvement were consistent with those from the Cox model.
Fcγ receptor genotype is a risk factor for progression of renal disease to ESRD. Since the frequency distribution of FCGR3A alleles does not vary significantly among the ethnic groups studied, the additional factors underlying the ethnic disparities in renal disease progression remain to be elucidated.
Fcγ receptor genotype is a risk factor for progression of renal disease to ESRD but does not explain the ethnic disparities in renal disease progression.
Editors' Summary
Systemic lupus erythematosis (SLE, commonly known as “lupus”) is an illness of many manifestations that appear to result from the immune system attacking components of the body's own cells. One of the unfortunate effects of SLE is kidney damage, which can, in a minority of patients, progress to kidney failure (formally called “end-stage renal disease,” or ESRD). Compared to White Americans, other ethnic groups tend to develop renal complications of lupus more often and with worse outcomes.
Why Was This Study Done?
It is unclear why some people with lupus develop kidney problems. The purpose of this US-based study was to confirm the factors that increase the risk of kidney damage and kidney failure, particularly in racial and ethnic minority patients, and to determine which of these factors accelerate the pace of kidney disease. Knowing these risk factors could allow the development and targeting of interventions, such as screening tests and preventive treatments, to prevent long-term loss of kidney function in patients with lupus.
What Did the Researchers Do and Find?
The researchers measured a number of factors in a multi-ethnic group of 1,008 patients with lupus, almost half of whom had some degree of kidney involvement. They found that those who developed kidney damage after being diagnosed with lupus tended to be younger, to have had lupus for a longer time, and to have experienced more effects of lupus in general than those who did not have kidney involvement. Those who developed kidney problems were also more likely to have been unemployed, to have had fewer years of formal education, and to have had high blood pressure before developing kidney involvement. African-American and Texan Hispanic individuals with lupus were more likely to develop kidney involvement, and tended to develop it more rapidly, than White Americans or Puerto Rican Hispanic ethnicity. Actual kidney failure (ESRD requiring dialysis or kidney transplantation) was more likely to occur among Texan Hispanics with kidney involvement than in the other ethnic groups. Diabetes and high blood pressure were not found to predict ESRD, but people with a particular variant of a protein that helps antibodies bind to cells (know as Fc-gamma receptor IIIa, or FcγRIIIa) were found to be more likely to develop ESRD, and to develop it more quickly.
What Do These Findings Mean?
These results suggest that the emergence and progression of kidney disease in patients with lupus depends on medical, genetic, and socioeconomic factors. Because no single test or intervention can be expected to address all of these factors, those treating patients with lupus must remain aware of the complexity of their patients lives at a variety of levels. In particular, ethnic disparities in the risk of serious kidney disease remain to be addressed.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus page on lupus
Lupus Foundation of America
American College of Rheumatology pages on lupus
Wikipedia entry on lupus (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
PMCID: PMC1626549  PMID: 17076550
4.  Comparison of quality-of-care measures in U.S. patients with end-stage renal disease secondary to lupus nephritis vs. other causes 
BMC Nephrology  2015;16:39.
Patients with end-stage renal disease (ESRD) due to lupus nephritis (LN-ESRD) may be followed by multiple providers (nephrologists and rheumatologists) and have greater opportunities to receive recommended ESRD-related care. We aimed to examine whether LN-ESRD patients have better quality of ESRD care compared to other ESRD patients.
Among incident patients (7/05–9/11) with ESRD due to LN (n = 6,594) vs. other causes (n = 617,758), identified using a national surveillance cohort (United States Renal Data System), we determined the association between attributed cause of ESRD and quality-of-care measures (pre-ESRD nephrology care, placement on the deceased donor kidney transplant waitlist, and placement of permanent vascular access). Multivariable logistic and Cox proportional hazards models were used to estimate adjusted odds ratios (ORs) and hazard ratios (HRs).
LN-ESRD patients were more likely than other ESRD patients to receive pre-ESRD care (71% vs. 66%; OR = 1.68, 95% CI 1.57-1.78) and be placed on the transplant waitlist in the first year (206 vs. 86 per 1000 patient-years; HR = 1.42, 95% CI 1.34–1.52). However, only 24% had a permanent vascular access (fistula or graft) in place at dialysis start (vs. 36%; OR = 0.63, 95% CI 0.59–0.67).
LN-ESRD patients are more likely to receive pre-ESRD care and have better access to transplant, but are less likely to have a permanent vascular access for dialysis, than other ESRD patients. Further studies are warranted to examine barriers to permanent vascular access placement, as well as morbidity and mortality associated with temporary access, in patients with LN-ESRD.
PMCID: PMC4389993  PMID: 25884409
5.  Simultaneous pancreas-kidney transplantation: The role in the treatment of type 1 diabetes and end-stage renal disease 
Type 1 diabetes mellitus (DM) is one of the most common and debilitating diseases to affect the world. Many patients are afflicted by microvascular and macrovascular complications, and succumb to end-stage renal disease (ESRD). Although dialysis and insulin therapy provides better glycemic control, it nonetheless significantly decreases a patient’s quality of life. Moreover, they cannot reverse ESRD or alleviate complications. Simultaneous pancreas-kidney (SPK) transplantation has revolutionized the way we manage type 1 DM; it provides a physiological means of achieving normoglycemia while rendering patients free of dialysis. Understanding this procedure is important because it is becoming a more common management strategy for patients with type 1 DM. In this review, we will begin with a brief summary of type 1 DM, followed by a comprehensive description of SPK procedure, including the history and technique. We will then present the outcomes of transplantation.
PMCID: PMC4001637  PMID: 24839485
6.  Diabetes and end-stage renal disease; a review article on new concepts 
It is well established that diabetic nephropathy is the most common cause or in combination with hypertensive nephropathy are the most common causes of end-stage renal disease (ESRD) in developed and developing countries. For this review, we used a variety of sources by searching through PubMed, Embase, Scopus, Current Content and Iran Medex from January 1990 up to December 2014. Manuscripts published in English and Persian languages, as full-text articles, and or as abstract were included in the study. Patient survival in diabetics on maintenance renal replacement therapy including hemodialysis (HD), peritoneal dialysis (PD) and kidney transplantation is significantly lower than that seen in nondiabetics with ESRD. The poor prognosis of diabetic patients with ESRD is partly due to presence of significant cardiovascular disease, problems with vascular access, more susceptible to infections, foot ulcer, and hemodynamic instability during HD. Although, many complications related to kidney transplantation may occur in diabetic ESRD patients, multiple studies have found that the kidney transplantation is the preferred renal replacement therapy for diabetic patients with ESRD and it is associated with a much better survival and quality of life than dialysis among these patients.
PMCID: PMC4459725  PMID: 26060834
Diabetic nephropathy; End-stage renal disease; Renal replacement therapy; Hemodialysis
7.  Kidney transplantation in a patient with absent right common iliac artery and congenital renal abnormalities 
•Congenital atresia of the common and external iliac arteries is a rare vascular anomaly that may pose potential problems during renal transplantation.•It may be useful to perform routine angiographic evaluation for ESRD patients with congenital genitourinary abnormalities being planned for kidney transplantation.•As some cases of congenital iliac artery anomalies remain asymptomatic, there is some evidence in literature suggesting the usefulness of routine pre-operative CT in a selective group of patients.•Kidney transplantation in patients with absent right common and external iliac arteries is safe with the appropriate pre-operative imaging and surgical technique.
Congenital atresia of the common and external iliac arteries is a rare vascular anomaly that may be associated with congenital renal or genitourinary malformations. In ESRD patients, its presence may pose potential problems during renal transplantation.
Case presentation
We report a rare case of kidney transplantation in a patient with VACTERL syndrome who was found to have absent right common and external iliac arteries during pre-operative imaging. Vascular supply to the right lower limb is derived from an anomalous branch from the left internal iliac artery which takes on a convoluted course across the pelvis. Kidney transplantation was performed successfully with implantation performed on the left side.
Isolated cases of congenital iliac artery atresia have been described in association with urological abnormalities but no clear association has yet been established. However, we feel that it may be useful to perform routine angiographic evaluation for ESRD patients with congenital genitourinary abnormalities being planned for kidney transplantation. While most cases of congenital iliac artery anomalies are symptomatic with claudication, some remain asymptomatic with normal physical examination findings. There is some evidence in literature suggesting the usefulness of routine pre-operative CT in a selective group of patients.
Kidney transplantation in such cases is safe and we recommend routine pre-operative imaging of patients known to have congenital genitourniary abnormalities. The kidney should be implanted heterotopically to the contralateral side of the vascular anomaly and care must be taken to preserve vascular supply to the lower limbs.
PMCID: PMC4430136  PMID: 25839434
CT, computed tomography; ESRD, end stage renal disease; LRRT, living related renal transplant; MAG-3, mercaptoacetyltriglycine-3; VACTERL, vertebral anomalies, anal atresia, cardiac defects, tracheo-esophageal fistula/atresia, renal and radial anomalies and limb defects; VUR, vesico-ureteric reflux; Kidney transplantation; Congenital vascular anomaly; Absent iliac artery; VACTERL; Crossed fused ectopia
8.  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.
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
9.  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
10.  Updates on the Management of Diabetes in Dialysis Patients 
Seminars in dialysis  2014;27(2):135-145.
Diabetes mellitus is the leading cause of end-stage renal disease (ESRD) in the U.S. and many countries globally. The role of improved glycemic control in ameliorating the exceedingly high mortality risk of diabetic dialysis patients is unclear. The treatment of diabetes in ESRD patients is challenging, given changes in glucose homeostasis, the unclear accuracy of glycemic control metrics, and the altered pharmacokinetics of glucose-lowering drugs by kidney dysfunction, the uremic milieu, and dialysis therapy. Up to one-third of diabetic dialysis patients may experience spontaneous resolution of hyperglycemia with hemoglobin A1c (HbA1c) levels <6%, a phenomenon known as “Burnt-Out Diabetes,” which remains with unclear biologic plausibility and undetermined clinical implications. Conventional methods of glycemic control assessment are confounded by the laboratory abnormalities and comorbidities associated with ESRD. Similar to more recent approaches in the general population, there is concern that glucose normalization may be harmful in ESRD patients. There is uncertainty surrounding the optimal glycemic target in this population, although recent epidemiologic data suggest that HbA1c ranges of 6% to 8%, as well as 7 to 9%, are associated with increased survival rates among diabetic dialysis patients. Lastly, many glucose-lowering drugs and their active metabolites are renally metabolized and excreted, and hence, require dose adjustment or avoidance in dialysis patients.
PMCID: PMC3960718  PMID: 24588802
Burnt-out diabetes; ESRD; hypoglycemia
11.  Trends in the Incidence, Demographics and Outcomes of End-Stage Renal Disease Due to Lupus Nephritis in the U.S., 1995–2006 
Arthritis and rheumatism  2011;63(6):1681-1688.
It is unknown whether recent advances lupus nephritis (LN) treatment have led to changes in the incidence of end-stage renal disease (ESRD) secondary to LN, or in the characteristics, therapies, and outcomes of patients with LN ESRD.
Patients with incident LN ESRD (1995–2006) were identified in the US Renal Datasystem. Trends in sociodemographic and clinical characteristics were assessed. We tested for temporal changes in standardized incidence rates (SIRs) for sociodemographic groups using Poisson regression. Changes in rates of waitlisting for kidney transplant, kidney transplantation, and all-cause mortality were examined using crude and adjusted time-to-event analyses.
12,344 incident cases of LN ESRD were identified. Mean age at ESRD onset was 41 years; 81.6% were female and 49.5% African American. SIRs for LN ESRD among those ages 5–39, African Americans, and in the US Southeast increased significantly from 1995–2006. Increases in body mass index and the prevalence of both diabetes and hypertension were detected. Mean serum hemoglobin at ESRD onset increased, while that of serum creatinine decreased over time. More patients used hemodialysis and fewer peritoneal dialysis. There was a slight increase in pre-emptive kidney transplantation at ESRD onset, but kidney transplantation rates within the first three years of ESRD declined. Mortality did not change over 12 years of study.
The characteristics of LN ESRD patients and their initial therapies have changed in recent years. While SIRs rose in younger patients, among African Americans and in the South, outcomes did not improve in over a decade of evaluation.
PMCID: PMC3106117  PMID: 21445962
incidence; dialysis; transplantation; survival; lupus; nephritis; end-stage renal disease; chronic kidney disease; systemic lupus erythematosus; African American; Hispanic; race; women
12.  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
13.  Pediatric Renal Transplantation 
Although the number of children with end-stage renal disease (ESRD) in need for renal transplantation is small compared with adults, the problem associated with renal transplant in children are numerous, varied, and often peculiar. Pre-emptive transplantation has recently been growing in popularity as it avoids many of the associated long-term complications of ESRD and dialysis. Changes in immunosuppression to more potent agents over the years will have affected transplant outcome; there is also evidence that tacrolimus is more effective than cyclosporine. This review will discuss the short- and long-term complications such as acute and chronic rejection, hypertension, infections, and malignancies as well as factors related to long-term graft function.
Chronic allograft nephropathy is the leading cause of renal allograft loss in pediatric renal transplant recipients. It is likely that it reflects a combination of both immune and nonimmune injury occurring cumulatively over time so that the ultimate solution will rely on several approaches. Transplant and patient survival have shown a steady increase over the years. The major causes of death after transplantation are cardiovascular disease, infection and malignancy. Transplantation in special circumstances such as children with abnormal urinary tracts and children with diseases that have the potential to recur after transplantation will also be discussed in this review. Non-compliance with therapeutic regimen is a difficult problem to deal with and affects patients and families at all ages, but particularly so at adolescence. Growth may be severely impaired in children with ESRD which may result in major consequences on quality of life and self-esteem; a better height attainment at transplantation is recognized as one of the most important factors in final height achievement.
Although pediatric kidney transplantation is active in some parts of many developing countries, it is still inactive in many others and mostly relying on living donors. The lacking deceased programs in most of these countries is one of the main issues to be addressed to adequately respond to organ shortage.
In conclusion, transplantation is currently the best option for children with ESRD. Although improvement in immunosuppression demonstrated excellent results and has led to greater 1-year graft survival rates, chronic graft loss remains relatively unchanged and opportunistic infectious complications remain a problem
PMCID: PMC4089282  PMID: 25013625
Transplantation; Kidney; End-stage renal disease; Pediatrics
14.  End-stage renal disease 
BMJ Clinical Evidence  2010;2010:2002.
End-stage renal disease (ESRD) affects more than 1500 people per million population in countries with a high prevalence, such as Japan, Taiwan, and the US. Approximately two-thirds of people with ESRD receive haemodialysis, one quarter have kidney transplants, and one tenth receive peritoneal dialysis.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of different doses for peritoneal dialysis? What are the effects of different doses and membrane fluxes for haemodialysis? What are the effects of interventions aimed at preventing secondary complications? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 26 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: cinacalcet, darbepoetin, erythropoietin, haemodialysis (standard-dose, increased-dose), high membrane-flux haemodialysis, increased-dose peritoneal dialysis, low membrane-flux haemodialysis, mupirocin, sevelamer, standard-dose dialysis, and statins.
Key Points
End-stage renal disease (ESRD) affects more than 1500 people per million population in countries with a high prevalence, such as the US and Japan. About two-thirds of people with ESRD receive haemodialysis, one quarter have kidney transplants, and one tenth receive peritoneal dialysis. Risk factors for ESRD include advanced age; hypertension; diabetes mellitus; obesity; a history of renal disease; and tobacco, heroin, or analgesic use.ESRD leads to fluid retention, anaemia, disturbances of bone and mineral metabolism, and increased risk of cardiovascular disease (CVD).
Increasing the dose of peritoneal dialysis does not seem to reduce mortality.
In people receiving haemodialysis, there seems no difference in mortality for high membrane-flux compared with low membrane-flux, or increased-dose haemodialysis compared with standard dose.
Erythropoietin and darbepoetin may help maintain haemoglobin levels in people with ESRD, although normalising haemoglobin levels in people with both ESRD and CVD may increase mortality.
Disorders of calcium and phosphate metabolism may contribute to the increased risk of CVD in people with ESRD. Phosphate binders (sevelamer) may slow down arterial calcification, and may reduce serum low-density lipoprotein cholesterol levels, but we don't yet know whether this reduces cardiovascular events or mortality. Cinacalcet is more effective than placebo at improving control of secondary hyperparathyroidism, but we don't know whether it reduces cardiovascular events or mortality.
Mupirocin reduces Staphylococcus aureus infections compared with placebo or no treatment.
The use of statins in people with ESRD does not seem to reduce mortality or cardiovascular events.
PMCID: PMC3217820  PMID: 21418665
15.  Polycystic kidney disease in patients on the renal transplant waiting list: trends in hematocrit and survival 
BMC Nephrology  2002;3:7.
The patient characteristics and mortality associated with autosomal dominant polycystic kidney disease (PKD) have not been characterized for a national sample of end stage renal disease (ESRD) patients on the renal transplant waiting list.
40,493 patients in the United States Renal Data System who were initiated on ESRD therapy between 1 April 1995 and 29 June 1999 and later enrolled on the renal transplant waiting list were analyzed in an historical cohort study of the relationship between hematocrit at the time of presentation to ESRD and survival (using Cox Regression) in patients with PKD as a cause of ESRD.
Hematocrit levels at presentation to ESRD increased significantly over more recent years of the study. Hematocrit rose in parallel in patients with and without PKD, but patients with PKD had consistently higher hemoglobin. PKD was independently associated with higher hematocrit in multiple linear regression analysis (p < 0.0001). In logistic regression, higher hematocrit was independently associated with PKD. In Cox Regression analysis, PKD was associated with statistically significant improved survival both in comparison with diabetic (hazard ratio, 0.64, 95% CI 0.53–0.77, p < 0.001) and non-diabetic (HR 0.68, 95% CI 0.56–0.82, p = 0.001) ESRD patients, adjusted for all other factors.
Hematocrit at presentation to ESRD was significantly higher in patients with PKD compared with patients with other causes of ESRD. The survival advantage of PKD in ESRD persisted even adjusted for differences in hematocrit and in comparison with patients on the renal transplant waiting list.
PMCID: PMC122070  PMID: 12194700
Polycystic kidney disease; Caucasian; female; EPO; peritoneal dialysis; transplantation; complications; dialysis; USRDS; age; albumin; hemoglobin; weight; dysrythmias; mortality; frequency
16.  Evaluating the Contribution of the Cause of Kidney Disease to Prognosis in CKD: Results From the Study of Heart and Renal Protection (SHARP) 
The relevance of the cause of kidney disease to prognosis among patients with chronic kidney disease is uncertain.
Study Design
Observational study.
Settings & Participants
6,245 nondialysis participants in the Study of Heart and Renal Protection (SHARP).
Baseline cause of kidney disease was categorized into 4 groups: cystic kidney disease, diabetic nephropathy, glomerulonephritis, and other recorded diagnoses.
End-stage renal disease (ESRD; dialysis or transplantation) and death.
During an average 4.7 years' follow-up, 2,080 participants progressed to ESRD, including 454 with cystic kidney disease (23% per year), 378 with glomerulonephritis (10% per year), 309 with diabetic nephropathy (12% per year), and 939 with other recorded diagnoses (8% per year). By comparison with patients with cystic kidney disease, other disease groups had substantially lower adjusted risks of ESRD (relative risks of 0.28 [95% CI, 0.24-0.32], 0.40 [95% CI, 0.34-0.47], and 0.29 [95% CI, 0.25-0.32] for glomerulonephritis, diabetic nephropathy, and other recorded diagnoses, respectively). Albuminuria and baseline estimated glomerular filtration rate were associated more weakly with risk of ESRD in patients with cystic kidney disease than the 3 other diagnostic categories (P for interaction, <0.001 and 0.01, respectively). Death before ESRD was uncommon in patients with cystic kidney disease, but was a major competing risk for participants with diabetic nephropathy, whose adjusted risk of death was 2-fold higher than that of the cystic kidney disease group (relative risk, 2.35 [95% CI, 1.73-3.18]).
Exclusion of patients with prior myocardial infarction or coronary revascularization.
The cause of kidney disease has substantial prognostic implications. Other things being equal, patients with cystic kidney disease are at much higher risk of ESRD (and much lower risk of death before ESRD) than other patients. Patients with diabetic nephropathy are at particularly high risk of death prior to reaching ESRD.
PMCID: PMC4068325  PMID: 24613056
Kidney disease etiology; disease trajectory; end-stage renal disease (ESRD); disease progression; prognosis; cystic kidney disease; risk factor
17.  Tubulointerstitial disease in diabetic nephropathy 
Diabetes mellitus is the major cause of end stage renal disease (ESRD). We cannot predict which patient will be affected. ESRD patients suffer an extremely high mortality rate, due to a very high incidence of cardiovascular disease. Several randomized, prospective studies have been conducted to quantify the impact of strict glycemic control on morbidity and mortality, and have consistently demonstrated an association between strict glycemic control and a reduction in ESRD. Within the past 20 years, despite the implementation of treatments that were presumed to be renoprotective, diabetes mellitus has continued to rank as the leading cause of ESRD, which clearly indicates that we are still far from understanding the mechanisms involved in the initiation of ESRD. Progressive albuminuria has been considered as the sine qua non of diabetic nephropathy, but we know now that progression to diabetic nephropathy may well happen in the absence of initial microalbuminuria. The search for new biomarkers of early kidney damage has received increasing interest, since early identification of the pathways leading to kidney damage may allow us to adopt measures to prevent the development of ESRD. Most of these biomarkers are deeply influenced by environment, genetics, sex differences, and so on, making it extremely difficult to identify the ideal biomarker to target. At present, there are no new drugs that come close to providing the solutions we desire for our patients (ie, reducing complications). Even when used in combination with standard care, renal complications are, at best, only modestly reduced, at the considerable expense of additional pill burden and exposure to serious off-target effects. In this review, some of the hypothesized mechanisms of this heterogeneous disease will be considered, with particular attention to the tubule–interstitial compartment.
PMCID: PMC3968088  PMID: 24711709
TGF-β1; ESRD; Ox-LDL; diabetes; ESRD
18.  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
19.  Variation in Initial Kidney Replacement Therapy for End-Stage Renal Disease Due to Lupus Nephritis in the U.S. 
Arthritis care & research  2011;63(12):1642-1653.
Little is known about patterns of use of initial kidney replacement therapies among patients with LN end-stage renal disease (LN ESRD). We aimed to identify sociodemographic and clinical factors associated with variation in initial kidney replacement therapies among LN ESRD patients.
Patients with incident LN ESRD (1995–2006) were identified in the US Renal Data System. Age, sex, race, ethnicity, medical insurance, employment status, residential region, clinical factors and comorbidities were considered as potential predictors of ESRD treatment choice -- peritoneal dialysis (PD), hemodialysis (HD) or pre-emptive kidney transplantation -- in age-adjusted and multivariable-adjusted logistic regression analyses.
Of 11,317 individuals with incident LN ESRD, 82.0% initiated HD; 12.2% PD, and 2.8% underwent pre-emptive kidney transplantation. Receiving initial PD was significantly associated with earlier calendar year, female sex, higher albumin and hemoglobin, and lower serum creatinine levels. African Americans (vs. Whites), Medicaid beneficiaries and those with no health insurance (vs. private insurance), and those unemployed (vs. employed) had significantly reduced PD initiation. Comorbidities including congestive heart failure, peripheral vascular disease and inability to ambulate were also associated with decreased PD. Many sociodemographic and clinical factors favoring PD were associated with pre-emptive kidney transplant (vs. dialysis) as well.
Few patients with LN ESRD receive initial PD or pre-emptive kidney transplantation. Race, ethnicity, employment and medical insurance type are strongly associated with initial kidney replacement therapy choice. Future studies need to investigate the appropriateness of sociodemographic and clinical variation and the comparative effectiveness of kidney replacement therapies for LN ESRD.
PMCID: PMC3227771  PMID: 22058067
peritoneal dialysis; hemodialysis; kidney transplantation; survival; lupus; nephritis; end-stage renal disease; chronic kidney disease; systemic lupus erythematosus; African American; Hispanic; race; women
20.  Rates and outcomes of diabetic end-stage renal disease among registered native people in Saskatchewan. 
OBJECTIVE: To determine the rates and outcomes of diabetic end-stage renal disease (ESRD) among registered native people and non-native people in Saskatchewan. DESIGN: Retrospective population-based study using data from the Canadian Organ Replacement Registry. SETTING: Saskatchewan. PATIENTS: All patients with diabetic ESRD diagnosed between Jan. 1, 1981, and Dec. 31, 1990. MAIN OUTCOME MEASURES: Incidence rates of diabetic ESRD in the general population, rates of diabetic ESRD among patients with diabetes mellitus, nature of initial dialysis treatment, length of survival from start of dialysis, cause of death and renal transplant rates. RESULTS: The 10-year incidence rates of diabetic ESRD were higher among all age groups among registered native people than among non-native people. The overall relative risk ratio for native people was 16.2. When a higher prevalence of diabetes among native people was taken into account, native diabetic people were still seven times as likely as non-native diabetic people to manifest diabetic ESRD. The median survival from start of dialysis was under 2 years in both groups, but more native people died of stroke and more non-native people died of heart disease. Non-native diabetic people were more likely than native diabetic people to receive renal transplants. CONCLUSIONS: Although the overall incidence of diabetic ESRD in Saskatchewan is increasing, registered native people have a disproportionate risk for this serious complication.
PMCID: PMC1486186  PMID: 8287342
21.  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
22.  Kidney transplant in diabetic patients: modalities, indications and results 
Diabetes is a disease of increasing worldwide prevalence and is the main cause of chronic renal failure. Type 1 diabetic patients with chronic renal failure have the following therapy options: kidney transplant from a living donor, pancreas after kidney transplant, simultaneous pancreas-kidney transplant, or awaiting a deceased donor kidney transplant. For type 2 diabetic patients, only kidney transplant from deceased or living donors are recommended. Patient survival after kidney transplant has been improving for all age ranges in comparison to the dialysis therapy. The main causes of mortality after transplant are cardiovascular and cerebrovascular events, infections and neoplasias. Five-year patient survival for type 2 diabetic patients is lower than the non-diabetics' because they are older and have higher body mass index on the occasion of the transplant and both pre- and posttransplant cardiovascular diseases prevalences. The increased postransplant cardiovascular mortality in these patients is attributed to the presence of well-known risk factors, such as insulin resistance, higher triglycerides values, lower HDL-cholesterol values, abnormalities in fibrinolysis and coagulation and endothelial dysfunction. In type 1 diabetic patients, simultaneous pancreas-kidney transplant is associated with lower prevalence of vascular diseases, including acute myocardial infarction, stroke and amputation in comparison to isolated kidney transplant and dialysis therapy.
Type 1 and 2 diabetic patients present higher survival rates after transplant in comparison to the dialysis therapy, although the prevalence of cardiovascular events and infectious complications remain higher than in the general population.
PMCID: PMC2758579  PMID: 19825194
23.  Prevalence, determinants and co-morbidities of chronic kidney disease among First Nations adults with diabetes: results from the CIRCLE study 
BMC Nephrology  2012;13:57.
Indigenous peoples worldwide are experiencing elevated rates of type 2 diabetes and its complications. To better understand the disproportionate burden of diabetic end stage renal disease (ESRD) among Canadian First Nations people (FN), we examined prevalence, determinants, and co-morbidities of chronic kidney disease (CKD) within this population.
The 2007 Canadian FN Diabetes Clinical Management and Epidemiologic (CIRCLE) study conducted a cross-sectional national medical chart audit of 885 FN adults with type 2 diabetes to assess quality of diabetes care. In this sub-study, participants were divided by estimated glomerular filtration rate (eGFR in ml/min/1.73 m2), as well as by albuminuria level in those with eGFRs = > 60. Those with eGFRs = > 60 and negative albuminuria were considered to have normal/near normal kidney function (non-CKD). Using univariate and logistic regression analysis, they were compared with participants having eGFRs = > 60 plus albuminuria (CKD-alb) and with participants having eGFRs <60 (CKD-eGFR <60).
While 84.5% of total CIRCLE participants had eGFRs = > 60, almost 60% of the latter had CKD-alb. Of the 15.5% of total participants with CKD-eGFR <60, 80% had eGFRs 30–60 (Stage 3 CKD) but over 10% (1.6% of total participants) had ESRD. Independent determinants of CKD-alb were male gender and increasing diabetes duration, systolic BP, A1C and total cholesterol. These plus smoking rates also discriminated between FN with micro- and macro-albuminuria. Independent determinants of CKD-eGFR <60 were increasing age at diabetes diagnosis, diabetes duration, total cholesterol and systolic BP. However, participants with CKD-eGFR <60 also displayed a decreasing mean age of diabetes diagnosis as eGFR declined. Micro-vascular co-morbidities were significantly associated with CKD-alb but both micro- and macro-vascular co-morbidities were associated with CKD-eGFR <60. Only 35-40% of participants with CKD used insulin.
High prevalences of CKD-alb and early CKD-eGFR <60 among diabetic FN were largely related to modifiable and treatable risk factors. However, an earlier age of diabetes diagnosis and longer duration of diabetes characterized those with ESRD. These findings suggest that a failure to meet current standards of diabetes care interacting with an age-related survival benefit contribute to the disproportionate burden of ESRD among FN and possibly other Indigenous peoples.
PMCID: PMC3438064  PMID: 22776036
Indigenous peoples; Aboriginal; First Nations; Diabetes; Chronic kidney disease; End stage renal disease; Risk factors.
24.  End stage renal disease 
BMJ Clinical Evidence  2007;2007:2002.
End stage renal disease (ESRD) affects over 1500 people per million population in countries with a high prevalence, such as the USA and Japan. Approximately two thirds of people with ESRD receive haemodialysis, a quarter have kidney transplants, and a tenth receive peritoneal dialysis.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of different doses and osmotic agents for peritoneal dialysis? What are the effects of different doses and membrane fluxes for haemodialysis? What are the effects of interventions aimed at preventing secondary complications? We searched: Medline, Embase, The Cochrane Library and other important databases up to April 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 20 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: cinacalcet, darbepoetin, dextrose solutions, erythropoietin, haemodialysis (standard-dose, increased-dose), high-membrane-flux haemodialysis, icodextrin, increased-dose peritoneal dialysis, low-membrane-flux haemodialysis, mupirocin, sevelamer, and standard-dose dialysis.
Key Points
End stage renal disease (ESRD) affects over 1500 people per million population in countries with a high prevalence, such as the USA and Japan. Approximately two thirds of people with ESRD receive haemodialysis, a quarter have kidney transplants, and a tenth receive peritoneal dialysis. Risk factors for ESRD include advanced age, hypertension, diabetes mellitus, obesity, a history of renal disease, and tobacco, heroin, or analgesic use.ESRD leads to fluid retention, anaemia, disturbances of bone and mineral metabolism, and increased risk of cardiovascular disease.
In people receiving peritoneal dialysis, 7.5% icodextrin solution may increase fluid loss compared with lower concentration dextrose solutions. Icodextrin may affect the accuracy of blood glucose measurement. Increasing the dose of peritoneal dialysis does not seem to reduce mortality.
In people receiving haemodialysis, there seems to be no difference in mortality for high membrane flux compared with low membrane flux, or increased-dose haemodialysis compared with standard dose.
Erythropoietin and darbepoetin may help maintain haemoglobin levels in people with ESRD, but are associated with mortality, and with serious cardiovascular, arterial, and venous thromboembolic events in people with kidney disease.
Disorders of calcium and phosphate metabolism may contribute to the increased risk of cardiovascular disease in people with ESRD. Phosphate binders (sevelamer) may slow down arterial calcification, and may reduce serum low density lipoprotein cholesterol levels, but we don't yet know whether this reduces cardiovascular events or mortality.
PMCID: PMC2943808  PMID: 19450356
25.  Pancreas Transplant Alone 
Diabetes Care  2013;36(8):2440-2447.
The goal of this review is to highlight the significant improvements, over the past four decades, in outcomes after a pancreas transplant alone (PTA) in patients with brittle diabetes and recurrent episodes of hypoglycemia and/or hypoglycemic unawareness. A successful PTA—in contrast to intensive insulin regimens and insulin pumps—restores normoglycemia without the risk of hypoglycemia and prevents, halts, or reverses the development or progression of secondary diabetes complications. In this International Pancreas Transplant Registry (IPTR) analysis, we reviewed the records of 1,929 PTA recipients from December 1966 to December 2011. We computed graft survival rates according to the Kaplan-Meier method and used uni- and multivariate analyses. In the most recent era (January 2007–December 2011), patient survival rates were >95% at 1 year posttransplant and >90% at 5 years. Graft survival rates with tacrolimus-based maintenance therapy were 86% at 1 year and 69% at 3 years and with sirolimus, 94 and 84%. Graft survival rates have significantly improved owing to marked decreases in technical and immunologic graft failure rates (P < 0.05). As a result, the need for a subsequent kidney transplant has significantly decreased, over time, to only 6% at 5 years. With patient survival rates of almost 100% and graft survival rates of up to 94% at 1 year, a PTA is now a highly successful long-term option. It should be considered in nonuremic patients with brittle diabetes in order to achieve normoglycemia, to avoid hypoglycemia, and to prevent the development or progression of secondary diabetes complications.
PMCID: PMC3714504  PMID: 23881967

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