Nephropathic Patients Research Articles

Palliative Care for Nephropathic Patients

A new light has recently been shed on palliative care, especially, on its multidisciplinary approach developed to improve the Quality of life of seriously ill patients and their families. However, palliative care is still often mistakenly referred to as an end-of-life care and wrongly interchanged with hospice care. Nephropathic patients usually present a decrease in expectancy and Quality of life and may benefit from palliative care as opposed to hospice care. Palliative care requires a tight collaboration among different health care professionals, patients and their families, to share diagnosis, prognosis, realistic goals of treatment and therapeutic decisions. Several approaches may be attempted to improve the Quality of life of chronic nephropathic patients, such as palliative dialysis, conservative management and peritoneal dialysis. For example, personalized goals and a wider concept of adequacy of extracorporeal treatment are the bases of palliative dialysis. In specific subgroups of frail patients, the pharmacological conservative management could be more appropriate than extracorporeal treatment, as the former reduces the burdens derived from invasive procedures. Finally, peritoneal dialysis could be an important option for frail patients to avoid an aggressive extracorporeal treatment while maintaining a gentle solute and fluid control. However, only limited evidences are available on palliative and hospice care performed on patients with Acute Kidney Injury (AKI). Herein, the main variables affecting the medical decision-making on palliative care in nephropathic patients are described, and the different approaches available to improve quality of palliative care during Chronic and Acute Kidney Injury are analyzed.

Evaluation of sOX-2 levels in type2 diabetic foot and nephropathic patients: association with disease activity

Evaluation of sOX-2 levels in type2 diabetic foot and nephropathic patients: association with disease activity

Usefulness of US imaging in overhydrated nephropathic patients

Achievement of a normal hydration status is one of the major targets of hemodialysis. It is based on the estimation of "dry weight", the term used to define normal body fluid content. The concept of dry weight in hemodialysis patients is clinically undisputed, but it is not always easy to achieve in this population. Assessment of hydration status by clinical evaluation is imprecise and often unreliable. Measurement of the inferior vena cava (IVC) diameter has been shown to reflect individual fluid status. The relationship between variation in IVC diameter before and after hemodialysis session and weight loss has been investigated. Ultrasound (US) measurement of the IVC diameter is considered a valid measure of the hydration status and is routinely used in hemodialysis patients. Moreover, a relationship between IVC diameter, respiratory activity and hydration status, evaluated by considering both plasma volume and central venous pressure, has been demonstrated. In conclusion, assessment of hydration status based on blood pressure and central venous pressure can be considered reliable only in patients without signs of heart failure.

Effects of Italian Mediterranean organic diet vs. low-protein diet in nephropathic patients according to MTHFR genotypes

Several reports associate an Italian-style Mediterranean diet (IMD) with lower risk of cardiovascular disease and morbidity. The present study aimed to explore the effects of an Italian Mediterranean organic diet (IMOD) versus low-protein diet (LPD) in chronic kidney disease (CKD) patients, according to patients' carrier status for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. A total of 40 male patients with CKD and stable renal function (Kidney Disease Outcomes Quality Initiative stages 2 and 3) were classified according to MTHFR polymorphism as carrier T(+) or non carrier T(-). At the time of enrolment (T0) patients' diet consisted of LPD; they were then administered IMD for 14 days (T1), thereupon IMOD for 14 days (T2). Patients underwent a complete medical history, body composition assessment and biochemical analysis. Baseline homocysteine levels were on average 8.24 mol/l higher (95 % confidence interval 6.47, 10.00) among T(+) than T(-) and the difference was statistically significant (p < 0.001). We found a significant interaction between MTHFR status and the effect of both the IMD and IMOD on homocysteine levels compared to LPD (p for interaction <0.001). Both the IMD and IMOD resulted in significant variations of anthropometric and laboratory measurements. IMD and IMOD diets could represent a viable alternative to LPD in CKD patients on conservative therapy. The effect of these diets seems to be influenced by MTHFR genotypes.

Does Erythropoietin Always Win?

The synthesis of recombinant human erythropoietin has marked a turning point in the treatment of anaemia secondary to chronic kidney disease. However, the potentially fatal cardio- and cerebrovascular complications of the intake of high-doses of ESAs (erythropoiesis-stimulating agents), such as those observed in athletes who resort to doping, reason out the ever-prevalent debate concerning the balance between the risks and benefits of ESA administration for therapeutic purposes. Hence, there is still a discussion as to what values haemoglobin should ideally be maintained at. Additional concerns arise in cancer patients due to the ability of erythropoietin to act as an angiogenic and, in general, as a cell growth factor, because this might favour the progression of neoplastic disease. We summarized the prominent points of the latest guidelines on the management of anaemia in nephropathic patients, also identifying the possible risks that may result from the tendency to aim at too low haemoglobin levels.

Evaluation of soluble CD200 levels in type 2 diabetic foot and nephropathic patients: association with disease activity.

BackgroundCD200 (OX-2) is a novel immune-effective molecule, existing in a cell membrane-bound form, as well as in a soluble form in serum (s OX-2), which acts to regulate inflammatory and acquired immune responses.Material/MethodsWe planned this study to evaluate the sOX-2 levels of type 2 diabetic foot (group B), and compare it with that of healthy controls (group A). The patient group had the following values: DM period: 27.9±10.3 year [mean ±SD], HbA1c: 9.52±2.44% [mean ±SD].ResultsBlood samples for sCD200 measurement were always taken in the morning between 8 and 10 A.M.. The results were reported as means of duplicate measurements. Concentrations of sOX-2 in the serum samples were quantified using an ELISA kit. Serum hs-CRP levels were measured using an hs-CRP assay kit. The sOX-2 level in group B was 173.8±3.1 and in group A was 70.52±1.2 [p<0.0001). In subgroup analysis of T2DM-DFI patients, we noticed that sOX-2 levels were higher in WGS (Wagner grading system) I and II patients than in WGS III and IV patients. The HbA1c, BUN, creatinine, hs-CRP levels, and sedimentation rates were higher in the patient group (p<0.0001, p<0.001, p<0.001, p<0.005, and p<0.0001, respectively).ConclusionsWe suggest that there are vascular, immunologic, and neurologic components in DFI, whereas autoimmune diseases and inflammatory skin disorders have only an immunologic component. This is possibly evidence of a pro-inflammatory effect seen in DFI as a vascular complication.

77-P: THE POLYMORPHISM OF LEUKOCYTE AND ERYTHROCYTE ANTIGENS IN NEPHROPATHIC PATIENTS FROM SOUTHERN BRAZIL

The aim of this study was to evaluate the polymorphisms of human leukocyte antigen (HLA) and Duffy erythrocyte antigen in nephropathic patients from southern Brazil. One hundred and eighty three chronic kidney patients from southern Brazil participated in this study. HLA typing was performed using the LABType SSO kits locus HLA-A, -B and-DRB1 (One Lambda, Inc.). Duffy phenotypes were defined by the gel agglutination method using monoclonal anti-Fya and anti-Fyb antisera. Fisher’s exact test was employed for statistical analysis. Odds Ratio (OR) and Confidence Interval (CI) at 95% were calculated. Data from other studies with healthy individuals (voluntary bone marrow donors) were used for the comparison of analysis. In the analysis of the total samples, Fy(a+b+) phenotype was the most frequent (35%) and Fy(a-b-) phenotype was the rarest (5%). Nineteen HLA-A, 30 HLA-B and 13 HLA-DRB1 allele groups were identified. The 15 most frequent HLA allele groups were HLA-A∗01, A∗02, A∗03, A∗11, A∗24, HLA-B∗07, B∗15, B∗35, B∗44, B∗51, HLA-DRB1∗03, DRB1∗04, DRB1∗07, DRB1∗11 and DRB1∗13. The frequencies of Fy(a+b-) and Fy(a+b+) phenotypes of this study compared with healthy individuals from the same region, showed statistically significant difference with p <0.0001, OR = 2.56 (95% CI = 1.60-4.07) and p = 0.0039, OR = 1.71 (95% CI = 1.18-2.51), respectively. When comparing the HLA allele frequencies of patients and healthy individuals, it was observed that HLA-B∗42, B∗45, B∗51, DRB1∗03 were more frequent in patients and HLA-B∗44 in healthy individuals (p < 0.05). The polymorphism of these two markers when compared between the nephropathic patients from southern Brazil and other studies, suggest that the Duffy antigen and HLA allele groups may be engaged with chronic kidney disease (CKD). Further studies are needed to evaluate the influence of these markers in the evolution of CKD, as well as the evolution of transplantation.

A comparison of ELISA and HPLC methods for determination of ochratoxin A in human blood serum in the Czech Republic

Ochratoxin A (OTA) is one of the most naturally occurring fungal toxins in food. It has been detected in high concentrations in serum samples of nephropathic patients and can be applied as one of the markers of potential risk of this disease. Also, OTA can cause adverse effects on human health such as genotoxicity and is anticipated to be a potential human carcinogen. In this study, enzyme-linked immunosorbent assay (ELISA) and high performance liquid chromatography (HPLC) were applied in analysis of 115 blood serum samples of women in the child rearing age from the Czech Republic and both methods were compared. The OTA was presented in a broad range of concentrations from 0.037 to 1.130μg/L. The outcome of ELISA and HPLC measurements were well correlated (r=0.907). However, it was observed that ELISA tend to result in underestimating the OTA level at the low serum concentrations. Both methods had the same limits of quantification of 0.050μg/L under standard operation conditions. When OTA concentration in a sample was too low, the sample was redissolved in only 300μL of methanol and the detection limit for HPLC was lowered to 0.030μg OTA/L.

Erythrocyte glutathione transferase: a non-antibody biomarker for systemic sclerosis, which correlates with severity and activity of the disease

Erythrocyte glutathione transferase (e-GST) is a detoxifying enzyme hyper-expressed in nephropathic patients and used recently as a biomarker for blood toxicity. Systemic sclerosis (SSc) is characterized by endothelial dysfunction and fibrosis of the skin and internal organs. Renal involvement is frequent in SSc patients. Here we show that e-GST is hyper-expressed in SSc patients (n=102) and correlates (R2=0.49, P<0.0001) with the Medsger DSS and DAI Valentini indices that quantify the severity and activity of this disease. Interestingly, e-GST does not correlate with the impairment of kidney or other specific organs taken separately. e-GST hyper-expression seems to be linked to the presence of a factor (i.e., toxin) that triggers the autoimmune disease, and not to the damage of specific organs or to oxidative stress. e-GST may be proposed as an innovative non-antibody biomarker for SSc useful to check the progress of this disease and the efficiency of new therapeutic strategies.

The association between diabetic nephropathy and polymorphisms in PPARγ Pro 12Ala and CCR5δ 32 genes in type 2 diabetes

Abstract Background Diabetic nephropathy is one of the debilitating complications of type 2 diabetes and the leading cause for end-stage renal disease requiring renal replacement therapy. Currently identified risk factors do not fully explain the susceptibility of some patients to diabetic nephropathy. Peroxisome proliferator-activated receptor γ (PPARγ) Pro12Ala gene polymorphisms modulate insulin sensitivity and oxidative stress in diabetic patients, and conflicting data exist on its association with kidney disease in diabetes. Several polymorphisms in another immune modulator set of genes, the C–C chemokine receptor 5 (CCR5) genes, were associated with diabetic nephropathy. However, CCR5δ 32 gene polymorphisms were not studied in patients with diabetic nephropathy. The aim of this study was to assess the association between polymorphisms in both PPARγ Pro12Ala and CCR5δ 32 genes and the presence of diabetic nephropathy in Egyptian patients with type 2 diabetes. Methods We included 51 patients having type 2 diabetes for at least 5 years. They were all normotensive patients selected from the outpatient clinic with no other clinically identifiable risk factor for kidney disease. Genotype detection for PPARγ Pro12Ala and CCR5δ 32 gene polymorphisms was carried out using the PCR technique. Clinical data, HbA1c levels, lipid profile, and fasting and postprandial blood sugar levels were recorded. Serum creatinine levels and the urinary albumin/creatinine ratio were measured to stratify the participants according to the presence or absence of diabetic nephropathy. Results Age, sex, BMI, HbA1c, and duration of diabetes were not significantly different among patients with and those without diabetic nephropathy. Diabetic nephropathy patients had a significantly higher urinary albumin/creatinine ratio and lower estimated glomerular filtration rate levels (P &lt; 0.0001). Homozygotes for the PPARγ Pro12Ala Pro–Pro allele constituted 82% of our total study population and 86.4% of patients with diabetic nephropathy; the remaining were Pro–Ala heterozygotes, and we had no Ala–Ala homozygotes. The odds ratio for diabetic nephropathy in Pro–Pro homozygotes was 3.5 (P= 0.075, 95% confidence interval, 0.8–15). The Pro allele was present in 75% of patients with nephropathy and 50% of those without nephropathy. The Pro allele was significantly associated with diabetic nephropathy compared with the Ala allele (odds ratio = 3.5, P=0.012, 95% confidence interval, 1.3–15). With regard to the CCR5δ32 insertion/deletion genotype, 24 patients were homozygous for the insertion polymorphism, two were homozygous for the deletion polymorphism, and the remaining 25 were insertion/deletion heterozygotes. There was no significant difference between nephropathic and non-nephropathic patients as regards the CCR5δ 32 genotype (P=0.3) or the frequency of allele distribution (P = 0.6). Conclusion The Pro allele of PPARγ Pro12Ala was associated with diabetic nephropathy. Polymorphisms in the CCR5δ 32 gene did not show an association with diabetic nephropathy.

P62/SQSTM1 prominently accumulates in renal proximal tubules in nephropathic cystinosis

Nephropathic cystinosis, a lysosomal storage disorder, is associated with generalized proximal tubular dysfunction and progressive renal failure. The underlying molecular and cellular mechanisms leading to renal tubular injury remain largely unknown. Abnormal induction of autophagy has been shown in cystinosis. We have studied the autophagic flux in cystinosis by evaluating autophagy-specific substrates. LC3 and p62 expression was evaluated by (1) immunohistochemistry performed on kidney biopsies obtained from four nephropathic cystinosis patients, four patients with renal injury due to causes other than cystinosis, and four normal kidney tissues and (2) fluorescence imaging in cultured renal proximal tubular epithelial (RPTE) cells obtained from four nephropathic cystinosis patients and two lots of normal primary RPTE cells, both in basal and starvation conditions. p62 expression was also corroborated by western blot analysis in RPTE cells. There was a significant buildup of p62 protein in patients with nephropathic cystinosis, specifically in the proximal tubules in kidney biopsies and RPTE cells (p = 0.0004), and the accumulation was further enhanced upon starvation. Cystinotic RPTE cells exhibited a significant co-localization of p62 with LC3. Our findings indicate a potential block in the autophagic flux in cystinosis, thus providing key insights into the underlying mechanisms of tubular injury in cystinosis.

Severe Hypoglycemia Is a Serious Complication and Becoming an Economic Burden in Diabetes

BackgroundThe prevalence of hypoglycemia is increasing due to the growing incidence of diabetes and the latest strict guidelines for glycated hemoglobin (HbA1c) levels under 7%. This study examined the clinical characteristics, causal factors, and medical costs of severely hypoglycemic patients in an emergency room (ER) of Uijeongbu St. Mary's Hospital.MethodsThe study consisted of a retrospective analysis of the characteristics, risk factors, and medical costs of 320 severely hypoglycemic patients with diabetes who presented to an ER of Uijeongbu St. Mary's Hospital from January 1, 2006 to December 31, 2009.ResultsMost hypoglycemic patients (87.5%, 280/320) were over 60 years old with a mean age of 69.5±10.9 years and a mean HbA1c level of 6.95±1.46%. Mean serum glucose as noted in the ER was 37.9±34.5 mg/dL. Renal function was decreased, serum creatinine was 2.0±2.1 mg/dL and estimated glomerular filtration rate (eGFR) was 48.0±33.6 mL/min/1.73 m2. In addition, hypoglycemic patients typically were taking sulfonylureas or insulin and a variety of other medications, and had a long history of diabetes.ConclusionSevere hypoglycemia is frequent in older diabetic patients, subjects with low HbA1c levels, and nephropathic patients. Therefore, personalized attention is warranted, especially in long-term diabetics with multiple comorbidities who may not have been properly educated or may need re-education for hypoglycemia.

Follow-up and Treatment of Renal Transplantation with Nephropathic Cystinosis in Central Taiwan

BackgroundCystinosis is a rare autosomal recessive disease caused by a defect in lysosomal cystine. The intracellular cystine accumulation causes damage in multiple organs and renal failure. We retrospectively evaluated the outcomes and complications of patients with nephropathic cystinosis after renal transplantation (RT) in Taiwan. MethodsOnly 2 nephropathic cystinosis patients (siblings) had RT out of the 1,196 RTs in our hospital over the past 30 years. The younger sister received a living-related RT from her mother. The elder sister received a second cadaveric RT owing to chronic allograft rejection one-half year before. ResultsThey were diagnosed with cystinosis at ages 5 and 9 years, and received allografts at ages 13.4 (younger) and 19.8 and 26.4 (elder) years. They each experienced 1 episode of acute rejection at 6 months after the first RT. The elder sister suffered from obstructive nephropathy with progressive graft failure at age 26.4 years and was treated for vulvar condyloma and carcinoma in situ of cervix. The second graft kidney then maintained good kidney function. The younger sister delivered a girl without complication during gestation, and her renal function also remained good. At latest follow-up, they both had crystalline keratopathy and nephropathy, but no other system involvement. ConclusionsThe extrarenal complications with nephropathic cystinosis are high. These 2 siblings had only have ocular involvement without further cysteamine therapy. However, long-term follow-up is required to monitor development of complications and determine their prognoses.

Interleukin (IL)-10 Gene Polymorphisms Are Associated with Type 2 Diabetes With and Without Nephropathy: A Study of Patients from the Southeast Region of Iran

The impact of several environmental and genetic factors on diabetes and its complications is well documented. It has also been established that cytokines play a key role in the regulation of immune responses which have been shown to be important in the pathogenesis of diabetes. Studies showed that single-nucleotide polymorphisms within the -592 region of interleukin-10 (IL-10) are associated with the regulation of its expression. In this study, we aimed to find polymorphisms of this region that may be associated to type 2 diabetic (T2D) patients with and without nephropathy. In this study, peripheral blood samples were collected from 100 T2D patients without nephropathy, 100 T2D patients with nephropathy, and 100 healthy controls. DNA was extracted, and a polymerase chain reaction-restriction fragment length polymorphism technique was performed to examine the polymorphisms within the -592 region of the IL-10 gene. Our results showed a significant difference between the genotypes and alleles of the -592 region of IL-10 in nephropathic and non-nephropathic patients in comparison to the healthy controls. The differences between the two patient groups in relation to genotypes and alleles were not significant. Results of this study suggest that the functional gene polymorphism of IL-10 reported here may play an important role in the pathogenesis of diabetes, but it seems that these polymorphisms do not have an effect on the nephropathic complications of the disease.

Urinary Peptides as a Diagnostic Tool for Renal Failure Detected by Matrix-Assisted Laser Desorption/Ionisation Mass Spectrometry: An Evaluation of Their Clinical Significance

The development of new analytical methodologies related to the proteome for the evaluation of renal physiology and pathology is surely of wide interest for physicians, giving them new tools for monitoring complications associated with diabetes, such as end-stage renal disease. In the present study, the clinical significance of the urinary abundance of two peptides, SGSVIDQSRVLNLGPITR (the uromodulin precursor, m/z 1912) and IGPHypGPHypGLMGPP [present in the collagen-α-5(IV) chain precursor, m/z 1219], detected by matrix- assisted laser desorption/ionisation mass spectrometry (MALDI/MS) in microalbuminuric or nephropathic diabetic patients and in non-diabetic nephropathic patients was evaluated. A progressive increase in the abundance of the ion at m/z 1219 and a decrease in the abundance of the ion at m/z 1912 have been found in diabetic microalbuminuric, diabetic-nephropathic and nephropathic patients. Linear correlations are present between serum creatinine values and the abundances of the ions at m/z 1219 (positive correlation, r=0.3645, P<0.0001) and at m/z 1912 (negative correlation, r=-0.3053, P<0.0005). Correlations between the MALDI data and the estimated glomerular filtration rate were also found, while relationships with urinary albumin excretion were found only in sub-sets of patients. Analysis of receiver operating characteristic curves showed a sensitivity up to 96% and a specificity of up to 84% for the two ionic species, or their ratio, for distinguishing diabetic patients with different degrees of nephropathy from healthy subjects, proving that the urinary abundance of the two peptides at m/z 1219 and m/z 1912, determined with MALDI/MS, may be considered as a possible diagnostic tool for the determination of progression toward renal failure, also with the aim of monitoring kidney function, in diabetic patients.

Detection of autoantibodies against reactive oxygen species modified glutamic acid decarboxylase-65 in type 1 diabetes associated complications

BackgroundAutoantibodies against glutamate decarboxylase-65 (GAD65Abs) are thought to be a major immunological tool involved in pathogenic autoimmunity development in various diseases. GAD65Abs are a sensitive and specific marker for type 1 diabetes (T1D). These autoantibodies can also be found in 6-10% of patients classified with type 2 diabetes (T2D), as well as in 1-2% of the healthy population. The latter individuals are at low risk of developing T1D because the prevalence rate of GAD65Abs is only about 0.3%. It has, therefore, been suggested that the antibody binding to GAD65 in these three different GAD65Ab-positive phenotypes differ with respect to epitope specificity. The specificity of reactive oxygen species modified GAD65 (ROS-GAD65) is already well established in the T1D. However, its association in secondary complications of T1D has not yet been ascertained. Hence this study focuses on identification of autoantibodies against ROS-GAD65 (ROS-GAD65Abs) and quantitative assays in T1D associated complications.ResultsFrom the cohort of samples, serum autoantibodies from T1D retinopathic and nephropathic patients showed high recognition of ROS-GAD65 as compared to native GAD65 (N-GAD65). Uncomplicated T1D subjects also exhibited reactivity towards ROS-GAD65. However, this was found to be less as compared to the binding recorded from complicated subjects. These results were further proven by competitive ELISA estimations. The apparent association constants (AAC) indicate greater affinity of IgG from retinopathic T1D patients (1.90 × 10-6 M) followed by nephropathic (1.81 × 10-6 M) and uncomplicated (3.11 × 10-7 M) T1D patients for ROS-GAD65 compared to N-GAD65.ConclusionIncreased oxidative stress and blood glucose levels with extended duration of disease in complicated T1D could be responsible for the gradual formation and/or exposing cryptic epitopes on GAD65 that induce increased production of ROS-GAD65Abs. Hence regulation of ROS-GAD65Abs could offer novel tools for analysing and possibly treating T1D complications.

Population pharmacokinetics and pharmacodynamics of cysteamine in nephropathic cystinosis patients

BackgroundNephropathic cystinosis is an autosomal recessive disorder resulting in an impaired transport of cystine trough the lysosomal membrane causing an accumulation of free cystine in lysosomes. The only specific treatment for nephropathic cystinosis is cysteamine bitartrate. This study was aimed to describe the relationship between cysteamine plasma concentrations and white blood cell cystine levels, and to simulate an optimized administration scheme to improve the management of patients with cystinosis.MethodsCysteamine and cystine concentrations were measured in 69 nephropathic cystinosis patients. A total of 250 cysteamine plasma concentrations and 243 intracellular cystine concentrations were used to perform a population pharmacokinetic and pharmacodynamic analysis. An optimized administration scheme was simulated in order to maintain cystine levels below 1 nmol half-cystine/mg of protein and to investigate the possibility of administrating the treatment less than 4 times a day (QID, recommended). The current dosing recommendations are 1.3 g/m2/day for less than 50 kg BW and 2 g/day thereafter; the maximum dose should not exceed 1.95 g/m2/day.ResultsCysteamine concentrations were satisfactorily described by a one-compartment model. Parameter estimates were standardized for a mean standard bodyweight using an allometric model. WBC cystine levels were adequately described by an indirect response model where the first-order removal rate constant is stimulated by the cysteamine concentrations.ConclusionsAccording to simulations, in order to increase the percentage of patient with cystine levels below 1 nmol half-cystine/mg of protein, the current dosages could be changed as follows: 80 mg/kg/day (QID) from 10 to 17 kg, 70 mg/kg/day (QID) from 17 to 25 kg, 60 mg/kg/day (QID) from 25 to 40 kg and 50 mg/kg/day (QID) from 40 to 70 kg (these dosages remain under the maximum recommended dose). However an 8-hourly daily treatment (TID) did not provide acceptable cystine levels and should not be proposed.

Insights into novel cellular injury mechanisms by gene expression profiling in nephropathic cystinosis

Nephropathic cystinosis is a rare, inherited metabolic disease caused by functional defects of cystinosin associated with mutations in the CTNS gene. The mechanisms underlying the phenotypic alterations associated with this disease are not well known. In this study, gene expression profiles in peripheral blood of nephropathic cystinosis patients (N = 7) were compared with controls (N = 7) using microarray technology. In unsupervised hierarchical clustering analysis, cystinosis samples co-clustered, and 1,604 genes were significantly differentially expressed between both groups. Gene ontology analysis revealed that differentially expressed genes in cystinosis were enriched in cell organelles such as mitochondria, lysosomes, and endoplasmic reticulum (p ≤ 0.030). The majority of the differentially regulated genes were involved in oxidative phosphorylation, apoptosis, mitochondrial dysfunction, endoplasmic reticulum stress, antigen processing and presentation, B-cell-receptor signaling, and oxidative stress (p ≤ 0.003). Validation of selected genes involved in apoptosis and oxidative phosphorylation was performed by quantitative real-time polymerase chain reaction (PCR). Electron microscopy and confocal imaging of cystinotic renal proximal tubular epithelial cells further confirmed anomalies in the cellular organelles and pathways identified by microarray analysis. Further analysis of these genes and pathways may offer critical insights into the clinical spectrum of cystinosis patients and ultimately lead to novel links for targeted therapy.

ACE gene polymorphism and serum ACE activity in Iranians type II diabetic patients with macroalbuminuria

There are controversial results related to the contribution of insertion (I)/deletion (D) polymorphism of the angiotensin I-converting enzyme (ACE) in the development of diabetic nephropathy. To assess the distribution of this polymorphism in diabetic patients with and without nephropathy we studied 140 unrelated type 2 diabetic patients from the Kermanshah Province of Iran with ethnic background of Kurds including 68 patients with macroalbuminuria and 72 normoalbuinuric diabetic patients as controls. Genotyping was done by polymerase chain reaction (PCR). The frequency of D allele in nephropathic and normoalbuminuric patients were 69.1 and 58.3%, respectively (P=0.061). In individuals with DD genotype the risk of macroalbuminuria increased 2.87-fold (P=0.057). Significant lower level of serum ACE activity was found in the normoalbuminuric (59.76IU/l) compared to macroalbuminuric (97.43IU/l) patients. The serum ACE activity was significantly higher in macroalbuminuric patients with ID (105.7IU/l) and ID+DD (100.7IU/l) genotypes compared to normoalbuminuric patients with the same genotypes (63.5 and 64.2IU/l, respectively). Treatment with captopril significantly (P=0.045) reduced the serum ACE activity in normoalbuminuric patients with DD genotype compared to macroalbuminuric patients with the same genotype (33.6 vs. 73.8IU/l). However, the greatest benefit effect of losartan therapy on ACE activity was observed only in macroalbuminuric patients with DD genotype compared to that in normoalbuminuric patients (61.0 vs. 109.0IU/l, P=0.06). Our study suggests the importance of ethnic origin in the development of diabetic nephropathy and demonstrates different responses to therapy according to genotype and stage of diabetes.

Polymorphisms within exon 9 but not intron 8 of the vitamin D receptor are associated with the nephropathic complication of type‐2 diabetes

The impact of several environmental and genetic factors on diabetes and its complications is well documented but there is an urgent need to understand more about genetic risk factors associated with this disease. The present study was aimed at examining the two single nucleotide polymorphisms (SNP) in intron 8 and exon 9 of the vitamin D receptor (VDR) gene in nephropathic and non-nephropathic type-2 diabetic patients. In this clinical study, peripheral blood samples were obtained from 100 type-2 diabetic patients, 100 nephropathic type-2 diabetic patients and 100 healthy controls. DNA was extracted and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to examine two SNP polymorphisms within the VDR gene. Our results showed a significant difference in the Taq-1 evaluated genotypes of exon 9 in the VDR gene of diabetic individuals with (P=0.012) and without (P ≤ 0.001) nephropathy. Analysis of the Taq-1 evaluated alleles of nephropathic (P=0.917) and non-nephropathic (P=1.000) did not show a significant difference. We also evaluated the intron 8 Apa-1 alleles in patients with (P=0.480) and without nephropathy (P=0.543) and determined there were no differences between these groups. Our results also showed that the frequency of Apa-1 genotypes did not differ in nephropathic (P=0.224) and non-nephropathic (P=0.236) diabetic patients. Based on our results, it can be concluded that VDR and its functional polymorphism in exon 9 may play an important role in pathogenesis of type-2 diabetes and more investigations are required to clarify their role in nephropathy.