Application of sparse linear discriminant analysis and elastic net for diagnosis of IgA nephropathy: statistical and biological viewpoints

Background: IgA nephropathy [IgAN] is the most common primary glomerulonephritis diagnosed based on renal biopsy. Mesangial IgA deposits along with the proliferation of mesangial cells are the histologic hallmark of IgAN. Non-invasive diagnostic tools may help to prompt diagnosis and therapy. The discovery of potential and reliable urinary biomarkers for diagnosis of IgAN depends on applying robust and suitable models. Applying two multivariate modeling methods on a urine proteomic dataset were obtained from IgAN patients, and comparison of the results of these methods were the purpose of this study

Methods: Two models were constructed for urinary protein profiles of 13 patients and 8 healthy individuals, based on sparse linear discriminant analysis [SLDA] and elastic net [EN] regression methods. A panel of selected biomarkers with the best coefficients were proposed and further analyzed for biological relevance using functional annotation and pathway analysis

Results: Transferrin, a1-antitrypsin, and albumin fragments were the most important up-regulated biomarkers, while fibulin-5, YIP1 family member 3, prasoposin, and osteopontin were the most important down-regulated biomarkers. Pathway analysis revealed that complement and coagulation cascades and extracellular matrix-receptor interaction pathways impaired in the pathogenesis of IgAN

Conclusion: SLDA and EN had an equal importance for diagnosis of IgAN and were useful methods for exploring and processing proteomic data. In addition, the suggested biomarkers are reliable candidates for further validation to non-invasive diagnose of IgAN based on urine examination

Costs of treatment after renal transplantation: is it worth to pay more?

The present study aimed to provide an estimation of the current financial burden of renal transplantation therapy for insurance organisations. An Excel-based model was developed to determine the treatment costs of current clinical practice in renal transplantation therapy [RTT]. Inputs were derived from Ministry of Health and insurance organizations' database, hospital and pharmacy records, clinical trials and available literature. A one-way sensitivity analysis and Monte-Carlo simulation were performed to illustrate total cost changes made by cost components and to test the reliability of model probabilities respectively. According to the model, 2200 patients received RTT in the study year which resulted in the first year total treatment cost of almost $14,000,000. These costs corresponded to annual total cost per patient of almost $6500 for the payers. According to the results of the study, treatment cost per patient in RTT is almost $6500 for the payers in Iran. Although RTT is almost fully reimbursed by government in Iran, an improvement in insurance decision making especially regarding new effective immunosuppressive drugs is quite necessary for controlling growing trends of OOP expenditures in these patients. The present study aimed to improve efficiency in budget allocation by providing insurance decision makers with an estimation of financial impact of current clinical practice in RTT, making it possible for them to compare current financial burden of the disease with the future cost burden of including newly submitted drugs to their formulary in RTT and also provided practical policy making recommendations in the end

Urinary proteomics in nephrotic syndrome

Nephrotic syndrome is the commonest glomerular disease. Typical symptoms could be proteinuria, low serum albumin and oedema. The mechanism of proteinuria in nephrotic syndrome is a defective glomerular ?ltration barrier. Renal biopsy is the gold standard for diagnosis of nephrotic syndrome currently which is invasive and based on histopathological features, therefore it seems to be necessary to search for noninvasive biomarkers to be used as the complementary tests in the diagnostics and prognostics of glomerular diseases, particularly when renal biopsy is limited or contraindicated. While a big proportion of urinary proteins originate from kidney tissue and these tissue specific proteins excrete more in kidney injury, therefore the identification of urinary proteins can further our understanding of renal dysfunction and renal disease including nephrotic syndrome. The interest of scientist to urinary proteomics is also growing for biomarker discovery. This review focuses on some types of nephrotic syndrome and proteomic studies applying urine specimen which have been reported

Effects of stem cells and granulocyte colony stimulating factor in reperfusion injury

Bone marrow-derived stem cells have a potential capacity to differentiate and accelerate recovery in injured sites of body. Also, factors like granulocyte colony stimulating factor [GCSF] can promote their mobilization to the injured sites. We aimed to investigate the role of GCSF as an alternative therapeutic option instead of mesenchymal stem cells [MSCs] in reperfusion injury. Twenty-nine rats with induced reperfusion injury were divided into 3 groups to receive MSC, GCSF, or nothing [control]. Kidney function was assessed by blood urea nitrogen and serum creatinine levels. Histological grading was performed to evaluate the extent of tubular injury and the rate of recovery. All the rats reached recovery after 14 days. Rats in the MSC group reached early functional and histological recovery compared to the controls on the 7th day of the study [P = .01 and P = .02, respectively]. Compared to the control group, the GCSF group showed a more significant histological recovery on the 7th day [P = .04], but kidney function was ameliorated on the 14th day [P = .04]. Both the GCSF and control groups had a significant number of CD34+ cells, which were detected by flow cytometry on the 7th day after reperfusion injury. We found therapeutic effects following administration of both MSC and GCSF which was more evident with MSC in the setting of reperfusion injury. More investigation is required to find optimal time, dose, and route of administration as well as other possible contributing factors

PDpoietin in comparison with eprex in treatment of anemic patients on hemodialysis

PDpoietin is a recombinant erythropoietin alfa that has been introduced by a manufacturer in Iran. We assessed the effectiveness and complications of PDpoietin in comparison with Eprex in anemic patients on hemodialysis. This clinical trial was performed in a multicenter setting. Patients with a hemoglobin level less than 12 g/dL were assigned into 2 groups in order to receive either Eprex [Janssen Cilag] or PDpoietin [Pooyesh Darou] for 3 months. Forty-one and 34 patients completed the study in the PDpoietin and Eprex groups, respectively. The mean hemoglobin levels at baseline were not significantly different between the two groups of patients with PDpoietin and Eprex. In both groups, hemoglobin levels increased significantly, but there were no significant differences between the two groups at months 1, 2, and 3. At the end of the study, the mean hemoglobin levels reached 11.6 +/- 1.7 g/dL and 11.8 +/- 1.9 g/dL, respectively [P = .002; P = .01]. The mean hemoglobin per cumulative of drug dose index [hemoglobin/[erythropoietin dose/1000 x injections per month]] was not significantly different between the two groups at different treatment stages, and it did not change significantly in each group during the course of the study. No serious complications were reported. Eprex and PDpoietin could equally increase the hemoglobin levels with no significant complication. Therefore, PDpoietin can be used for treatment of anemia in patients on dialysis, and the patients will have the advantages of its availability and low price

Burden of chronic kidney disease in Iran. A screening program is of essential need

The latent nature of chronic kidney disease [CKD] in primary stages precludes early diagnosis. This necessitates plans such as screening, but we should first introduce CKD as a public health problem. This study was designed to define the burden of CKD in Iran. We calculated disability-adjusted life years [DALYs] according to the World Health Organization's practical guidelines for national burden of disease studies. The sum of years of life lost and years lived with disability were estimated for CKD stages 1 to 4 and end-stage renal disease [ESRD] based on the national registry data and the published reports about CKD in Iran in 2004. Over 700 000 people were estimated to have CKD in Iran in 2004 and 61 000 new cases of CKD were anticipated. The prevalence rate of CKD was estimated to be 1083 and its incidence rate was 173.5 per 100 000 population. Chronic kidney disease was responsible for 1 145 654 DALYs. The highest DALYs for stages 1 to 4 of CKD were due to unknown etiology, diabetes mellitus, and hypertension [382 000 years, 347 400 years, and 311 800 years, respectively]. The DALY for ESRD and CKD stages 1 to 4 were 21 490 years and 1 124 164 years, respectively. The present study provides an estimate of the burden of CKD in Iran. As CKD can be controlled by practical cost-effective plans, we strongly recommend the information given by this study be considered for future action plans

Posttransplant lymphoproliferative disorders in kidney transplant recipients. An Iranian multicenter experience

Limited data with adequate sample size exist on the development of posttransplant lymphoproliferative disorder [PTLD] in living donor kidney recipients. We conducted a retrospective cohort study on the data of 10 transplant centers to identify the incidence of PTLD in Iran. Data of 9917 kidney transplant recipients who received their kidneys between 1984 and 2008 were reviewed. Fifty-one recipients [0.5%] who developed PTLD were evaluated with a median follow-up of 47.5 months [range, 1 to 211] months. Patients with PTLD represented 24% of all posttransplant malignancies [51 out of 211 cases]. There was no relationship between PTLD and sex [P = .20]. There were no statistically significance differences considering the age at transplantation between patients with and without PTLD. The late-onset PTLD [70.6%] occurred more frequently compared to the early form. There was no signification relationship between early-onset and late-onset groups in terms of clinical course and outcome. In patients who received azathioprine, PTLD was more frequent when compared to those who received mycophenolate mofetil [P < .001]. The lymph nodes were the predominantly involved site [35.3%], followed by the gastrointestinal tract, brain, kidney allograft, lung, ovary, vertebrae, and palatine. Age at diagnosis and the time from transplantation to diagnosis were comparable for various involvement sites of PTLDs. The overall mortality in this series of patients was 51.0%. Posttransplant lymphoproliferative disorder is a rare but devastating complication and long-term prognosis can be improved with early recognition and appropriate therapy

Spirometry parameters in patients undergoing hemodialysis with bicarbonate and acetate dialysates

End-stage renal disease causes impairment of all body organs including the heart and the lung. The main problems in the afflicted patients are pulmonary edema due to increased permeability of the capillaries, intravascular and interstitial volume overload, hypertension, and congestive heart failure. These changes cause altered physiologic and mechanical function of the lungs and subsequently increase in airway resistance. We aimed to study the impact of hemodialysis on spirometry parameters. In a cross-sectional study performed on 41 patients on maintenance hemodialysis, spirometry was done before and after the dialysis session. The patients were on either acetate or bicarbonate hemodialysis with the same method, dialysis machine, and duration of dialysis. Alterations in spirometry parameters including forced expiratory volume in the first second [FEV1], forced vital capacity [FVC], FEV1/FVC ratio, and maximal midexpiratory flow rate were determined and their relation with serum electrolytes, serum creatinine, blood urea nitrogen, and hemoglobin were analyzed. Twenty-nine patients undergoing dialysis with bicarbonate dialysate and 21 on dialysis with acetate were compared. Improvement in spirometry parameters was only significant in patients undergoing dialysis with bicarbonate dialysate. All spirometry parameters showed significant increases in the bicarbonate group except for the FEV1/FVC ratio. Furthermore, significant increase in these parameters was only prominent in the men. Postdialysis weight reduction and laboratory indexes had no significant correlation with improvement of spirometry parameters. Dialysis with bicarbonate dialysate causes significant improvement in spirometry parameters in men on maintenance dialysis. This effect might be independent of the effect of removing the volume overload by dialysis

Outcome of kidney transplantation in type 1 and type 2 diabetic patients and recipients with posttransplant diabetes mellitus

We aimed to assess the effects of different types of diabetes mellitus [DM] on patients receiving living donor kidney allografts. A total of 111 kidney transplant patients with DM and 111 randomly selected kidney transplant recipients without DM were enrolled in the study. The characteristics of the kidney allograft recipients and the allograft and patient outcomes were assessed and compared between 4 groups of kidney recipients without DM and patients with type 1 DM, type 2 DM, and posttransplant DM. Of the 111 patients with DM, 36 [32.4%], 20 [18.0%], and 55 [49.6%] had been diagnosed with type 1 DM, type 2 DM, and posttransplant DM, respectively. Diabetic patients had significantly higher rates of rejection episodes [P = .049] and suffered more frequently from delayed graft function [P = .03] compared to the kidney recipients in the control group. Patient and allograft survival rates were significantly lower in the patients with DM [regardless of their DM type] compared to the nondiabetic patients [P = .03 and P = .04, respectively]. Prominently, type 1 DM had significantly adverse effects on patient and allograft survival. Patients with posttransplant DM had a relatively better patient survival compared to those with type 1 DM and type 2 DM. We found that kidney recipients with DM, especially preexisting DM, had worse patient and graft survival rates compared to the nondiabetics. These findings suggest that kidney transplant patients presenting with any type of DM should be more closely followed

Atherosclerosis after kidney transplantation Changes of intime-media thichness of carotids during early posttransplant period

The aim of this study was to evaluate atherosclerotic changes in the carotid artery following kidney transplantation. Twenty- sis nonsmoker kidney allograft recipients who did not have cardiovascular disease or diabetes mellitus were enrolled in the study. The carotid intima-media thickness [IMT] was measured at 12 points using the patient's IMT. We followed the patients and changes in the carotid IMT were evaluated every 2 months up to the 6 th posttransplant month. The mean age of the patients at transplantation was 41.5 +/- 11.1 years. The mean baseline IMT was 0.84 +/- 0.22 mm. During the follow-up period it reached 0.85 +/- 0.22mm, 0.87 +/- 0.23 mm [P=0.1], and 0.88 +/- 0.24 mm /[P=.002] after 2, 4, and 6 months, respectively. The IMT measures significantly correlated stroke and 0.82 mm for MI, we found that 57.7% and 68% of the patients were at the risk of stroke at baseline and 6 months after transplantation [P<.001]. Also, 46.2% of the patients were at the risk of MI at baseline that rose to 53.8% at the end of the study [P<.001]. Atherosclerosis is an early event after kidney transplantation even in asymptomatic patients and those without major risk factors such as cardiovascular disease, diabetes mellitus, and smoking. Early diagnosis and treatment of atherosclerosis is of utmost importance

established rat model of inducing reversible acute tubular necrosis

Acute tubular necrosis [ATN] is a challenging problem that still requires to be studied in animal models. Our aim was to prepare an established experimental model of inducing reversible ATN in rats by determining the optimum duration of ischemia induction to the kidney. Twenty-four hour after nephrectomy of the right kidney and clamping the pedicle of the left kidney for durations ranging from 10 to 55 minutes, the kidney function and the histologic changes were evaluated. Accordingly, the optimum duration of clamping was determined and in the next step, it was considered for induction of reversible ATN in another group of rats. This group was followed up for 14 days and the pathologic course and function of the kidney were observed. Reversible ATN developed by 47-minute clamping of the renal pedicle. Blood urea nitrogen and serum creatinine levels were elevated up to threefold within 24 hours after the induction of ischemia and they decreased to their reference ranges after 12 and 6 days, respectively. In the histologic study of the kidneys, the least extend of injury was noted by the 14th day following the ATN induction. Even on the 14th day of the follow-up, some signs of ATN remained indicating that the tissue regeneration was not complete yet. To integrate the experimental models of ATN, a rat model with 47-minute clamping of the renal pedicle for induction of ischemia seems appropriate. The resultant ATN remains for a long duration, while kidney function is alleviated

Posttransplant malignancies and their relationship with human leukocyte antigens in kidney allograft recipients

Kidney transplant recipients are at increased risk of cancers, most frequently skin cancers, and in some regions, Kaposi sarcoma and non-Hodgkin lymphoma. We sought to investigate the associate of the most frequent malignancies among our patients with human leukocyte antigens [HLAs]. We performed a retrospective study on 44 kidney allograft recipients who had posttransplant malignancy and 44 kidney allograft recipients without malignant lesions [control group]. All of the patients had been treated by immunosuppressive regimens including cyclosporine plus prednisolone or cyclosporine, prednisolone, and mycophenolate mofetil. Data on HLA typing were achieved from their transplant records. There were 15 patients [34.1%] with Kaposi sarcoma; 13 [29.6%] with non-Hodgkin lymphoma, 6 [13.6%] with skin cancer, 2 [4.5%] with ovary cyst adenocarcinoma, and 8 [18.2%] with other tumors. The mean interval from transplantation to diagnosis of malignancy was 15.3 month. Twelve patients died of cancer during the follow-up [mean, 12.3 years]. No significant difference was noted in the age, sex, and time of transplantation between these patients and those in the control group. Kaposi sarcoma was associated with HLA-CW4 [P = .03] with an odds ratio of 4.96 [95% confidence interval, 2.90 to 8.12]. We found HLA-CW4 as a risk factor of Kaposi sarcoma in kidney allograft recipients. Screening for malignancies after kidney transplantation sounds very important with special attention to the specific environmental and genetic factors in each population