Posttransplantation Anemia in Kidney Transplant Recipients.

Posttransplantation anemia (PTA) is common among kidney transplant patients. Early PTA is usually defined as anemia which develops up to 6 months after transplantation, and late PTA is defined as anemia which develops after 6 months. There are multiple causes, with iron deficiency being the major contributor. The occurrence of late PTA has been associated with impaired graft function. Early PTA has been shown to be a predictor of late PTA. PTA is associated with reduced mortality, reduced graft survival, and a decline in GFR. The association with mortality is related to the severity of the anemia and to specific causes of anemia. Treatment of PTA should probably begin as soon as possible after kidney transplantation. The optimal target hemoglobin level in kidney transplant recipients with anemia is higher than recommended in chronic kidney disease and should probably be up to 12.5-13 g/dL. In order to achieve this target, appropriate treatment with erythropoiesis-stimulating agents (ESA) and iron is indicated.

Post renal transplant anemia: severity, causes and their association with graft and patient survival.

BACKGROUND: Post transplantation anemia (PTA) is common among kidney transplant patients. PTA is associated with increased graft loss and in most studies with increased mortality. However, the effect of the severity of anemia on this associations was not thoroughly evaluated. METHODS: Patients who underwent kidney transplantation in Rabin Medical Center (RMC) were included in the study. Data were collected during the years 2002-2016. Anemia was defined as hemoglobin (Hb) level less than 12 g/dL in women and less than 13 g/dL in men, in accordance with World Health Organization (WHO) criteria. Severe anemia was defined as hemoglobin lower than 11 g/dL. Primary outcome was a composite of patient and graft survival. We used univariate and multivariate models to evaluate association between severity and specific causes of anemia with the outcomes. As the risk associated with anemia changed over time we analyzed the risk separately for the early and the late period (before and after 1251 days). RESULTS: Our cohort included 1139 patients, 412 (36.2%) of which had PTA and 134 (11.7%) had severe anemia. On multivariable analysis, severe anemia was highly associated with the primary outcome at the early period (HR 6.26, 95% CI 3.74-10.5, p < 0.001). Anemia due to either AKI & acute rejection (11.9% of patients) or infection (16.7%), were associated with primary outcome at the early period (HR 9.32, 95% CI 5.3-26.41, p < 0.001 and HR 3.99, 95% CI 2.01-7.95, p < 0.001, respectively). There was non-significant trend for association between anemia due to Nutritional deficiencies (29.1%) and this outcome (HR 3.07, 95% CI 0.93-10.17, p = 0.067). CONCLUSION: PTA is associated with graft loss and mortality especially during the first three years. Anemia severity affects this association. An anemia workup is recommended for PTA.

Association of the combination of time-weighted variability of tacrolimus blood level and exposure to low drug levels with graft survival after kidney transplantation.

Background: The variability of tacrolimus blood levels has been shown to be associated with inferior graft survival. However, the effect of variability during the early post-transplantation period has not been evaluated. We sought to evaluate the association between time-weighted variability in the early post-transplantation period and graft survival. We also explored the interaction between drug level variability and exposure to inadequate drug levels. Methods: This retrospective cohort study included all patients who underwent kidney transplantation in the Rabin Medical Center and were treated with tacrolimus. Time-weighted coefficient of variability (TWCV) was defined as time-weighted standard deviation divided by the mean drug level. Univariate and multivariate Cox proportional hazard model was used with the primary outcome of patients and graft survival. Results: The study population included 803 patients who underwent kidney transplantation between 1 January 2000 and 29 September 2013. The high tertile of TWCV of tacrolimus blood levels was associated with reduced graft survival by univariate and multivariate analyses [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.14-2.53, P = 0.01 and HR 1.74, 95% CI 1.14-2.63, P = 0.01, respectively]. The interaction between high TWCV and exposure to inadequately low drug levels was significantly associated with reduced survival (P = 0.004), while the interaction between TWCV and high drug blood levels was not. One hundred and thirty patients (16.2%) had the combination of high TWCV and exposure to low drug values (<5 ng/mL). These patients had reduced graft survival by univariate and multivariate analyses (HR 2.42, 95% CI 1.57-3.74, P < 0.001 and HR 2.6, 95% CI 1.65-4.11, P < 0.001, respectively). Conclusions: The combination of high TWCV and exposure to low drug levels might identify high-risk patients in the early post-transplantation period.

The incidence of post-transplant cancer among kidney transplant recipients is associated with the level of tacrolimus exposure during the first year after transplantation.

PURPOSE: Immunosuppressive therapy plays a major role in the development of post-transplant cancer. In this nested case-control study of kidney transplant recipients (KTRs), we investigated whether the incidence of post-transplant cancer is associated with the level of tacrolimus exposure over time. METHODS: We screened the Rabin Medical Center database for adults who received kidney transplants between 2001 and 2014 and developed post-transplant cancer (excluding basal and squamous cell skin cancers). They were matched against KTRs without cancer. All patients received a maintenance immunosuppressive treatment with tacrolimus, mycophenolate mofetil and corticosteroids. The degree of exposure to tacrolimus was estimated as the time-weighted average (tTWA) value of tacrolimus blood levels. The tTWA was calculated as the area under the curve divided by time at 1, 6, and 12 months after transplantation and at time of cancer diagnosis. RESULTS: Thirty-two cases were matched against 64 controls. tTWA values above 11 ng/mL at 6 and 12 months after transplantation were associated with odds ratio (OR) of 3.1 (95% CI 1.1-9) and 11.7 (95% CI = 1.3-106), respectively, for post-transplant cancer; and with OR of 5.2 (95% CI 1.3-20.5) and 14.1 (95% CI = 1.5-134.3), respectively, for cancer diagnosed more than 3 years after transplantation. CONCLUSION: Exposure to a tacrolimus time-weighted average level above 11 ng/mL at 6 or 12 months after kidney transplantation is associated with an increased risk of developing cancer.

G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes.

Obesity and diabetes mellitus are the leading causes of renal disease. In this study, we determined the regulation and role of the G protein-coupled bile acid receptor TGR5, previously shown to be regulated by high glucose and/or fatty acids, in obesity-related glomerulopathy (ORG) and diabetic nephropathy (DN). Treatment of diabetic db/db mice with the selective TGR5 agonist INT-777 decreased proteinuria, podocyte injury, mesangial expansion, fibrosis, and CD68 macrophage infiltration in the kidney. INT-777 also induced renal expression of master regulators of mitochondrial biogenesis, inhibitors of oxidative stress, and inducers of fatty acid ß-oxidation, including sirtuin 1 (SIRT1), sirtuin 3 (SIRT3), and Nrf-1. Increased activity of SIRT3 was evidenced by normalization of the increased acetylation of mitochondrial superoxide dismutase 2 (SOD2) and isocitrate dehydrogenase 2 (IDH2) observed in untreated db/db mice. Accordingly, INT-777 decreased mitochondrial H2O2 generation and increased the activity of SOD2, which associated with decreased urinary levels of H2O2 and thiobarbituric acid reactive substances. Furthermore, INT-777 decreased renal lipid accumulation. INT-777 also prevented kidney disease in mice with diet-induced obesity. In human podocytes cultured with high glucose, INT-777 induced mitochondrial biogenesis, decreased oxidative stress, and increased fatty acid ß-oxidation. Compared with normal kidney biopsy specimens, kidney specimens from patients with established ORG or DN expressed significantly less TGR5 mRNA, and levels inversely correlated with disease progression. Our results indicate that TGR5 activation induces mitochondrial biogenesis and prevents renal oxidative stress and lipid accumulation, establishing a role for TGR5 in inhibiting kidney disease in obesity and diabetes.

Intravenous Versus Oral Iron Supplementation for the Treatment of Anemia in CKD: An Updated Systematic Review and Meta-analysis.

BACKGROUND: Iron supplementation is crucial for the treatment of anemia of chronic kidney disease (CKD). Although intravenous (IV) iron is preferred for patients with CKD receiving dialysis (CKD stage 5D), the method of iron replacement for patients with CKD stages 3 to 5 is controversial. STUDY DESIGN: Systematic review and meta-analysis. A search was performed until October 2015 of MEDLINE, Cochrane Library, conference proceedings in nephrology, and reference lists of included trials. SETTING & POPULATION: Patients with CKD stages 3 to 5 or 5D. SELECTION CRITERIA FOR STUDIES: All randomized controlled trials, regardless of publication status or language. INTERVENTION: IV versus oral iron supplementation. OUTCOMES: The primary outcome was defined as percentage of patients reaching an elevation in hemoglobin (Hb) concentration > 1g/dL. Secondary end points included percentage of patients who reached Hb levels > 11g/dL, absolute Hb concentration, change in Hb concentration, transferrin saturation, ferritin levels, erythropoiesis-stimulating agents and blood transfusion requirement, and quality of life. Safety analysis included all-cause mortality and serious and all adverse events. RESULTS: 24 trials were identified, 13 including 2,369 patients with CKD stages 3 to 5 and 11 including 818 patients with CKD stage 5D. Patients treated with IV iron were more likely to reach an Hb response > 1g/dL (risk ratios [RRs] of 1.61 [95% CI, 1.39-1.87] for CKD stages 3-5 and 2.14 [95% CI, 1.68-2.72] for CKD stage 5D). Safety analysis showed similar rates of mortality and serious and any adverse effects. IV iron replacement was associated with higher risk for hypotension (RR, 3.71; 95% CI, 1.74-7.94) and fewer gastrointestinal adverse events (RR, 0.43; 95% CI, 0.28-0.67). LIMITATIONS: Significant heterogeneity between trials; follow-up was usually limited to 3 months. CONCLUSIONS: Our results agree with current recommendations for IV iron replacement for patients with CKD stage 5D and support increased use of IV iron for patients with CKD stages 3 to 5.

A New Cutoff for Abnormal Proteinuria in Diabetes Mellitus Patients: Relationship to Albuminuria.

BACKGROUND: Proteinuria and albuminuria are markers of kidney injury and function, serving as a screening test as well as a means of assessing the degree of kidney injury and risk for cardiovascular disease and death in both the diabetic and the non-diabetic general population. OBJECTIVES: To evaluate the association between proteinuria below 300 mg/24 hours and albuminuria, as well as a possible association with kidney function in patients with diabetes mellitus (DM). METHODS: The medical files of patients with type 1 and type 2 DM with proteinuria below 300 mg/24 hours at three different visits to the Diabetic Nephropathy Clinic were screened. This involved 245 patient files and 723 visits. The data collected included demographics; protein, albumin and creatinine levels in urine collections; blood biochemistry; and clinical and treatment data. RESULTS: The association between proteinuria and albuminuria is non-linear. However, proteinuria in the range of 162-300 mg/24 hours was found to be linearly and significantly correlated to albuminuria (P < 0.001, r = 0.58). Proteinuria cutoff, based on albuminuria cutoff of 30 mg/24 hours, was found to be 160.5 mg/24 hr. Body mass index (BMI) was the sole independent predictor of proteinuria above 160.5 mg/24 hr. Changes in albuminuria, but not proteinuria, were associated with changes in creatinine clearance. CONCLUSIONS: A new cutoff value of 160.5 mg/hr was set empirically, for the first time, for abnormal proteinuria in diabetic patients. It appears that proteinuria below 300 mg/24 hr is not sufficient as a sole prognostic factor for kidney failure.

Guanine polynucleotides are self-antigens for human natural autoantibodies and are significantly reduced in the human genome.

In the course of investigating anti-DNA autoantibodies, we examined IgM and IgG antibodies to poly-G and other oligonucleotides in the sera of healthy persons and those diagnosed with systemic lupus erythematosus (SLE), scleroderma (SSc), or pemphigus vulgaris (PV); we used an antigen microarray and informatic analysis. We now report that all of the 135 humans studied, irrespective of health or autoimmune disease, manifested relatively high amounts of IgG antibodies binding to the 20-mer G oligonucleotide (G20); no participants entirely lacked this reactivity. IgG antibodies to homo-nucleotides A20, C20 or T20 were present only in the sera of SLE patients who were positive for antibodies to dsDNA. The prevalence of anti-G20 antibodies led us to survey human, mouse and Drosophila melanogaster (fruit fly) genomes for runs of T20 and G20 or more: runs of T20 appear > 170,000 times compared with only 93 runs of G20 or more in the human genome; of these runs, 40 were close to brain-associated genes. Mouse and fruit fly genomes showed significantly lower T20/G20 ratios than did human genomes. Moreover, sera from both healthy and SLE mice contained relatively little or no anti-G20 antibodies; so natural anti-G20 antibodies appear to be characteristic of humans. These unexpected observations invite investigation of the immune functions of anti-G20 antibodies in human health and disease and of runs of G20 in the human genome.

Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy.

Animal models link ectopic lipid accumulation to renal dysfunction, but whether this process occurs in the human kidney is uncertain. To this end, we investigated whether altered renal TG and cholesterol metabolism results in lipid accumulation in human diabetic nephropathy (DN). Lipid staining and the expression of lipid metabolism genes were studied in kidney biopsies of patients with diagnosed DN (n = 34), and compared with normal kidneys (n = 12). We observed heavy lipid deposition and increased intracellular lipid droplets. Lipid deposition was associated with dysregulation of lipid metabolism genes. Fatty acid ß-oxidation pathways including PPAR-α, carnitine palmitoyltransferase 1, acyl-CoA oxidase, and L-FABP were downregulated. Downregulation of renal lipoprotein lipase, which hydrolyzes circulating TGs, was associated with increased expression of angiopoietin-like protein 4. Cholesterol uptake receptor expression, including LDL receptors, oxidized LDL receptors, and acetylated LDL receptors, was significantly increased, while there was downregulation of genes effecting cholesterol efflux, including ABCA1, ABCG1, and apoE. There was a highly significant correlation between glomerular filtration rate, inflammation, and lipid metabolism genes, supporting a possible role of abnormal lipid metabolism in the pathogenesis of DN. These data suggest that renal lipid metabolism may serve as a target for specific therapies aimed at slowing the progression of glomerulosclerosis.

Pemphigus vulgaris is characterized by low IgG reactivities to specific self-antigens along with high IgG reactivity to desmoglein 3.

Pemphigus vulgaris (PV) is an autoimmune skin disease, which has been characterized by IgG autoantibodies to desmoglein 3. Here we studied the antibody signatures of PV patients compared with healthy subjects and with patients with two other autoimmune diseases with skin manifestations (systemic lupus erythematosus and scleroderma), using an antigen microarray and informatics analysis. We now report a previously unobserved phenomenon--patients with PV, compared with the healthy subjects and the two other diseases, show a significant decrease in IgG autoantibodies to a specific set of self-antigens. This novel finding demonstrates that an autoimmune disease may be associated with a loss of specific, healthy IgG autoantibodies and not only with a gain of specific, pathogenic IgG autoantibodies.

Epstein-Barr virus antibodies mark systemic lupus erythematosus and scleroderma patients negative for anti-DNA.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities - anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein-Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease.

The very old on hemodialysis: 8 years' experience in a single unit.

BACKGROUND: Elderly patients constitute a significant proportion of chronically dialyzed patients. This study evaluated mortality rates and predictors of mortality among very old patients receiving chronic hemodialysis (HDx). METHODS: A single-center retrospective analysis was carried out on patients >84 years of age who started chronic dialysis between 2004 and 2012. Univariate and multivariate analyses determined which parameters predicted survival. RESULTS: Twenty-nine hemodialyzed patients (19 males) were studied. Mean age was 88 ± 3 years. Median survival time was 38 months (range 4-96). One-year and 2-year survival probability was 80 and 65%, respectively. The most common cause of death was complicated peripheral vascular disease. Multivariate analysis revealed the following: for each 1 g/dl decrease in serum albumin level, the hazard ratio for patient death was 2.63 (p = 0.017), and for each weekly HDx treatment time decrease of 1 h, the hazard ratio for patient death was 1.40 (p = 0.006). CONCLUSION: Very elderly patients can be hemodialyzed with cautious optimism.

Atypical HUS due to factor H antibodies in an adult patient successfully treated with eculizumab.

BACKGROUND: Anti-complement factor H (CFH) antibodies is an extremely rare cause of atypical hemolytic uremic syndrome (aHUS) in adults, with less than 10 cases reported thus far. Although infectious diarrhea is a common inciting trigger for aHUS episode, there are no reports of an association with inflammatory bowel disease. Eculizumab is an emerging treatment for aHUS. Eculizumab has not been reported thus far to be given for aHUS due to anti-CFH antibodies. We report here for the first time on an adult patient with ulcerative colitis (UC) who developed aHUS due to anti-CFH antibodies, presented with decreased serum levels of both C3 and C4. She had an excellent response to treatment with eculizumab. CASE PRESENTATION: A 27-year-old Caucasian woman, who suffered from steroid-dependent UC, was admitted with microangiopathic hemolytic anemia and acute kidney injury with nephrotic syndrome. ADAMTS 13 was normal and comprehensive workout for secondary causes of HUS was negative. Both serum complement level of C3 and C4 were low. Kidney biopsy was compatible with the diagnosis of HUS with negative immunofluorescence. Because of only partial response to plasma exchange and high dose steroids, eculizumab was commenced. After two weeks signs of microangiopathy subsided, and kidney function began to recover. Few months after the diagnosis, a complement components investigation revealed antibodies against CFH at high titer of 2000 arbitrary units. Today her creatinine is stable with no proteinuria and no signs of HUS.

TGFß1-dependent podocyte dysfunction.

PURPOSE OF REVIEW: The glomerular filtration barrier is a unique structure characterized by a specialized framework of podocytes. Transforming growth factor-ß1 (TGFß1) upregulation occurs in virtually all chronic kidney diseases and is associated with podocyte injury and proteinuria. This review is aimed at describing the latest advances made in the understanding of TGFß-induced podocyte injury. RECENT FINDINGS: During the past decade, progress has been made in understanding the biology and mechanisms of TGFß-induced podocyte injury. Most forms of glomerular diseases, including diabetic nephropathy, are associated with increased TGFß1 signaling and thus TGFß1 plays a central role in the pathogenesis of podocytopathy. The mechanism of podocyte injury is complex, involving a number of independent and overlapping cellular and molecular pathways. This review will examine these direct and indirect effects of TGFß1 on podocyte dysregulation as reflected in their growth, differentiation, and motility. SUMMARY: These new developments in understanding the podocyte response to injury are critical for establishing better therapeutic interventions that target specific pathways, which otherwise could lead to irreversible injury.

Regression of left ventricular hypertrophy in patients with primary aldosteronism/low-renin hypertension on low-dose spironolactone.

BACKGROUND: The incidence of left ventricular hypertrophy (LVH) in primary aldosteronism (PA) is higher than in essential hypertension. LVH is an independent cardiovascular risk factor. Treatment of PA with mineralocorticoid receptor blockers (MRBs) improves LVH. Previous studies included relatively small groups, low incidence of LVH and used high MRB dose. We tested the hypothesis that long-term regression of LVH in PA/low-renin hypertension may be achieved with low-dose MRB. METHODS: Forty-eight patients (male/female 28/20, age 61.4 years, range 47-84) had PA (low renin, high aldosterone and high aldosterone/renin ratio, n=24) or low-renin hypertension (low renin, normal aldosterone and high aldosterone/renin ratio, n=24). All had either LVH or concentric remodelling. All had an echocardiogram both at baseline and at 1 year after the initiation of spironolactone. A subgroup of 29 patients had an echocardiogram at baseline, 1 year (range 0.5-1.5) and 3 years (range 1.8-7). RESULTS: At baseline, spironolactone was commenced in all patients. The dose was 33.3±13.7 and 29.0±11.7 mg/day at 1 year and 3 years, respectively. A total of 73% of the patients received ≤37.5 mg/day. Introduction of spironolactone enabled the reduction of other antihypertensive medications (from 2.6±1.2 to 1.5±1.0 at 1 year). At 1 year, systolic and diastolic blood pressure decreased (149.3±14.1 to 126.2±12.0 mmHg, P<0.001, and 88.2±9.8 to 78.3±7.1 mmHg, P<0.001, respectively). At baseline, LVH was present in 39 of the 48 (81%) patients, and concentric remodelling, i.e. increased relative wall thickness (RWT) with a normal left ventricular mass index (LVMI), in 36 (75%). At 1 year, LVMI decreased in 44 of the 48 (92%) patients (142.9±25.4 versus 117.7±20.4 g/m2, P<0.001). LVH normalized in 16 of the 39 (41%) patients. RWT normalized in 36% of the patients. The changes in blood pressure and LVMI did not correlate. At 3 years, LVH decreased further and normalized in 57% of the patients. CONCLUSIONS: In patients with PA/low-renin hypertension, long-term regression of LVH may be achieved with low-dose MRB.

Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia - systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Current guidelines are inconclusive regarding intravenous (IV) iron for treatment of chemotherapy-induced anaemia (CIA). MATERIAL AND METHODS: Systematic review and meta-analysis of randomised controlled trials comparing IV iron with no iron or oral iron for treatment of chemotherapy induced anaemia (CIA). PRIMARY OUTCOMES: haematopoietic response and red blood cell (RBC) transfusion requirements. For dichotomous data, relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. For continuous data, weighted mean differences were calculated. RESULTS: Eleven trials included 1681 patients, the majority examining the addition of IV iron to erythropoiesis stimulating agents (ESA) (1562 patients, 92.9%). IV iron significantly increased haematopoietic response rate [RR 1.28 (95% CI 1.125-1.45), seven trials with ESA] and decreased the rate of blood transfusions both in trials with ESA [RR 0.76 (95% CI 0.61-0.95), seven trials] and without ESA [RR 0.52 (95% CI 0.34-0.80)]. The increase in haematopoietic response rate correlated with total IV iron dose, regardless of baseline iron status. Mortality and safety profile was comparable between groups. CONCLUSIONS: IV iron added to ESA results in an increase in haematopoietic response and reduction in the need for RBC transfusions, with no difference in mortality or adverse events.

Cytokine secretion and markers of inflammation in relation to acidosis among chronic hemodialysis patients.

BACKGROUND: Various cytokines are increased in hemodialysis (HD) patients, and are considered prognostic markers. Metabolic acidosis is common among chronic HD patients and is associated with survival. The relationship between acidosis and cytokines in HD patients has not been fully explored. The study aim was to measure pro- and anti-inflammatory cytokines in HD patients, with relation to bicarbonate levels. METHODS: Forty-seven stable HD patients were included (male/female 28/19, mean age 70.4 ± 14.5 years). Blood tests were taken before a midweek dialysis session. Cytokine secretion from peripheral blood mononuclear cells was measured. RESULTS: Acidosis versus no acidosis (serum HCO3 ­ 21.5 ± 0.2 vs. 24.9 ± 0.3 mEq/l, p < 0.001) was associated with decreased secretion of the anti-inflammatory interleukin-10 (IL-10, 1.16 ± 0.11 vs. 1.71 ± 0.20 ng/ml, p = 0.023). Patients with acidosis had higher parathyroid hormone (PTH), calcium-phosphate product, protein intake and transferrin. Higher IL-10 was associated with increased IL-6 secretion, higher bicarbonate, younger age and lower PTH. CONCLUSIONS: In stable chronic HD patients, a possible direct relation exists between metabolic acidosis and IL-10.

Haemoglobin variability in the early post-transplant period: association with graft survival and mortality.

AIM: Haemoglobin (Hb) variability is associated with poor survival in patients with chronic kidney disease. Association of Hb variability after kidney transplantation with patients' and graft survival has not been adequetly studied. METHODS: This retrospective study used registry data to examine the association between Hb variability in the early post-transplant period (first 6 months) and graft survival after kidney transplantatin. Kaplan-Meier and Cox regression analyses were used for univariate and multivariate associations between mortality, death censored graft survival and the composite outcome of both, in 752 patients after kidney transplantation. Hb values were collected each month during the first 6 months after transplantation, and Hb variavility was calculated using the residual standard deviation method. RESULTS: The highest quartile of Hb variability was associated with inferior graft and patients' survival in univariate (hazard ratio (HR) 2.18; 95% confidence interval (CI) 1.51 to 3.13; P < 0.001) and multivariate models (HR 1.5; 95% CI 1.029 to 2.18; P = 0.035). This association was mainly due to increased death censored graft failure in the high variability group (HR 2.75; 95% CI 1.73 to 4.38; P < 0.001) and (HR 1.67; 95% CI 1.023 to 2.74; P = 0.04) in the univariate and multivariate models, respectively. There was no association between Hb variability and the risk of death (HR 1.51; 95% CI 0.88 to 2.57; P = 0.132). CONCLUSION: High Hb variability is independently associated with inferior graft survival in patients after kidney transplantation.

Intravenous iron supplementation after kidney transplantation.

BACKGROUND: We sought to evaluate the effect of intravenous (IV) iron supplementation on hemoglobin (Hb) levels and detect predictors for response. METHODS: This is a retrospective cohort study of 81 patients who were treated with IV iron post-transplant. We evaluated predictors of response to treatment defined as an increase in Hb value of more than 1 g/dL by linear regression analysis. RESULTS: Three months after treatment, the mean Hb level increased significantly from 9.8 ± 1.4 g/dL to 11.1 ± 1.6 g/dL (p < 0.001). A lower baseline Hb value (OR: 0.51, 95% CI: 0.33-0.78 per 1 g/dL increase) was the only predictor of response at three months. The Hb value in the evaluable 60 patients at one yr increased from 9.9 ± 1.4 g/dL to 11.7 ± 1.7 g/dL (p < 0.001). Lower baseline Hb value (OR: 0.34, 95% CI: 0.18-0.65 per 1 g/dL increase) and a shorter time from transplantation (OR: 0.8, 95% CI: 0.68-0.94 per one yr increase) were predictors of response. Adverse events were reported in five patients (0.7% of doses). The rate of estimated glomerular filtration rate decline was reduced following the IV iron treatment -0.34 ± 1.05 mL/min/month after treatment compared with -0.81 ± 1.11 mL/min/month before treatment (p = 0.013). CONCLUSIONS: IV iron treatment was safe and associated with Hb increase in a cohort of patients after kidney transplantation.

URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews.

BACKGROUND: Hereditary renal hypouricemia may be complicated by nephrolithiasis or exercise-induced acute renal failure. Most patients described so far are of Japanese origin and carry the truncating mutation W258X in the uric acid transporter URAT1 encoded by SLC22A12. Recently, we described severe renal hypouricemia in Israeli patients with uric acid transporter GLUT9 (SLC2A9) loss-of-function mutations. Renal hypouricemia in Iraqi Jews has been previously reported, but its molecular basis has not been ascertained. METHODS: Three Jewish Israeli families of Iraqi origin with hereditary hypouricemia and hyperuricosuria were clinically characterized. DNA was extracted and the URAT1 gene was sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of URAT1 mutants found. RESULTS: A missense URAT1 mutation, R406C, was detected in all three families. Two affected siblings were found to carry in addition a homozygous missense URAT1 mutation, G444R. Both mutations dramatically impaired urate uptake into X. laevis oocytes. Moreover, we demonstrate for the first time that URAT1 facilitates urate efflux, which was abolished in the mutants, indicating also a secretion defect. Homozygous patients had serum uric acid concentrations of 0.5-0.8 mg% and a fractional excretion of uric acid of 50-85%. Most individuals studied were asymptomatic, two had nephrolithiasis and none developed exercise-induced acute renal failure. CONCLUSIONS: The URAT1 R406C mutation detected in all three families is likely to be the founder mutation in Iraqi Jews. Our findings contribute to a better definition of the different types of hereditary renal hypouricemia and suggest that the phenotype of this disorder depends mainly on the degree of inhibition of uric acid transport.