Showing papers in "Journal of The American Society of Nephrology in 2007"

Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis

Abstract: Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups.

Incidence and Outcomes in Acute Kidney Injury: A Comprehensive Population-Based Study

Abstract: Epidemiological studies of acute kidney injury (AKI) and acute-on-chronic renal failure (ACRF) are surprisingly sparse and confounded by differences in definition. Reported incidences vary, with few studies being population-based. Given this and our aging population, the incidence of AKI may be much higher than currently thought. We tested the hypothesis that the incidence is higher by including all patients with AKI (in a geographical population base of 523,390) regardless of whether they required renal replacement therapy irrespective of the hospital setting in which they were treated. We also tested the hypothesis that the Risk, Injury, Failure, Loss, and End-Stage Kidney (RIFLE) classification predicts outcomes. We identified all patients with serum creatinine concentrations > or =150 micromol/L (male) or > or =130 micromol/L (female) over a 6-mo period in 2003. Clinical outcomes were obtained from each patient's case records. The incidences of AKI and ACRF were 1811 and 336 per million population, respectively. Median age was 76 yr for AKI and 80.5 yr for ACRF. Sepsis was a precipitating factor in 47% of patients. The RIFLE classification was useful for predicting full recovery of renal function (P < 0.001), renal replacement therapy requirement (P < 0.001), length of hospital stay [excluding those who died during admission (P < 0.001)], and in-hospital mortality (P = 0.035). RIFLE did not predict mortality at 90 d or 6 mo. Thus the incidence of AKI is much higher than previously thought, with implications for service planning and providing information to colleagues about methods to prevent deterioration of renal function. The RIFLE classification is useful for identifying patients at greatest risk of adverse short-term outcomes.

Dual Action of Neutrophil Gelatinase–Associated Lipocalin

Abstract: Neutrophil gelatinase-associated lipocalin (NGAL) is expressed and secreted by immune cells, hepatocytes, and renal tubular cells in various pathologic states. NGAL exerts bacteriostatic effects, which are explained by its ability to capture and deplete siderophores, small iron-binding molecules that are synthesized by certain bacteria as a means of iron acquisition. Consistently, NGAL deficiency in genetically modified mice leads to an increased growth of bacteria. However, growing evidence suggests effects of the protein beyond fighting microorganisms. NGAL acts as a growth and differentiation factor in multiple cell types, including developing and mature renal epithelia, and some of this activity is enhanced in the presence of siderophore:iron complexes. This has led to the hypothesis that eukaryotes might synthesize siderophore-like molecules that bind NGAL. Accordingly, NGAL-mediated iron shuttling between the extracellular and intracellular spaces may explain some of the biologic activities of the protein. Interest in NGAL has been sparked by the observation that NGAL is massively upregulated after renal tubular injury and may participate in limiting kidney damage. This review summarizes the current knowledge about the dual effects of NGAL as a siderophore:iron-binding protein and as a growth factor and examines the role of these effects in renal injury.

Fibroblast Growth Factor 23 (FGF23) Predicts Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease (MMKD) Study

Abstract: It has not been firmly established whether disturbed calcium-phosphate metabolism affects progression of chronic kidney disease (CKD) in humans. In this cohort study of 227 nondiabetic patients with CKD, we assessed fibroblast growth factor 23 (FGF23) plasma concentrations in addition to other variables involved in calcium-phosphate metabolism, and we followed 177 of the patients prospectively for a median of 53 months to assess progression of renal disease. In the baseline cohort, we found a significant inverse correlation between glomerular filtration rate and both c-terminal and intact FGF23 levels (both P < 0.001). The 65 patients who experienced a doubling of serum creatinine and/or terminal renal failure were significantly older, had a significantly lower glomerular filtration rate at baseline, and significantly higher levels of intact parathormone, c-terminal and intact FGF23, and serum phosphate (all P < 0.001). Cox regression analysis revealed that both c-terminal and intact FGF23 independently predict progression of CKD after adjustment for age, gender, GFR, proteinuria, and serum levels of calcium, phosphate, and parathyroid hormone. The mean follow-up time to a progression end point was 46.9 (95% CI 40.2 to 53.6) months versus 72.5 (95% CI 67.7 to 77.3) months for patients with c-terminal FGF23 levels above or below the optimal cut-off level of 104 rU/mL (derived by receiver operator curve analysis), respectively. In conclusion, FGF23 is a novel independent predictor of progression of renal disease in patients with nondiabetic CKD. Its pathophysiological significance remains to be elucidated.

Age Affects Outcomes in Chronic Kidney Disease

Abstract: Chronic kidney disease (CKD) is common among the elderly. However, little is known about how the clinical implications of CKD vary with age. We examined the age-specific incidence of death, treated end-stage renal disease (ESRD), and change in estimated glomerular filtration rate (eGFR) among 209,622 US veterans with CKD stages 3 to 5 followed for a mean of 3.2 years. Patients aged 75 years or older at baseline comprised 47% of the overall cohort and accounted for 28% of the 9227 cases of ESRD that occurred during follow-up. Among patients of all ages, rates of both death and ESRD were inversely related to eGFR at baseline. However, among those with comparable levels of eGFR, older patients had higher rates of death and lower rates of ESRD than younger patients. Consequently, the level of eGFR below which the risk of ESRD exceeded the risk of death varied by age, ranging from 45 ml/min per 1.73 m(2) for 18 to 44 year old patients to 15 ml/min per 1.73 m(2) for 65 to 84 year old patients. Among those 85 years or older, the risk of death always exceeded the risk of ESRD in this cohort. Among patients with eGFR levels 3 ml/min per 1.73 m(2). In conclusion, age is a major effect modifier among patients with an eGFR of <60 ml/min per 1.73 m(2), challenging us to move beyond a uniform stage-based approach to managing CKD.

Significance of frailty among dialysis patients

Abstract: The construct of frailty has been associated with adverse outcomes among elderly individuals, but the prevalence and significance of frailty among patients with end-stage renal disease have not been established. The aim of the current study was to determine the prevalence and predictors of frailty

Evaluation of the Modification of Diet in Renal Disease Study Equation in a Large Diverse Population

Abstract: Glomerular filtration rate (GFR) estimates facilitate detection of chronic kidney disease. Performance of the Modification of Diet in Renal Disease (MDRD) Study equation varies substantially among populations. To describe the performance of the equation in a large, diverse population, estimated GFR (eGFR) was compared to measured GFR (mGFR) in a cross-sectional analysis of 5504 participants in 10 studies that included measurements of standardized serum creatinine and urinary clearance of iothalamate. At eGFR or =60 ml/min per 1.73 m(2). The accuracy of the equation, measured by the percent of estimates that fell within 30% of mGFR, was similar for eGFR values above or below 60 ml/min per 1.73 m(2) (82% and 84%, respectively). Differences in performance among subgroups defined by age, sex, race, diabetes, transplant status, and body mass index were small when eGFR was <60 ml/min per 1.73 m(2). The MDRD Study equation therefore provides unbiased and reasonably accurate estimates across a wide range of subgroups when eGFR is <60 ml/min per 1.73 m(2). In individual patients, interpretation of GFR estimates near 60 ml/min per 1.73 m(2) should be interpreted with caution to avoid misclassification of chronic kidney disease in the context of the clinical setting.

Antibody-Mediated Renal Allograft Rejection: Diagnosis and Pathogenesis

Abstract: Alloantibodies to HLA class I or II and other antigens expressed by endothelium cause a variety of effects on renal transplants, ranging from acute to chronic rejection, and even apparent graft acceptance (accommodation). Recognition of these conditions and appropriate therapy requires demonstration of C4d in biopsies, commonly confirmed by tests for circulating alloantibody. Substantial practical experience by pathologists in the interpretation and pitfalls of C4d stains are reviewed along with considerations of the clinical significance and pathologic mechanisms of the different effects of antibody on the endothelium of the renal allograft. Clinical trials will be needed to ascertain the optimal treatment for the newly appreciated conditions chronic humoral rejection and accommodation.

Urinary N-Acetyl-β-(D)-Glucosaminidase Activity and Kidney Injury Molecule-1 Level Are Associated with Adverse Outcomes in Acute Renal Failure

Abstract: The role of urinary biomarkers of kidney injury in the prediction of adverse clinical outcomes in acute renal failure (ARF) has not been well described. The relationship between urinary N-acetyl-β-(D)-glucosaminidase activity (NAG) and kidney injury molecule-1 (KIM-1) level and adverse clinical outcomes was evaluated prospectively in a cohort of 201 hospitalized patients with ARF. NAG was measured by spectrophotometry, and KIM-1 was measured by a microsphere-based Luminex technology. Mean Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score was 16, 43% had sepsis, 39% required dialysis, and hospital mortality was 24%. Urinary NAG and KIM-1 increased in tandem with APACHE II and Multiple Organ Failure scores. Compared with patients in the lowest quartile of NAG, the second, third, and fourth quartile groups had 3.0-fold (95% confidence interval [CI] 1.3 to 7.2), 3.7-fold (95% CI 1.6 to 8.8), and 9.1-fold (95% CI 3.7 to 22.7) higher odds, respectively, for dialysis requirement or hospital death ( P P = 0.034). NAG or KIM-1 in combination with the covariates cirrhosis, sepsis, oliguria, and mechanical ventilation yielded an area under the receiver operator characteristic curve of 0.78 (95% CI 0.71 to 0.84) in predicting the composite outcome. Urinary markers of kidney injury such as NAG and KIM-1 can predict adverse clinical outcomes in patients with ARF.

Stromal Cells Protect against Acute Tubular Injury via an Endocrine Effect

Abstract: Emerging evidence suggests that the intravenous injection of bone marrow-derived stromal cells (BMSC) improves renal function after acute tubular injury, but the mechanism of this effect is controversial. In this article, we confirm that intravenous infusion of male BMSC reduced the severity of cisplatin-induced acute renal failure in adult female mice. This effect was also seen when BMSC (or adipocyte-derived stromal cells (AdSC)), were given by intraperitoneal injection. Infusion of BMSC enhanced tubular cell proliferation after injury and decreased tubular cell apoptosis. Using the Y chromosome as a marker of donor stromal cells, examination of multiple kidney sections at one or four days after cell infusion failed to reveal any examples of stromal cells within the tubules, and only rare examples of stromal cells within the renal interstitium. Furthermore, conditioned media from cultured stromal cells induced migration and proliferation of kidney-derived epithelial cells and significantly diminished cisplatin-induced proximal tubule cell death in vitro. Intraperitoneal administration of this conditioned medium to mice injected with cisplatin diminished tubular cell apoptosis, increased survival, and limited renal injury. Thus, marrow stromal cells protect the kidney from toxic injury by secreting factors that limit apoptosis and enhance proliferation of the endogenous tubular cells, suggesting that transplantation of the cells themselves is not necessary. Identification of the stromal cell-derived protective factors may provide new therapeutic options to explore in humans with acute kidney injury.

Glycated Albumin Is a Better Glycemic Indicator than Glycated Hemoglobin Values in Hemodialysis Patients with Diabetes: Effect of Anemia and Erythropoietin Injection

Abstract: The significance of glycated albumin (GA), compared with casual plasma glucose (PG) and glycated hemoglobin (HbA(1c)), was evaluated as an indicator of the glycemic control state in hemodialysis (HD) patients with diabetes. The mean PG, GA, and HbA(1c) levels were 164.5 +/- 55.7 mg/dl, 22.5 +/- 7.5%, and 5.85 +/- 1.26%, respectively, in HD patients with diabetes (n = 538), which were increased by 51.5, 31.6, and 17.7%, respectively, compared with HD patients without diabetes (n = 828). HbA(1c) levels were significantly lower than simultaneous PG and GA values in those patients in comparison with the relationship among the three parameters in patients who had diabetes without renal dysfunction (n = 365), as reflected by the significantly more shallow slope of regression line between HbA(1c) and PG or GA. A significant negative correlation was found between GA and serum albumin (r = -0.131, P = 0.002) in HD patients with diabetes, whereas HbA(1c) correlated positively and negatively with hemoglobin (r = 0.090, P = 0.036) and weekly dose of erythropoietin injection (r = -0.159, P < 0.001), respectively. Although PG and GA did not differ significantly between HD patients with diabetes and with and without erythropoietin injection, HbA(1c) levels were significantly higher in patients without erythropoietin. Categorization of glycemic control into arbitrary quartile by HbA(1c) level led to better glycemic control in a significantly higher proportions of HD patients with diabetes than those assessed by GA. Multiple regression analysis demonstrated that the weekly dose of erythropoietin, in addition to PG, emerged as an independent factor associated with HbA(1c) in HD patients with diabetes, although PG but not albumin was an independent factor associated with GA. In summary, it is suggested that GA provides a significantly better measure to estimate glycemic control in HD patients with diabetes and that the assessment of glycemic control by HbA(1c) in these patients might lead to underestimation likely as a result of the increasing proportion of young erythrocyte by the use of erythropoietin.

Remission of Proteinuria Improves Prognosis in IgA Nephropathy

Abstract: Proteinuria has been shown to be an adverse prognostic factor in IgA nephropathy. The benefit of achieving a partial remission of proteinuria, however, has not been well described. We studied 542 patients with biopsy-proven primary IgA nephropathy in the Toronto Glomerulonephritis Registry and found that glomerular filtration rate (GFR) declined at -0.38 +/- 0.61 ml/min per 1.73 m2/mo overall, with 30% of subjects reaching end-stage renal disease. Multivariate analysis revealed that proteinuria during follow-up was the most important predictor of the rate of GFR decline. Among the 171 patients with 3 g/d (n = 121) lost renal function 25-fold faster than those with or =3 g/d who achieved a partial remission (<1 g/d) had a similar course to patients who had < or =1 g/d throughout, and fared far better than patients who never achieved remission. These results underscore the relationship between proteinuria and prognosis in IgA nephropathy and establish the importance of remission.

End-Stage Renal Disease in the United States: An Update from the United States Renal Data System

Abstract: Patients with ESRD consume a vastly disproportionate amount of financial and human resources. Approximately 0.03% of the US population began renal replacement therapy in 2004, an adjusted incidence rate of 339 per million. Declining incidence rates were observed for most primary causes of ESRD and in most major demographic categories; the worry is that rates of diabetic ESRD continue to rise in younger black adults. Although diabetes and hypertension remain the most commonly reported cause of ESRD, rates of end-stage atherosclerotic renovascular disease seem to be on the rise in older patients. Although clinical care indicators, such as the proportion of hemodialysis patients using fistulas, continue to improve gradually, the proportion of patients overshooting target hemoglobin levels under epoetin therapy may be a source of concern. Survival probabilities have improved steadily in the US ESRD population since the late 1980s, which is remarkable when one considers the ever-expanding burden of comorbidity in incident patients. However, although first-year dialysis mortality rates have clearly improved since 1987, meaningful improvements do not seem to have accrued since 1993, in contrast to steady annual improvements in years 2 through 5. Although most of these findings are grounds for cautious optimism, the same cannot be said for issues of cost; reflecting the growth in the size of the ESRD population, associated costs grew by 57% between 1999 and 2004 and now account for 6.7% of total Medicare expenditures.

Mineral Metabolism and Arterial Functions in End-Stage Renal Disease: Potential Role of 25-Hydroxyvitamin D Deficiency

Abstract: In ESRD, arterial function is abnormal, characterized by decreased capacitive function (arterial stiffening) and reduced conduit function, shown by diminished flow-mediated dilation (FMD). The pathophysiology of these abnormalities is not clear, and this cross-sectional study analyzed possible relationships among arterial alterations and cardiovascular risk factors, including mineral metabolism parameters, such as serum parathormone, and vitamin D "nutritional" and "hormonal" status by measuring serum 25-hydroxyvitamin D [25(OH)D(3)] and 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels. Aortic stiffness (pulse wave velocity), brachial artery (BA) distensibility (echotracking; n = 42), BA FMD (hand-warming; n = 37), and arterial calcification scores (echography and plain x-rays) were measured in 52 stable and uncomplicated patients who were on hemodialysis. 25(OH)D(3) and 1,25(OH)(2)D(3) serum levels were low and weakly correlated (r = 0.365, P < 0.05). After adjustment for BP and age, multivariate analyses indicated that 25(OH)D(3) and 1,25(OH)(2)D(3) were negatively correlated with aortic pulse wave velocity (P < 0.001) and positively correlated with BA distensibility (P < 0.01) and FMD (P < 0.001). Arterial calcification scores were not independently associated with 25(OH)D(3) and 1,25(OH)(2)D(3) serum concentrations. These results suggest that nutritional vitamin D deficiency and low 1,25(OH)(2)D(3) could be associated with arteriosclerosis and endothelial dysfunction in patients who have ESRD and are on hemodialysis.

Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease.

Abstract: Fabry disease, an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human alpha-galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase beta and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase beta for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n = 8) maintained complete GL-3 clearance in renal capillary endothelial cells and multiple cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n = 41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time. Long-term agalsidase beta therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.

How Fibroblast Growth Factor 23 Works

Abstract: There is a discontinuum of hereditary and acquired disorders of phosphate homeostasis that are caused by either high or low circulating levels of the novel phosphaturic hormone fibroblastic growth factor 23 (FGF23). Disorders that are caused by high circulating levels of FGF23 are characterized by hypophosphatemia, decreased production of 1,25-dihydroxyvitamin D, and rickets/osteomalacia. On the other end of the spectrum are disorders that are caused by low circulating levels of FGF23, which are characterized by hyperphosphatemia, elevated production of 1,25-dihydroxyvitamin D, soft tissue calcifications, and hyperostosis. Knowledge of the genetic basis of these hereditary disorders of phosphate homeostasis and studies of their mouse homologues have uncovered a bone-kidney axis and new systems biology that govern bone mineralization, vitamin D metabolism, parathyroid gland function, and renal phosphate handling. Further understanding of this primary phosphate homeostatic pathway has the potential to have a significant impact on the diagnosis and treatment of disorders of bone and mineral metabolism.

Differential Impact of Complement Mutations on Clinical Characteristics in Atypical Hemolytic Uremic Syndrome

Abstract: Mutations in factor H (CFH), factor I (IF), and membrane cofactor protein (MCP) genes have been described as risk factors for atypical hemolytic uremic syndrome (aHUS). This study analyzed the impact of complement mutations on the outcome of 46 children with aHUS. A total of 52% of patients had mutations in one or two of known susceptibility factors (22, 13, and 15% of patients with CFH, IF, or MCP mutations, respectively; 2% with CFH+IF mutations). Age <3 mo at onset seems to be characteristic of CFH and IF mutation-associated aHUS. The most severe prognosis was in the CFH mutation group, 60% of whom reached ESRD or died within <1 yr. Only 30% of CFH mutations were localized in SCR20. MCP mutation-associated HUS has a relapsing course, but none of the children reached ESRD at 1 yr. Half of patients with IF mutation had a rapid evolution to ESRD, and half recovered. Plasmatherapy seemed to have a beneficial effect in one third of patients from all groups except for the MCP mutation group. Only eight (33%) of 24 kidney transplantations that were performed in 15 patients were successful. Graft failures were due to early graft thrombosis (50%) or HUS recurrence. In conclusion, outcome of HUS in patients with CFH mutation is catastrophic, and posttransplantation outcome is poor in all groups except for the MCP mutation group. New therapies are urgently needed, and further research should elucidate the unexplained HUS group.

Ferric Gluconate Is Highly Efficacious in Anemic Hemodialysis Patients with High Serum Ferritin and Low Transferrin Saturation: Results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study

Abstract: Few data exist to guide treatment of anemic hemodialysis patients with high ferritin and low transferrin saturation (TSAT). The Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) trial was designed to evaluate the efficacy of intravenous ferric gluconate in such patients. Inclusion criteria were hemoglobin or=225 IU/kg per wk or >or=22,500 IU/wk. Patients with known infections or recent significant blood loss were excluded. Participants (n=134) were randomly assigned to no iron (control) or to ferric gluconate 125 mg intravenously with eight consecutive hemodialysis sessions (intravenous iron). At randomization, epoetin was increased 25% in both groups; further dosage changes were prohibited. At 6 wk, hemoglobin increased significantly more (P=0.028) in the intravenous iron group (1.6 +/- 1.3 g/dl) than in the control group (1.1 +/- 1.4 g/dl). Hemoglobin response occurred faster (P=0.035) and more patients responded after intravenous iron than in the control group (P=0.041). Ferritin 800 ng/ml had no relationship to the magnitude or likelihood of responsiveness to intravenous iron relative to the control group. Similarly, the superiority of intravenous iron compared with no iron was similar whether baseline TSAT was above or below the study median of 19%. Ferritin decreased in control subjects (-174 +/- 225 ng/ml) and increased after intravenous iron (173 +/- 272 ng/ml; P<0.001). Intravenous iron resulted in a greater increase in TSAT than in control subjects (7.5 +/- 7.4 versus 1.8 +/- 5.2%; P<0.001). Reticulocyte hemoglobin content fell only in control subjects, suggesting worsening iron deficiency. Administration of ferric gluconate (125 mg for eight treatments) is superior to no iron therapy in anemic dialysis patients receiving adequate epoetin dosages and have a ferritin 500 to 1200 ng/ml and TSAT

Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.

Abstract: Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, duplication of PKD1, and a high level of unclassified variants (UCV). Present mutation detection levels are 60 to 70%, and PKD1 and PKD2 UCV have not been systematically classified. This study analyzed the uniquely characterized Consortium for Radiologic Imaging Study of PKD (CRISP) ADPKD population by molecular analysis. A cohort of 202 probands was screened by denaturing HPLC, followed by direct sequencing using a clinical test of 121 with no definite mutation (plus controls). A subset was also screened for larger deletions, and reverse transcription-PCR was used to test abnormal splicing. Definite mutations were identified in 127 (62.9%) probands, and all UCV were assessed for their potential pathogenicity. The Grantham Matrix Score was used to score the significance of the substitution and the conservation of the residue in orthologs and defined domains. The likelihood for aberrant splicing and contextual information about the UCV within the patient (including segregation analysis) was used in combination to define a variant score. From this analysis, 44 missense plus two atypical splicing and seven small in-frame changes were defined as probably pathogenic and assigned to a mutation group. Mutations were thus defined in 180 (89.1%) probands: 153 (85.0%) PKD1 and 27 (15.0%) PKD2. The majority were unique to a single family, but recurrent mutations accounted for 30.0% of the total. A total of 190 polymorphic variants were identified in PKD1 (average of 10.1 per patient) and eight in PKD2. Although nondefinite mutation data must be treated with care in the clinical setting, this study shows the potential for molecular diagnostics in ADPKD that is likely to become increasingly important as therapies become available.

Nephronophthisis-Associated Ciliopathies

Abstract: Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, represents the most frequent genetic cause of end-stage kidney disease in the first three decades of life. Contrary to polycystic kidney disease, NPHP shows normal or diminished kidney size, cysts are concentrated at the corticomedullary junction, and tubulointerstitial fibrosis is dominant. NPHP can be associated with retinitis pigmentosa (Senior-Loken syndrome), liver fibrosis, and cerebellar vermis aplasia (Joubert syndrome) in approximately 10% of patients. Positional cloning of six novel genes (NPHP1 through 6) as mutated in NPHP and functional characterization of their encoded proteins have contributed to the concept of "ciliopathies." It has helped advance a new unifying theory of cystic kidney diseases. This theory states that the products of all genes that are mutated in cystic kidney diseases in humans, mice, or zebrafish are expressed in primary cilia or centrosomes of renal epithelial cells. Primary cilia are sensory organelles that connect mechanosensory, visual, osmotic, and other stimuli to mechanisms of cell-cycle control and epithelial cell polarity. The ciliary theory explains the multiple organ involvement in NPHP regarding retinitis pigmentosa, liver fibrosis, ataxia, situs inversus, and mental retardation. Mutations in NPHP genes cause defects in signaling mechanisms, including the noncanonical Wnt signaling pathway. The "ciliopathy" NPHP thereby is caused by defects in tissue differentiation and maintenance as a result of impaired processing of extracellular cues. Nephrocystins, the proteins that are encoded by NPHP genes, are highly conserved in evolution. Positional cloning of additional causative genes of NPHP will elucidate further signaling mechanisms that are involved, thereby establishing therapeutic approaches using animal models in mouse, zebrafish, and Caenorhabditis elegans.

Psychosocial Aspects of Chronic Disease: ESRD as a Paradigmatic Illness

Abstract: Psychosocial issues are an understudied yet important concern in the overall health of hemodialysis (HD) patients. Stress is a concomitant of chronic illness and its treatment, and may have meaningful influences on psychological and medical outcomes. This article reviews the influences of psychopathology, social support, family issues, dialysis unit culture, and socioeconomic status on patients treated with center HD. Depressive affect and decreased perception of social support have been linked with mortality in several studies of ESRD patients. Decreased marital satisfaction, disturbances in family dynamics, and lower socioeconomic status (SES) have been associated with poorer health outcomes and can affect patients' perception of social support and depressive affect. Chronically ill ESRD patients who undergo treatment with constant interaction and observation by medical staff are potentially an ideal group for evaluation of the effects of stress and psychosocial factors on outcomes in those with chronic disease, as well as an excellent patient population for intervention to reduce morbidity and mortality. These interactions between potentially modifiable psychosocial risk factors for disease and medical aspects of illness form a paradigm for the study of interventions related to adjustment to chronic illness in the ESRD population.

Microalbuminuria and the Risk for Early Progressive Renal Function Decline in Type 1 Diabetes

Abstract: This study aimed to establish the time of initiation and the determinants of renal function decline in type 1 diabetes. Until now, such decline has been assumed to be a late-occurring event associated with proteinuria. A total of 267 patients with normoalbuminuria and 301 patients with microalbuminuria were followed for 8 to 12 yr. Linear trends (slopes) in GFR were estimated by serial measurement of serum cystatin C. Cases of early renal function decline were defined by loss in cystatin C GFR that exceeded -3.3%/yr, a threshold that corresponds to the 2.5th percentile of the distribution of GFR slopes in an independent nondiabetic normotensive population. Cases of early renal function decline occurred in 9% (mean slope -4.4; range -5.9 to -3.3%/yr) of the normoalbuminuria group and 31% (mean slope -7.1; range -23.8 to -3.3%/yr) of the microalbuminuria group (P < 0.001). Risk for early renal function decline depended on whether microalbuminuria regressed, remained stable, or progressed, rising from 16 to 32 and 68%, respectively (P < 0.001). In multivariate analysis, risk for decline was higher after age 35 yr or when glycosylated hemoglobin exceeded 9% but did not vary with diabetes duration, smoking, BP, or angiotensin-converting enzyme inhibitor treatment. Contrary to the existing paradigm of diabetic nephropathy, progressive renal function decline in type 1 diabetes is an early event that occurs in a large proportion of patients with microalbuminuria. Together with testing for microalbuminuria, clinical protocols using cystatin C to diagnose early renal function decline and track response to therapeutic interventions should be developed.

Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy

Abstract: The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.

Reduced Kidney Function as a Risk Factor for Incident Heart Failure: The Atherosclerosis Risk in Communities (ARIC) Study

Abstract: Reduced kidney function is a risk factor for cardiovascular morbidity and mortality, and both heart failure (HF) and kidney failure incidences are increasing. This study therefore sought to determine the effect of decreased kidney function on HF incidence in a population-based study of middle-aged adults. From 1987 through 2002, 14,857 participants of the Atherosclerosis Risk in Communities (ARIC) study who were free of prevalent HF at baseline were followed for incident HF hospitalization or death (International Classification of Diseases, Ninth Revision/10th Revision 428/I50). Estimated GFR (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) Study equation, and kidney function was categorized as normal (eGFR > or =90 ml/min per 1.73 m(2); n = 7143), mildly reduced (eGFR 60 to 89 ml/min per 1.73 m(2); n = 7311), and moderately/severely reduced (eGFR or =90 ml/min per 1.73 m(2) (18 versus 6 per 1000 person-years). The overall adjusted relative hazard of developing HF was 1.94 (1.49 to 2.53) for individuals with eGFR <60 ml/min per 1.73 m(2) compared to the reference group and was significantly increased for individuals with and without prevalent coronary heart disease at baseline. A substantially greater decline in kidney function occurred in individuals concomitant with HF hospitalization/death compared to those who did not develop HF. In summary, middle-aged adults with moderately/severely reduced kidney function are at high risk for developing HF.

Molecular Control of Iron Transport

Abstract: The iron-regulatory hormone hepcidin is a 25-amino acid peptide that is synthesized in hepatocytes. Hepcidin binds to the cellular iron export channel ferroportin and causes its internalization and degradation and thereby decreases iron efflux from iron exporting tissues into plasma. By this mechanism, hepcidin inhibits dietary iron absorption, the efflux of recycled iron from splenic and hepatic macrophages, and the release of iron from storage in hepatocytes. Hepcidin synthesis is stimulated by plasma iron and iron stores and is inhibited by erythropoietic activity, ensuring that extracellular plasma iron concentrations and iron stores remain stable and the erythropoietic demand for iron is met. During inflammation, increased hepcidin concentrations cause iron sequestration in macrophages, resulting in hypoferremia and eventually anemia of inflammation. Hepcidin deficiency plays a central role in most iron overload disorders. The role of hepcidin abnormalities in anemias that are associated with renal disease and in resistance to erythropoietic therapies remains to be elucidated.

Epithelial to Mesenchymal Transition and Peritoneal Membrane Failure in Peritoneal Dialysis Patients: Pathologic Significance and Potential Therapeutic Interventions

Abstract: Peritoneal dialysis (PD) is a form of renal replacement and is based on the use of the peritoneum as a semipermeable membrane across which ultrafiltration and diffusion take place. Nevertheless, continuous exposure to bioincompatible PD solutions and episodes of peritonitis or hemoperitoneum cause acute and chronic inflammation and injury to the peritoneal membrane, which progressively undergoes fibrosis and angiogenesis and, ultimately, ultrafiltration failure. The pathophysiologic mechanisms that are involved in peritoneal functional impairment have remained elusive. Resident fibroblasts and infiltrating inflammatory cells have been considered the main entities that are responsible for structural and functional alterations of the peritoneum. Recent findings, however, demonstrated that new fibroblastic cells may arise from local conversion of mesothelial cells (MC) by epithelial-to-mesenchymal transition (EMT) during the inflammatory and repair responses that are induced by PD and pointed to MC as protagonists of peritoneal membrane deterioration. Submesothelial myofibroblasts, which participate in inflammatory responses, extracellular matrix accumulation, and angiogenesis, can originate from activated resident fibroblasts and from MC through EMT. This heterogeneous origin of myofibroblasts reveals new pathogenic mechanisms and offers novel therapeutic possibilities. This article provides a comprehensive review of recent advances on understanding the mechanisms that are implicated in peritoneal structural alterations, which have allowed the identification of the EMT of MC as a potential therapeutic target of membrane failure.

Lipoprotein Metabolism and Lipid Management in Chronic Kidney Disease

Abstract: Dyslipidemia is an established cardiovascular (CV) risk factor in the general population. In chronic kidney disease (CKD), however, epidemiologic studies ([1][1]–[3][2]) and clinical trials ([4][3]–[12][4]) have raised uncertainties regarding the impact of dyslipidemia on clinical outcomes and,

Progressive Exercise for Anabolism in Kidney Disease (PEAK): A Randomized, Controlled Trial of Resistance Training during Hemodialysis

Abstract: Skeletal muscle wasting is common and insidious in patients who receive maintenance hemodialysis treatment for the management of ESRD. The objective of this study was to determine whether 12 wk of high-intensity, progressive resistance training (PRT) administered during routine hemodialysis treatment could improve skeletal muscle quantity and quality versus usual care. Forty-nine patients (62.6 +/- 14.2 yr; 0.3 to 16.7 yr on dialysis) were recruited from the outpatient hemodialysis unit of the St. George Public Hospital (Sydney, Australia). Patients were randomized to PRT + usual care (n = 24) or usual care control only (n = 25). The PRT group performed two sets of 10 exercises at a high intensity (15 to 17/20 on the Borg Scale) using free weights, three times per week for 12 wk during routine hemodialysis treatment. Primary outcomes included thigh muscle quantity (cross-sectional area [CSA]) and quality (intramuscular lipid content via attenuation) evaluated by computed tomography scan. Secondary outcomes included muscle strength, exercise capacity, body circumference measures, proinflammatory cytokine C-reactive protein, and quality of life. There was no statistically significant difference in muscle CSA change between groups. However, there were statistically significant improvements in muscle attenuation, muscle strength, mid-thigh and mid-arm circumference, body weight, and C-reactive protein in the PRT group relative to the nonexercising control group. These findings suggest that patients with ESRD can improve skeletal muscle quality and derive other health-related adaptations solely by engaging in a 12-wk high-intensity PRT regimen during routine hemodialysis treatment sessions. Longer training durations or more sensitive analysis techniques may be required to document alterations in muscle CSA.

Renal L-Type Fatty Acid–Binding Protein in Acute Ischemic Injury

Abstract: Fatty acid-binding proteins (FABPs) bind unsaturated fatty acids and lipid peroxidation products during tissue injury from hypoxia. We evaluated the potential role of L-type FABP (L-FABP) as a biomarker of renal ischemia in both human kidney transplant patients and animal models. Urinary L-FABP levels were measured in the first urine produced from 12 living-related kidney transplant patients immediately after reperfusion of their transplanted organs, and intravital video analysis of peritubular capillary blood flow was performed simultaneously. A significant direct correlation was found between urinary L-FABP level and both peritubular capillary blood flow and the ischemic time of the transplanted kidney (both P < 0.0001), as well as hospital stay (P < 0.05). In human-L-FABP transgenic mice subjected to ischemia-reperfusion injury, immunohistological analyses demonstrated the transition of L-FABP from the cytoplasm of proximal tubular cells to the tubular lumen. In addition, after injury, these transgenic mice demonstrated lower blood urea nitrogen levels and less histological injury than injured wild-type mice, likely due to a reduction of tissue hypoxia. In vitro experiments using a stable cell line of mouse proximal tubule cells transfected with h-L-FABP cDNA showed reduction of oxidative stress during hypoxia compared to untransfected cells. Taken together, these data show that increased urinary L-FABP after ischemic-reperfusion injury may find future use as a biomarker of acute ischemic injury.

Exercise in the End-Stage Renal Disease Population

Abstract: Many of the known benefits of exercise in the general population are of particular relevance to the ESRD population. In addition, the poor physical functioning that is experienced by patients who are on dialysis is potentially addressable through exercise interventions. The study of exercise in the ESRD population dates back almost 30 yr, and numerous interventions, including aerobic training, resistance exercise training, and combined training programs, have reported beneficial effects. Recently, interventions during hemodialysis sessions have become more popular and have been shown to be safe. The risks of exercise in this population have not been rigorously studied, but there have been no reports of serious injury as a result of participation in an exercise training program. It is time that we incorporate exercise into the routine care of patients who are on dialysis, but identification of an optimal training regimen or regimens, according to patient characteristics or needs, is still needed to facilitate implementation of exercise programs.