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Monocyte/macrophage recruitment correlates strongly with the progression of renal impairment in diabetic nephropathy (DN). C-C chemokine receptor (CCR)2 regulates monocyte/macrophage migration into injured tissues. However, the direct role of CCR2-mediated monocyte/macrophage recruitment in diabetic kidney disease remains unclear. We report that pharmacological blockade or genetic deficiency of CCR2 confers kidney protection in Ins2Akita and streptozotocin (STZ)-induced diabetic kidney disease. Blocking CCR2 using the selective CCR2 antagonist RS504393 for 12 wk in Ins2Akita mice significantly attenuated albuminuria, the increase in blood urea nitrogen and plasma creatinine, histological changes, and glomerular macrophage recruitment compared with vehicle. Furthermore, mice lacking CCR2 (CCR2−/−) mimicked CCR2 blockade by reducing albuminuria and displaying less fibronectin mRNA expression and inflammatory cytokine production compared with CCR2+/+ mice, despite comparable blood glucose levels. Bone marrow-derived monocytes from CCR2+/+ or CCR2−/− mice adoptively transferred into CCR2−/− mice reversed the renal tissue-protective effect in diabetic CCR2−/− mice as evaluated by increased urinary albumin excretion and kidney macrophage recruitment, indicating that CCR2 is not required for monocyte migration from the circulation into diabetic kidneys. These findings provide evidence that CCR2 is necessary for monocyte/macrophage-induced diabetic renal injury and suggest that blocking CCR2 could be a novel therapeutic approach in the treatment of DN.

To characterize the pharmacokinetic, pharmacodynamic and safety profiles of donepezil in subjects with moderate renal impairment and matched healthy controls during single-dose and multiple-dose phases.This open-label study enrolled subjects with moderate renal impairment (creatinine clearance [CL(Cr)] 17-33 ml min(-1) 1.73 m(-2) body surface area) and age, weight and sex-matched healthy controls. A single-dose (5 mg donepezil) phase was followed by a 23-day multiple dose (5 mg day(-1) donepezil) steady-state phase. The pharmacokinetic and pharmacodynamic parameters of donepezil were determined for up to 144 h after the first dose and 168 h after the last dose.Thirty-six subjects were enrolled, 19 renally impaired and 17 healthy controls. All pharmacokinetic and pharmacodynamic parameters were similar between groups after a single dose of donepezil (C(max) 5.17 +/- 0.36 and 6.07 +/- 0.49 ng ml(-1); AUC(0-24) 76.05 +/- 5.54 and 77.45 +/- 4.49 ng.h ml(-1); mean maximum percentage inhibition [I(max)] red blood cell (RBC) AChE activity 32.07 +/- 2.00 and 31.69 +/- 2.45%; for subjects with renal impairment and healthy subjects, respectively). Pharmacokinetic parameters under steady-state conditions did not differ between renally impaired and healthy subjects (C(SS) 20.83 +/- 1.78 and 18.38 +/- 1.52 ng ml(-1); AUC(0-24) 500.0 +/- 42.8 and 441.1 +/- 36.4 ng.h ml(-1); degree of accumulation [R(A)] 6.98 +/- 0.59 and 5.94 +/- 0.53; for subjects with renal impairment and healthy subjects, respectively). Main pharmacodynamic parameters were also similar in renally impaired and healthy subjects at steady state (average percentage inhibition [I(SS)] RBC AChE activity 65.11 +/- 2.52 and 60.62 +/- 2.95, respectively). Protein binding was also similar between groups (% free donepezil 23.54 +/- 1.96 and 20.23 +/- 0.64, respectively). Donepezil was well tolerated by both groups.These results indicate that the pharmacokinetics of donepezil are not altered after dosing to steady state, and that donepezil can be administered safely to subjects with moderate renal impairment.

Anemia is a complication of chronic kidney disease and may contribute to adverse clinical outcomes. Early identification and treatment of anemia may improve cardiovascular morbidity and mortality. No large-scale population data are available specifically for patients with chronic kidney disease regarding prevalence of anemia, subpopulations at risk, and relationships between anemia and kidney function. This study was undertaken to address these questions in patients with chronic kidney disease, and investigate the relationship between anemia and glomerular filtration rate.Large-scale, cross-sectional, US multicenter survey; 5222 patients (mean age, 68.2 years; 46.6% male); 237 physician practices. Eligible patients:or = 18 years of age; serum creatinine: 1.5 mg/dL-6.0 mg/dL (females), 2.0 mg/dL-6.0 mg/dL (males).Primary study end point: prevalence and severity of anemia (hemoglobinor = 12 g/dL). Data further stratified by hemoglobin (or = 12 g/dL,or = 10 g/dL).Primary etiologies of chronic kidney disease (5222 evaluable patients): diabetes (49.5%); hypertension (33.0%). Glomerular filtration rate:60 mL/min/1.73 m2 for 97.7% of evaluable patients. Mean +/- SD serum creatinine level: 2.2 mg/dL +/- 0.9 mg/dL; 2.5 mg/dL +/- 1.0 mg/dL for males, 2.0 mg/dL +/- 0.8 mg/dL for females. Mean +/- SD hemoglobin: 12.2 g/dL +/- 1.6 g/dL (47.7% had hemoglobinor = 12 g/dL; 8.9% had hemoglobinor = 10 g/dL). Prevalence of anemia was strongly associated with declining glomerular filtration rate. Percentage of patients with hemoglobinor = 12 g/dL increased from 26.7% to 75.5% when glomerular filtration rate decreased fromor = 60 mL/min/1.73 m2 to15 mL/min/1.73 m2. Prevalence of hemoglobinor = 10 g/dL increased substantially from 5.2% to 27.2% when glomerular filtration rate diminished fromor = 60 mL/min/1.73 m2 to15 mL/min/1.73 m2. After controlling for other patient characteristics associated with increased prevalence of anemia, the prevalence odds ratio for hemoglobinor = 10 g/dL was 0.54 (0.49-0.60) and for hemoglobinor = 12 g/dL was 0.68 (0.65-0.72), with each 10-mL/min/1.73 m2 increase in glomerular filtration rate. Predictors of anemia: diabetes, female sex, and race/ethnicity.Anemia was present in 47.7% of 5222 predialysis patients with chronic kidney disease. Prevalence of anemia increased as kidney function decreased. Certain subgroups are at increased risk for anemia.

Partial correction of anemia by erythropoietin improves hemodialysis (HD)-associated immunosuppression. It is not known whether hemoglobin normalization improves immune status further. The authors prospectively compared the immune function of HD patients with congestive heart failure or ischemic heart disease on erythropoietin therapy randomized to normal versus anemic blood hemoglobin concentration. HD patients were randomized into a normal hemoglobin group (n = 17, target hemoglobin of 14 +/- 1 g/dl) or an anemic hemoglobin group (n = 18, target hemoglobin 10 +/- 1 g/dl). Delayed-type hypersensitivity, CD4 and CD8 counts, anti-tetanus toxoid antibody levels, erythrocyte complement receptor 1 expression, and lymphocyte proliferative responsiveness were measured. The observation period was 1 yr, and the trial was open label. Target hemoglobin was achieved and maintained in both groups. Significantly improved cutaneous reactivity was seen in the normal hemoglobin group (P = 0.003). The prevalence of anergy decreased in the normal hemoglobin group (from 60 to 20%) but increased in the anemic hemoglobin group (from 57 to 86%). The anemic hemoglobin group had higher CD8 counts compared with baseline (P = 0.0001) and compared with the normal hemoglobin group (P = 0.038). Both groups had significant increases in tetanus toxoid antibody levels after vaccination but without significant differences between groups. The anemic hemoglobin group had a progressive increase in erythrocyte complement receptor 1 levels compared with baseline (P = 0.002) and relative to the normal hemoglobin group (P = 0.023). There was no consistent pattern of altered proliferative responsiveness of lymphocytes. The data suggest that certain aspects of immune function, particularly delayed-type hypersensitivity, may be improved in HD patients by normalization of hemoglobin through the administration of increased doses of erythropoietin.

Focal segmental glomerulosclerosis (FSGS) is the histologic expression of diverse processes affecting the renal glomeruli and occurring in primary and secondary forms. A number of pathogenic factors have been identified in primary FSGS, and multiple etiologies have been defined as contributing factors for the development of secondary FSGS. There is a complex interplay between etiologic and pathogenic factors, progression factors and intervention in the phenotypic expression of FSGS. Key components include genetic predisposition, environmental influences and the impact on phenotype of pharmacologic intervention. The phenotypic spectrum for FSGS ranges from mild proteinuria and slow progression to a devastating clinical syndrome characterized by heavy proteinuria and rapid loss of renal function over a period of months. While the pathogenesis is unknown, much is known about factors which are involved in the development and progression of both primary and secondary FSGS. The ultimate goal of understanding pathogenesis is to provide specific nontoxic therapy for those patients who have a definable form of FSGS. While this goal is not yet in sight, many types of intervention, not addressed in the current chapter, can influence the course of various diseases presenting as FSGS. Until specific therapy can be fashioned, it is necessary for the clinician caring for these patients to appreciate the complex interaction of pathogenetic factors involved in the development and pregression of FSGS, as a rationale for providing intervention to prevent development of the disease and to slow its course.

Chronic renal insufficiency (CRI) is underrecognized and undertreated even in sophisticated health care systems. This is particularly distressing in light of the growing number of effective interventions available to slow the progression of kidney disease and ameliorate many of its comorbid conditions. Progress, to a certain extent, is impeded by the lack of generally accepted definitions, clear diagnostic criteria, and practical screening tests. Available epidemiologic data suggest that 800,000 Americans have creatinine levels ≥2.0 mg/dL and over 6 million have levels ≥1.5 mg/dL. Population-based surveys show that age, male gender, and black race are predictors of kidney disease. For reasons that are not well understood, the incidence of kidney failure has nearly doubled over the last 15 years, indicating a parallel increase in CRI. This trend has significant economic implications. Other implications of CRI related to the use and availability of health care resources are appropriate referrals to nephrologists and early intervention to optimize care of patients with CRI. A multipronged approach to providing optimal care involves interventions that may delay the progression of renal dysfunction, proactive prevention of uremic complications, measures to forestall the progress of comorbid conditions, and timely preparation of patients for renal replacement therapy. Early recognition of CRI, expeditious referral for specialty care, and the utilization of a comprehensive program of care optimization will help meet the nation's goals as articulated in the National Institutes of Health's Healthy People 2010: Chronic Kidney Disease.

ACE inhibition or angiotensin receptor blockade: Impact on potassium in renal failure. Background Inhibition of the renin-angiotensin system is known to raise serum potassium [K + ] levels in patients with renal insufficiency or diabetes. No study has evaluated the comparative effects of an angiotensin-converting enzyme (ACE) inhibitor versus an angiotensin receptor blocker (ARB) on the changes in serum [K + ] in people with renal insufficiency. Methods The study was a multicenter, randomized, double crossover design, with each period lasting one month. A total of 35 people (21 males and 14 females, 19 African Americans and 16 Caucasian) participated, with the mean age being 56 ± 2 years. Mean baseline serum [K + ] was 4.4 ± 0.1 mEq/L. The glomerular filtration rate (GFR) was 65 ± 5 mL/min/1.73 m 2 , and blood pressure was 150 ± 2/88 ± 1 mm Hg. The main outcome measure was the difference from baseline in the level of serum [K + ], plasma aldosterone, and GFR following the initial and crossover periods. Results For the total group, serum [K + ] changes were not significantly different between the lisinopril or valsartan treatments. The subgroup with GFR values of ≤60 mL/min/1.73 m 2 who received lisinopril demonstrated significant increases in serum [K + ] of 0.28 mEq/L above the mean baseline of 4.6 mEq/L ( P = 0.04). This increase in serum [K + ] was also accompanied by a decrease in plasma aldosterone ( P = 0.003). Relative to the total group, the change in serum [K + ] from baseline to post-treatment in the lisinopril group was higher among those with GFR values of ≤60 mL/min/1.73 m 2 . The lower GFR group taking valsartan, however, demonstrated a smaller rise in serum [K + ], 0.12 mEq/L above baseline ( P = 0.1), a 43% lower value when compared with the change in those who received lisinopril. This blunted rise in [K + ] in people taking valsartan was not associated with a significant decrease in plasma aldosterone ( P = 0.14). Conclusions In the presence of renal insufficiency, the ARB valsartan did not raise serum [K + ] to the same degree as the ACE inhibitor lisinopril. This differential effect on serum [K + ] is related to a relatively smaller reduction in plasma aldosterone by the ARB and is not related to changes in GFR. This study provides evidence that increases in serum [K + ] are less likely with ARB therapy compared with ACE inhibitor therapy in people with renal insufficiency.

Recent trials have demonstrated a trend for increased mortality when patients with end-stage renal disease (ESRD) or chronic kidney disease (CKD) are treated with erythropoietin-stimulating agents (ESAs) to hemoglobin levels higher than recommended (>13g/dl). Recent studies suggest that higher doses of ESAs, in themselves, may be at least partly responsible for this mortality risk. This is important, as more than 90% of patients with ESRD and approximately 20% of patients with CKD receive ESAs. Two new studies address this.

Use of iohexol to quantify hemodialysis delivered and residual renal function . Background Classically, urea (molecular wt=60) is used to determine the urea reduction ratio (URR) or clearance, based on volume of distribution (Kt/V). These methods are subject to many errors. The purpose of this study was to determine whether iohexol (Io; molecular wt=821) could be used instead of urea and provide better information as well as middle molecule clearance data. Methods Ten hemodialysis (HD) patients were evaluated. All were dialyzed for three hours, and a single bolus of 100ml of Io was injected immediately post-HD. For direct dialysis quantification (DDQ), the spent dialysate was collected in a drum, and urea and iodine (I) determined immediately prior to, at the end of, and 30minutes post-HD. As routinely used, DDQ measures clearance directly rather than estimates the levels. Results Calculated Kt/V urea (1.21 ± 0.05) significantly overestimated DDQ Kt/V urea (0.78 ± 0.04, P P 30min 0.59 ± 0.02, P urea ), 247 ± 21ml/min, significantly overestimated DDQ C urea (157 ± 10ml/min P Io and DDQ C Io , however, were similar (109 ± 8 vs. 104 ± 7ml/min). Total body clearance (TBC) in six anuric subjects was 2.5 ± 0.3ml/min, and in four oliguric subjects was 5.2 ± 0.5ml/min. In 10 additional patients, direct urine measurements demonstrated a non-renal clearance (NRC) of 2.97 ± 0.18ml/min, which was 4.0 ± 0.3% of body wt. Use of this factor allowed an estimation of residual renal function (RRF) that accurately reflected measured RRF (1.32 ± 0.53 vs. 1.42 ± 0.55ml/min) Conclusion A single injection of Io can be used to determine Kt/V, RR, and RRF without rebound or the inconvenience of urine collection. It may also represent middle molecule clearance better than urea kinetics, and may serve as a superior method for determining HD delivered and dialysis adequacy.

DKD is a complex and multifaceted disease. A substantial portion of patients remain unable to attain clinical targets for glycosylated hemoglobin, lipids, and blood pressure. Improving outcomes requires multifactorial interventions that are best delivered through collaborative care. Targets for improvement should include screening, diagnosis, and early referral. Following referral, the patient should be cared for in an integrated framework using the 4 elements of an effective DKD care delivery model: clear roles and responsibilities, integrated QI programs, MDT approach, and effective communication facilitated through access to a shared EMR. Given the differences in the pathophysiology of DM in the renal population, a nephrologist and endocrinologist can be invaluable in improving care for this population. Large-scale trials are needed to validate the cost and usefulness of collaborative care as current data are insufficient. Based on available data, models such as the one proposed here should serve to maximize the strengths of individual providers and provide improved quality of care to patients.

A 59-year-old white man with a history of recurrent pleural effusions, coal worker's pneumoconiosis, and a positive PPD presented with hemoptysis beginning on the morning of admission. The patient had coughed up small amounts of dark blood totaling approximately 4 ounces; although this was his first episode of hemoptysis, he had experienced epistaxis approximately once weekly in the previous year. The patient was married, had smoked one pack of cigarettes/day for 30 years, but had quit four years ago. He occasionally drank alcoholic beverages, and he was a retired coal miner who had worked directly in the mines. He denied fever, chills, night sweats, weight loss, decreased appetite, nausea, vomiting, shortness of breath, or cough. The patient complained of a transient nonspecific rash in the previous weeks that had resolved. The medical history was notable for a recurrent left-sided pleural effusion 5 years previously with a negative workup for collagen-vascular disease, malignancy, and infection. He had had nephrotic-range proteinuria four years prior to admission; renal biopsy then demonstrated focal segmental glomeruloselerosis. Treatment with an angiotensin-convertingenzyme inhibitor reduced the proteinuria to below 400 mg/24 hours. The family history was negative. Physical examination revealed a well-appearing white man in no apparent distress. His temperature was 37°C; respirations, 20/mm; pulse, 80 beats/mm; and blood pressure, 120/60 mm Hg. The head, eyes, ears, nose, and throat were normal, as was the neck. The lungs were clear to auscultation. Cardiac examination was unremarkable. His abdomen was soft, nontender, and his extremities showed no evidence of clubbing, cyanosis, or edema. Neurologic examination was normal. Laboratory evaluation revealed a white blood cell count of 9700/mm3; hematocrit, 41%; and platelets, 192,000/mm3. Blood urea nitrogen (BUN) was 40 mgJdl and serum creatinine concentration 2.3 mg/dl; two months ago, the BUN was 25 mg/dl and the serum ereatinine, 1.4 mg/dl. Total

Summary: Acute crescentic-rapidly progressive glomerulonephritis is an uncommon but devastating disease which comes in several forms. That associated with anti-glomerular basement membrane (GBM) antibodies is most vexing to treat and has by far the worst prognosis. Despite conventional wisdom that plasma exchange and immunosuppression are optimal therapy, the cost constraints and issues raised in the present review suggest that this needs to be readdressed. Non-anti-GBM disease appears to respond well to aggressive immunosuppression and/or plasma exchange. A possible zided benefit of plasma exchange in patients with vasculitis on dialysis needs to be further addressed, especially in terms of a possible differential effect of very large doses of pulse methylprednisolone (30 mg/kg) as opposed to smaller doses.

Study of EHS type IV collagen lacking Goodpasture's epitope in glomerulonephritis in rats. The Goodpasture's epitope has been mapped to the α 3 non-collagenous chain (NC1) of type (IV) collagen [α 3 col(IV)]. We have developed a model of experimental autoimmune glomerulonephritis (EAG) in rats immunized once with collagenase solubilized GBM (csGBM). Engelbreth-Holm-Swarm (EHS) tumor contains abundant col(IV) with little or no α 3 col(IV). To test the hypothesis that antigens related to Goodpasture epitope are required to produce EAG in our model, we immunized rats once with 40 µg csEHS. Positive controls immunized with csGBM developed typical EAG with GBM bound antibody, proteinuria, and glomerulonephritis. EHS rats developed circulating and bound antibody to mesangium and tubular basement membrane with minimal GBM deposits, but did not develop proteinuria or glomerulonephritis. Although circulating antibody in EHS rats bound to csGBM by ELISA, there was no binding in ELISA to M2 antigen containing the Goodpasture epitope while EAG rat's serum did bind. By Western blot with antisera to Goodpasture epitope, EHS antigen was less complex than GBM in the monomer/dimer regions and appeared to lack NC1 corresponding to α 3 col(IV). Blotting with sera from EHS rats demonstrated reactivity to various components of GBM but not to α 3 col(IV). EAG sera and renal eluates bound to α 3 col(IV). EAG rats evidenced cell mediated immunity while EHS rats did not (stimulation index EHS 1.1, EAG rats 8.0). These studies show that the development of antibody to col(IV) in a setting conducive to EAG does not cause EAG in the absence of α 3 col(IV) NC1, that the antibody response in EHS rats was not associated with a cellular response to the antigen and that an epitope on the same NC1 α 3 col(IV) which contains the Goodpasture epitope appears necessary to induce EAG in this model. These studies further implicate the α 3 col(IV) as a pathogenetic factor in the development of Goodpasture syndrome in humans as well as a marker of disease.

Background Ferumoxytol is a unique intravenous (i.v.) iron therapy. This report examines factors affecting hemoglobin response to i.v. ferumoxytol, and the relationship between hematologic parameters, concomitant erythropoiesis-stimulating agents (ESA), and adverse events (AEs) in nondialysis CKD patients. Methods A series of post-hoc efficacy and safety analyses were performed using pooled data from two identically designed Phase III studies in 608 nondialysis CKD patients randomized to receive two 510 mg i.v. injections of ferumoxytol within 5 ± 3 days versus oral iron. Results Ferumoxytol resulted in a significant increase in hemoglobin in the presence and absence of ESA, and across a range of baseline hemoglobin, transferrin saturation, ferritin, and reticulocyte hemoglobin content levels. Adverse event rates with ferumoxytol were similar across quartiles of change in hemoglobin; there were no trends suggesting an increased rate of cardiovascular AEs with higher maximum achieved hemoglobin or faster rate of hemoglobin rise. There was no meaningful difference in the rate of AEs, serious AEs, and cardiovascular AEs between patients receiving or not receiving ESA. Conclusions These analyses add to the knowledge of predictors of response and safety outcomes associated with i.v. iron therapy in nondialysis CKD patients.

Aims: The role of kidney infiltrating T cells in the pathology of lupus nephritis is unclear. This study was undertaken to investigate whether CD4+ T cell responses to a surrogate mesangial antigen can initiate glomerulonephritis. Methods: Ovalbumin (OVA) was deposited in the glomerular mesangium of C57BL/6 (B6) mice using anti-α8-integrin immunoliposomes (α8ILs). This was followed by injection of activated OVA-reactive CD4+ transgenic OT2 T cells. Trafficking of antigen-specific OT2 T cells to kidneys and lymph nodes was studied by flow cytometry. Glomerular pathology and immune cell infiltration was characterized by immunostaining. Role of CCR2 deficiency on T cell-mediated glomerulonephritis was investigated using B6.ccr2–/– mice. Results: α8ILs delivered OVA specifically to the renal glomeruli. Adoptively transferred OT2 T cells preferentially accumulated in renal lymph nodes and in the renal cortex. Kidneys showed glomerular inflammation with recruitment of endogenous T cells, dendritic cells and macrophages. T cell-mediated inflammation induced mesangial cell activation and an increase in glomerular MCP1 and fibronectin. The formation of inflammatory foci was driven by Ly6C monocytes and was CCR2 dependent. Conclusions: The findings from this study show that T cells reactive with antigens in the mesangium are sufficient to initiate glomerular pathology. Antigen-specific CD4 T cells act by inducing glomerular MCP1 production which mediates recruitment of inflammatory monocytes resulting in glomerulonephritis. Thus, downmodulation of T cell responses within the kidneys of lupus patients will be a beneficial therapeutic approach.

The pulmonary renal syndrome is a symptom complex with simultaneous involvement of the kidneys and lungs. While this can be related to any concomitant kidney and lung dysfunction, the usual connotation is that of kidney dysfunction associated with pulmonary hemorrhage frequently manifesting as hemoptysis. Many causes of the pulmonary renal syndrome have been defined, and therapy is directed at the underlying etiologic factor for the syndrome. At times the presentation is life-threatening. In those situations emergency therapy must be initiated as soon as possible. A number of therapies are now available for this syndrome including pulse methylprednisolone and plasmapheresis. Emerging novel therapies show promise of augmenting the armamentarium of the clinician's therapeutic options. This review addresses the author's approach to the elaboration of the etiology of pulmonary renal syndrome and the therapeutic options available to the clinician.

The pulmonary renal syndrome is a symptom complex with simultaneous involvement of the kidneys and lungs. While this can be related to any concomitant kidney and lung dysfunction, the usual connotatio

This group previously identified a peptide p13 of alpha 3(IV)NC1 domain of type IV collagen that induces experimental autoimmune glomerulonephritis (EAG) in rats with generation of antibodies to sites on alpha 3(IV)NC1 external to the peptide as a result of intramolecular epitope spreading. It was hypothesized that intermolecular epitope spreading to other collagen IV chains also was induced. Rats were immunized with nephritogenic peptide that was derived from the amino terminal part of rat alpha 3(IV)NC1 domain, and serum and kidney eluate were examined for antibodies to both native and recombinant NC1 domains of collagen IV. Peptide induced EAG with proteinuria and decreased renal function and glomerular basement membrane IgG deposits. Sera from these rats were examined by ELISA, which revealed reactivity not only to immunizing peptide but also to human and rat alpha 3(IV)NC1 and to human alpha 4(IV)NC1 domains. Kidney eluate that was depleted of alpha 3(IV)NC1 antibodies still reacted to alpha 4(IV)NC1, and alpha 3(IV)NC1 column-bound antibody reacted with alpha 3(IV)NC1. There was minimal reactivity to other collagen chains. Eluate that was adsorbed to NC1 hexamer from rat glonterular basement membrane lost all reactivity to glomerular constituents, and the eluted antibodies reacted to alpha 3(IV)NC1 and alpha 4(IV)NC1 domains. These studies show that a T cell epitope of alpha 3(IV)NC1 induces EAG, intramolecular epitope spreading along alpha 3(IV)NC1, and intermolecular epitope spreading to alpha 4(IV)NC1 domain with minimal or no reactivity to other collagen chains or glomerular constituents. This is the first demonstration in EAG of intermolecular epitope spreading and identification of the spread epitopes. (Less)

We previously demonstrated the anti-inflammatory effects and renal tissue protection in response to adenosine A2A-receptor (A2AR) activation in acute renal injury. We sought to extend these studies and determine the efficacy of A2AR agonists in a chronic model of renal injury. We hypothesized that A2Aagonists mediate renal tissue protection in diabetic nephropathy by reducing glomerular inflammation. Diabetes was induced with single intravenous injection of streptozotocin in Sprague-Dawley rats (50 mg/kg). Increases in urinary albumin excretion (UAE) and plasma creatinine at week 6 in the diabetes group (26- and 6-fold over control, respectively) were markedly reduced by continuous subcutaneous administration of ATL146e (10 ng·kg−1·min−1), a selective A2Aagonist. The increase in UAE in the diabetes group was associated with a significant reduction in the expression of slit diaphragm-associated molecules compared with control (nephrin; P < 0.05 and podocin; P < 0.005) that was reversed by ATL146e treatment. Diabetes led to an increase in urinary excretion of monocyte chemoattractant protein-1 (705% of control), TNF-α (1,586% of control), IFN-γ (298% of control), kidney fibronectin mRNA (457% of control), and glomerular infiltration of macrophages (764% of control), effects significantly reduced by ATL146e treatment. Mesangial expansion and basement membrane thickness were reduced with ATL146e. To further confirm the selectivity of ATL146e, we used wild-type (WT) or A2Aknockout (A2A-KO) mice. Four weeks after diabetes, UAE increased significantly in both WT and A2A-KO diabetic mice (3.0- and 3.3-fold over control). A2Aagonist treatment blocked the increase in UAE in WT diabetic mice ( P < 0.001), whereas it had no effect on the A2A-KO diabetic mice. These results demonstrate that chronic A2AR activation in diabetic rats 1) ameliorates histological and functional changes in kidneys induced by diabetes and 2) causes reduced inflammation associated with diabetic nephropathy.

● Patients with kidney disease have few signs and symptoms early in disease course; laboratory evaluation may be only way of detecting disease ● Tests should detect abnormalities early enough to allow corrective therapy ● Important for measuring renal disease progression and efficacy of therapies ● Help predict when renal replacement therapy may be necessary ● Aid in appropriate dosing of medications ● Tests that best detect abnormalities of renal function measure glomerular filtration rate (GFR)

Background: Currently available intravenous iron preparations are not ideal, either because of safety concerns or dose limitations. We investigated the safety and pharmacokinetics of ferumoxytol, a new iron replacement therapy, in normal subjects and hemodialysis patients. Methods: In a randomized, double-blind, ascending-dose study in normal volunteers (n = 41), 6 subjects received placebo, and 8 subjects each received ferumoxytol, at 1, 2 or 4 mg iron/kg, injected at 60 mg iron/min. The remaining subjects received 4 mg iron/kg at injection rates of 90 (n = 3), 180 (n = 3) or 1,800 mg iron/min (n = 5). In the second, open-label, ascending-dose study, 20 hemodialysis patients received 125 or 250 mg of iron over 5 min. Results: In normal subjects, the blood half-life of ferumoxytol increased with increasing dose from 9.3 to 14.5 h (p < 0.05) but not with increasing rate of injection. The drug half-life in hemodialysis patients was similar to normal subjects. Ferumoxytol was not removed with hemodialysis. Serum iron (p < 0.001), transferrin saturation (p < 0.001) and ferritin increased in both populations. No serious adverse events were attributable to ferumoxytol. Conclusion: Ferumoxytol was well tolerated in this study. Its pharmacokinetic properties and simplicity of administration suggest that it will be an attractive form of iron replacement therapy.

JASN is cooperating with the Renal Physicians Association and other renal journals in publishing this executive summary of a clinical practice guideline on appropriate patient preparation for renal replacement therapy. The full text of the guideline is available from the Renal Physicians Association

Hyperglycaemia is directly involved in causing long-term diabetic complications. The non-enzymatic glycation of proteins, yielding irreversible advanced glycation end products and advanced glycation end products-derived protein crosslinking, participates in the development of diabetic complications, such as diabetic nephropathy. Diabetic nephropathy is becoming a major medical problem with increasing numbers of these patients progressing to end stage renal disease, thus requiring renal replacement therapy. While several interventions may slow the development and progression of diabetic nephropathy, there is no effective treatment to prevent or reverse the disease. Pimagedine (aminoguanidine HCl) has been shown to be an effective agent in reducing the severity of the structural and functional alterations associated with experimental diabetic nephropathy. Preliminary studies suggest a beneficial effect of pimagedine in treating patients with diabetic nephropathy. In summary, these observations support a role for advanced glycation end products inhibitors, like pimagedine, in the management of diabetic nephropathy, either alone or in combination with other therapies.

Delivered dose of hemodialysis (HD) in large patients with end-stage renal disease is often less than adequate. Fourteen chronic HD patients with weights greater than 80 kg participated in a prospective, cross-over study comparing urea reduction ratio (URR +/- SEM) and the fractional clearance index for urea (eKt/V(urea) +/- SEM) on a single polysulfone dialyzer for a control (HDC) period of 4 weeks versus clearances obtained with two dialyzers in parallel during an intervention (HDP) period of 4 weeks. Clearance of the surrogate middle molecule iohexol (C(Io)) was also measured. Health status was assessed with the SF-36. Blood and dialysate flow rates and duration of HD sessions were constant. URR increased from 0.67 +/- 0.006 during HDC to 0.72 +/- 0.006 with HDP (P < 0.0001). eKt/V(urea) increased from 1.16 +/- 0.021 to 1.34 +/- 0.021 (P < 0.0001). Increased URR and eKt/V(urea) occurred in all 14 during HDP (P < 0.05). C(Io) during HDP averaged 182 +/- 7.7 mL/min compared with 131 +/- 5.4 mL/min in HDC sessions (P < 0.00001). Health status improved in six of eight categories. Expense increased approximately $14.27 per dialysis with HDP. In 11 of 14 patients continued on two dialyzers in parallel for 1 year, monthly eKt/V averaged 1.46 +/- 0.066, and health status further improved in five of eight categories. In large patients, two dialyzers in parallel increased urea and iohexol clearance. Increased urea clearance was maintained for 1 year, and health status improved.

Goodpasture's epitope in development of experimental autoimmune glomerulonephritis in rats. The Goodpasture's epitope (GP) has recently been localized to the last 36 AA of the non-collagenous (NC1) domain of the α 3 chain of type IV collagen [ α 3 (IV)]. Since α 3 (IV) induces glomerulonephritis (GN) in rats and rabbits, the purpose of the present study was to determine if the GP epitope itself could induce GN. We immunized rats with synthetic peptides of GP epitope, 36-mer, alone or as protein conjugates. Rats immunized with bovine GBM served as positive controls. Peptide immunized rats developed high titer antibodies to peptides, but only unconjugated 36-mer induced antibody against human and bovine GBM, but not to rat GBM. Acidic residues and the full length 36-mer were important in production of GBM reactive antibodies. Positive controls developed antibody to GBM without reactivity against 36-mer, had IgG and fibrin on the basement membrane, GN and proteinuria. Kidney eluted antibody was reactive with rat, bovine, and human GBM but not 36-mer. GN rat lymphocytes underwent blast transformation to GBM but not peptide, and peptide immunized animals responded only to the respective peptides. None of the animals immunized with GP peptide epitope, despite the development of anti-peptide antibodies or anti-GBM antibodies, developed any in vivo fixation of antibody to the GBM, abnormal proteinuria, or GN. The present study shows that the GP epitope is sufficient to induce an immune response to the epitope, but it is not sufficient to induce GN. This demonstrates that other factors or epitopes are important in the pathogenicity of GBM induced GN in this model. These remain to be delineated.

Glomerular involvement in primary Sjogren's syndrome is rare and only five cases of membranoproliferative glomerulonephritis have been reported. We present a case of a 31-year-old white woman with primary Sjogren's syndrome who developed nephrotic syndrome. Evaluation showed no evidence of an associated connective tissue disease. Kidney biopsy was consistent with type I membranoproliferative glomerulonephritis. The patient's nephrotic syndrome resolved spontaneously, a course that has not been reported previously in this setting.

The Authors Reply: Below is our response to the open commentary1 on the Normal Hematocrit Cardiac Trial (NHCT).

A case of skin necrosis in a patient receiving intravenous (IV) heparin during routine intermittent hemodialysis is reported. Multiple erythematous, tender lesions developed over the abdomen and thighs and rapidly became necrotic. Biopsies showed fibrin thrombi in the dermal venules and capillaries, but no cellular infiltrate. The patient was in her third month of regular hemodialysis. Skin necrosis associated with the use of heparin usually occurs within 2 weeks of beginning heparin therapy and has not been reported in patients receiving heparin with hemodialysis. Possible mechanisms, including acquired antithrombin III deficiency leading to heparin-induced skin necrosis, are discussed.

Idiopathic acute crescentic rapidly progressive glomerulonephritis (RPGN) with oliguria, proteinuria and rapid decline of renal function is usually associated with death or the need for support by dialysis. Spontaneous recovery is rare, and various modes of therapy have been generally unsuccessful. We describe nine patients with rapidly progressive glomerulonephritis of less than six weeks' duration whose creatinine clearance decreased over 50 per cent. All had normal-sized kidneys and were proteinuric, six of nine were oliguric, and five of nine required dialysis. Renal biopsy specimens were examined by light, electron and immunofluorescence microscopy. Rapidly progressive glomerulonephritis without immune deposits was present in six, immune complex disease in two and antiglomerular basement membrane disease in one. All were treated with intravenous pulse methylprednisolone followed by oral steroids. Serum creatinines decreased in seven of nine patients from one to four weeks after pulse therapy and remained stable or improved in six of these. Three of five patients undergoing dialysis were able to discontinue that support. The mean creatinines of 10.6 ± 2.2 mg/dl before therapy decreased to 2.2 ± 0.5 mg/dl after four to 24 months in the six responding patients. Two other patients died of causes unrelated to therapy. Tissue obtained from four patients four to 12 months after pulse therapy showed resolution of inflammatory changes and regression of crescents. The marked and sustained improvement of renal function in six of our nine (67 per cent) patients with rapidly progressive glomerulonephritis who were treated with pulse methylprednisolone is in sharp contrast to experience previously reported and suggests the need for further evaluation in a prospective controlled study.

Three cases of amyloidosis-like glomerulopathy are presented in which renal amyloidosis was initially diagnosed on the basis of ultrastructural findings, despite negative Congo red staining. The histologic and immunofluorescence findings and, on careful examination, ultrastructural features of this amyloidosis-like glomerulopathy all serve to distinguish it from true amyloidosis. The clinical behavior suggests that it is a primary glomerulopathy since, with time, no other systems become involved.

Two macrolide antibiotics, josamycin and erythromycin stearate, were administered orally to healthy, adult male volunteers for a comparative study of their pharmacological properties. In comparable doses, josamycin and erythromycin produced similar plasma concentrations, with similar half-lives and elimination constants. An initial loading dose of 1.5 g of josamycin produced greater peak concentrations of antibiotic throughout a 10-day period with a regimen of every 6 h. In addition, josamycin tended to reach higher peak and trough concentrations after regimens of every 6 or 8 h were maintained for 2 days. Josamycin penetrated into saliva, sweat, and tears, and it was better tolerated in fasting subjects than was erythromycin stearate.

Acute pulmonary silicoproteinosis, massive proteinuria and fatal renal failure developed in a 23 year old male sandblaster. Examination of the kidney by immunofluorescence revealed granular deposits of immunoglobulin M (IgM) and the third component of complement (C3) along the glomerular basement membrane. Light microscopy disclosed mild proliferative glomerulonephritis with loss of colloidal iron staining for sialoprotein, and electron microscopy disclosed an increased density of epithelial cytoplasm, altered lysosomes and endothelial cell microtubular structures. The silicon content of the kidney was 264 parts per million (ppm), but particles of silicon were not demonstrated by electron microscopy. No primary or systemic causes of renal diseases were elucidated. The renal dysfunction apparently resulted from acute renal silicon toxicity, a new complication of acute pulmonary silicoproteinosis.

Sphingosine 1-phosphate (S1P), a pleiotropic lipid mediator, binds to five related G-protein-coupled receptors to exert its effects. As S1P1 receptor (S1P1R) activation blocks kidney inflammation in acute renal injury, we tested whether activation of S1P1Rs ameliorates renal injury in early-stage diabetic nephropathy (DN) in rats. Urinary albumin excretion increased in vehicle-treated diabetic rats (single injection of streptozotocin), compared with controls, and was associated with tubule injury and increased urinary tumor necrosis factor-α (TNF-α) at 9 weeks. These effects were significantly reduced by FTY720, a non-selective, or SEW2871, a selective S1P1R agonist. Interestingly, only FTY720 was associated with reduced total lymphocyte levels. Albuminuria was reduced by SEW2871 in both Rag-1 (T- and B-cell deficient) and wild-type diabetic mice after 6 weeks, suggesting that the effect was independent of lymphocytes. Another receptor, S1P3R, did not contribute to the FTY720-mediated protection, as albuminuria was also reduced in diabetic S1P3R knockout mice. Further, both agonists restored WT-1 staining along with podocin and nephrin mRNA expression, suggesting podocyte protection. This was corroborated in vitro, as SEW2871 reduced TNF-α and vascular endothelial growth factor mRNA expression in immortalized podocytes grown in media containing high glucose. Whether targeting kidney S1P1Rs will be a useful therapeutic measure in DN will need direct testing.

Renal TGF-β regulation in spontaneously diabetic NOD mice with correlations in mesangial cells. Diabetic nephropathy is characterized by excessive glomerular matrix accumulation, basement membrane thickening and sclerosis. Although it is clear that systemic metabolic disturbances precipitate such renal changes, the signals and pathways involved in this process are not fully elucidated. Recent evidence suggests that growth factors/cytokines are intimately involved in the pathogenesis of diabetic nephropathy. Because of its prosclerotic properties, transforming growth factor-β (TGF-β) is a prime candidate mediator of diabetic nephrosclerosis. We examined perfused kidney tissues isolated from spontaneously diabetic, non-obese diabetic mice (NOD) for TGF-β content. By using murine isotype specific TGF-β probes, we demonstrate that within 5 to 10 days of hyperglycuria renal TGF-β2 mRNA and protein content increases. By immunohistochemical analysis, de novo TGF-β immunoreactivity was detected within both glomeruli and the interstitium. In order to determine the signals involved in promoting kidney TGF-β content in vivo , TGF-β regulation was examined in renal mesangial cells in vitro . Murine mesangial cells stimulated with glycosylated protein secrete bioactive TGF-β and demonstrate a disproportionate increase in the steady state levels of TGF-β2 mRNA. These data suggest that a major early renal response in NOD mice to hyperglycemia or to glycosylated proteins is characterized by increases in TGF-β2.

Effect of hemodialysis and peritoneal dialysis on aztreonam pharmacokinetics. Aztreonam, a new monobactam, will be widely used because of its broad aerobic gram-negative bacterial coverage and its apparent low risk of allergic phenomena in penicillin/cephalosporin-sensitive patients. We examined aztreonam kinetics in patients during hemodialysis and in the interdialytic period and in patients on continuous ambulatory peritoneal dialysis (CAPD), and related aztreonam to urea clearance (CL). In hemodialysis patients, aztreonam serum half-life was 7.9 hr between and 2.7 hr during dialysis sessions. CLserum, CLrenal, and CLother were 24.4, 0.5, and 23.9 ml/min, respectively, during the interdialytic period. Four hours of dialysis removed 38.2% (range, 27 to 58%) of antibiotic. CL of aztreonam by hemodialysis was 36.6 to 43.2 ml/min, 50 to 77% greater than interdialytic CL. CL of urea by hemodialysis was 112.4 to 155.6 ml/min; CLaztreonam/CLurea ratio was 0.28 to 0.33 during the hemodialysis sessions. During CAPD, aztreonam serum half-life after intravenous dosing was 7.1 hr; dialysate recovery, 9.7% of the dose; CLserum, CLrenal, CLperitoneal dialysis, and CLother were 23.8, 0.5, 2.1, and 21.3 ml/min, respectively. CLurea by CAPD was 6.5 ml/min. Thus, CLaztreonam during CAPD was 32% of CLurea. Aztreonam was detectable in dialysate at 48 hr (eight exchanges) after peritoneal administration in the first exchange. Hemodialysis and CAPD patients given aztreonam treatment should receive the standard dose of aztreonam as a loading dose, followed by one-fourth the loading dose at standard dose intervals. Hemodialysis patients should receive a supplemental dose equal to half their usual maintenance dose immediately after each dialysis session. For CAPD patients with peritonitis due to susceptible organisms, a 1-g i.v. loading dose followed by a 0.5-g i.p. dose every 6 hr is suggested. In any individual patient undergoing hemodialysis or CAPD, the relationship between CLurea and CLaztreonam should allow appropriate antibiotic dose adjustment.Effet de l'hémodialyse et de la dialyse péritonéale sur la pharmacocinétique de l'aztréonam. L'aztréonam, une nouvelle monobactame, sera largement employée en raison de son vaste spectre bactérien gramnégatif aérobie et de son faible risque apparent de phénomènes allergiques chez les malades sensibles à la pénicilline/céphalosporine. Nous avons examiné la cinétique de l'aztréonam chez des malades pendant l'hémodialyse et durant la période interdialytique, et chez des malades en dialyse péritonéale continue ambulatoire (CAPD) et nous avons relié la clearance de l'aztréonam à celle de l'urée (CL). Chez les hémodialysés, la demi-vie sérique de l'aztréonam était de 7,9 hr entre et 2,7 hr pendant les séances de dialyse. CLsérum, CLrénale, et CLautres étaient de 24,4, 0,5, et 23,9 ml/min, respectivement pendant la période interdialytique. Quatre heures de dialyse épuraient 38,2% (de 27 à 58%) de l'antibiotique. CL de l'aztréonam par l'hémodialyse était de 36,6 à 43,2 ml/min, 50 à 77% plus élevée que CL interdialytique. CL de l'urée par hémodialyse était de 112,4 à 155,6 ml/min; le rapport CLaztréonam/CLurée était de 0,28 à 0,33 pendant les séances d'hémodialyse. Au cours de la CAPD, la demi-vie sérique de l'aztréonam après administration i.v. était de 7,1 hr; la récupération dans le dialysat de 9,7% de la dose; CLsérum, CLrénale, CLdialyse péritonéale, et CLautres étaient de 23,8, 0,5, 2,1, et 21,3 ml/min respectivement. CLurée par CAPD était de 6,5 ml/min. Ainsi, CLaztréonam pendant la CAPD était de 32% de CLurée. L'aztréonam etait détectable dans le dialysat 48 hr (nuit échanges) après administration péritonéale lors du premier échange. Les malades en hémodialyse ou CAPD traités par l'aztréonam devraient recevoir la dose standard d'aztréonam comme dose de charge suivie par un quart de la dose de charge aux intervalles de la dose standard. Les hémodialysés devraient recevoir une dose supplémentaire égale à la moitié de leur dose d'entretien habituelle immédiatement après chaque séance de dialyse. Chez les malades en CAPD atteints de péritonite par des organismes sensibles, il est suggéré une dose de charge de 1-g i.v., suivie de 0,5-g par voie intrapéritonéale toutes les 6 hr. Chez tout malade en hémodialyse ou CAPD individuellement, la relation entre CLurée et CLaztréonam devrait permettre l'ajustement posologique approprié de l'antibiotique.

T-cells and macrophages in rapidly progressive glomerulonephritis: Clinicopathologic correlations. We phenotyped with monoclonal antibodies (MAb) the cellular infiltrates in kidneys of patients with rapidly progressive glomerulonephritis (RPGN) responsive (R) or nonresponsive (NR) to pulse methylprednisolone therapy (PM)-eight anti-GBM, six no immune deposits, three immune complex, two vasculitis, and one proliferative GN. There were glomerular, periglomerular, crescentic, and interstitial T and T-cell subsets. Few interstitial and no glomerular B and NK cells were observed. TH cells were much more common than TS. Phenotypes were quantitatively evaluated in 221 nephritic and 32 control glomeruli.T and/or TH cells were positively correlated with MΦ, r = 0.30 to 0.74,P < 0.05 to 0.0005. Although differences in phenotypes were observed, these differences were insufficient to distinguish between subtypes. Analysis of R and NR revealed no relationship to percent crescents, entry serum creatinine, oliguria, or need for dialysis. NR was related to presence of anti-GBM disease,P = 0.001, as was ability to stop dialysis, 0 of 7 GBM versus 9 of 10 other,P < 0.001. Mild infiltrates of lymphocytes and MΦ correlated with R,P ≤ 0.02. R had fewer numbers of TH and MΦ in glomeruli,P = 0.0001, in crescents,P < 0.02, and total TH and MΦ compared to NR, P < 0.001. Crescentic and total TH/S ratios were lower in NR than R, P < 0.05. These findings demonstrate that components of the cell-mediated immune (CMI) system are present by MAb analysis, that subtypes cannot be differentiated by CMI constitution, and R to PM is related to intensity and composition of CMI involvement. Independence of the CMI system relative to anti-GBM disease remains to be clarified.

Hyperacute rejection of renal allografts is usually mediated by IgG antibody, but recent studies indicate that cold-reacting IgM alloantibodies are also associated with immediate malfunction of renal

The pharmacokinetics of cefaclor and cephalexin were characterized in patients with creatinine clearances ranging from 0 to 147 ml/min. Each of 24 fasted subjects received a single 500-mg oral dose of cefaclor, and 13 of these subjects later received 500 mg of cephalexin. Serum and urine levels of the antibiotics were measured by bioassay. The serum half-lives were highly correlated with corrected creatinine clearance (cefaclor r = 0.92, cephalexin r = 0.94). Linear regression estimates of the half-life of cefaclor were 2.3 h in the anephric patient and 40 min in the patient with a corrected creatinine clearance of 100 ml/min. For cephalexin, corresponding half-lives were 15.4 h and 58 min. We present a dosage nomogram for calculating the appropriate adjustments to the loading dose based on patient weight and maintenence dose based on corrected creatinine clearance.

Transfer of experimental glomerulonephritis in chickens by mononuclear cells. We have produced experimental autoimmune glomerulonephritis (EAG) in histocompatible SC chickens by immunization with different types of glomerular antigen. The development of EAG was time, but not antigen, dependent. Transfer of mononuclear cells from spleens and kidneys of nephritic animals resulted in EAG in naive recipients. Transferred EAG developed earlier than in immunized donors and was not associated with circulating or bound anti-GBM antibodies. Control recipients did not develop disease from control cells alone, soluble antigen, or antigen plus control cells. The cells which transferred EAG appeared morphologically by light and electron microscopy to be lymphocytes, sedimented as lymphocytes, were positive with anti-serum to thymocytes but negative with anti-bursa anti-serum, stained as T-cells with monoclonal antibodies and underwent blast transformation in response to mitogen and GBM antigen. Other organ specific diseases have been transferred by cells alone; to our knowledge this is the first description of glomerulonephritis transferred by cells alone. This new pathogenetic process may play an important role in the development of glomerulonephritis in other animal models as well as in humans.