Fair enough? Decreased equity of dyadic coping across the transition to parenthood associated with depression of first-time parents.

The transition to parenthood (TTP) is a stressful life event for most couples. Therefore, the way both partners jointly cope with stress (i.e., dyadic coping) is important for the prevention of individual adjustment problems (e.g., depression). For dyadic coping to be effective in reducing depressive symptoms, efforts of both partners should be equal. However, many couples experience a decrease of equity in task division within the domestic sphere across the TTP. The current study investigates the equity of a specific skill within the 'relationship sphere', because similarly to a decreased equity in household and childcare, a decreased equity of dyadic coping is likely to be associated with poorer individual adjustment. We collected longitudinal self-report data on dyadic coping and depressive symptoms from 104 mixed-gender first-time parents (n = 208 individuals) from pregnancy until 40 weeks postpartum. We created an equity score for men and women that measured their perceived difference between received and provided dyadic coping. On average, women reported providing more and receiving less dyadic coping than men. While both genders agreed on this distribution, men did perceive a higher equity of dyadic coping than women. Furthermore, the decrease of equity perceived by women across TTP was not visible in men. In line with our assumptions based on the equity theory, perceived equity of dyadic coping was associated with depressive symptoms in a curvilinear manner: Decreases in women's perceived equity in either direction (over- or underbenefit) were associated with more depressive symptoms in women and their male partners. This association was found above and beyond the beneficial effect of dyadic coping itself. This implies that not only how well partners support each other in times of stress, but also how equal both partners' efforts are, is important for their individual adjustment across TTP.

Investigational therapies for renal disease-induced anemia.

INTRODUCTION: The main pillars for the treatment of chronic kidney disease (CKD) associated anemia are peptidic erythropoiesis stimulating agents (ESAs) and iron preparations. Both approaches benefit from long-term efficacy and safety data but are surrounded by clinical and economic concerns, driving the search for novel anti-anemic drugs. AREAS COVERED: By answering pivotal questions, the authors describe the recent developments of next generation ESAs, introduce cutting-edge iron formulations and focus on investigational approaches that interact with pathways involved in erythropoietin (Epo) synthesis and myeloid hematopoiesis. Finally, the challenges encountered with these drug candidates are discussed. EXPERT OPINION: Current peptidic ESAs are effective and well-tolerated, but are costly, require parenteral application and iron supplementation. ESA resistance may develop calling for increased doses. Therefore, orally available hypoxia-inducible factor (HIF) stabilizing compounds are attractive alternatives, which may be approved in the near future. Prominent compounds are molidustat, daprodustat and roxadustat. HIF stabilizers suppress hepcidin production and improve iron balance as the present ESAs, but also raise safety concerns in association with their pleiotropic actions. Other investigational erythropoietic biologics are growth-differentiation factor-11 (GDF11) ligand traps (sotatercept, luspatercept), which are also well advanced in development. Possibly, they will provide an add-on for established therapies. However, immunogenicity of these compounds still needs to be carefully investigated.

Biosimilars: A Multidisciplinary Perspective.

A biosimilar is an officially regulated and approved copy of an originator biologic therapy. Improved affordability and consequent wider patient access compared with biologics are a significant appeal of biosimilars. Regulatory guidelines for biosimilar development and approval are rigorous and undergoing constant refinement. The process of licensing approval for all biosimilars requires demonstration of comparability in quality, efficacy, and safety between the biosimilar and reference (originator) product, which is undertaken in a stepwise procedure of nonclinical and clinical evaluation. The approval of >20 biosimilars in Europe in several drug classes, including the first monoclonal antibody biosimilar, bears testimony to the increasing regulatory acceptance of these agents. In contrast, the clinical application of biosimilars remains underrecognized by physicians across therapy areas. Therefore, this article aims to provide a comprehensive review of the biosimilar development process and to provide multidisciplinary guidance on the potential therapeutic utility of biosimilars in clinical practice. Specifically, experts discuss clinical developments in the introduction of biosimilars across the disciplines of gastroenterology, nephrology, oncology, and rheumatology, and from a payer perspective, and also highlight a common need for ongoing pharmacovigilance, robust head-to-head clinical studies, and real-world data to establish the long-term risk-benefit profile of biosimilars. In conclusion, significant potential exists for biosimilars to revolutionize biologic therapy by widening patient access across therapy areas.

Methoxy polyethylene glycol-epoetin beta for the treatment of anemia associated with chronic renal failure.

Since more than two decades erythropoiesis-stimulating agents are the main pillar for treatment of anemia associated with chronic kidney disease. Methoxy polyethylene glycol-epoetin beta (MPG-EPO), also called continuous erythropoietin receptor activator, is the longest acting erythropoiesis-stimulating agent currently available. MPG-EPO is characterized by an elimination half-life of approximately 137 h and offers extended dosing intervals up to 4 weeks. Numerous phase I/II studies and a comprehensive clinical phase III program demonstrated the feasibility of MPG-EPO therapy for anemia correction and maintenance of stable hemoglobin levels in adult chronic kidney disease patients. Due to patent disputes MPG-EPO was only available outside the US market so far. In view of a prevailing US market introduction, this review focuses on efficacy and safety data from pivotal trials, summarizes recent clinical research and finally tries to substantiate potential benefits associated with the use of this anti-anemic drug.

Novel iron-containing phosphate binders for treatment of hyperphosphatemia.

INTRODUCTION: Hyperphosphatemia is a frequent complication of chronic kidney disease and is associated with increased mortality. Despite side effects, risk of accumulation and high costs, phosphate binders (PBs) have become the crucial cornerstone of therapy. The iron-containing PB sucroferric oxyhydroxide (SO) and ferric citrate hydrate (FCH) have entered the market and other candidates are prior market entry. AREAS COVERED: A literature search was performed using MEDLINE and EMBASE databases to identify references on iron-containing PB with particular regard to efficacy, safety and potential benefits. Additional hand searches were conducted along with a full-text review of any citation that appeared relevant. EXPERT OPINION: On the highly competitive market, where the 'ideal' PB is still unknown, novel substances that offer clear benefits over available drugs are desired. Although SO and FCH showed similar efficacy and safety compared to sevelamer, head-to-head studies with lanthanum carbonate are absent. Clinical 1-year data in a limited patient cohort suggested improved adherence for SO and a large randomized controlled trial showed significant reduction in hospitalizations and costs for FCH. Additional large randomized controlled trials have now to prove these possible advantages. Cost-effectiveness in comparison to other PB and the exclusion of significant harms under long-term treatment will determine the future use of both drugs.

Cost-effectiveness of continuous erythropoietin receptor activator in anemia.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the mainstay of anemia therapy. Continuous erythropoietin receptor activator (CERA) is a highly effective, long-acting ESA developed for once-monthly dosing. A multitude of clinical studies has evaluated the safety and efficiency of this treatment option for patients with renal anemia. In times of permanent financial pressure on health care systems, the cost-effectiveness of CERA should be of particular importance for payers and clinicians. OBJECTIVE: To critically analyze, from the nephrologists' point of view, the published literature focusing on the cost-effectiveness of CERA for anemia treatment. METHODS: The detailed literature search covered electronic databases including MEDLINE, PubMed, and Embase, as well as international conference abstract databases. RESULTS: Peer-reviewed literature analyzing the definite cost-effectiveness of CERA is scarce, and most of the available data originate from conference abstracts. Identified data are restricted to the treatment of anemia due to chronic kidney disease. Although the majority of studies suggest a considerable cost advantage for CERA, the published literature cannot easily be compared. While time and motion studies clearly indicate that a switch to CERA could minimize health care staff time in dialysis units, the results of studies comparing direct costs are more ambivalent, potentially reflecting the differences between health care systems and variability between centers. CONCLUSION: Analyzed data are predominantly insufficient; they miss clear evidence and have to thus be interpreted with great caution. In this day and age of financial restraints, results from well-designed, head-to-head studies with clearly defined endpoints have to prove whether CERA therapy can achieve cost savings without compromising anemia management.

Predictors of adolescent smoking cessation and smoking reduction.

OBJECTIVE: To investigate the processes of change, demographic, health- and smoking-related predictors of both smoking cessation and smoking reduction in adolescents. METHODS: Data were drawn from a sample of 755 adolescent smokers who participated in a study testing the efficacy of a text messaging-based intervention for smoking cessation. Demographic, health- and smoking-related variables were assessed at baseline. Five processes of smoking cessation, derived from the Transtheoretical Model and the Social Cognitive Theory, as well as outcome measures were assessed at 6-month follow up. Univariate and multivariate regression analyses were conducted to identify baseline and process variables to predict smoking abstinence and smoking reduction. RESULTS: Male gender (OR=0.43, p<.01), lower alcohol consumption (OR=0.90, p=.05) and a lower number of cigarettes smoked per day at baseline (OR=0.87, p<.01) predicted smoking abstinence. Baseline physical activity predicted smoking reduction (OR=1.04, p=.03). None of the examined process variables significantly predicted smoking abstinence. The process variable "counter-conditioning" predicted smoking reduction (OR=1.46, p=.03). CONCLUSIONS: Baseline predictors of smoking cessation differ from predictors of smoking reduction. Dynamic or modifiable variables play an important role in predicting adolescent smoking cessation. PRACTICE IMPLICATIONS: Counter-conditioning might be an important element in adolescent smoking cessation interventions.

Neuropsychological profile of children after an episode of neuroborreliosis.

BACKGROUND: In the majority of patients with Lyme neuroborreliosis (LNB), neurological symptoms are transient. The extent of neuropsychological and neuropsychiatric problems in children is not well researched. OBJECTIVES: The study aimed to investigate cognitive functions and behavioral problems in children after LNB. PATIENTS AND METHODS: A total of 20 children between 6 and 16 years of age with an episode of LNB at least 4 month before neuropsychological testing were enrolled in the study and compared with 20 healthy controls. Children with LNB had cranial nerve palsies or meningoencephalitis, immunoglobulin G and immunoglobulin M antibodies for Borrelia burgdorferi in the peripheral blood, pleocytosis in the cerebrospinal fluid (leukocytes > 10 cells/µL) and/or an intrathecal synthesis of antibodies for B. burgdorferi.Neuropsychological tests assessing intellectual skills, memory, and executive functions were used. Two parental questionnaires assessing behavior, psychiatric problems, and executive functions were administered. RESULTS: Intellectual skills, memory, and executive functions of children after an episode of LNB were within the normal range. In the subcategory of working memory, children after an episode of LNB performed worse than controls. The questionnaires did not reveal behavior or psychiatric problems, although there was a tendency that children after an episode of LNB had more physical complaints. CONCLUSION: Neuropsychological deficits resulting from LNB in childhood are rare. Most children had a good cognitive, emotional, and behavioral outcome.

Persistent nasal methicillin-resistant staphylococcus aureus carriage in hemodialysis outpatients: a predictor of worse outcome.

BACKGROUND: Nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) is a well defined risk factor for subsequent bacteremia and death in various groups of patients, but its impact on outcome in patients receiving long-term hemodialysis (HD) is under debate. METHODS: This prospective interventional cohort study (performed 2004 to 2010) enrolled 289 HD outpatients of an urban dialysis-unit. Nasal swab cultures for MRSA were performed in all patients upon first admission, at transfer from another dialysis facility or readmission after hospitalisation. Nasal MRSA carriers were treated in a separate ward and received mupirocin nasal ointment. Concomitant extra-nasal MRSA colonization was treated with 0.2% chlorhexidine mouth rinse (throat) or octenidine dihydrochloride containing antiseptic soaps and 2% chlorhexidine body washes (skin). Clinical data and outcome of carriers and noncarriers were systematically analyzed. RESULTS: The screening approach identified 34 nasal MRSA carriers (11.7%). Extra-nasal MRSA colonization was observed in 11/34 (32%) nasal MRSA carriers. History of malignancy and an increased Charlson Comorbidity Index were significant predictors for nasal MRSA carriers, whereas traditional risk factors for MRSA colonization or markers of inflammation or malnutrition were not able to discriminate. Kaplan-Meier analysis demonstrated significant survival differences between MRSA carriers and noncarriers. Mupirocin ointment persistently eliminated nasal MRSA colonization in 26/34 (73.5%) patients. Persistent nasal MRSA carriers with failure of this eradication approach had an extremely poor prognosis with an all-cause mortality rate >85%. CONCLUSIONS: Nasal MRSA carriage with failure of mupirocin decolonization was associated with increased mortality despite a lack of overt clinical signs of infection. Further studies are needed to demonstrate whether nasal MRSA colonization represents a novel predictor of worse outcome or just another surrogate marker of the burden of comorbid diseases leading to fatal outcome in HD patients.

Development of a sensitive phospho-p70 S6 kinase ELISA to quantify mTOR proliferation signal inhibition.

BACKGROUND: Drug blood levels can only serve as a surrogate because of the lack of information on the drug's direct pharmacological effects in the individual patient. Measurement of the mammalian target of rapamycin (mTOR) activity dependent on the phosphorylation status of p70 S6 kinase (p70 S6K) offers a practical way for monitoring pharmacodynamic drug activity, with the potential to better assess the state of immunosuppression in individual patients. MATERIAL AND METHODS: Here, we established a novel in vitro model system by treating Jurkat cells and peripheral blood mononuclear cells with different concentrations of sirolimus after stimulation with phorbol 12-myristate 13-acetate. RESULTS: A dose-dependent reduction of the p70 S6K phosphorylation status was demonstrated by Western blot and a newly established enzyme-linked immunosorbent assay (ELISA). Relative phospho-p70 S6K values from ELISA and relative densities from Western blot analysis in peripheral blood mononuclear cells revealed a strong correlation (Spearman correlation coefficient r s = 0.7, P = 0.01). Finally, parallel assays confirmed a sirolimus dose-dependent reduction of cytokine production and cell proliferation in the in vitro model. CONCLUSIONS: Pharmacodynamic monitoring of mTOR inhibition with a p70 S6K ELISA could guide mTOR inhibitor immunosuppression therapy toward a more individualized therapy. The usage of this technique now has to be evaluated in a clinical series of patients.

Peginesatide for the treatment of renal disease-induced anemia.

INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) are the mainstay of treatment in anemic chronic kidney disease (CKD) patients. A tailored ESA therapy should combine maximal efficacy and safety with greatest convenience in dosing. Peginesatide, recently approved in the US for once-monthly dosing in adult patients on dialysis, is a promising novel PEGylated erythropoietin-mimetic peptide for the treatment of renal disease-induced anemia. AREAS COVERED: Published animal and human studies that evaluated the pharmacodynamics, pharmacokinetics, clinical efficacy and safety of peginesatide were critically analyzed. EXPERT OPINION: Peginesatide has a well-studied pharmacological and immunological profile, and latest published data favor the use of peginesatide in place of epoetin in dialysis patients. A more detailed evaluation of its safety profile particularly in trials with CKD patients not requiring dialysis is urgently needed, as peginesatide could be a perfect treatment solution for these patients. In addition, clinical long-term data and results from supplemental studies, e.g., with the PEGylated continuous erythropoietin receptor activator as comparator, should briefly follow. The fate of peginesatide on the highly competitive ESA market is currently not predictable and depends on safety and efficacy results of upcoming trials as well as finally on market and price policy.

Macro CK2 accumulation in tenofovir-treated HIV patients is facilitated by CK oligomer stabilization but is not predictive for pathology.

BACKGROUND: Ubiquitous mitochondrial creatine kinase (uMtCK) accumulates as macroenzyme creatine kinase type 2 (macro CK2) in the serum of HIV-infected patients under a tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimen. The genesis and clinical significance of this finding is unclear. METHODS: A prospective observational 5-year follow-up study was performed on those patients in which macro CK2 appearance was initially described ('TDF switch study' cohort). In addition, tenofovir (TFV), its prodrug TDF and its active, intracellular derivative TFV diphosphate (TDP) were tested in vitro for their effects on different key properties of uMtCK to clarify possible interactions of uMtCK with TFV compounds. RESULTS: In just under 5 years of continuous TDF treatment, only 4/12 (33%) patients remained macro CK2-positive, whereas 8/12 (66%) originally positive patients were macro CK2-negative at the end of follow-up. Prospective clinical follow-up data indicate that macro CK2 appearance under TDF is not associated with significant cell damage or occurrence of malignancies. A trend towards grade 1 hypophosphataemia suggests subclinical proximal tubular dysfunction in macro-CK2-positive patients, although it was not associated with a significant decrease in estimated glomerular filtration rate. In vitro, TFV, TDF and TDP did not interfere with uMtCK enzyme activity as competitive inhibitors or pseudo-substrates, but TFV and TDF stabilized the native uMtCK octameric structure in dilute solutions. CONCLUSIONS: Appearance of octameric uMtCK as macro CK2 in the serum of TDF-treated patients is suggested to result from a combination of low-level mitochondrial damage caused by subclinical renal tubular dysfunction together with possible compensatory uMtCK overexpression and a putative concomitant stabilization of uMtCK octamers by higher levels of TFV in proximal tubules.

Hemodiafiltration and survival of end-stage renal disease patients: the long journey goes on.

Survival of end-stage renal disease (ESRD) patients remains unacceptably poor. The excessive mortality of hemodialysis (HD) patients may result, at least in part, from the insufficient removal of medium or high molecular weight uremic toxins and from the systemic inflammatory response induced by the bioincompatibility of HD systems. Hemodiafiltration (HDF) combines diffusion and convection in a single modality, and it appears to be a promising method to improve ESRD patient outcomes. Emerging evidence suggests that this technique may be superior to classic diffusive HD in terms of patient morbidity. Despite the more widespread use of online HDF, evidence for survival benefits of HDF over other treatment modalities is scarce. Results of observational studies suggest lower mortality of HDF patients as compared to HD patients. Recent prospective randomized trials, however, failed to demonstrate any improvement in survival. Subanalyses of these trials, however, showed a significant survival benefit of HDF patients receiving high substitution volumes (17 L per session and more) compared to HD patients and to HDF patients receiving lower volumes. The explanation for this volume-dependent effect remains elusive. There is an urgent need for further randomized controlled trials to confirm previous findings and to identify those ESRD patients that are likely to benefit mostly from HDF.

New strategies for managing anemia of chronic kidney disease.

Anemia is a prevalent and premature comorbidity in chronic kidney disease (CKD) and associated with multiple adverse clinical consequences including increased mortality. Today Erythropoiesis-stimulating agents (ESAs), together with iron supplementation, are the cornerstones of therapy for correcting anemia in CKD patients. As no generally accepted dosing algorithms for these agents exist, current recommendations prefer a partial but not complete anemia correction thereby favoring a more conservative and individualized ESA and iron dosing. Here we discuss in detail current evidence derived from large randomized trials about the proposed hemoglobin targets to aim at in CKD and End-Stage renal disease patients and report recent data from the thriving European market of biosimilar erythropoietins. We summarize promising investigational strategies including peginesatide and prolyl hydroxylase inhibitors for stabilization of the hypoxia inducible factor and provide a clinical review of novel high dose iron formulations like ferumoxytol or iron (III)-carboxymaltose. Taking these findings together, treatment strategies for anemia of CKD have got considerably more complicated so that a careful balance between maximization of patient`s quality of life while minimizing all risks associated with anemia treatment has become a major task of current nephrology.

Activation of innate immune defense mechanisms contributes to polyomavirus BK-associated nephropathy.

Polyomavirus-associated nephropathy (PVAN) is a significant complication after kidney transplantation, often leading to premature graft loss. In order to identify antiviral responses of the renal tubular epithelium, we studied activation of the viral DNA and the double-stranded RNA (dsRNA) sensors Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I) in allograft biopsy samples of patients with PVAN, and in human collecting duct cells in culture after stimulation by the dsRNA mimic polyriboinosinic:polyribocytidylic acid (poly(I:C)), cytokines, or infection with BK virus. Double staining using immunofluorescence for BK virus and TLR3 showed strong signals in epithelial cells of distal cortical tubules and the collecting duct. In biopsies microdissected to isolate tubulointerstitial lesions, TLR3 but not RIG-I mRNA expression was found to be increased in PVAN. Collecting duct cells in culture expressed TLR3 intracellularly, and activation of TLR3 and RIG-I by poly(I:C) enhanced expression of cytokine, chemokine, and IFN-ß mRNA. This inflammatory response could be specifically blocked by siRNA to TLR3. Finally, infection of the collecting duct cells with BK virus enhanced the expression of cytokines and chemokines. This led to an efficient antiviral immune response with TLR3 and RIG-I upregulation without activation of IL-1ß or components of the inflammasome pathway. Thus, PVAN activation of innate immune defense mechanisms through TLR3 is involved in the antiviral and anti-inflammatory response leading to the expression of proinflammatory cytokines and chemokines.

Erythropoiesis-stimulating agents, hypertension and left ventricular hypertrophy in the chronic kidney disease patient.

PURPOSE OF REVIEW: Left-ventricular hypertrophy (LVH) represents an important marker of cardiovascular morbidity and mortality. Numerous noninterventional studies in patients with chronic kidney disease (CKD) revealed a consistent relationship of LVH with modifiable risk factors attributable to failing renal function, particularly anemia and hypertension. RECENT FINDINGS: Given the clear role for anemia in initiating or accelerating LVH, it seems imperative to correct renal anemia with erythropoiesis-stimulating agents (ESAs). A few nonrandomized studies have described a regression of LVH with correction of anemia, but prospective randomized trials showed no evidence that ESA treatment is able to improve cardiac prognosis in the CKD patient. Current data alert physicians that normalization of hemoglobin in patients with advanced CKD is harmful. Recent studies are now trying to clarify the mechanisms for harm focussing on the influence of comorbidities, ESA doses, and hemoglobin variability. The pathogenesis of hypertension in CKD is multifactorial and only a small percentage of CKD patients have controlled their blood pressure, indicating poor medication adherence, insufficient control of volume overload and undertreatment. SUMMARY: This review provides an update of ESA treatment, hypertension and LVH in the CKD patient, indicating that pathogenesis of LVH in this population is currently not completely understood. In addition, the impact of pharmacological interventions targeted to prevent or reduce LVH in anemic or hypertensive CKD patients is not well defined. As adoption of the Framingham approach seems not feasible in the CKD patient, evidence from large-scale randomized clinical trials is mandatory to resolve this dilemma.

Improved outcome with rituximab in patients with HIV-associated multicentric Castleman disease.

Although HIV-associated multicentric Castleman disease (HIV-MCD) is not classified as an AIDS-defining illness, mortality is high and progression to lymphoma occurs frequently. At present, there is no widely accepted recommendation for the treatment of HIV-MCD. In this retrospective (1998-2010), multicentric analysis of 52 histologically proven cases, outcome was analyzed with respect to the use of different MCD therapies and potential prognostic factors. After a mean follow-up of 2.26 years, 19 of 52 patients died. Median estimated overall survival (OS) was 6.2 years. Potential risk factors, such as older age, previous AIDS, or lower CD4 T cells had no impact on OS. Treatment was heterogeneous, consisting of cytostatic and/or antiviral agents, rituximab, or combinations of these modalities. There were marked differences in the outcome when patients were grouped according to MCD treatment. Patients receiving rituximab-based regimens had higher complete remission rates than patients receiving chemotherapy only. The mean estimated OS in patients receiving rituximab alone or in combination with cytostatic agents was not reached, compared with 5.1 years (P = .03). Clinical outcome and overall survival of HIV-MCD have markedly improved with rituximab-based therapies, considering rituximab-based therapies (with or without cytostatic agents) to be among the preferred first-line options in patients with HIV-MCD.

An orally active chemokine receptor CCR2 antagonist prevents glomerulosclerosis and renal failure in type 2 diabetes.

The progression of diabetic nephropathy is associated with an infiltration of macrophages expressing different phenotypes. As classically activated chemokine receptor CCR2+ macrophages are thought to drive tissue inflammation and remodeling, we tested whether blocking CCR2 could reduce intrarenal inflammation and prevent glomerulosclerosis in type 2 diabetes. This was achieved with RO5234444, an orally active small-molecule CCR2 antagonist that blocks ligand binding, its internalization, and monocyte chemotaxis. Male type 2 diabetic db/db mice were uninephrectomized to increase glomerular hyperfiltration to accelerate the development of glomerulosclerosis. From 16 weeks until killing at 24 weeks of age, mice were chow fed with or without admixed antagonist to achieve a trough plasma concentration above IC50 for binding in the mouse. CCR2 blockade reduced circulating monocyte levels, but did not affect total leukocyte or neutrophil numbers, and was associated with a reduction in the number of macrophages and apoptotic podocytes in the glomerulus. This treatment resulted in a higher total number of podocytes, less glomerulosclerosis, reduced albuminuria, and a significantly improved glomerular filtration rate. This successful pre-clinical trial suggests that this antagonist may now be ready for testing in humans with the nephropathy of diabetes mellitus.