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To study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24 h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults.
In the present study, we tested the hypothesis that the renoprotective effect of an angiotensin receptor blocker depends on the angiotensin II type 1 (AT(1)) receptor on podocytes. For this purpose, we generated podocyte-specific knockout mice for the AT(1) gene (Agtr1a) and crossed with NEP25, in which selective podocyte injury can be induced by immunotoxin, anti-Tac(Fv)-PE38. Four weeks after the addition of anti-Tac(Fv)-PE38, urinary albumin:creatinine ratio was not attenuated in Agtr1a knockout/NEP25 mice (n=18) compared with that in control NEP25 mice (n=13; 8.08+/-2.41 in knockout versus 4.84+/-0.73 in control). Both strains of mice showed similar degrees of sclerosis (0.66+/-0.17 versus 0.82+/-0.27 on a 0 to 4 scale) and downregulation of nephrin (5.78+/-0.45 versus 5.65+/-0.58 on a 0 to 8 scale). In contrast, AT(1) antagonist or an angiotensin I-converting enzyme inhibitor, but not hydralazine, remarkably attenuated proteinuria and sclerosis in NEP25 mice. Moreover, continuous angiotensin II infusion induced microalbuminuria similarly in both Agtr1a knockout and wild-type mice. Thus, angiotensin inhibition can protect podocytes and prevent the development of glomerulosclerosis independent of podocyte AT(1). Possible mechanisms include inhibitory effects on AT(1) of other cells or through mechanisms independent of AT(1). Our study further demonstrates that measures that directly affect only nonpodocyte cells can have beneficial effects even when sclerosis is triggered by podocyte-specific injury.
Angiotensin type 1 (AT1) receptor blocker (ARB) ameliorates progression of chronic kidney disease. Whether this protection is due solely to blockade of AT1, or whether diversion of angiotensin II from the AT1 to the available AT2 receptor, thus potentially enhancing AT2 receptor effects, is not known. We therefore investigated the role of AT2 receptor in ARB-induced treatment effects in chronic kidney disease. Adult rats underwent 5/6 nephrectomy. Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equivalent glomerulosclerosis: no further treatment, ARB, AT2 receptor antagonist, or combination. By week 12 after nephrectomy, systolic blood pressure was decreased in all treatment groups, but proteinuria was decreased only with ARB. Glomerulosclerosis increased significantly in AT2 receptor antagonist vs. ARB. Kidney cortical collagen content was decreased in ARB, but increased in untreated 5/6 nephrectomy, AT2 receptor antagonist, and combined groups. Glomerular cell proliferation increased in both untreated 5/6 nephrectomy and AT2 receptor antagonist vs. ARB, and phospho-Erk2 was increased by AT2 receptor antagonist. Plasminogen activator inhibitor-1 mRNA and protein were increased at 12 wk by AT2 receptor antagonist in contrast to decrease with ARB. Podocyte injury is a key component of glomerulosclerosis. We therefore assessed effects of AT1 vs. AT2 blockade on podocytes and interaction with plasminogen activator inhibitor-1. Cultured wild-type podocytes, but not plasminogen activator inhibitor-1 knockout, responded to angiotensin II with increased collagen, an effect that was completely blocked by ARB with lesser effect of AT2 receptor antagonist. We conclude that the benefical effects on glomerular injury achieved with ARB are contributed to not only by blockade of the AT1 receptor, but also by increasing angiotensin effects transduced through the AT2 receptor.
BACKGROUND AND OBJECTIVES - Acute kidney injury (AKI) is associated with adverse outcomes in critically ill patients. The influence of preexisting chronic kidney disease (CKD) on AKI outcomes is unclear.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - We analyzed data from a prospective observational cohort study of AKI in critically ill patients who received nephrology consultation: the Program to Improve Care in Acute Renal Disease. In-hospital mortality rate, length of stay, and dialysis dependence were compared in patients with and without a prior history of CKD, defined by an elevated serum creatinine, proteinuria, and/or abnormal renal ultrasound within a year before hospitalization. We hypothesized that patients with AKI and prior history of CKD would have lower mortality rates, shorter lengths of stay, and higher rates of dialysis dependence than patients without prior history of CKD.
RESULTS - Patients with AKI and a prior history of CKD were older and underwent nephrology consultation earlier in the course of AKI. In-hospital mortality rate was lower (31 versus 40%, P = 0.04), and median intensive care unit length of stay was 4.6 d shorter (14.7 versus 19.3 d, P = 0.001) in patients with a prior history of CKD. Among dialyzed survivors, patients with prior CKD were also more likely to be dialysis dependent at hospital discharge. Differences in outcome were most evident in patients with lower severity of illness.
CONCLUSIONS - Among critically ill patients with AKI, those with prior CKD experience a lower mortality rate but are more likely to be dialysis dependent at hospital discharge. Future studies should determine optimal strategies for managing AKI with and without a prior history of CKD.
BACKGROUND - Many have called for more comprehensive follow-up of living kidney donors, both for the donor's benefit and to establish a high-quality database of donor outcomes. United Network for Organ Sharing currently requires transplant centers to report donor follow-up information at several time points after donation, but little is known about how frequently this information is obtained, or which barriers exist to compliance with United Network for Organ Sharing requirements.
METHODS - To assess practices and barriers in providing follow-up care to living donors, we sent a questionnaire to all program directors at U.S. transplant centers.
RESULTS - Few transplant centers are currently seeing donors for long-term follow-up. Many centers recommend that donor follow-up care be provided by primary care physicians, but follow-up information is rarely received from primary care physicians. The main barriers to collecting more complete information are donor inconvenience, costs, and lack of reimbursement to the transplant center for providing follow-up care.
CONCLUSIONS - Significant changes are required to improve long-term donor follow-up by U.S. transplant centers.
BACKGROUND - Composition of nonselective proteinuria includes several endogenous ligands of Toll-like receptors (TLRs) not normally present in Bowman's space, thus raising the possibility that TLRs are involved in proteinuria-mediated podocyte injury.
METHODS - Kidneys of NEP25 mice, a model of glomerular sclerosis induced by podocyte-specific injury, were immunohistochemically evaluated for the presence of fibrin/fibrinogen, which are potent ligands for TLRs. A podocyte cell line was treated with fibrinogen or lipopolysaccharides and examined for expression of cytokines. siRNAs were used to knockdown components of TLR signaling.
RESULTS - We found deposits of fibrin/fibrinogen only in the damaged podocytes of proteinuric kidneys, indicating that podocytes are exposed to these potent TLR ligands in proteinuric state. In cultured podocytes, we confirmed mRNA expressions of TLR2, TLR4, as well as their major TLR signal transducer, MyD88. Fibrinogen and lipopolysaccharides dose-dependently upregulated mRNA expressions of MCP-1, TNF-alpha and TLR2 in podocytes as well as increased the MCP-1 protein in the medium. Knockdown of TLR2 and TLR4 inhibited the fibrinogen-induced MCP-1 mRNA upregulation. Knockdown of MyD88 also inhibited the upregulation.
CONCLUSION - These results suggest that plasma macromolecules that appear in Bowman's space in proteinuric conditions have the capacity to induce podocyte cytokines through TLRs, and thereby accelerate podocyte injury.
(c) 2009 S. Karger AG, Basel.
Proteinuria has emerged as a key predictor of progression from renal insufficiency to end-stage renal disease, and clearly plays a pathogenic role in loss of renal function. Control of proteinuria is seen as critical to delaying disease progression, and myriad treatments which appear to reduce proteinuria have been reported and have entered clinical practice. Despite the increasing emphasis on control of proteinuria, the precise mechanism by which the kidney retains proteins in the blood remains a subject of dispute in the literature. In the past decade, mechanisms for protein retention by the kidney which transcend simple molecular sieve heuristics have been proposed. This renewed interest in renal physiology is exciting, as new insights may drive forward mechanism-based treatments for renal disease. In this review article, four schools of thought on renal protein retention are described, including three from other groups and our own hypothesis. Arguments and data supporting and refuting each paradigm are discussed without the intent or effect of supporting one to the exclusion of others.
BACKGROUND AND OBJECTIVES - alpha- and beta-dystroglycan (DG), which link the actin cytoskeleton of the podocyte to the glomerular basement membrane, are maintained in FSGS but decreased in minimal change disease (MCD). Fibrosis has been linked to increased fibroblast-specific protein-1 (FSP1) and epithelial-mesenchymal transition. We studied DG, FSP1, and podocyte differentiation in FSGS variants and cases of suspected FSGS.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - We studied renal biopsies with FSGS, not otherwise specified (NOS), tip lesion, or collapsing variants (COLL), versus secondary FSGS or cases without segmental sclerotic lesions where a diagnosis of MCD versus FSGS could not be established (undefined [UNDEF]) and compared the expression of DG, FSP1, and podocyte Wilms' tumor antigen (WT1).
RESULTS - WT1 is markedly decreased in NOS versus normal and correlates with the extent of sclerosis. alpha- and beta-DG are maintained in most primary and secondary FSGS cases. In contrast, alpha-DG is significantly decreased in UNDEF, supporting a diagnosis of MCD. Furthermore, follow-up shows remission or decreased proteinuria in four of six of these UNDEF cases in response to therapy. Interstitial FSP1 is numerically highest in COLL but is only rarely found in tubules or podocytes in any other forms of FSGS.
CONCLUSIONS - We conclude that increased FSP1 may be a marker of the aggressive course of collapsing FSGS. Furthermore, DG staining is a useful adjunct to assist in distinction of FSGS versus MCD in biopsies without defining lesions.
Focal segmental glomerulosclerosis (FSGS) is a progressive renal disease, and the glomerular visceral cell hyperplasia typically observed in cellular/collapsing FSGS is an important pathological factor in disease progression. However, the cellular features that promote FSGS currently remain obscure. To determine both the origin and phenotypic alterations in hyperplastic cells in cellular/collapsing FSGS, the present study used a previously described FSGS model in p21-deficient mice with visceral cell hyperplasia and identified the podocyte lineage by genetic tagging. The p21-deficient mice with nephropathy showed significantly higher urinary protein levels, extracapillary hyperplastic indices on day 5, and glomerular sclerosis indices on day 14 than wild-type controls. X-gal staining and immunohistochemistry for podocyte and parietal epithelial cell (PEC) markers revealed progressive podocytopenia with capillary collapse accompanied by PEC hyperplasia leading to FSGS. In our investigation, non-tagged cells expressed neither WT1 nor nestin. Ki-67, a proliferation marker, was rarely associated with podocytes but was expressed at high levels in PECs. Both terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and electron microscopy failed to show evidence of significant podocyte apoptosis on days 5 and 14. These findings suggest that extensive podocyte loss and simultaneous PEC hyperplasia is an actual pathology that may contribute to the progression of cellular/collapsing FSGS in this mouse model. Additionally, this is the first study to demonstrate the regulatory role of p21 in the PEC cell cycle.
BACKGROUND AND OBJECTIVES - Patients with primary focal segmental glomerulosclerosis (FSGS) who are resistant to standard therapy are at high risk for progressive chronic kidney disease. Prevention of renal fibrosis represents a promising strategy to slow or halt kidney function decline. This paper presents the results of a Phase I clinical trial of rosiglitazone, a thiazolidinedione, that exerts antifibrotic effects in animal models of FSGS. The primary goal was assessment of safety, tolerability, and pharmacokinetics (PK) of rosiglitazone.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - Eleven patients, including eight boys/men and three girls/women, with mean age 15 +/- 6 yr and estimated GFR 131 +/- 62 ml/min/1.73 m(2), received rosiglitazone, 3 mg/m(2)/d for 16 wk. PK was assessed twice, after the initial dose and after attaining steady state, in a General Clinical Research Center.
RESULTS - There were no serious adverse events or cardiovascular complications. Rosiglitazone was well tolerated by all patients, as judged by the Treatment Satisfaction Questionnaire for Medication. The PK studies indicated that the area under the curve was decreased by 40 to 50% and oral clearance of rosiglitazone was increased by 250 to 300% in patients with resistant FSGS compared with healthy controls and patients with nonproteinuric stage 2 chronic kidney disease.
CONCLUSIONS - Rosiglitazone therapy was safe and well tolerated. PK assessment of potential novel therapies for resistant FSGS is necessary to define appropriate dosing regimens. There is rationale to evaluate the efficacy of rosiglitazone as an antifibrotic agent for resistant FSGS in Phase II/III clinical trials.