Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
Renal AND Proteinuria [keywords]
- A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease. [JOURNAL ARTICLE]
- Kidney Int 2014 Oct 29.
It has been suggested that soluble urokinase receptor (suPAR) is a causative circulating factor for and a biomarker of focal and segmental glomerulosclerosis (FSGS). Here we undertook validation of these assumptions in both mouse and human models. Injection of recombinant suPAR in wild-type mice did not induce proteinuria within 24 h. Moreover, a disease phenotype was not seen in an inducible transgenic mouse model that maintained elevated suPAR concentrations for 6 weeks. Plasma and urine suPAR concentrations were evaluated as clinical biomarkers in 241 patients with glomerular disease from the prospective, longitudinal multicenter observational NEPTUNE cohort. The serum suPAR concentration at baseline inversely correlated with estimated glomerular filtration rate (eGFR) and the urine suPAR/creatinine ratio positively correlated with the urine protein/creatinine ratio. After adjusting for eGFR and urine protein, neither the serum nor urine suPAR level was an independent predictor of FSGS histopathology. A multivariable mixed-effects model of longitudinal data evaluated the association between the change in serum suPAR concentration from baseline with eGFR. After adjusting for baseline suPAR concentration, age, gender, proteinuria, and time, the change in suPAR from baseline was associated with eGFR, but this association was not different for patients with FSGS as compared with other diagnoses. Thus these results do not support a pathological role for suPAR in FSGS.Kidney International advance online publication, 29 October 2014; doi:10.1038/ki.2014.346.
- Dipstick proteinuria is an independent predictor of high on treatment platelet reactivity in patients on clopidogrel, but not aspirin, admitted for major adverse cardiovascular events. [JOURNAL ARTICLE]
- Platelets 2014 Oct 29.:1-7.
Abstract The effectiveness of aspirin and clopidogrel in patients with chronic kidney disease (CKD) suffering from acute cardiovascular events is unclear. High on treatment platelet reactivity (HTPR) has been associated with worse outcomes. Here, we assessed the association of dipstick proteinuria (DP) and renal function on HTPR and clinical outcomes. Retrospective cohort analysis of 261 consecutive, non-dialysis patients admitted for Major Adverse Cardiovascular Events (MACE) that had VerifyNow P2Y12 and VerifyNow Aspirin assays performed. HTPR was defined as P2Y12 reactivity unit (PRU) > 208 for clopidogrel and aspirin reaction units (ARU) > 550 for aspirin. Renal function was classified based on the estimated glomerular filtration rate (eGFR), and dipstick proteinuria was defined as ≥30 mg/dl of albumin detected on a spot analysis. All cause mortality, readmissions, and cardiac catheterizations were reviewed over 520 days. In patients on clopidogrel (n = 106), DP was associated with HTPR, independent of eGFR, diabetes mellitus, smoking or use of proton pump inhibitor (AOR = 4.76, p = 0.03). In patients with acute coronary syndromes, HTPR was associated with more cardiac catheterizations (p = 0.009) and readmissions (p = 0.032), but no differences in in-stent thrombosis or re-stenosis were noted in this cohort. In patients on aspirin (n = 155), no associations were seen between DP and HTPR. However, all cause mortality was significantly higher with HTPR in this group (p = 0.038). In this cohort, DP is an independent predictor of HTPR in patients on clopidogrel, but not aspirin, admitted to the hospital for MACE.
- Nodular glomerulosclerosis with anti-glomerular basement membrane-like glomerulonephritis; a distinct pattern of kidney injury observed in smokers. [JOURNAL ARTICLE]
- Clin Kidney J 2014 Aug; 7(4):361-366.
Cigarette smoking has recently been recognized as a risk factor for developing nodular glomerulosclerosis and has also been frequently encountered in patients with anti-glomerular basement membrane (anti-GBM) disease. However, the concurrent presence of both patterns of glomerular injury has not been previously reported.In this article, we describe three patients with non-diabetic nodular glomerulosclerosis, anti-GBM-like glomerulonephritis (GN) and a history of heavy smoking.Our cohort included three patients, of which two were men (53 and 77 years old) and one a 28-year-old woman. None of the patients had a history of diabetes mellitus but all of them were heavy smokers who presented with renal insufficiency and proteinuria. Nodular glomerulosclerosis and occasional small, non-circumferential crescents in different stages of development were found on kidney biopsy. Immunofluorescence microscopy studies showed intense linear IgG staining along the glomerular basement membranes in the absence of granular immune-type deposits. Electron microscopy evaluation revealed prominent endothelial cell injury without detectable electron-dense deposits. One patient was dialysis-dependent a few months post-biopsy while the other two patients maintained their kidney function 18 and 24 months post-biopsy but without a significant improvement of serum creatinine.The combination of nodular glomerulosclerosis and anti-GBM-like GN appears to be a distinct pattern of injury observed in a small subset of heavy smokers. Although this pattern of glomerular injury might be less aggressive than the typical anti-GBM GN, it does not appear to carry a favorable prognosis.
- Rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms. [JOURNAL ARTICLE]
- Exp Biol Med (Maywood) 2014 Oct 27.
IgA nephropathy is the most frequent type of glomerulonephritis worldwide. The role of cell cycle regulation in the pathogenesis of IgA nephropathy has been studied. The present study was designed to explore whether rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms. After establishing an IgA nephropathy model, rats were randomly divided into four groups. Coomassie Brilliant Blue was used to measure the 24-h urinary protein levels. Renal function was determined using an autoanalyzer. Proliferation was assayed via Proliferating Cell Nuclear Antigen (PCNA) immunohistochemistry. Rat mesangial cells were cultured and divided into the six groups. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) and flow cytometry were used to detect cell proliferation and the cell cycle phase. Western blotting was performed to determine cyclin E, cyclin-dependent kinase 2, p27(Kip1), p70S6K/p-p70S6K, and extracellular signal-regulated kinase 1/2/p- extracellular signal-regulated kinase 1/2 protein expression. A low dose of the mammalian target of rapamycin (mTOR) inhibitor rapamycin prevented an additional increase in proteinuria, protected kidney function, and reduced IgA deposition in a model of IgA nephropathy. Rapamycin inhibited mesangial cell proliferation and arrested the cell cycle in the G1 phase. Rapamycin did not affect the expression of cyclin E and cyclin-dependent kinase 2. However, rapamycin upregulated p27(Kip1) at least in part via AKT (also known as protein kinase B)/mTOR. In conclusion, rapamycin can affect cell cycle regulation to inhibit mesangial cell proliferation, thereby reduce IgA deposition, and slow the progression of IgAN.
- Nephron Deficiency and Predisposition to Renal Injury in a Novel One-Kidney Genetic Model. [JOURNAL ARTICLE]
- J Am Soc Nephrol 2014 Oct 27.
Some studies have reported up to 40% of patients born with a single kidney develop hypertension, proteinuria, and in some cases renal failure. The increased susceptibility to renal injury may be due, in part, to reduced nephron numbers. Notably, children who undergo nephrectomy or adults who serve as kidney donors exhibit little difference in renal function compared with persons who have two kidneys. However, the difference in risk between being born with a single kidney versus being born with two kidneys and then undergoing nephrectomy are unclear. Animal models used previously to investigate this question are not ideal because they require invasive methods to model congenital solitary kidney. In this study, we describe a new genetic animal model, the heterogeneous stock-derived model of unilateral renal agenesis (HSRA) rat, which demonstrates 50%-75% spontaneous incidence of a single kidney. The HSRA model is characterized by reduced nephron number (more than would be expected by loss of one kidney), early kidney/glomerular hypertrophy, and progressive renal injury, which culminates in reduced renal function. Long-term studies of temporal relationships among BP, renal hemodynamics, and renal function demonstrate that spontaneous single-kidney HSRA rats are more likely than uninephrectomized normal littermates to exhibit renal impairment because of the combination of reduced nephron numbers and prolonged exposure to renal compensatory mechanisms (i.e., hyperfiltration). Future studies with this novel animal model may provide additional insight into the genetic contributions to kidney development and agenesis and the factors influencing susceptibility to renal injury in individuals with congenital solitary kidney.
- Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling. [JOURNAL ARTICLE]
- J Am Soc Nephrol 2014 Oct 27.
Proteinuria and hyperphosphatemia are cardiovascular risk factors independent of GFR. We hypothesized that proteinuria induces relative phosphate retention via increased proximal tubule phosphate reabsorption. To test the clinical relevance of this hypothesis, we studied phosphate handling in nephrotic children and patients with CKD. Plasma fibroblast growth factor 23 (FGF-23) concentration, plasma phosphate concentration, and tubular reabsorption of phosphate increased during the proteinuric phase compared with the remission phase in nephrotic children. Cross-sectional analysis of a cohort of 1738 patients with CKD showed that albuminuria≥300 mg/24 hours is predictive of higher phosphate levels, independent of GFR and other confounding factors. Albuminuric patients also displayed higher plasma FGF-23 and parathyroid hormone levels. To understand the molecular mechanisms underlying these observations, we induced glomerular proteinuria in two animal models. Rats with puromycin-aminonucleoside-induced nephrotic proteinuria displayed higher renal protein expression of the sodium-phosphate co-transporter NaPi-IIa, lower renal Klotho protein expression, and decreased phosphorylation of FGF receptor substrate 2α, a major FGF-23 receptor substrate. These findings were confirmed in transgenic mice that develop nephrotic-range proteinuria resulting from podocyte depletion. In vitro, albumin did not directly alter phosphate uptake in cultured proximal tubule OK cells. In conclusion, we show that proteinuria increases plasma phosphate concentration independent of GFR. This effect relies on increased proximal tubule NaPi-IIa expression secondary to decreased FGF-23 biologic activity. Proteinuria induces elevation of both plasma phosphate and FGF-23 concentrations, potentially contributing to cardiovascular disease.
- Murine Double Minute-2 Prevents p53-Overactivation-Related Cell Death (Podoptosis) of Podocytes. [JOURNAL ARTICLE]
- J Am Soc Nephrol 2014 Oct 27.
Murine double minute-2 (MDM2), an E3 ligase that regulates the cell cycle and inflammation, is highly expressed in podocytes. In podocyte injury, MDM2 drives podocyte loss by mitotic catastrophe, but the function of MDM2 in resting podocytes has not been explored. Here, we investigated the effects of podocyte MDM2 deletion in vitro and in vivo. In vitro, MDM2 knockdown by siRNA caused increased expression of p53 and podocyte death, which was completely rescued by coknockdown of p53. Apoptosis, pyroptosis, pyronecrosis, necroptosis, ferroptosis, and parthanatos were excluded as modes of occurrence for this p53-overactivation-related cell death (here referred to as podoptosis). Podoptosis was associated with cytoplasmic vacuolization, endoplasmic reticulum stress, and dysregulated autophagy (previously described as paraptosis). MDM2 knockdown caused podocyte loss and proteinuria in a zebrafish model, which was consistent with the phenotype of podocyte-specific MDM2-knockout mice that also showed the aforementioned ultrastructual podocyte abnormalities before and during progressive glomerulosclerosis. The phenotype of both animal models was entirely rescued by codeletion of p53. We conclude that MDM2 maintains homeostasis and long-term survival in podocytes by preventing podoptosis, a p53-regulated form of cell death with unspecific features previously classified as paraptosis.
- Risk Factors of Pulmonary Thrombosis/Embolism in Nephrotic Syndrome. [JOURNAL ARTICLE]
- Am J Med Sci 2014 Nov; 348(5):394-398.
Nephrotic syndrome is associated with an increased risk for thromboembolic complications. Until now, few studies have ever specified the risk of pulmonary thrombosis/embolism (PTE) in patients with nephrotic syndrome. In this study, we assessed the risk of PTE in a large cross-sectional study to identify risk factors in this population.Three hundred twelve patients with NS who had screened PTE through lung ventilation-perfusion scan were collected and analyzed. Multivariate Logistic regression was used to detect the independent risk factors for PTE. Logistic regression was used to identify the threshold value of D-dimer.Sixty-five patients (20.8%) had PTE in individuals with NS. Elevated level of plasma D-dimer was identified as an independent risk factor of PTE on multivariate analysis (odds ratio = 1.54; 95% confidence interval: 1.27-1.88). While proteinuria at presentation and serum albumin were not associated with PTE after adjusted for D-dimer (P > 0.05). The cumulative probability of PTE was in a nearly linear association with the plasma D-dimer level even within the normal range. Based on the plasma D-dimer level, we had developed a concise model to predict the risk of pulmonary embolism using logistic curve.In adult patients with NS, high level of plasma D-dimer was closely associated with PTE, whereas proteinuria or serum albumin level was not in this study. Using plasma D-dimer level, we developed a concise model to predict the risk of PTE.
- Refractory atypical hemolytic uremic syndrome with monoclonal gammopathy responsive to bortezomib-based therapy. [JOURNAL ARTICLE]
- Clin Nephrol 2014 Oct 27.
Atypical hemolytic uremic syndrome (aHUS) is a relatively rare disorder described by the triad of hemolytic anemia, thrombocytopenia, and renal failure. Atypical HUS could be genetic, acquired, or idiopathic (without known genetic changes or environmental triggers). Monoclonal protein has uncommonly been reported as a cause of microangiopathic hemolytic anemia (MAHA). We report a 59-year-old white man who presented with acute kidney injury (AKI) with MAHA and was given a diagnosis of aHUS with monoclonal gammopathy. His kidney function and proteinuria worsened with persistent hemolysis despite eculizumab and later cyclophosphamide and prednisone treatment. He responded well to VRD (bortezomib, lenalidomide, and dexamethasone) regimen. Renal function, proteinuria, and hemolysis all improved, and he was been in remission for more than 15 months. To our knowledge, this is the first report of successful treatment with bortezomib-based regimen for a patient with aHUS and monoclonal protein refractory to eculizumab therapy.
- Cystinosis: clinical presentation, pathogenesis and treatment. [Journal Article]
- Pediatr Endocrinol Rev 2014 Sep.:176-84.
Nephropathic cystinosis is a rare lysosomal storage disorder caused by mutations in the CTNS gene ncoding the lysosomal cystine transporter cystinosin. Cystinosin deficiency leads to accumulation of cystine in the lysosomes of cells throughout the body and deregulation of endocytosis, trafficking of intracellular vesicles and related cell signalling processes. One of the early features of the disease is renal Fanconi syndrome characterized by polyuria, proteinuria and urinary loss of various solutes. Later in life, extrarenal complications become apparent, and decline of kidney function leads to the development of end-stage renal disease. Modern therapy of the disease is based on treatment with cystine-lowering drug cysteamine, which helps to postpone the disease progression and development of extra-renal pathologies, but offers no cure for the Fanconi syndrome. Besides the improvement of cystine-lowering therapy based on new formulations of cysteamine, further development of therapy is necessary. Some steps forward were done in the recent years, including studies of cell signalling abnormalities in cystinosis and development of stem cell and gene therapy approaches.