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Renal AND Proteinuria [keywords]
- Association of Non-alcoholic Fatty Liver Disease with Chronic Kidney Disease: A Systematic Review and Meta-analysis. [JOURNAL ARTICLE]
- PLoS Med 2014 Jul; 11(7):e1001680.
Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69-2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65-1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58-4.05) and incidence (HR 2.12, 95% CI 1.42-3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14-8.61) and incidence (HR 3.29, 95% CI 2.30-4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.The presence and severity of NAFLD are associated with an increased risk and severity of CKD. Please see later in the article for the Editors' Summary.
- An emerging molecular understanding and novel targeted treatment approaches in pediatric kidney diseases. [Journal Article, Review]
- Front Pediatr 2014.:68.
The evaluation and treatment of the heterogeneous group of kidney diseases poses a challenging field in pediatrics. Many of the pediatric disorders resulting in severe renal affection are exceedingly rare and therapeutic approaches have remained symptomatic for most of these disease entities. The insights obtained from cellular and molecular studies of rare disorders by recent genetic studies have now substantially changed our mechanistic understanding of various important pediatric renal diseases and positive examples of targeted treatment approaches are emerging. Three fields of recent breathtaking developments in pediatric nephrology are the pathophysiology of nephrotic syndrome and proteinuria, the molecular mechanisms underlying atypical hemolytic uremic syndrome, and the genetics and cellular biology of inherited cystic kidney diseases. In all three areas, the combined power of molecular basic science together with deeply characterizing clinical approaches has led to the establishment of novel pathophysiological principles and to the first clinical trials of targeted treatment approaches.
- Targeting multiple signaling axes and oxidative stress using a synthetic triterpenoid prevents murine lupus nephritis. [JOURNAL ARTICLE]
- Arthritis Rheumatol 2014 Jul 21.
Objective. Current treatment options for lupus are far from optimal. Previously, we reported that PI3K/AKT/mTOR, MEK1/Erk1,2, p38, STAT3, STAT5, NF-κB, multiple Bcl-2 family members, and various cell cycle molecules were over-expressed in splenic B-cells in an age-dependent and gene-dose-dependent manner in mouse strains with spontaneous lupus. As the synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) has been shown to inhibit AKT, MEK1/2, and NF-κB, and to induce caspase-mediated apoptosis, we tested the therapeutic potential of this agent in murine lupus nephritis. Methods. The synthetic triterpenoid CDDO-Me, or placebo, was administered to two month old B6.Sle1.Sle3 mice or MRL.lpr mice, which develop spontaneous lupus. All mice were phenotyped for disease. Results. CDDO-Me-treated mice exhibited significantly reduced splenic cellularity, with decreased CD4(+) T-cells and activated CD69(+) /CD4(+) T-cells compared to the placebo-treated mice. These mice also exhibited significant reduction in serum autoantibody levels, including anti-dsDNA and anti-glomerular antibodies. Finally, CDDO-Me treatment attenuated renal disease in mice, as marked by reduced 24-hour proteinuria, blood urea nitrogen, and glomerulonephritis. At the mechanistic level, CDDO-Me treatment dampened MEK1/2, ERK, and STAT3 signaling within lymphocytes and oxidative stress. Importantly, the NF-E2-Related Factor 2 (Nrf2) pathway was activated after CDDO-Me treatment, indicating that CDDO-Me may be modulating renal damage in lupus via the inhibition of oxidative stress. Conclusion. These findings underscore the importance of AKT/MEK1/2/NF-κB signaling in engendering murine lupus. Our studies reveal that the blockade of multiple signaling nodes and oxidative stress may effectively prevent and reverse the hematological, autoimmune and pathological manifestations of lupus. © 2014 American College of Rheumatology.
- Case report on renal failure reversal in lambda chain multiple myeloma with bortezomib and dexamethasone. [Journal Article]
- Case Rep Nephrol 2014.:940171.
Renal failure (RF) reversal in multiple myeloma (MM) is associated with an improved prognosis. Light chain myeloma, serum creatinine (SCr) > 4 mg/dL, extensive proteinuria, early infections, and certain renal biopsy findings are associated with lower rates of RF reversal. Our patient is a 67-year-old female with multiple poor prognostic factors for RF reversal who demonstrated a rapid renal response with bortezomib and dexamethasone (BD) regimen. She presented initially with altered mental status. On exam, she appeared lethargic and dehydrated and had generalized tenderness. She had been taking ibuprofen as needed for pain for a few weeks. Labs showed a white cell count-18,900/μL with no bandemia, hemoglobin 10.8 gm/dL, potassium-6.7 mEq/L, bicarbonate-15 mEq/L, blood urea nitrogen-62 mg/dL, SCr-5.6 mg/dL (baseline: 1.10), and corrected calcium-11.8 mg/dL. A rapid flu test was positive. Imaging studies were unremarkable. Her EKG showed sinus tachycardia and her urinalysis was unremarkable. The unexplained RF in an elderly individual in conjunction with hypercalcemia and anemia prompted a MM work-up; eventually, lambda variant MM was diagnosed. An immediate (4 days) renal response defined as 50% reduction in SCr was noticed after initiation of the BD regimen.
- IgG4-Related Tubulointerstitial Nephritis Associated with Membranous Nephropathy in Two Patients: Remission after Administering a Combination of Steroid and Mizoribine. [Journal Article]
- Case Rep Nephrol 2014.:678538.
We report two cases of Japanese men who presented with proteinuria, eosinophilia, hypocomplementemia, and high serum immunoglobulin G4 (IgG4) concentration and were diagnosed with membranous nephropathy associated with IgG4-related tubulointerstitial nephritis on renal biopsy. The typical renal lesions of IgG4-related disease are tubulointerstitial nephritis, which improves remarkably with steroid therapy, and occasional glomerular changes. In our two cases, renal biopsy revealed IgG4-positive immune complex deposits in glomeruli in a pattern of membranous nephropathy and concurrent tubulointerstitial nephritis with IgG4 plasma cells. In both cases, proteinuria persisted with initial prednisolone treatment and was resolved only after the addition of mizoribine. We report the first two cases in which the combination of prednisolone and mizoribine was effective for treating membranous nephropathy associated with IgG4-related tubulointerstitial nephritis.
- Vitamin D and chronic kidney disease. [REVIEW]
- Korean J Intern Med 2014 Jul; 29(4):416-427.
Chronic kidney disease (CKD) has been recognized as a significant global health problem because of the increased risk of total and cardiovascular morbidity and mortality. Vitamin D deficiency or insufficiency is common in patients with CKD, and serum levels of vitamin D appear to have an inverse correlation with kidney function. Growing evidence has indicated that vitamin D deficiency may contribute to deteriorating renal function, as well as increased morbidity and mortality in patients with CKD. Recent studies have suggested that treatment with active vitamin D or its analogues can ameliorate renal injury by reducing fibrosis, apoptosis, and inflammation in animal models; this treatment also decreases proteinuria and mortality in patients with CKD. These renoprotective effects of vitamin D treatment are far beyond its classical role in the maintenance of bone and mineral metabolism, in addition to its pleiotropic effects on extra-mineral metabolism. In this review, we discuss the altered metabolism of vitamin D in kidney disease, and the potential renoprotective mechanisms of vitamin D in experimental and clinical studies. In addition, issues regarding the effects of vitamin D treatment on clinical outcomes are discussed.
- Rituximab-cyclophosphamide-dexamethasone is highly effective in patients with monoclonal Ig deposit-related glomerulopathy and indolent non-Hodgkin lymphomas. [JOURNAL ARTICLE]
- Am J Hematol 2014 Jul 5.
Indolent non-hodgkin lymphomas (iNHL) are a rare cause of monoclonal immunoglobulin deposits-related glomerulopathy (mIgGN). In patients with iNHL-related mIgGN, whether treatment should include either single or a combination of drug(s) to target the malignant clone and renal inflammation remains elusive. In this retrospective study, we report a cohort of 14 patients with iNHL-related mIgGN (cryoglobulinemic glomerulonephritis [n=5], membranous nephropathy [n=3], membranoproliferative glomerulonephritis [n=3], AL or AL/AH amyloidosis [n=2] and Light Chain Deposits Disease [n=1]) and who received a treatment combining rituximab, cyclophosphamide and dexamethasone (RCD). After a mean follow-up of 18 ± 4 months, nine patients (63%) had complete haematological response. Renal response was observed in 12 of the 14 patients (86%; complete response: n=9; partial: n=3). Estimated glomerular filtration rate increased from 47±7 to 63±8 mL/min/1.73m(2) , and proteinuria decreased from 6.5±0.7 to 1.4±0.8 g/24h at one year. Following hematological relapse, renal relapse occurred in two patients suggesting sustained clonal eradication offers the best renal protection. Tolerance of RCD was good and the most frequent adverse event was pneumonia (3/14, 21%). RCD is a promising regimen for patients with iNHL and mIgGN, irrespective of glomerular pathologic pattern. Whether steroids can be avoided or minimized remains to be addressed.
- Objective sleep, a novel risk factor for alterations in kidney function: the CARDIA study. [JOURNAL ARTICLE]
- Sleep Med 2014 Jun 13.
To determine the association between objectively measured sleep and 10-year changes in estimated glomerular filtration rate (eGFR).From 2003 to 2005, an ancillary sleep study was conducted at the Chicago site of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Community-based black and white adults (aged 32-51 years) wore a wrist actigraph for up to six nights to record sleep duration and fragmentation. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI). Participants without history of cardiovascular or chronic kidney diseases, proteinuria, or hypertension at the 2000-2001 CARDIA examination were followed over 10 years (n = 463). eGFR was estimated from serum creatinine (eGFRCr) at the 2000-2001, 2005-2006, and 2010-2011 CARDIA examinations, whereas cystatin-C-estimated eGFR (eGFRCys) was measured at the 2000-2001 and 2005-2006 examinations. Generalized estimating equation regression and linear models estimated the associations of each sleep parameter with changes in eGFRCr and eGFRCys, controlling for cardiovascular and renal risk.Sleep parameters were not related to 5-year change in eGFRCys. However, each 1 h decrease in sleep duration was significantly associated with a 1.5 mL/min/1.73 m(2) higher eGFRCr [95% confidence interval (CI), 0.2-2.7], and each one-point increase in PSQI was significantly associated with a 0.5 mL/min/1.73 m(2) higher eGFRCr (95% CI, 0.04-0.9) over 10 years.In this community-based sample, shorter sleep and poorer sleep quality were related to higher kidney filtration rates over 10 years.
- Tubular Overexpression of Gremlin Induces Renal Damage Susceptibility in Mice. [JOURNAL ARTICLE]
- PLoS One 2014; 9(7):e101879.
A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci-immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-β. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1) specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2- to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule-specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-β and αSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild-type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage progression. This transgenic mouse model could be used as a new tool for enhancing the knowledge of renal disease progression.
- A novel case report of sickle cell disease-associated immunoglobulin A nephropathy: the diagnostic value of erythrocyte dysmorphism evaluation. [Journal Article]
- Int J Clin Exp Med 2014; 7(6):1619-22.
Sickle cell disease is a severe disease with a genetic pattern; it may cause anemia, vaso-occlusive phenomena, and multiorgan injury. It may damage any renal compartment, thereby causing tubular abnormalities, papillary necrosis, or glomerulopathies such as focal and segmental glomerulosclerosis and membranoproliferative pattern. The clinical consequences are hematuria and proteinuria. Hematuria associated with SCD is characteristically isomorphic (non-glomerular). This case report describes a novel case of a patient with sickle cell disease who presented with proteinuria and microscopic dysmorphic (glomerular) hematuria. A renal biopsy revealed immunoglobulin A nephropathy. Despite the fact that immunoglobulin A nephropathy is the most commonly diagnosed glomerulonephritis worldwide, an association between this entity and sickle cell disease has not yet been reported, probably because all cases of hematuria in patients with sickle cell disease have been regarded as secondary to sickle cell disease. Thus, new approaches are necessary to differentiate these conditions, such as evaluation of urinary erythrocyte dysmorphism, even more so because these two entities have different therapeutic options, morbidity, and mortality rates.