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Renal AND Proteinuria [keywords]
- Phase I Study of 30-Minute Infusion of Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma. [JOURNAL ARTICLE]
- J Clin Oncol 2014 Sep 15.
Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed.Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m(2), followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m(2). Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk).Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m(2) were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m(2). Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m(2) cohort). Increasing carfilzomib dosing from 20 to 56 mg/m(2) resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m(2) of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib.Carfilzomib administered as a 30-minute IV infusion at 56 mg/m(2) (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.
- Increased Levels of Copeptin Before Clinical Diagnosis of Preelcampsia. [JOURNAL ARTICLE]
- Hypertension 2014 Sep 15.
Copeptin, a surrogate biomarker of vasopressin, has been associated with renal function decline and may serve as a useful early biomarker for preeclampsia. We measured serum copeptin using samples collected longitudinally during pregnancy among unaffected controls (n=136) and cases of preeclampsia (n=169), gestational diabetes mellitus (n=92), gestational hypertension (n=101), and preterm birth (n=86) in the Calcium for Preeclampsia Prevention trial (1992-1995). Preeclampsia and gestational hypertension were defined as having a diastolic blood pressure ≥90 mm Hg on 2 occasions with and without proteinuria, respectively. The risk of pregnancy complications associated with copeptin was estimated by logistic regression adjusting for maternal age, race, body mass index, insurance status, marital status, current smoking, and clinical site. Baseline copeptin levels, at mean 16 weeks of gestation, were associated with increased preeclampsia risk (adjusted odds ratios and 95% confidence interval being 1.55 per log unit; 1.03-2.31) when compared with controls (P=0.03). The association was stronger among cases diagnosed before 37 weeks (1.86; 1.08-3.20) than those diagnosed later (1.45; 0.91-2.32). Copeptin levels rose with increasing gestational age in both cases and controls but remained significantly higher among those who were diagnosed with preeclampsia. Differences in levels of copeptin between cases and controls became more apparent closer to time of diagnosis. No significant associations were found for gestational hypertension without proteinuria, gestational diabetes mellitus, or preterm birth without preeclampsia. Copeptin levels are elevated in pregnant women before diagnosis of preeclampsia with elevation specific to this pregnancy complication rather than hypertension alone.
- Evaluation of cardiopulmonary biomarkers during classic adulticide treatment versus the American Heartworm Society recommended treatment protocol in dogs infected by Dirofilaria immitis. [JOURNAL ARTICLE]
- Vet Parasitol 2014 Aug 30.
Adulticide treatment of dogs with canine heartworm disease causes the death of the adult Dirofilaria immitis lodged in the vascular system of the host. During the death of the worms, pulmonary thromboembolisms (PTE), pulmonary inflammation, congestive heart failure, or renal disease are possible consequences. The aim of this study was to evaluate cardiopulmonary biomarkers and renal parameters during adulticide treatment of canine heartworm to compare the classic two-injection treatment protocol versus the American Heartworm Society (AHS) recommended protocol. Fourteen heartworm-infected dogs with high parasite burdens were divided in three groups and allocated to adulticide protocols as follows: Group A (n=5) was treated with the classic two-injection protocol; group B (n=5) was treated using the AHS recommended protocol, and group C (n=4) was treated as for group B but received diminishing anti-inflammatory doses of prednisone. To assess cardiorespiratory status, cardiac troponin I (cTnI), myoglobin, and D-dimer were measured. Renal function was evaluated by measuring urea, creatinine, and urine protein:creatinine (UP:C). Serum and urine samples were collected day 0 (day of diagnosis), 7 and 14 days after the first dose of adulticide, and 1 month after the last adulticide injection. Dogs that received classic treatment presented pathologic concentrations of D-dimer more frequently and showed higher average D-dimer levels, which may indicate the presence of more severe PTE. Group C showed the highest levels of D-dimer during treatment, which may be due to an exacerbation of PTE caused by the administration of prednisone. CTnI and myoglobin values remained above reference values in all groups during the study but reached the lowest values 1 month after the last injection. Levels of urea and creatinine were within normal ranges in all groups, and 28.5% of the dogs were proteinuric on day 0, progressing to better UP:C values at the end of the treatment, except in group A. The results of this study justify the treatment of canine heartworm disease using the AHS recommended adulticide guidelines and recommends re-evaluation of the role of glucocorticosteroids in the prevention and treatment of PTE.
- [Clinical features of Bardet-Biedl syndrome with renal abnormalities as initial manifestations]. [English Abstract, Journal Article]
- Zhonghua Er Ke Za Zhi 2014 Aug; 52(8):611-5.
To study the clinical characteristics and diagnostic methods of rare autosomal recessive inherited Bardet-Biedl syndrome in patients presented with renal abnormalities.Comprehensive analyses were performed on data of 4 confirmed Bardet-Biedl syndrome cases seen at nephrology department of Beijing Children Hospital affiliated to Capital Medical University, including clinical features, laboratory examination and diagnostic criteria.(1) Four cases were confirmed to meet Bardet-Biedl syndrome diagnostic criteria (male: female = 1: 1): first diagnosis age was 10 y, 9 y 8 m, 10 y 10 m, 8 y 2 m. (2) Cases 1, 2, and 3 had a history of polyuria and polydipsia, cases 4 began with edema and oliguria. (3) All had slight change in urine routine test. Case 3 and Case 4 were presented with small to medium amount of proteinuria. None had microscopic hematuria. (4) All had different degree of renal injury, Case 1 and 3 were at the third phase of chronic kidney disease (CKD), Case 4 was at the fourth phase of CKD, Case 4 was at the fifth phase of CKD and needed dialysis. (5) All cases had obvious abnormalities of urinary tract ultrasound, 3 of them had chronic diffuse lesions with cyst formation of both kidneys. The rest one had dysplasia of right kidney and fused kidney. (6) All cases were presented with vision loss with 100% of electroretinogram abnomalities and 50% of fundus examination abnomalities. (7) Three cases were presented with obesity. (8) Multiple organs were involved in all cases, including electrocardiographic abnormality and/or thickening of the left ventricular wall (4/4) , polydactyly (2/4) , small penis and testicles (2/4) and short stature (2/4) .Clinical manifestations of Bardet-Biedl syndrome (BBS) conceals, routine urine test changes slightly, abnormalities of renal structure and (or) tubular interstitial function is a typical manifestation of children with BBS. Urinary tract ultrasound screening may show diffuse lesions with double kidney with cyst formation or structural abnormalities. Clinical manifestation accompany with retinal degeneration, obesity, myocardial involvement, polydactyly, and hypogonadism.
- Dietary sodium restriction: a neglected therapeutic opportunity in chronic kidney disease. [JOURNAL ARTICLE]
- Curr Opin Nephrol Hypertens 2014 Sep 12.
Restriction of dietary sodium is recommended at a population level as well as for groups at high cardiovascular risk, and chronic kidney disease (CKD). This review addresses recent evidence for the protective effect of dietary sodium restriction in CKD patients specifically.Sodium intake in CKD populations is generally high, and often above population average. Recent data demonstrated that moderately lower sodium intake in CKD patients is associated with substantially better long-term outcome of renin-angiotensin-aldosterone system (RAAS)-blockade, in diabetic and nondiabetic CKD, related to better effects of RAAS-blockade on proteinuria, independent of blood pressure. This is in line with better short-term efficacy of RAAS-blockade during moderate sodium restriction in diabetic and nondiabetic CKD. This effect of sodium restriction is likely mediated by its effects on volume status. Sustainable sodium restriction can be achieved by approaches on the basis of behavioral sciences.Moderate restriction of dietary sodium can substantially improve the protective effects of RAAS-blockade in CKD, by specific renal effects apparent from proteinuria reduction. The latter precludes straightforward extrapolation of data from nonrenal populations to CKD. Concerns regarding the adverse effects of a very low sodium intake should not distract from the protective effects of moderate sodium restriction. Prospective studies should assess the efficacy and sustainability of different strategies to target high sodium intake in CKD, along with measures at population level.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0.
- Retinoids and Glomerular Regeneration. [REVIEW]
- Semin Nephrol 2014 Jul; 34(4):429-436.
Retinoids are essential in the development and function of several organs, exerting potent effects on stem cell systems. All-trans retinoic acid, through binding to the retinoic acid response elements, alters transcription of numerous genes in stem cells, leading to an exit from the self-renewing state and promoting differentiation. In the kidney, retinoids protect against injury and ameliorate function in multiple experimental models of disease. Recent evidence suggests that retinoids act on renal progenitors by promoting their differentiation into mature podocytes and retinoic acid-induced podocyte differentiation is impaired by proteinuria because of sequestration of retinoic acid by albumin. However, retinoic acid administration can revert renal progenitor differentiation and promote podocyte regeneration. A more complete understanding of retinoid-dependent renal progenitor differentiation into podocytes should reward us with new insights into the mechanisms of progression toward glomerulosclerosis.
- Tubulointerstitial nephritis and uveitis syndrome complicated by IgA nephropathy and Graves' disease: a case report. [JOURNAL ARTICLE]
- J Med Case Rep 2014 Sep 12; 8(1):305.
Tubulointerstitial nephritis and uveitis syndrome is a disorder characterized by a combination of acute tubulointerstitial nephritis and uveitis. Immunoglobulin A nephropathy is defined by the presence of immunoglobulin A deposits in glomerular mesangial areas. In this report, we describe a rare case of tubulointerstitial nephritis and uveitis syndrome complicated by immunoglobulin A nephropathy and Graves' disease, which was successfully treated with corticosteroids. To the best of our knowledge, this is the first time such a case has been documented since tubulointerstitial nephritis and uveitis syndrome was first described.A 64-year-old Japanese woman presented with tubulointerstitial nephritis and uveitis syndrome accompanied by immunoglobulin A nephropathy and Graves' disease. She had renal dysfunction, proteinuria, and hematuria. Two weeks after her admission, she developed anterior chamber uveitis. She received corticosteroids, resulting in significant clinical improvement.Tubulointerstitial nephritis and uveitis syndrome is a relatively uncommon cause of tubulointerstitial nephritis. Clinicians should recognize that tubulointerstitial nephritis and uveitis syndrome with immunoglobulin A nephropathy can occur in the presence of Graves' disease. Additionally, this report may provide important clues in terms of the management of a concomitant case of these diseases.
- Pre-eclampsia - The "uterine reinnervation" view. [JOURNAL ARTICLE]
- Med Hypotheses 2014 Aug 28.
Difficult vaginal deliveries, gynaecological surgery, and, persistent straining during defaecation injure uterine nerves. Cytokines released from injured, uterine nerves cause regeneration of new nerves with altered structures and functions. In structural terms, these new nerves proliferate in chaotic and dysfunctional patterns with abnormal, cross-sectional profiles. In functional terms they are particularly sensitive to "stretch" or mechanosensory transduction. Release of neural cytokines also causes hyperplasia of the walls of adjacent, denervated uterine arterioles that may reduce uteroplacental blood flow during pregnancy. In the "uterine reinnervation" view, "stretch" applied to injured uterine nerves triggers uterorenal nerves to cause vasoconstriction in the renal cortex, hypertension and proteinuria i.e. the key features of preeclampsia. There are two intrauterine mechanisms that stretch injured, uterine nerves (a) in the placental bed, (b) in the extraplacental myometrium, respectively. In "early-onset" preeclampsia (<34weeks), continuing increases in maternal plasma volume, increase blood flow through denervated, and, narrowed uterine arterioles in the placental bed, stretching injured perivascular nerves resulting in preeclampsia with a small-for-gestational-age fetus. In "late-onset" preeclampsia (>34weeks), nulliparity, multiple pregnancy, concealed abruption and polyhydramnios increase myometrial tension and results in preeclampsia with an appropriate-for-gestational-age fetus. Widespread activation of autonomic nerves results in multi-system features of these syndromes. Changes in placental site and circulatory compliance may contribute to different phenotypes of the preeclamptic syndromes in subsequent pregnancies. The "uterine reinnervation" view offers an explanation of the common clinical features of the preeclamptic syndromes through a single pathophysiological mechanism, namely, prepregnancy injury to uterine nerves. Importantly, it offers an explanation for resolution of the symptoms and signs of preeclampsia with delivery of the fetus, the "early" and "late-onset" preeclamptic syndromes, and, the established clinical associations of the condition including nulliparity, hydramnios, multiple pregnancy, molar pregnancy, concealed abruption, etc. Establishing the presence of injured nerves expressing mechanoreceptors in the uterus, and, neural cytokines in thickened, uterine arterioles, will assist in developing this view. However, myometrial hyperplasia during the second half of pregnancy separates injured uterine nerves from injured uterine arterioles ensuring that the key pathoanatomical relationship in preeclampsia will be difficult to demonstrate.
- Hydralazine induces myeloperoxidase and proteinase 3 anti-neutrophil cytoplasmic antibody vasculitis and leads to pulmonary renal syndrome. [Journal Article]
- Case Rep Nephrol 2014.:868590.
We report a case of hydralazine-induced ANCA-associated glomerulonephritis with pulmonary hemorrhage. A 62-year-old Hispanic man with hypertension, who was being treated with hydralazine 100 mg three times a day for four and half years, presented to the hospital with severe anemia. He had acute kidney injury and urinalysis showed proteinuria, dysmorphic RBCs, and rare RBC cast. CT scan of the chest revealed bilateral pulmonary ground-glass infiltrates. Transbronchial biopsy was consistent with pulmonary hemorrhage. Serologic tests showed high titer PR3 ANCA and, to a lesser extent, MPO ANCA. Kidney biopsy revealed focal segmental necrotizing glomerulonephritis with crescents, without evidence of immune complex deposits. Hydralazine was discontinued and the patient was treated with corticosteroids and intravenous cyclophosphamide. At one-year follow-up, he had no symptoms and anemia had resolved. Kidney function improved dramatically. Serology showed undetectable PR3 ANCA and minimally elevated MPO ANCA. To our knowledge, hydralazine-associated PR3 ANCA has not been previously reported. The possibility of ANCA systemic vasculitis should be included in the differential diagnosis of any patient with hydralazine use and pulmonary renal syndrome. This is a potentially life threatening condition requiring prompt cessation of the drug and treatment with glucocorticoids and immunosuppression.
- Anti-VEGF Cancer Therapy in Nephrology Practice. [Journal Article, Review]
- Int J Nephrol 2014.:143426.
Expanded clinical experience with the antivascular endothelial growth factor (VEGF) agents has come with increasing recognition of their renal adverse effects. Although renal histology is rarely sought in antiangiogenic-treated cancer patients, kidney damage related to anti-VEGF is now established. Its manifestations include hypertension, proteinuria, and mainly glomerular thrombotic microangiopathy. Then, in nephrology practice, should we continue to perform kidney biopsy, and what should be done with the anti-VEGF agents in case of renal toxicity?