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Current therapies for lupus nephritis in an ethnically heterogeneous cohort

Rivera, Tania L; Belmont, H Michael; Malani, Seema; Latorre, Melissa; Benton, Lauri; Weisstuch, Joseph; Barisoni, Laura; Tseng, Chung-E; Izmirly, Peter M; Buyon, Jill P; Askanase, Anca D
OBJECTIVE: To evaluate responses to mycophenolate mofetil (MMF) and intravenous cyclophosphamide (CYC) in lupus nephritis in a multiethnic population. METHODS: This was a retrospective study of all patients with systemic lupus erythematosus (SLE) that underwent kidney biopsy at New York University Medical Center. Patients with followup of at least 6 months were included. Clinical response was defined as complete (return to +/- 10% of normal) or partial (improvement of 50% in abnormal renal measurements). RESULTS: Ninty-nine patients were included in the study: 86% females, 86% non-Caucasian, age 34.2 +/- 1.1 years, 62% with proliferative nephritis (PN; ISN/RPS-III and IV), and 32% with membranous nephritis (MN; ISN/RPS-V). Of the 70 patients with PN, 37 were treated with CYC and 33 with MMF. The baseline characteristics of the 2 treatment groups were different in the incidence of ISN/RPS-IV, values of serum creatinine and serum albumin, and type of insurance (p < 0.05). The response rate was greater in the MMF than in the CYC group (70% vs 41%). Responses to MMF were different in Asians (11/11), Caucasians (4/5), African Americans (3/5), and Hispanics (5/11). Responses to CYC had a similar distribution (Asians 6/10, Caucasians 4/5, African Americans 4/9, Hispanics 1/11). In the MN group (N = 23) responses were similar to the PN group (73% MMF and 38% CYC). After adjusting for race, serum creatinine, serum albumin, type of insurance, and class of nephritis, in a logistic regression model, response to MMF was superior to CYC: OR 6.2 (95% CI 1.9-20.2). Hispanics had worse outcome than Caucasians (OR 0.17). Longterm followup suggested no difference in maintenance with MMF or CYC. CONCLUSION: After controlling for the fact that less severe nephritis is preferentially treated with MMF, we found overall that response to MMF was superior to CYC. In this US population, ethnicity was observed to have an influence on response
PMID: 19040310
ISSN: 0315-162x
CID: 93732

VEGF inhibition and renal thrombotic microangiopathy [Case Report]

Eremina, Vera; Jefferson, J Ashley; Kowalewska, Jolanta; Hochster, Howard; Haas, Mark; Weisstuch, Joseph; Richardson, Catherine; Kopp, Jeffrey B; Kabir, M Golam; Backx, Peter H; Gerber, Hans-Peter; Ferrara, Napoleone; Barisoni, Laura; Alpers, Charles E; Quaggin, Susan E
The glomerular microvasculature is particularly susceptible to injury in thrombotic microangiopathy, but the mechanisms by which this occurs are unclear. We report the cases of six patients who were treated with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in whom glomerular disease characteristic of thrombotic microangiopathy developed. To show that local reduction of VEGF within the kidney is sufficient to trigger the pathogenesis of thrombotic microangiopathy, we used conditional gene targeting to delete VEGF from renal podocytes in adult mice; this resulted in a profound thrombotic glomerular injury. These observations provide evidence that glomerular injury in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy
PMCID:3030578
PMID: 18337603
ISSN: 1533-4406
CID: 81335

Metformin clearance is poor with continuous veno-venous hemodiafiltration (CVVHDF) [Meeting Abstract]

Bouchard NC; Weisstuch JM; Hoffman RS; Nelson LS; Howland MA
ORIGINAL:0005850
ISSN: 0731-3810
CID: 70365

Onset of glomerular hypertension with aging precedes injury in the spontaneously hypertensive rat

Tolbert EM; Weisstuch J; Feiner HD; Dworkin LD
The changes in renal hemodynamics that develop with aging in spontaneously hypertensive rats (SHR) were examined. Micropuncture studies revealed that glomerular capillary pressure was elevated in SHR at 9 mo of age compared with 3-mo-old SHR and 9-mo-old normotensive Wistar-Kyoto rats. Glomerular hypertension developed because of a small increase in systemic blood pressure and a decline in preglomerular vascular resistance, allowing transmission of elevated systemic pressure to the glomerular capillaries. The hemodynamic alterations were not a compensatory response to injury, inasmuch as vascular and glomerular morphology were normal in 9-mo-old SHR. To determine the mechanism of these changes, the activity of several vasoactive systems was examined. Similar changes in renal hemodynamics were observed in young and old SHR after blockade of nitric oxide production and after intravenous administration of endothelin. However, ANG II produced a proportionally greater reduction in glomerular filtration rate than renal blood flow in older SHR. These data suggest that reduced endogenous activity of the renin-angiotensin system leads to glomerular hypertension in aging SHR. Late development of glomerular hypertension may contribute to the subsequent appearance of glomerular sclerosis and progressive renal failure in these rats
PMID: 10807597
ISSN: 1931-857x
CID: 35816

Does essential hypertension cause end-stage renal disease?

Weisstuch JM; Dworkin LD
The number of patients developing end-stage renal disease (ESRD) as a consequence of hypertension is increasing and accounts for 25% of new cases of ESRD in the United States. However, the diagnosis of hypertensive ESRD is one of exclusion and no pathologic data corroborate this classification. Undoubtedly, these patients suffer from a variety of diseases, including accelerated hypertension and atherosclerotic disease of the large arteries. Also included are patients with an undiagnosed primary renal disease. The prevalence of these conditions in the hypertensive population is unknown. It is also proposed that mild to moderate hypertension can lead to ESRD. In support of this view, early investigators noted that nephrosclerosis was correlated with hypertension and/or left ventricular hypertrophy. More recently, in the Hypertension Detection and Follow-up Program, renal function was found to decline in some patients despite treatment. Data from the Baltimore Longitudinal Study of Aging indicate that the rate at which creatinine clearance declines with aging is correlated with blood pressure. A recent retrospective study reported that serum creatinine increased significantly in approximately 15% of treated hypertensive patients. However, in none of these studies was the presence of intrinsic renal disease definitively excluded. Furthermore, although an increase in serum creatinine or decline in clearance has been reported, progression to end-stage renal disease has not been documented. Therefore, additional studies are necessary to determine the frequency with which essential hypertension leads to end-stage renal disease
PMID: 1614065
ISSN: 0098-6577
CID: 13605