10 research outputs found
Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites
Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites. To investigate the capacity of lupus autoAb to produce glomerular immune deposits (ID) and nephritis, 24 murine monoclonal (m) anti-DNA antibodies (Ab), derived from either MRL-lpr/lpr, SNF1 or NZB lupus-prone mice and selected based on properties shared with nephritogenic Ig, were administered i.p. (as hybridomas) and i.v. (as purified Ig) to normal mice; at least four mice/mAb were evaluated. Three general patterns of immune deposit formation (IDF) were observed: extracellular ID within glomeruli (± blood vessels, N = 8); intranuclear ID (N = 5); or minimal or no ID (N = 11). The four MRL m anti-DNA Ab that produced significant extracellular ID demonstrated different disease profiles including: (a) mesangial and subendothelial ID with anti-basement membrane staining, associated with proliferative glomerulonephritis, PMN infiltration, and proteinuria; (b) diffuse fine granular mesangial and extraglomerular vascular ID, associated with proliferative glomerulonephritis and proteinuria; (c) dense intramem-branous ID and intraluminal ID, associated with capillary wall thickening, mesangial interposition and expansion, aneurysmal dilatation and intraluminal occlusion of glomerular capillary loops, and heavy proteinuria; and (d) mesangial and extraglomerular vascular ID, associated with mild segmental mesangial expansion, without proteinuria. These MRL mAb were derived from four different mice, and they had variable pis and isotypes. They all cross reacted with multiple autoantigens (autoAg), however, their autoAg binding profiles were distinguishable. Among the SNF1 derived mAb, four produced histologically and clinically indistinguishable disease characterized by diffuse mesangial and capillary wall ID, associated with cellular proliferation/infiltration and proteinuria. Three of the four mAb were derived from the same mouse and were clonally related; they were: IgG2b with SWR allotype, relatively cationic, highly cross reactive with similar Ag binding patterns, idiotypically related and encoded by identical VH and nearly identical VL sequences. We conclude that both the capacity of lupus autoAb to form ID and the location of IDF are dependent on properties unique to individual Ig. The results also indicate that the Ag binding region of the autoAb is influential in this process, and they suggest that multiple Ab-Ag interactions contribute to IDF in individuals with lupus nephritis. Furthermore, these observations raise the possibility that the pathologic and clinical abnormalities resulting from these interactions are influenced by the location of IDF, and that the dominant interaction, in a given individual, may be highly influential in the phenotypic expression of nephritis
Chronic acid-base perturbations in hemodialysis patients treated with sevelamer hydrochloride: A two-year follow-up study
Sevelamer hydrochloride (HCl) contains multiple amines that may cause a
significant dietary acid load. To evaluate the impact of sevelamer on
arterial blood gases, we followed two groups of stable hemodialysis
patients for 24 months. The Sevelamer Group (n = 7) did not achieve the
National Kidney Foundation Kidney Disease Outcomes Quality Initiative
(K/DOQI) goals for phosporus and Ca x P product and was switched from a
calcium-based to sevelamer-based regimen. The Calcium Group (n = 7)
achieved those goals and remained on calcium salts. Following sevelamer
administration, a deterioration of chronic metabolic acidosis was
revealed, which lasted throughout the study. Sevelamer therapy was
associated with reduced cholesterol levels, improved serum phosphate,
and Ca x P product, which facilitated the management of secondary
hyperparathyroidism. No significant changes in acid-base status or other
parameter tested were found in the Control Group. In conclusion,
sevelamer intake caused small but persistent acid-base disturbances,
which did not neutralize sevelamer’s beneficial effects on mineral and
lipid metabolism
Comparative proteomic analysis in microdissected renal vessels from hypertensive SHR and WKY normotensive rats
Systemic hypertension leads to renal damage known as hypertensive nephrosclerosis without obvious clinical symptoms in the initial stages and it has a profound impact on the renal vascular physiology. Despite its major role in End Stage Renal Disease, many aspects of hypertensive nephrosclerosis remain unknown. In order to elucidate the biological pathways and macromolecules deregulated by hypertension, renal vessels were obtained by Laser Capture Microdissection (LCM) from Spontaneously Hypertensive Rats (SHR) and age-matched controls (20 weeks). Proteomic analysis was performed aiming to detect molecular alterations associated with hypertension at the renal vessels before the onset of vascular damage. This analysis identified 688 proteins, of which 58 were differentially expressed (15 up-regulated and 43 down-regulated) in SHR. Many of these proteins are involved in vascular tone regulation by modulating the activity of endothelial Nitric Oxide Synthase (eNOS) (Xaa-Pro aminopeptidase 1 (XPP1), N(G) N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1), Dehydropteridine reductase (DHPR)) or in blood pressure control by regulating the renin-angiotensin system (Glutamyl aminopeptidase/Aminopeptidase A (AMPE), Aminopeptidase N (AMPN)). Moreover, pathway enrichment analysis revealed that the eNOS activation pathway is deregulated only in SHR. Our study demonstrates that hypertension causes early proteomic changes in the renal vessels of SHR. These changes are relevant to vascular tone regulation and consequently may be involved in the development of vascular damage and hypertensive nephrosclerosis. Further validation and interference studies to investigate potential therapeutic impact of these findings are warranted
Discontinuation of the renin-angiotensin system inhibitors improves erythropoiesis in patients with lower-risk myelodysplastic syndromes
Renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme
inhibitors (ACEis) or angiotensin-receptor blockers (ARBs) has been
related to anemia in various situations. We aimed to investigate whether
discontinuation of RAS inhibitors improves erythropoiesis in patients
with lower-risk myelodysplastic syndromes (LR-MDSs). Seventy-four
patients with LR-MDS were divided into three groups matched for gender
and age. Group A consisted of 20 hypertensive patients who discontinued
RAS inhibitors and received alternative medications. Group B consisted
of 26 patients who continued to receive ACEi/ARB and Group C included 28
patients (50% hypertensive) never exposed to ACEi/ARB. Half of the
patients in each group were under treatment with recombinant human
erythropoietin (rHuEPO). Data were collected at baseline and after 3, 6
and 12 months. Group A showed a significant increase in hemoglobin from
10.4 +/- 1g/dL at baseline to 12.6 +/- 1.2 g/dL after 12 months (p =
0.035) and in hematocrit (31.4 +/- 3% versus 37.9 +/- 4%, p = 0.002).
Incident anemia decreased from 100% at baseline to 60% at 12 months (p
= 0.043) despite a concomitant dose reduction in rHuEPO by 18% (p =
0.035). No changes in hemoglobin and hematocrit were observed in both
Group B and Group C. In the subset of patients not treated with rHuEPO,
improvement of erythropoiesis was found only in Group A, as measured by
changes in hemoglobin (11.5 +/- 1 g/dL versus 12.4 +/- 1.3 g/dL, p =
0.041) and hematocrit (34.5 +/- 3% versus 37.1 +/- 4%, p = 0.038)
after 12 months. In contrast, Group B and Group C decreased hemoglobin
and hematocrit after 12 months (p < 0.05). In conclusion,
discontinuation of ACEi/ARB in LR-MDS patients is followed by a
significant recovery of erythropoiesis after 12 months
Impact of Hemodialysis on Dyspnea and Lung Function in End Stage Kidney Disease Patients
Background. Respiratory symptoms are usually underestimated in patients with chronic kidney disease undergoing maintenance hemodialysis. Therefore, we set out to investigate the prevalence of patients chronic dyspnea and the relationship of the symptom to lung function indices. Methods. Twenty-five clinically stable hemodialysis patients were included. The mMRC dyspnea scale was applied before and after hemodialysis. Spirometry, single breath nitrogen test, arterial blood gases, static maximum inspiratory (Pimax) and expiratory (Pemax) muscle pressures, and mouth occlusion pressure (P0.1) were also measured. Results. Despite normal spirometry, all patients (100%) reported mild to moderate degree of chronic dyspnea pre which was reduced after hemodialysis. The sole predictor of (Δ) mMRC was the (Δ) P0.1 (r=0.71, P<0.001). The Pimax was reduced before and correlated with the duration of hemodialysis (r=0.614, P<0.001), whilst after the session it was significantly increased (P<0.001). Finally (Δ) weight was correlated with the (Δ) Pimax %pred (r=0.533, P=0,006) and with the (Δ) CV (%pred) (r=0.65, P<0.001). Conclusion. We conclude that dyspnea is the major symptom among the CKD patients that improves after hemodialysis. The neuromechanical dissociation observed probably is one of the major pathophysiologic mechanisms of dyspnea
Impact of Hemodialysis on Dyspnea and Lung Function in End Stage Kidney Disease Patients
Background. Respiratory symptoms are usually underestimated in patients
with chronic kidney disease undergoing maintenance hemodialysis.
Therefore, we set out to investigate the prevalence of patients chronic
dyspnea and the relationship of the symptom to lung function indices.
Methods. Twenty-five clinically stable hemodialysis patients were
included. The mMRC dyspnea scale was applied before and after
hemodialysis. Spirometry, single breath nitrogen test, arterial blood
gases, static maximum inspiratory (P-i max) and expiratory (P-e max)
muscle pressures, and mouth occlusion pressure (P-0.1) were also
measured. Results. Despite normal spirometry, all patients (100%)
reported mild to moderate degree of chronic dyspnea pre which was
reduced after hemodialysis. The sole predictor of (Delta) mMRCwas the
(Delta) P-0.1 (r = 0.71, P < 0.001). The P-i max was reduced before and
correlated with the duration of hemodialysis (r = 0.614, P < 0.001),
whilst after the session it was significantly increased (P < 0.001).
Finally (Delta) weight was correlated with the (Delta) P-i max % pred
(r = 0.533, P = 0, 006) and with the (Delta) CV (% pred) (r = 0.65, P <
0.001). Conclusion. We conclude that dyspnea is the major symptom among
the CKD patients that improves after hemodialysis. The neuromechanical
dissociation observed probably is one of the major pathophysiologic
mechanisms of dyspnea