Role of Calcium Oxalate Monohydrate Crystal Interactions with Renal Epithelial Cells in the Pathogenesis of Nephrolithiasis: A Review

Renal tubular fluid in the distal nephron is supersaturated with calcium and oxalate ions that nucleate to form crystals of calcium oxalate monohydrate (COM), the most common crystal in renal stones. How these nascent crystals are retained in the nephron to form calculi in certain individuals is not known. Recent studies from this laboratory have demonstrated that COM crystals can bind within seconds to the apical surface of renal epithelial cells, suggesting one mechanism whereby crystals could be retained in the tubule. Adherence of crystals to cells along the nephron may be opposed by specific urinary anions such as glycosaminoglycans, uropontin, nephrocalcin, and citrate. In culture, adherent crystals are quickly internalized by renal cells, and reorganization of the cytoskeleton, alterations in gene expression, and initiation of proliferation can ensue. Each of these cellular events appears to be regulated by extra-cellular factors. Identification of molecules in tubular fluid and on the cell surface that determine whether a crystal-cell interaction results in retention of the crystal or its passage out of the nephron appears critical for understanding the pathogenesis of nephrolithiasis

A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease

A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease.BackgroundWe prospectively evaluated 3 treatment regimens of argatroban, a direct thrombin inhibitor, for providing adequate, safe anticoagulation in patients with end-stage renal disease (ESRD) during hemodialysis.MethodsIn this randomized, 3-way crossover study, ESRD patients underwent hemodialysis sessions of 3- or 4-hour duration using high-flux membranes and each of 3 argatroban treatment regimens (A: 250-μg/kg bolus, with an additional 250-μg/kg bolus allowed; B: 250-μg/kg bolus followed by 2-μg/kg/min infusion; C: steady-state, 2-μg/kg/min infusion initiated 4 hours before dialysis). Pharmacodynamic effects including activated clotting times (ACTs); hemodialysis efficacy including single-pool Kt/V, urea reduction ratio (URR), and circuit flow; and safety through a 3-day follow-up were monitored. Argatroban pharmacokinetic parameters including dialytic clearance were evaluated during regimen C.ResultsThirteen patients completed 38 hemodialysis sessions (1 patient withdrew consent after 2 sessions). Mean ± SD ACTs increased from 131 ± 14 seconds at baseline to 153 ± 24, 200 ± 30, and 197 ± 33 seconds, respectively, after 60 minutes of hemodialysis using regimens A, B, and C. Across regimens, mean Kt/Vs (1.5–1.6) and URRs (70%-73%) were comparable. No dialyzer was changed; 1 session was shortened 15 minutes because of circuit clot formation. Systemic argatroban clearance increased ∼20% during hemodialysis, without clinically significantly affecting ACTs. Upon argatroban discontinuation, ACTs and plasma argatroban decreased concurrently (elimination half-life, 35 ± 6 min). No thrombosis, bleeding, serious adverse events, or clinically significant changes in vital signs or routine laboratory measures occurred.ConclusionArgatroban, administered by each treatment regimen, provides safe, adequate anticoagulation to enable successful hemodialysis in ESRD patients. Argatroban dialytic clearance by high-flux membranes is clinically insignificant

Medical Complications in Hemodialysis Patients Requiring Vascular Access Radiology Procedures

Vascular access maintenance is crucial to providing adequate hemodialysis (HD) and hence preventing signs and symptoms of uremia. The best vascular assess is a permanent arteriovenous fistula (AVF) because it has the longest survival with the least number of complications. However, because of problems with AVF maturation, the majority of HD in the United States is provided via an arteriovenous graft (AVG) or tunneled cuffed central venous catheter. The most common access complications include infection and thrombosis. For these reasons, a patient is often referred to interventional radiology for a procedure such as a catheter placement, change, or a thrombectomy with angioplasty and/or stent placement. Commonly, a HD patient will present after missing a dialysis session. This might predispose the patient to further complications. This review is intended to provide insight into some of the common medical problems (infectious, hematologic, and cardiac) facing a HD patient as a consequence of uremia. Increased awareness to these medical issues provides guidance to prevent unnecessary complications in this difficult patient population

Calcium oxalate monohydrate crystals stimulate gene expression in renal epithelial cells

Calcium oxalate monohydrate crystals stimulate gene expression in renal epithelial cells. Primary or secondary hyperoxaluria is associated with calcium oxalate nephrolithiasis, interstitial fibrosis and progressive renal insufficiency. Monolayer cultures of nontransformed monkey kidney epithelial cells (BSC-1 line) and calcium oxalate monohydrate (COM) crystals were used as a model system to study cell responses to crystal interactions that might occur in the nephrons of patients during periods of hyperoxaluria. To determine if COM crystals signal a change in gene expression, Northern blots were prepared from total renal cellular RNA after the cells were exposed to crystals. The immediate early genes c-myc, EGR-1, and Nur-77 were induced at one hour. At two to six hours stimulated expression of the genes encoding plasminogen activator inhibitor (PAI-1) and platelet-derived growth factor (PDGF)-A chain was detected, but constitutive expression of urokinase-type plasminogen activator (u-PA) was not altered. Expression of connective tissue growth factor (CTGF) was induced at one hour and persisted up to 24 hours. The stimulation of gene expression by COM crystals was relatively crystal- and renal cell-type specific. Thus the interaction of kidney epithelial cells with COM crystals alters expression of genes that encode three classes of proteins: transcriptional activators, a regulator of extracellular matrix (ECM), and growth factors. Activation of PAI-1 gene expression without a change in u-PA favors accumulation of ECM proteins, as does increased expression of PDGF and CTGF which can also stimulate fibroblast proliferation in a paracrine manner. These results suggest that COM crystal-mediated stimulation of specific genes in renal tubular cells may contribute to the development of interstitial fibrosis in hyperoxaluric states

Increased Inlet Blood Flow Velocity Predicts Low Wall Shear Stress in the Cephalic Arch of Patients with Brachiocephalic Fistula Access

Background: An autogenous arteriovenous fistula is the optimal vascular access for hemodialysis. In the case of brachiocephalic fistula, cephalic arch stenosis commonly develops leading to access failure. We have hypothesized that a contribution to fistula failure is low wall shear stress resulting from post-fistula creation hemodynamic changes that occur in the cephalic arch. Methods: Twenty-two subjects with advanced renal failure had brachiocephalic fistulae placed. The following procedures were performed at mapping (pre-operative) and at fistula maturation (8–32 weeks post-operative): venogram, Doppler to measure venous blood flow velocity, and whole blood viscosity. Geometric and computational modeling was performed to determine wall shear stress and other geometric parameters. The relationship between hemodynamic parameters and clinical findings was examined using univariate analysis and linear regression. Results: The percent low wall shear stress was linearly related to the increase in blood flow velocity (p Conclusions: The curvature and hemodynamic changes during fistula maturation increase the percentage of low wall shear stress regions within the cephalic arch. Low wall shear stress may contribute to subsequent neointimal hyperplasia and resultant cephalic arch stenosis. If this hypothesis remains tenable with further studies, ways of protecting the arch through control of blood flow velocity may need to be developed.</p

Increased Inlet Blood Flow Velocity Predicts Low Wall Shear Stress in the Cephalic Arch of Patients with Brachiocephalic Fistula Access

<div><p>Background</p><p>An autogenous arteriovenous fistula is the optimal vascular access for hemodialysis. In the case of brachiocephalic fistula, cephalic arch stenosis commonly develops leading to access failure. We have hypothesized that a contribution to fistula failure is low wall shear stress resulting from post-fistula creation hemodynamic changes that occur in the cephalic arch.</p><p>Methods</p><p>Twenty-two subjects with advanced renal failure had brachiocephalic fistulae placed. The following procedures were performed at mapping (pre-operative) and at fistula maturation (8–32 weeks post-operative): venogram, Doppler to measure venous blood flow velocity, and whole blood viscosity. Geometric and computational modeling was performed to determine wall shear stress and other geometric parameters. The relationship between hemodynamic parameters and clinical findings was examined using univariate analysis and linear regression.</p><p>Results</p><p>The percent low wall shear stress was linearly related to the increase in blood flow velocity (<i>p</i> < 0.01). This relationship was more significant in non-diabetic patients (<i>p</i> < 0.01) than diabetic patients. The change in global measures of arch curvature and asymmetry also evolve with time to maturation (<i>p</i> < 0.05).</p><p>Conclusions</p><p>The curvature and hemodynamic changes during fistula maturation increase the percentage of low wall shear stress regions within the cephalic arch. Low wall shear stress may contribute to subsequent neointimal hyperplasia and resultant cephalic arch stenosis. If this hypothesis remains tenable with further studies, ways of protecting the arch through control of blood flow velocity may need to be developed.</p></div

Scatterplot depicting the relationship of blood flow velocity and WSS at maturation.

<p>Maximum blood flow velocity (cm/sec) is shown on the <i>x</i>-axis and percent low wall shear stress is shown on the <i>y</i>-axis. Blood flow velocity is correlated with changes in low wall shear stress (solid line) (<i>p</i> < 0.05). The patients with diabetes are represented by closed circles, the patients without diabetes by open circles with significant correlation in non-diabetics (<i>p</i> < 0.05).</p

Wall shear stress at mapping in 12 subjects.

<p>WSS (log <i>Pa</i>) at mapping for 12 subjects. Within-patient log-transformed wall shear stress values in the upper (dark grey) and lower wall (light grey). Red reference lines show the normal range on the original scale log scale [log(0.076)-log(0.76)].</p

Computational flow plot of cephalic arch.

<p>Terminal cephalic arch with inflow from right to left. Critical wall shear regions (< 0.076 Pa) are denoted with bold, red lines and are superimposed on streamlines. Computational flow plot for subject 7 at baseline (Panel A) and 30 weeks (Panel B). Computational flow plot for subject 2 at baseline (Panel C) and 8 weeks (Panel D). Black arrow on Panel D shows tiny area of low wall shear stress.</p