Does blood flow accurately predict thrombosis or failure of hemodialysis synthetic grafts? A meta-analysis.

A number of studies have reported that a single low blood flow (Qa) measurement in synthetic hemodialysis grafts predicts thrombosis or failure. In a meta-analysis of these studies, we computed receiver operating characteristic (ROC) curves that evaluated the predictive accuracy of a Qa measurement. The ROC curves plotted sensitivity versus false-positive rate for predicting thrombosis or failure at different Qa thresholds. A perfect predictor has an area under the curve (AUC) of 1.0, whereas a predictor with no discriminative ability has an AUC of 0.5. We identified studies through a literature search and included our own unpublished data. A random-effects model was used to combine the ROC curves from different studies. Of 19 identified studies, 12 were suitable for computing binormal ROC curves (6 predicted thrombosis; 6 predicted failure). The studies measured Qa and then observed outcome during periods of 1.5 to more than 6 months. The combined AUCs from these studies indicate Qa was a relatively poor predictor, with 0.70 +/- 0. 04 (range, 0.61 to 0.84) for thrombosis and 0.76 +/- 0.07 (range, 0. 62 to 0.90) for failure. The wide range of AUCs also shows there was much heterogeneity between studies. We conclude that a single Qa measurement does not appear to have enough accuracy to be a clinically useful predictor of graft thrombosis or failure. Serial Qa measurements and identification of factors that caused heterogeneity between studies may be needed to achieve sufficient accuracy.

Accuracy of decrease in blood flow in predicting hemodialysis graft thrombosis.

We recently showed that a single low graft blood-flow measurement (Qa) does not accurately predict graft thrombosis. In this study, we prospectively determined whether percentage of decrease in Qa (DeltaQa) or adjustment of Qa for mean arterial pressure (Qa/MAP; Delta(Qa/MAP)) provides greater predictive accuracy than a single Qa. We monitored 83 grafts from 80 patients for thrombosis over periods up to 12 months. Qa (by ultrasound dilution) and MAP were measured monthly during the study. Receiver operating characteristic curves were used to determine whether Qa, DeltaQa, Qa/MAP, or Delta(Qa/MAP) provided the combination of high sensitivity (>80%) and low false-positive rate (FPR; <20%) needed for clinical use. This level of predictive accuracy requires an area under the curve (AUC) of approximately 0.90. We analyzed the four predictors by a number of criteria and found that all AUCs were less than 0.90 and adjustment for MAP reduced the AUC. In predicting thrombosis within 1 month, for example, AUCs for Qa and net DeltaQa (over 3 months) were 0.84 and 0.82, respectively, whereas AUCs for Qa/MAP and net Delta(Qa/MAP) were 0.78 and 0.75, respectively. At a sensitivity of 80%, FPRs for all predictors were at least 30%. Thus, a high sensitivity always required a high FPR. These results show that DeltaQa and adjustment for MAP are not more accurate than a single low Qa in predicting thrombosis. None of these predictors provide enough predictive accuracy to be the sole criterion for clinical decision making. A successful monitoring and intervention program will likely require the inclusion of other predictors that, together with Qa, may provide the needed accuracy.

Hemodynamic reproducibility during blood flow measurements of hemodialysis synthetic grafts.

We have previously shown that graft blood flow (Qa) has a poor accuracy in predicting graft thrombosis. In this study, we determined whether hemodynamic variation helps explain this poor predictive accuracy. We also determined whether standardized timing of Qa measurements, which is widely recommended, will promote measurement reproducibility. We analyzed variations in mean arterial pressure (MAP) in seven consecutive dialysis sessions for 51 patients and determined the influence of MAP on Qa (by ultrasound dilution). We used a pooled coefficient of variation (CV) to summarize MAP variation within individual patients (computed as +/-2 CVs). MAPs from the seven sessions varied widely, and most variation was present with the first MAPs at the beginning of the sessions. These first MAPs varied by +/-23%, whereas variation for the entire session was +/-28%. The influence of MAP on Qa was determined by measuring the two together during consecutive thirds of a single session. The percentage of change in MAP (DeltaMAP) and Qa (DeltaQa) from the first to middle or last thirds of the session varied over wide ranges: -37% to 86% and -43% to 78%, respectively. The DeltaQa versus DeltaMAP correlation was relatively strong for changes between the first and middle thirds (r = 0.666) and first and last thirds (r = 0.646) of the session (both P: < 0.01). We conclude that MAP varies far more widely during dialysis than previously recognized. This variation is associated with large changes in Qa that may impair accuracy in predicting thrombosis. This wide MAP variation also indicates hemodynamic reproducibility is not feasible when measuring Qa. Thus, we do not recommend standardized timing of Qa measurements during dialysis. A practical method of addressing poor Qa reproducibility may be to take frequent measurements so that trends can be recognized before thrombosis occurs.

Cl- permeability of human sweat duct cells monitored with fluorescence-digital imaging microscopy: evidence for reduced plasma membrane Cl- permeability in cystic fibrosis.

Salt reabsorption by the human sweat duct is markedly reduced in cystic fibrosis (CF). We used fluorescence-digital imaging microscopy in combination with a halide-specific fluorescent dye [6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ)] to determine if this defective salt reabsorption is referable to a reduced plasma membrane Cl- permeability of the epithelial cells that line the sweat duct. Sweat duct cells were cultured from explants of normal and CF reabsorptive duct and loaded with SPQ, the fluorescence of which is specifically quenched by halide ions (Br- greater than Cl-) and provides a relative index of intracellular halide concentration. Two lines of evidence indicate that normal sweat duct cells exhibit a substantial permeability to Cl- and Br-. First, the replacement of extracellular Cl- with an impermeant anion (i.e., gluconate) resulted in a rapid and reversible increase in the intracellular fluorescence, as expected if the cells rapidly lost Cl- to the extracellular media. Second, the replacement of extracellular Cl- with Br- resulted in a rapid and reversible quenching of the intracellular fluorescence, as expected if the cells accumulated Br- (a more effective quencher of SPQ fluorescence) in exchange for Cl-. The rate of fluorescence change that was induced by either maneuver was inhibited by the Cl- channel blocker, diphenylamine-2-carboxylate (10 microM). Moreover, CF cells exhibited markedly reduced rates of fluorescence change in response to either maneuver. Our results document the utility of this imaging strategy for assessing the Cl- permeabilities of individual epithelial cells that are affected in cystic fibrosis and indicate that the defective salt reabsorption by the CF sweat duct is referable, at least in part, to a reduced plasma membrane Cl- permeability of sweat duct cells.

Regulation of Cl- permeability in normal and cystic fibrosis sweat duct cells.

Reabsorptive cells of the human sweat gland normally exhibit a high basal Cl- permeability but are markedly impermeable to Cl- in cystic fibrosis (CF). We examined the possibility that the reduced basal Cl- permeability of CF sweat duct cells in primary culture is due to a defective regulation of plasma membrane Cl- permeability by prostaglandin E2 (PGE2), which is endogenously produced by cultured sweat duct cells. The macroscopic Cl- permeabilities of normal and CF sweat duct cells were assessed using a halide-specific fluorescent dye, 6-methoxy-N-(3-sulfopropyl)quinolinium, in combination with fluorescence digital-imaging microscopy. The Cl- and Br- permeabilities of normal sweat duct cells were markedly reduced by inhibiting endogenous PGE2 production with indomethacin. This inhibition of Cl- permeability by indomethacin was largely reversed by the addition of PGE2 (10 nM to 1 microM), but not forskolin. Conversely, PGE2 failed to stimulate the low Cl- permeabilities of sweat duct cells cultured from CF subjects. Our results support the following conclusions: 1) a defective regulation of Cl- permeability in CF is a feature of reabsorptive as well as secretory epithelial cells, and 2) the nature of this regulatory defect extends beyond altered Cl- permeability regulation by adenosine 3',5'-cyclic monophosphate-dependent protein kinase.