Estimated glomerular filtration rate progression in UK primary care patients with type 2 diabetes and diabetic kidney disease: a retrospective cohort study.

AIMS: To examine the rates of diabetic kidney disease (DKD) progression and associated factors, we undertook a study of estimated glomerular filtration rate (eGFR) in a historical cohort of UK primary care patients with type 2 diabetes mellitus (T2DM) and associated DKD from the Clinical Practice Research Datalink. METHODS: Our eligible population were patients with definitive T2DM from a recorded diagnostic code with either a diagnosis of chronic kidney disease (CKD) or renal function test values and renal abnormalities consistent with a CKD diagnosis, identified between 1 October 2006 and 31 December 2011. Only patients with albuminuria results reported in mg/l were used for the longitudinal statistical analyses of the eGFR rate of change using multilevel models. RESULTS: We identified 111,030 patients with T2DM. Among them 58.6% (95% confidence interval (CI): 58.3-58.9) had CKD and 37.2% (95% CI: 36.9-37.5%) had presumed DKD at baseline. Only 19.4% of patients had urinary albumin test results expressed as mg/l in the year prior to index date. Almost two-thirds (63.8%) of patients with T2DM and presumed DKD received prescriptions for angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 1 receptor blockers (ARB) or both. Time-dependent variables that predict subsequent eGFR decline include increased albuminuria, time from index date and older age. CONCLUSION: Only a minority of diabetic patients with DKD had quantitative albuminuria assessments. The relatively low proportion of DKD patients with ACEi or ARB prescriptions suggests a gap between healthcare practice and available scientific evidence during the study period. Increased albuminuria and older age were the most consistent predictors of subsequent eGFR decline.

Improved HPLC-radioimmunoassay for quantifying angiotensin II in plasma.

To measure the octapeptide angiotensin II (Ang II) in plasma, we developed a sensitive, specific assay that interfaces solid-phase extraction, HPLC, and RIA. A reversed-phase HPLC system involving isocratic elution at 38 degrees C with a volatile mobile phase of acetonitrile and the ion-pairing reagent heptafluorobutyric acid produced baseline separation of angiotensin peptides. Ang II was collected as a single fraction, concentrated by evaporation to dryness, and measured by RIA after resuspension in RIA buffer. Even including column washing between sample injections to prevent carryover of plasma constituents, two plasma extracts could be processed per hour by HPLC. Assay validation experiments demonstrated < 2% cross-reactivity with Ang II-related peptides; a 75% recovery from plasma at physiological concentrations of Ang II; intra- and interassay precision (CVs) of 6.2% and 10.3%, respectively; and a lower limit of quantification of 1.3 ng/L. Two clinical protocols designed to measure plasma Ang II concentration under basal and stimulated conditions confirmed the utility of the assay.

Binding inhibitors restore furosemide potency in tubule fluid containing albumin.

We have previously suggested that albumin in tubule fluid at concentrations found in the nephrotic syndrome (NS) binds furosemide, thereby diminishing diuretic effect. This mechanism may contribute to diuretic resistance in NS. If this hypothesis is correct, displacement of albumin from furosemide should restore diuretic response in tubule fluid containing albumin. To test this supposition, in vivo loop microperfusion was performed in rats using perfusates containing 6 microM furosemide in the presence or absence of 3.8 microM albumin, or furosemide and albumin to which 12 microM warfarin or 5.4 mM sulfisoxazole had been added. These drugs are inhibitors of albumin-furosemide binding in plasma. Albumin in the perfusate impaired furosemide effect on loop chloride reabsorption (1248 +/- 59 vs. 886 +/- 65 pEq/min; P less than 0.05). Addition of warfarin or sulfisoxazole to perfusate containing albumin normalized furosemide's effect. Neither drug affected furosemide response in the absence of albumin. Dansylsarcosine, a probe that binds albumin at a different site than furosemide, failed to normalize furosemide response in albumin perfusates. These data suggest that albumin in tubule fluid reduces diuretic response through a diminution in the free furosemide concentration. In as much as this mechanism contributes to diuretic resistance observed clinically in NS, displacement of furosemide from albumin binding sites may be a therapeutic strategy warranting study.

Tubular resistance to furosemide contributes to the attenuated diuretic response in nephrotic rats.

A blunted response to loop diuretics frequently occurs in nephrotic syndrome (NS). Observations that nephrotic humans have reduced sodium excretion at normal rates of diuretic excretion have suggested that tubular resistance to the drug may contribute to diuretic resistance. To determine if tubular resistance to furosemide exists in NS, late proximal and early distal tubular micropuncture was performed in rats with puromycin aminonucleoside-induced NS and in control rats after an i.v. bolus dose of furosemide of 1 mg/kg body wt. Absolute and fractional urinary sodium excretions were less (P less than 0.05) in NS rats than in control rats after furosemide. Inulin clearance and total urinary furosemide excretion, however, were not different between groups. Thus, similar to reports in humans, the urinary sodium-to-furosemide excretion ratio was less (P less than 0.05) in NS than in control rats. Single-nephron GFR and chloride delivery to late proximal sites were not different between groups after furosemide. In contrast, absolute and fractional chloride deliveries to early distal sites were less (P less than 0.05) in NS rats after furosemide. Calculated loop chloride reabsorption after furosemide was greater (P less than 0.05) in NS than in control rats when expressed either as percentage of filtered load (39.4 +/- 3.1 versus 28.2 +/- 2.0%) or delivered load (67.9 +/- 4.7 versus 48.3 +/- 3.0%). Loop fluid reabsorption was not different between groups. Thus, loop chloride reabsorption is inhibited to a lesser extent by i.v. furosemide in NS than in normal rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Intratubular albumin blunts the response to furosemide-A mechanism for diuretic resistance in the nephrotic syndrome.

An attenuated response to loop diuretics is a frequent observation in the nephrotic syndrome. To determine if the presence of albumin in renal tubular fluid attenuates diuretic response in normal rats, in vivo loop segment microperfusion was performed in normal rats at 20 nl/min with perfusates containing 6.0 microM furosemide in the presence and absence of 3.8 microM albumin. Compared to loop segments perfused without diuretic (control), furosemide reduced (P less than .001) fractional chloride uptake from 56 +/- 2 to 34 +/- 2%. After addition of albumin to furosemide perfusate, fractional loop chloride reabsorption was 45 +/- 1%; a value greater (P less than .01) than that observed in furosemide perfused loop segments, but less (P less than .05) than that observed in control loop segments. Albumin added to perfusate in the absence of furosemide had no effect on fractional loop segment chloride uptake. Addition of 1.7 microM immunoglobulin G to furosemide perfusate failed to attenuate furosemide response. Absolute loop segment chloride reabsorption demonstrated a similar pattern. Tubule fluid perfusion rates determined in vivo and loop segment fluid reabsorption were equivalent in all groups. Thus, albumin in renal tubule fluid attenuates the effect of furosemide on loop segment chloride reabsorption in the rat. This blunted response presumably occurs because of a reduction in the amount of pharmacologically active drug due to albumin-furosemide binding. Consequently, albumin-furosemide binding in the renal tubule may contribute to the diuretic resistance in nephrotic syndrome.

In vitro evidence that urine composition affects the fraction of active furosemide in the nephrotic syndrome.

Diuretic resistance to furosemide in the nephrotic syndrome (NS) may result from binding of drug to filtered albumin within the renal tubule. In buffer solutions intended to partially mimic the luminal environment of the distal nephron during the NS, we examined several chemical properties to determine their effect on furosemide-albumin binding equilibria. Dissociation constants were obtained by measuring furosemide's quenching of human serum albumin's intrinsic tryptophan fluorescence over ranges of pH, ionic strength (IS) and osmolarity. Neither pH nor osmolarity significantly affected binding; however, incremental increases in IS between 0.0 and 1.0 produced increases in Kd from 0.65 +/- 0.05 to 34.38 +/- 1.72 microM, resulting in a 5- and 28-fold increase in the unbound furosemide fraction when the furosemide-albumin concentrations were 3.0:5.0 and 10.0:45.0 microM, respectively. Our results indicate that human serum albumin contains one high affinity binding site for furosemide that is sensitive to IS. Because of changes in the concentrations of reactants as well as IS that can occur in nephron segments distal to furosemide's site of action, we conclude that the amount of unbound (i.e., pharmacologically active) drug in voided urine will not necessarily correspond to the amount at the active site. To clinically assess the pharmacodynamic consequence of protein binding in the NS, changes in the concentration of the reactants and IS in the distal nephron must be minimized so that the unbound furosemide measured in voided urine will accurately reflect the amount at the drug's active site.

Loop diuretics for chronic renal insufficiency: a continuous infusion is more efficacious than bolus therapy.

OBJECTIVE: To test the hypothesis that a continuous, low-dose infusion of a loop diuretic is more efficacious and better tolerated than conventional intermittent bolus therapy in patients with severe chronic renal insufficiency (CRI). DESIGN: Randomized, crossover clinical trial with subjects serving as their own controls. SETTING: The General Clinical Research Center of Indiana University Hospital, Indianapolis, Indiana. PATIENTS: Eight adult volunteers with severe stable CRI (mean creatinine clearance, 0.28 mL/s; range, 0.15 to 0.47 mL/s) were recruited from the outpatient nephrology clinics of Indiana University Medical Center. INTERVENTIONS: On admission, diuretic drugs were withdrawn and patients were equilibrated on an 80 mmol/d sodium, 60 mmol/d potassium metabolic diet. Patients were randomized to receive a 12-mg intravenous dose of bumetanide given either as two 6-mg bolus doses separated by 6 hours or as the same total dose administered as a 12-hour continuous infusion. When sodium balance was re-established, each patient was crossed over to the alternative study limb. All patients completed both phases of the study. MEASUREMENTS AND RESULTS: Comparable amounts of bumetanide appeared in the urine during the study period (infusion, 912 +/- 428 micrograms; bolus, 944 +/- 421 micrograms; difference, 32 micrograms; 95% CI, -16 micrograms to 80 micrograms, P = 0.16). The continuous infusion resulted in significantly greater net sodium excretion (infusion, 236 +/- 77 mmol; bolus, 188 +/- 50 mmol; difference, 48 mmol; CI, 16 mmol to 80 mmol, P = 0.01). No patient had episodes of drug-induced myalgias during the continuous infusion compared with 3 of 8 patients with bolus therapy. CONCLUSIONS: In patients with severe CRI, a continuous intravenous infusion of bumetanide is more effective and less toxic than conventional intermittent bolus therapy. Continuous administration will probably be useful in patients with severe CRI who have not achieved an adequate natriuresis or who show evidence of drug toxicity with standard diuretic dosing regimens. A similar benefit may occur in selected diuretic-resistant patients with cardiac or hepatic disease, and studies in these patients seem warranted.

Pharmacokinetics and pharmacodynamics of torasemide in patients with chronic renal insufficiency--preliminary evaluation.

The pharmacokinetics and pharmacodynamics of torasemide were studied in 24 subjects with chronic renal insufficiency. The subjects were divided into two groups of patients, half having a creatinine clearance < 30 ml/min and the other half having a creatinine clearance between 30 and 60 ml/min. Three different intravenous doses were studied in each patient group. Pharmacokinetic analysis revealed dose proportionality when relating area under the concentration curve to dose. There was a progressive decrease in renal clearance of torasemide with declining renal function. In contrast, there was no difference in serum elimination half-life among the patients. In addition, this half-life was not different from that observed in healthy young or elderly control subjects. In previous reports on patients with congestive heart failure and liver disease, serum half-life values were prolonged compared to that of control subjects, presumably due to decreased hepatic, nonrenal clearance of torasemide. Supportive of this hypothesis is the considerably increased area under the serum vs. concentration time curve in such patients. In summary, this study has shown that the serum half-life of torasemide would be unchanged in patients with renal disease. The ceiling dose for torasemide (i.e., the dose above which no further drug-induced natriuresis is obtained) has been preliminarily found to be a single 100-mg intravenous dose in patients with moderate renal insufficiency and a single 200-mg intravenous dose in patients with severe disease.

Comparison of loop diuretics in patients with chronic renal insufficiency.

Furosemide and bumetanide share a number of characteristics including reduced natriuretic effects in azotemic patients. It has been presumed that this condition affects each drug equally. Previous studies, however, suggest dissimilar pathways of delivery to their sites of action. Though not rigorously tested, this potential disparity might cause them to differ when used in azotemia. We, therefore, assessed the pharmacokinetic and pharmacodynamic characteristics of intravenously administered furosemide and bumetanide in ten adult patients with stable, chronic renal insufficiency (mean creatinine clearance = 14.1 +/- 2.0 ml/min/1.73 m2) in a randomized, cross-over study during controlled sodium intake. Our goals were to assess differences in diuretic effectiveness and in so doing to determine the dose required to produce a maximal response. The mean diuretic doses of 172 and 4.3 mg for furosemide and bumetanide, respectively (ratio = 40:1) were sufficient to produce a maximum response. Despite similarities in maximal fractional excretion of sodium (18.2 +/- 2.6% with furosemide vs. 19.4 +/- 4.5% with bumetanide, P = 0.687) demonstrating an equal tubular responsiveness to both drugs, overall response as quantified by cumulative natriuresis in the initial eight hour period was 52% greater with furosemide (108 +/- 17 vs. 71 +/- 7 mEq; P = 0.042). The difference in total excreted sodium was accounted for by a preserved nonrenal clearance of bumetanide (113 +/- 12 compared to 53 +/- 5 ml/min for furosemide, P = 0.001) which resulted in relatively less bumetanide in serum available to be delivered into the urine.(ABSTRACT TRUNCATED AT 250 WORDS)