G. C. M. Koomen

Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate

Creatinine clearance inaccurately estimates true glomerular filtration rate (GFR) because of tubular secretion of creatinine. We studied the ability of oral cimetidine, a blocker of tubular creatinine secretion, to improve the accuracy of measuring creatinine clearance. Clearances of inulin and endogenous creatinine were simultaneously measured in 16 patients with renal disease before administration of cimetidine and during 8 successive 3 h clearance periods with cimetidine 400 mg as priming dose followed by 200 mg every 3 h. At baseline, creatinine relative to inulin clearance (ClC/Cll) ranged from 1.14 to 2.27. With cimetidine, ClC/Cll approached unity in 8 patients (mean 1.02 [SD 0.03]), but considerably exceeded unity in 8 others (1.33 [0.14]). Plasma cimetidine/creatinine ratio was smaller in this second group, due to significantly higher renal clearance of cimetidine (333 [136] vs 165 [89] ml/min, p = 0.01). In a further study, cimetidine dose and, consequently plasma cimetidine concentration, was increased in 6 additional patients who had incomplete inhibited previously. This increased dose completely inhibited tubular creatinine secretion in the third until the sixth hour, so that creatinine clearance equalled GFR. Provided an adequate dose of cimetidine is given, 24 h creatinine clearance during administration of drug measures GFR accurately in patients with renal disease. However, because of the maximum daily dose of cimetidine that is advised, short clearance times (3 h) are recommended.

The Time Course of Peritoneal Transport Kinetics in Continuous Ambulatory Peritoneal Dialysis Patients Who Develop Sclerosing Peritonitis

The time course of measurements of peritoneal solute transport in four continuous ambulatory peritoneal dialysis (CAPD) patients who developed sclerosing peritonitis is described. Loss of fluid removal capacity was found in all of them. In three, this loss was associated with an increase in peritoneal absorption of glucose from the dialysate and an increase in the transperitoneal transport rates of low-molecular-weight solutes and proteins. In the other patient a decrease in all these parameters was found. This seems to imply that the effective peritoneal surface area was increased in three patients and decreased in one. Peritoneal permeability to macromolecules remained unchanged as judged by the ratio between the clearance of IgG and albumin. Among the possible factors that contribute to the development of sclerosing peritonitis, some are likely to lead to a larger effective peritoneal surface area, like prostacyclin and the formation of new capillaries in poorly vascularized parts of the peritoneum. Others, such as extensive formation of collagen, could lead to a smaller effective surface area. Individual differences in susceptibility to these factors may lead to an increase or decrease in peritoneal solute transport rates. Follow-up measurements of peritoneal solute kinetics are necessary to identify those patients who are at risk.

Fluid Kinetics in CAPD Patients during Dialysis with a Bicarbonate-Based Hypoosmolar Solution

The magnitude of transcapillary backfiltration by the colloidosmotic pressure within the peritoneal capillaries compared to the effective lymphatic absorption was investigated in continuous ambulatory peritoneal dialysis patients. This was done during a 4-hour dwell period, using a hypoosmolar dialysis fluid (280 mosm/kg H2O) in 8 patients and compared to 5 of these patients using a 1.36% glucose (GS; 324 mosm/kg H2O). The low molecular weight solute transport did not differ between the two solutions. The intraperitoneal dextran 70 concentration increased during the dwell with the hypoosmolar dialysis fluid (from 770 to 945 mg/l; p = 0.000002) and decreased with the GS (from 859 to 719 mg/l; p = 0.007). With the GS the transcapillary ultrafiltration was directed towards the abdominal cavity during the dwell period. With the hypoosmolar fluid, the transcapillary ultrafiltration was continuously directed towards the circulation. In this solution, the magnitude of transcapillary backfiltration due to colloidosmotic pressure within the peritoneal capillaries was 0.4 +/- 0.1 ml/min. In conclusion, intraperitoneal markers can be used in continuous ambulatory peritoneal dialysis patients for determination of effective lymphatic absorption and transcapillary fluid passage in both transport directions.

Clearance ratios of amylase isoenzymes and IgG subclasses: do they reflect glomerular charge selectivity?

The clearance ratios of endogenous plasma proteins with the same size but a different charge, such as the amylase isoenzymes and the immunoglobulin (Ig) G subclasses, have been used to assess glomerular charge selectivity in man. These proteins are, however, subject to tubular reabsorption. In this study we measured the IgG subclass/IgG clearance ratios for IgG1 (pI 8.0-9.5), IgG2 (pI 7.0-7.5) and IgG4 (pI < 6) in 6 healthy volunteers. Our results suggested a selective influence of tubular reabsorption: the IgG1/IgG clearance ratio was 0.68 +/- 0.14 (mean +/- SD) and lower than IgG2/IgG (2.02 +/- 1.06, p < or = 0.01). IgG4/IgG was 0.89 +/- 0.39. In addition, we studied the clearance ratios of pancreatic (PA, pI 7.0) and salivary amylase (SA, pI 5.9-6.4) and of IgG1 and IgG2 in 8 patients with minimal change nephrotic syndrome (MCNS), 11 patients recovering from acute tubular necrosis (ATN) and 9 healthy volunteers (controls). In MCNS glomerular charge selectivity is lost, while in recovering ATN tubular function is severely disturbed. The PA/SA clearance ratio was 3.25 +/- 0.89 in controls, reflecting intact glomerular charge selectivity. In MCNS patients the PA/SA clearance ratio had decreased to 1.21 +/- 0.23 (p < or = 0.001). In ATN patients the PA/SA clearance ratio was reduced as well: 1.55 +/- 0.41 (p < or = 0.001), although the aselective nature of the proteinuria and the modest albuminuria indicated intact glomerular charge selectivity. The IgG1/ IgG2 clearance ratio was 0.54 +/- 0.15 in controls, again suggesting preferential tubular reabsorption of IgG1. In MCNS patients the IgG1/IgG2 clearance ratio was 0.16 +/- 0.10 (p < or = 0.001); this probably reflects the relatively increased glomerular sieving of IgG2 when glomerular charge selectivity is lost. In ATN patients the IgG1/IgG2 clearance ratio was 1.07 +/- 0.47 (p < or = 0.001), which suggests a partial loss of preferential reabsorption of IgG1. It was concluded that the PA/SA clearance ratio is influenced by loss of tubular function and therefore does not reflect glomerular charge selectivity specifically. The IgG1/IgG2 ratio cannot be used to assess glomerular charge selectivity either because of the interference of selective tubular reabsorption of the subclasses. These findings put the assessment of glomerular charge using endogenous proteins in a new light and bring forward the necessity to interpret these ratios with the utmost cautiousness.

Effects of Tracer, Volume, Osmolarity and Infection on Fluid Kinetics during CAPD

A review is given on various aspects of using the disappearance rate of intraperitoneally administered macromolecules for the determination of fluid kinetics in CAPD patients. The rationale and mathematics for the calculation of transcapillary ultrafiltration and of indirect measurement of lymphatic absorption are described. A comparison is made between autologous haemoglobin, human albumin and dextran 70. Dextran 70 appeared most useful; one brand of human albumin increased solute transport. Lymphatic absorption was higher after the installation of a 3-litre dialysate volume than after a 2-litre one, and also higher during peritonitis than after recovery from infection. A gradual increase in intraperitoneal volume, as obtained with glucose 3.86% dialysate, had no apparent effect on the disappearance rate of dextran 70. It is concluded that intraperitoneally administered dextran 70 is a clinically useful marker for the description of fluid kinetics in CAPD patients under various conditions.

Use of the disappearance rate for the estimation of lymphatic absorption during CAPD.

Several studies are discussed which investigated the usefulness of the disappearance rate of macromolecules from the peritoneal cavity for estimating convective fluid loss from the peritoneal cavity into the peritoneal lymphatic system. It is shown that dextrans are removed from the peritoneal cavity by a size-independent process at a mean rate of 1.37 +/- 0.15 ml/min, whereas the clearance from blood to dialysate of dextrans is size-dependent. The fluid removal rate estimated by the difference in bidirectional transport of inulin (1.79 +/- 0.38 ml/min; p < 0.0005) was of the same order of magnitude as has been found using the removal rate of macromolecules from the peritoneal cavity. Also, the role of local accumulation of macromolecules was studied during continuous administration of dextrans. No differences were found in the dextran disappearance rate before and after saturation of the peritoneal interstitium with dextran (1.1 +/- 0.6 vs. 1.0 +/- 0.4 ml/min). During a study using a hypoosmotic solution we calculated a net transcapillary backfiltration of fluid, whereas the dextran removal rate was in the same order of magnitude as found using commercially available dialysate. In our opinion, the disappearance rate of macromolecules is an estimate of convective fluid loss from the peritoneal cavity into the peritoneal lymphatic system.