Frieder Keller

OUTCOME PREDICTION OF ACUTE RENAL FAILURE IN MEDICAL INTENSIVE CARE

Data acquired prospectively from 134 patients with acute renal failure requiring dialysis in a medical intensive care unit (ICU) were analysed in order to derive indicators predicting ICU-survival Mortality in the ICU was 56.7%. Linear discriminant analysis correctly predicted outcome in 79.9% at the start of dialysis, and 84.7% at 48 h after the first dialysis. The most important predictive variables were mechanical ventilation and low blood pressure. On the other hand, the total correct classification rates achieved by a standardised system for scoring ICU-patients (APACHE II) did not exceed 58.2%. It is concluded that outcome prediction by APACHE II and even by the discriminant functions is too inaccurate to become the basis for clinical decisions either concerning the initiation or the continuation of dialysis treatment in ARF.

Low cyclosporin A blood levels and acute graft rejection in a renal transplant recipient during rifampin treatment.

Cyclosporin A trough blood levels were unusually low during rifampin treatment in a kidney transplant patient. Simultaneously, acute graft rejection occurred. Pharmacokinetic investigation revealed a rapid turnover of cyclosporin A leading to low blood levels. Cessation of rifampin therapy reversed these changes. Rifampin substantially reduces the bioavailability of cyclosporin A and should not be used in transplant recipients on cyclosporin A.

Risk Factors and Outcome of 107 Patients with Decompensated Liver Disease and Acute Renal Failure (Including 26 Patients with Hepatorenal Syndrome): The Role of Hemodialysis

The prognosis of acute renal failure in patients with preexisting liver decompensation is poor, and hemodialysis is considered futile, especially for hepatorenal syndrome (HRS). Since we observed a more favorable outcome in some patients, we retrospectively evaluated 107 patients with decompensated liver disease and acute renal failure (serum creatinine > 200 mumol/L) treated at the medical department of a university hospital in a 10-year period (1980-1990). HRS in the strict sense (urine-Na < 20 mmol/L while on furosemide) was diagnosed in 26 of 107 patients (24%). Renal function remained compensated in 25 patients, while 82 patients fulfilled the criteria for dialysis treatment (creatinine > 500 mumol/L and/or diuresis < 500 mL/day). In contrast to the current doctrine, 38 of the 82 patients were given hemodialysis (46%). Using the Cox proportional hazard model, the relative risk (presence vs. absence of a risk factor) of dying was increased 8.2-fold (3.9-17.2) in patients with thrombocytopenia < 100/nL, 3.9-fold (1.4-11.3) in those with hepatic encephalopathy and prothrombin time < 30%, 2.8-fold (1.6-4.8) in patients with malignoma, and 2.7-fold (1.5-4.8) in patients not submitted to dialysis despite its indication. In the CART statistics (classification and regression trees), the 33 patients with the poorest outcome were characterized exclusively by thrombocytopenia < 100/nL. HRS in the strict sense was not an independent risk factor. The CART group of 43 patients with favorable prognosis (compensated renal failure or treatment by hemodialysis, absent malignancy) had a 1-year survival rate of 38%. We conclude that thrombocytopenia, encephalopathy, and malignoma, but not HRS per se, are fatal signs that make hemodialysis futile in patients with acute renal failure and decompensated liver disease.

Pharmacokinetic effects of altered plasma protein binding of drugs in renal disease

SummaryThe measurement of plasma drug concentrations provides no insight into the relationship between the free and the plasma-protein-bound fractions of drugs. Plasma protein binding may decrease in renal disease due to uremia, hypoalbuminemia, or due to drug interactions. Decreased plasma protein binding leads to an increase in free plasma fraction causing an increase in volume of distribution and a shorter elimination half life. The increase in the apparent volume of distribution and the shorter elimination half life cause a decrease in total plasma concentration. Therefore, the free drug concentration is more reliable than the total plasma concentration for therapeutic drug monitoring. However, the free amount in plasma and in tissue and the tissue-bound amount remain unchanged under steady state conditions. Thus, a decrease in plasma protein binding in renal disease usually does not lead to increased drug toxicity, and alteration of drug dosage is not required, although the total plasma concentration may be found to be considerably lower than normal. In addition to plasma protein binding, alteration of tissue binding must also be considered for the determination of the appropriate dosage of some drugs in renal disease.

Granulomatous Interstitial Nephritis after Nonsteroidal Anti-Inflammatory Drugs

Electrolyte and renal hemodynamic imbalance, acute interstitial nephritis with nephrotic-range proteinuria, papillary necrosis, tubular necrosis, and vasculitis are complications after intake of nonsteroidal anti-inflammatory drugs (NSAID). We report on 2 cases of biopsy-proven granulomatous interstitial nephritis with rapidly progressing renal insufficiency. Patient 1 was on ketoprofen for 7 months and indomethacin for 10 weeks before admission to hospital. The medication was not discontinued and renal insufficiency progressed to end-stage renal failure. Renal function did not respond to steroid and tuberculostatic treatment. Patient 2 was on diclofenac for 6 months and indomethacin for 7 weeks before admission to hospital. These drugs were withdrawn at diagnosis and renal function rapidly improved. We conclude that granulomatous interstitial nephritis may be a complication of NSAID medication indicating a cell-mediated immunologic disorder. False diagnosis (sarcoidosis, tuberculosis) may lead to end-stage renal disease (case 1). Discontinuation of medication obviates further therapy (case 2).

Increased Procollagen III Production in Patients with Kidney Disease

Measurements of elevated procollagen III peptide (PIIIP) levels are used to monitor fibrosing activity in hepatic and various other diseases. Elevated PIIIP levels have also been reported in renal failure patients without such diseases. Therefore, the serum levels and renal clearance of PIIIP were investigated in 17 healthy volunteers and 100 patients with different types of acute (n = 15) and chronic (n = 85) kidney disease. PIIIP was measured by conventional and Fab radioimmunoassays. Median PIIIP levels in serum (18, range 5-55 ng/ml) and urine (34, range 1-110 micrograms/day) were significantly higher in kidney patients than serum (9, range 6-14 ng/ml) and urine levels (17, range 6-24 micrograms/day) in normal volunteers (p = 0.01). No significant differences (Kruskal-Wallis H test) were found, however, within the different kidney disease groups (acute, chronic/glomerulonephritis, interstitial nephritis). Median renal clearance of PIIIP-related peptides in kidney patients (1.5, range 0.5-2.4 ml/min) did not differ significantly (Wilcoxon U test) from that in normal volunteers (1.3, range 0.4-2.2 ml/min). These findings indicate that PIIIP elimination does not depend on renal function. PIIIP-related peptides in serum and urine, however, increase with renal failure irrespective of the activity or type of renal disease. This can be explained most probably by enhanced turnover of collagen type III by the affected kidney itself.

Value of Human Chorionic Gonadotropin Measurements in Blood as a Pregnancy Test in Women on Maintenance Hemodialysis

Human chorionic gonadotropin (hCG beta) values were determined in the blood of 19 women and 4 men on maintenance hemodialysis. Blood samples were taken 3 times at an interval of 1 week. Measurements were done by an hCG beta RIA kit (Serono). The median hCG beta values were 9 mIU/ml (range 0-116) in 7 menstruating women, 6 (0-25) in 11 postmenopausal women and 0 (0-7) in 4 men. There was no statistically significant difference between the 3 groups. The median hCG beta values in all 3 groups were below the upper normal limit. However, the individual measurements varied considerably with elevation in 32% of 52 measured values (10-fold elevation in 2 cases). We conclude that in the blood of non-pregnant women on chronic hemodialysis, elevated hCG beta values can be found, erroneously indicating an intact pregnancy of 3-5 weeks duration or a nonintact pregnancy (e.g. impending abortion, extrauterine gravidity).

Supplementary Dose after Hemodialysis

It is the aim of this paper to review in tabulated form the supplementary dose of drugs required after hemodialysis and to discuss the basic pharmacokinetics of these drugs in the presence of reduced renal function. This review is intended to point out practical aspects of clinical nephrology, It refers to data available from the literature. The descriptions of pharmacokinetics focus on the amount of drug in the body. The fraction of this amount removed by dialysis is replaced by the supplementary dose to maintain effective drug action. The rebound phenomenon affecting plasma drug levels after dialysis renders the calculation of the supplementary dose difficult. Linear extrapolation from plasma drug concentrations measured 6-12 h or more after dialysis may offer a solution to this problem.

Elimination kinetics of plasma exchange

SummaryInterest in the therapeutic use of plasma exchange for various diseases is growing. The two different effects of plasma exchange are elimination and activation. The kinetics are linear for elimination by plasma exchange, but not for activation. Plasma exchange is performed intermittently and can be described by intermittent kinetics. According to intermittent kinetics, plasma exchange removes 50% to 75% of a substance in plasma within 1–2 h, corresponding to an elimination half-life of 30–40 min. Hybrid kinetics, a mixture of actually intermittent but theoretically continuous elimination by plasma exchange, can however also be applied. Hybrid kinetics are more convenient and more reliable than intermittent kinetics. This is because hybrid kinetics are based solely on the concentrations before each plasma exchange; hybrid kinetics also reflect removal from the entire body and not just from the plasma compartment. According to hybrid kinetics, the amount of a substance in the body removed within 3–4 days is 50% of the difference between the initial and the final plasma concentration, depending on the intensity of plasma exchange. The intensity may well contribute at least in part to the beneficial effect of plasma exchange in various diseases.

Nonparametric meta-analysis of published data on kidney-function dependence of pharmacokinetic parameters for the aminoglycoside netilmicin

SummaryThe distribution and elimination of various drugs depend on kidney function. This dependence is published either as a linear regression equation or as the discrete extreme values for normal kidney function and anuria. A meta-analysis of the published pharmacokinetic data is required to build up a knowledge-based computer system for dosage adjustment in renal failure. A sample comparison of 4 statistical methods for meta-analysis was performed by applying them to 13 publications about the aminoglycoside netilmicin.Parametric meta-analytical methods I and II are based on regression equations alone (Z-transformation, maximum likelihood) and yield unreliable data, especially with regard to extreme values for anuria. The parametric meta-analytical method III is based on means of extreme values (standard 2-stage approach) and does not permit a decision as to whether linear interpolation of a parameter (e.g. volume of distribution) can be used for all degrees of renal insufficiency.In contrast, the nonparametric median (meta-analytical method IV) is based on the extreme values calculated from regression equations and empirical extreme values combined into 1 group of data on normal kidney function and another on anuria. For netilmicin, the meta-analytical median with the 95% confidence interval (95% CI) yields a significant increase in the dominant elimination half-life from 2h (95% CI 1.9h, 2.6h) in patients with normal kidney function to 45h (95% CI 41h, 301h) in those with anuria (p = 0.001). For a normal bodyweight of 65kg, the volume of distribution also increases significantly from 13L (95% CI 9L, 15L) to 20L (95% CI 14L, 21L) in patients with anuria (p = 0.04). Thus, drug dosage adjustment according to therapeutic peak and trough concentrations requires knowledge of the distribution and elimination parameters, since they can both be independently altered in renal failure. We conclude that the most robust meta-analysis of these alterations is achieved with the nonparametric median of extreme values.