Seizures in patients with kidney diseases: a neglected problem?

Nephrologists may encounter many systemic problems in their patients, including involvement of the neurological system and the development of seizures. Seizures are defined as abnormal neurological functions that cause overstimulation of neurons in the cerebral cortex or limbic system. Seizures may be focal or generalized depending on their origin and may have tonic, clonic, tonic-clonic, or myoclonic character depending on the level of involvement of the motor movements. Patients with kidney disease may develop seizures due to etiologies seen in general population (such as intracranial bleeding, cerebrovascular events, tumours, infections, and intoxications) or due to kidney related etiologies (such as uremic encephalopathy, dialysis disequilibrium syndrome, and hyponatremia). Management of seizures in kidney patients is challenging for proper determination of the type and dosage of antiepileptic drugs due to varying renal clearances. This review covers the major causes of new-onset seizures in patients with acute kidney injury, electrolyte imbalances, chronic kidney disease, dialysis, renal transplantation, or hypertension and the management approaches.

DEPENDENCE OF RENAL FUNCTION ON THE STATE OF WATER-SALT BALANCE IN CHILDREN WITH CYSTIC FIBROSIS

The aim is to study the osmoregulatory renal function as a key mechanism for cell volume regulation in patients with cystic fibrosis (CF). Materials and methods of research: 59 children were examined (CF, n=24; pneumonia, n=19; healthy children, n=15). Osmoregulatory function was assessed after fluid restriction during the night and water load of 10 ml per kg of body weight. Results: CF patients showed a positive correlation between the renal clearances of solute free water and sodium free water in night urine specimens. After water loading, similar renal reaction was found in all groups of examined children, which confirmed the assumption about the changes in regulation of renal function in patients with CF. A provision on increasing the sensitivity of the osmoregulation system to maintain cell volume in children with CF is justified.

MO703URINE VOLUME AS A MARKER OF RESIDUAL KIDNEY FUNCTION IN PERITONEAL DIALYSIS PATIENTS: QUANTITATIVE ASSESSMENT

Background and Aims In dialysis patients, urine volume is an easy-to-obtain marker of residual kidney function but information is lacking of its potential value as an estimate of the renal contribution to total clearance of small solutes. We explored whether correlations of urine volume with different estimations of the residual renal function for urea, creatinine, and phosphorus, could be used to assess renal solute clearances and renal mass removal for investigated solutes. Method In an observational study of 94 non-anuric (urine output ≥ 100 mL per 24 hours) patients (54% men, median age 59 [45 - 68] year, BMI 25.8 [21.4 - 27.7] kg/m2) undergoing automated (n = 59) or continuous ambulatory (n = 35) peritoneal dialysis (PD), we evaluated renal, peritoneal and total (renal plus peritoneal) solute removal (g/week) and clearance (L/week) in relation to urine volume (L/day). Urine volume, renal clearances, ratio of urine solute to serum solute concentration, removed mass of each solute and the ratio of mass removed by urine (renal clearance) over total mass removed by urine and dialysate (total clearance) for urea, creatinine and phosphorus were estimated from 24 h collections of urine and dialysate and determination of solute concentrations in serum, urine and dialysate. Statistical dependence between variables was tested using Spearman’s correlation coefficient (rho). Data are expressed as median with interquartile range. Results Median 24-hour urine output was 560 [323 – 938] mL. Renal mass removal for urea, creatinine and phosphorus was 10.1 [4.5 – 17.1], 3.5 [1.8 – 5.6] and 1.0 [0.4 – 1.7] g/week, respectively. The average contribution of residual renal removal to the total mass removed was 28% [17% - 41%] for urea, 56% [30% - 72%] for creatinine and 44% [24% - 58%] for phosphorus. Serum creatinine correlated weakly and negatively with urine volume (rho = -0.26, p < 0.05), but no such relationship was observed for urea and phosphorus. Only urine concentration of creatinine correlated weakly with urine volume with rho = -0.28 and p < 0.01. Urine concentration over plasma concentration did not correlate with urine volume for any solute. Renal urea clearance (20.1 [11.4 - 35.7] L/week) correlated positively with creatinine renal clearance (43.0 [18.9 - 75.1] L/week), (rho = 0.92), and with phosphorus renal clearance (17.3 [7.6 - 32.9] L/week), (rho = 0.89, p < 0.001; Fig. 1A), while renal creatinine clearance correlated positively with phosphorus renal clearance (rho = 0.86, p<0.001). Urine volume correlated positively with urea, creatinine and phosphorus clearances at rho 0.78, 0.63 and 0.73, respectively (all p< 0.001), and with renal removal of mass of urea, creatinine, and phosphorus with rho= 0.83, 0.68 and 0.74 (Fig. 1B), respectively; all p<0.001. Conclusion In PD patients, solute renal clearances and renal mass removal for urea, creatinine and phosphorus may be predicted from urine volume. Among renal clearances for urea, creatinine, and phosphorus two of them may be assessed based on measurements of the third one.

Effects of Tenofovir on the Single-Dose Pharmacokinetics of Intravenous Morinidazole in Healthy Chinese Subjects

ABSTRACT The effects of multiple-dose administration of tenofovir disoproxil fumarate (TDF) on the pharmacokinetics of morinidazole (MOR) were compared in healthy subjects. MOR exposure was similar, with an area under the curve from 0 h to infinity (AUC0-∞) treatment ratio for MOR+TDF/MOR of 1.01 (90% confidence interval, 0.97 to 1.06). No relevant differences were observed regarding plasma exposure of metabolites. Renal clearances of MOR and its metabolites were not affected by TDF. No unexpected safety or tolerability issues were observed.

Synergistic and Pharmacotherapeutic Effects of Gemcitabine and Cisplatin Combined Administration on Biliary Tract Cancer Cell Lines

Gemcitabine (GEM) and cisplatin (CDDP) combination therapy (GC) is the standard chemotherapy for advanced biliary tract cancer (BTC); however, its pharmacotherapeutic efficacy remains unclear. To investigate the effects of GC, we selected 11 from 17 BTC cell lines, according to their GEM sensitivity, to be assessed using the MTS assay. The presence of synergistic effects of GC was determined using the Bliss additivism model (BM) and the combination index (CI) at a GEM:CDDP molar ratio of 7:1; this ratio was based on the respective human renal clearances of the two drugs. The pharmacotherapeutic effects were evaluated by comparing the IC50 values for administrations of GEM alone and GC in combination. All cell lines showed synergistic effects when analyzed using the BM. Based on the CI values, strong synergism, synergism, and additive effects were seen in four, five, and two cell lines, respectively. For all four GEM-resistant cell lines, on which GC had strong synergistic effects, the pharmacotherapeutic effects of GC were disappointing, with all IC50 values > 1 µM. For the GEM-effective cell lines, on which GC had synergistic or additive effects, the IC50 values were all <1 µM, and the differences were small between the IC50s for administration of GEM alone and GC in combination. Our results suggest that GC has synergistic effects on BTC cell lines but that its pharmacotherapeutic effects are inadequate.

Creatinine clearance after cimetidine administration in a new short procedure: comparison with plasma and renal clearances of iohexol

Background Creatinine clearance after cimetidine administration (Cim-CreatClr) was once proposed as a method of glomerular filtration rate (GFR) measurement, but has been largely abandoned. We investigated whether a new short procedure for Cim-CreatClr determination could be considered an appropriate method for GFR measurement. Methods A 150-min protocol involving oral cimetidine administration was developed to determine Cim-CreatClr. In total, 168 patients underwent simultaneous assessments of creatinine clearance before and after cimetidine administration [basal creatinine clearance (Basal-CreatClr) and Cim-CreatClr, respectively], renal iohexol clearance and plasma iohexol clearance (R-iohexClr and P-iohexClr, respectively). We compared the agreement between the various methods of GFR measurement, using Bland–Altman plots to determine biases, precisions (standard deviation of the biases) and accuracy (proportions of GFR values falling within 10, 15 and 30% of the mean: P10, P15 and P30, respectively). Results After cimetidine administration, Basal-CreatClr decreased by 19.8% [95% reference limits of agreement (95% LoA): −2.2 to 41.7%]. The bias between Cim-CreatClr and P-iohexClr was −0.6% (95% LoA −26.8 to 28%); the precision was 14.0%; P10, P15 and P30 were 57.1% [95% confidence interval (95% CI) 49.3 to 64.7%], 73.2% (95% CI 65.8 to 79.7%) and 97.0% (95% CI 93.2 to 99.0%), respectively. Due to the positive bias (16.7%; 95% LoA −3.6 to 36.9%) of Cim-CreatClr relative to R-iohexClr, accuracy of Cim-CreatClr relative to R-iohexClr was poor despite a good precision (10.3%). Conclusions Our study shows a high level of agreement between Cim-CreatClr and P-iohexClr. These results suggest that this short Cim-CreatClr procedure is a valid method for GFR measurement, which might be useful, in particular, in situations in which P-iohexClr is not suitable or not available.

In Vitro Stimulation of Multidrug Resistance-Associated Protein 2 Function Is Not Reproduced In Vivo in Rats

Previously we reported that coproporphyrin-I (CP-I) is an optimal probe substrate for multidrug resistance-associated protein 2 (MRP2), and stimulation of MRP2-mediated transport is probe substrate-dependent. In the present investigation, we assessed if the in vitro stimulation is physiologically relevant. Similar to human MRP2 transport, CP-I was transported by rat Mrp2 in a typical Michaelis-Menten kinetics with apparent Km and Vmax values of 15 ± 6 µM and 161 ± 20 pmol/min/mg protein, respectively. In vivo Mrp2 functions were monitored by biliary and renal secretion of CP-I and its isomer CP-III, in bile-duct cannulated rats before and after treatment with mitoxantrone, progesterone, and verapamil. These compounds stimulated Mrp2-mediated CP-I transport in vitro. No significant increase in biliary or renal clearances, as well as in the cumulative amount of CP-I or CP-III eliminated in bile, were detected following treatment with the in vitro stimulators, indicating an in vitro to in vivo disconnect. In presence of 10 µM bilirubin, the in vitro stimulation was suppressed. We concluded that the in vitro stimulation of CP-I transport mediated by Mrp2 is not translatable in vivo, and proposed that the presence of endogenous compounds such as bilirubin in the liver may contribute to the in vitro to in vivo disconnect.

Diurnal and Long-term Variation in Plasma Concentrations and Renal Clearances of Circulating Markers of Kidney Proximal Tubular Secretion

BACKGROUND The renal proximal tubule is essential for removing organic solutes and exogenous medications from the circulation. We evaluated diurnal, prandial, and long-term biological variation of 4 candidate endogenous markers of proximal tubular secretion. METHODS We used LC-MS to measure plasma and urine concentrations of hippurate (HA), cinnamoylglycine (CMG), indoxyl sulfate (IS), and p-cresol sulfate (PCS) in 25 healthy adults. We measured plasma concentrations of secreted solutes at 13 time points over a 24-h period, and again after 2 weeks and 14 weeks of follow-up. We further measured 24-h renal clearances of secreted solutes at baseline, 2 weeks, and 14 weeks. RESULTS Plasma concentrations of secreted solutes varied over the 24-h baseline period. Diurnal variation was greatest for HA, followed by CMG, IS, and PCS. Plasma concentrations of HA (P = 0.002) and IS (P = 0.02), but not CMG and PCS, increased significantly following meals. Long-term intraindividual biological variation (CVI) in plasma concentrations of secreted solutes over 14 weeks varied from 21.8% for IS to 67.3% for PCS, and exceeded that for plasma creatinine (CVI, 7.1%). Variation in 24-h renal clearances was similar among the secreted solutes [intraindividual variation (CVA+I), 33.6%–47.3%] and was lower using pooled plasma samples from each study visit. CONCLUSIONS Plasma concentrations of HA, CMG, IS, and PCS fluctuate within individuals throughout the day and over weeks. Renal clearances of these secreted solutes, which serve as estimates of renal proximal tubule secretion, are also subject to intraindividual biological variation that can be improved by additional plasma measurements.

Concentrations of Water-Soluble Vitamins in Blood and Urinary Excretion in Patients with Diabetes Mellitus

We examined the concentrations of water-soluble vitamins in blood and urinary excretion of 22 patients with type 2 diabetes mellitus (type 2DM) and 20 healthy control participants. Macronutrient and vitamin intakes of type 2DM subjects were measured using a weighed food record method. Control participants consumed a semipurified diet for eight days. Multiple linear regression models were used to determine whether significant differences existed in vitamin concentrations in blood independent of age, sex, and other confounding factors. Concentrations of vitamins B2, B6, C, niacin, and folate in blood were significantly lower in type 2DM subjects than in controls, independent of confounding factors. Renal clearances of vitamins B6, C, niacin, and folate were significantly higher in type 2DM subjects than in controls. In conclusion, concentrations of vitamins B2, B6, C, niacin, and folate in blood were significantly lower in type 2DM subjects than in controls, independent of confounding factors; based on the evidence of increased urinary clearance of these vitamins, the lower levels were likely due to impaired reabsorption processes.