Gert A. Verpooten

Conversion from Cyclosporine to Sirolimus in Stable Renal Transplant Recipients

Background. Conversion from cyclosporine (CsA) to sirolimus (SRL) has mainly been done in clinical conditions warranting calcineurin inhibitor discontinuation. Little is known about the clinical outcome of conversion in renal transplant recipients without transplant dysfunction. Methods. This prospective, open-label, multicentric pilot study evaluates the safety and efficacy of converting patients with stable renal function from CsA to SRL. Results. Forty stable patients on CsA, mycophenolate mofetil (MMF) (1.5 g/day), and steroids (ST) were converted at 7.6±1.4 months after renal transplantation. At 1 year, graft and patient survival was 100% and the incidence of acute rejection 5%. Calculated glomerular filtration rate (GFR) increased from 54±18 to 66±16 ml/min (P<0.0001). Blood pressure remained unchanged. A gradual increase in the incidence and severity of proteinuria was observed from month 6 onwards with de novo proteinuria in 30% of the patients at 1 year. Protein excretion was below 1 g/day in 12.5%, between 1 and 3 g/day in 17.5% and above 3 g/day in 7.5% of the proteinuric cohort (P=0.0043, compared to baseline). No predictors could be identified for the development of proteinuria. All patients had a reduction in protein excretion following renin-angiotensin blockade and were continued on SRL. Conclusion. Conversion of stable renal transplant recipients from a CsA-MMF-ST to a SRL-MMF-ST regimen is safe and results in improved renal function but is associated with the development of proteinuria in 30% of the patients requiring renin-angiotensin blockade.

Propylene glycol-induced side effects during intravenous nitroglycerin therapy

Propylene glycol, an alcohol frequently used as a solvent in medical preparations, is considered non-toxic. We found that this solvent, used in a commercially available IV nitroglycerin solution, may cause hyperosmolality, hemolysis and lactic acidosis. The influence of kidney function as the main determinant in causing accumulation of this solvent and consequently hyperosmolality is emphasized. A review of the literature dealing with propylene glycol is given. The possible mechanisms of neurological disturbances occurring during IV nitroglycerin therapy are discussed.

Choice of drug and dosage regimen: Two important risk factors for aminoglycoside nephrotoxicity

Since the clinical use of aminoglycosides may be limited by the development of nephrotoxicity, it is important to be aware of those risk factors associated with a greater incidence of renal damage. Some of these factors are related to the drug and its administration and others are related to the patients clinical condition. In the human kidney, the toxicity mechanism is very likely the same for all aminoglycosides, although the risk of nephrotoxicity increases for a given aminoglycoside as cortical concentrations increase. Kinetic studies in the rat demonstrated a nonlinear increase in renal cortical uptake of gentamicin and netilmicin, a linear relationship for tobramycin uptake, and a mixed kinetic pattern for amikacin, that is, saturation kinetics at low serum concentrations and a linear pattern at high serum levels. At comparable steady-state low serum levels, amikacin and tobramycin showed lower cortical concentrations than gentamicin or netilmicin, demonstrating a lower affinity for the uptake of amikacin and tobramycin in the rat. Since drug uptake kinetics determine the extent of cortical concentrations achieved, dosing strategies may affect cortical accumulation of aminoglycosides. Our kinetic data show that continuous infusions of low doses of gentamicin and amikacin resulted in higher cortical levels, but the differences between regimens were more remarkable for gentamicin than for amikacin. For tobramycin, however, cortical concentrations were similar regardless of the dosing strategy used. In addition, our data show that dosage regimens also determine cortical accumulation in humans. A second major determinant of nephrotoxicity is intrinsic toxicity. At therapeutic doses, gentamicin, tobramycin, netilmicin, and amikacin induce an early lysosomal phospholipidosis in the human kidney cortex comparable to that observed in animals treated with low doses of these drugs. However, animal and human studies have shown that amikacin induces significantly less lysosomal overloading than the other aminoglycosides with no loss of phospholipase A1 activity. Based on the examination of cortical drug levels and the detection of early biochemical and morphologic alterations induced by aminoglycosides, the data suggest that amikacin has less pronounced nephrotoxic effects than gentamicin, netilmicin, or tobramycin, when used in strictly comparable clinical conditions.

Immunogenicity of a recombinant DNA hepatitis B vaccine in renal transplant patients

In renal transplant patients hepatitis B infection is associated with a higher morbidity and mortality. Therefore, we investigated the immunogenicity of an enhanced vaccination scheme with a recombinant DNA hepatitis B vaccine in renal allograft recipients. Injections of 40 micrograms were given at months 0, 1, 2 and 6. Conversion rate (anti-HBS antibody titre > 10 mIU ml-1) was only 36%. On the other hand, in patients vaccinated before transplantation, a booster injection of 40 micrograms was highly successful, resulting in a rise of antibody titre > 10 mIU ml-1 in 86%. In view of the poor vaccination results after transplantation, we strongly recommend hepatitis B vaccination prior to transplantation.

Unusual D‐Lactic Acid Acidosis from Propylene Glycol Metabolism in Overdose

Objective: To report a case of D‐lactic acid acidosis owing to massive oral ingestion of propylene glycol. Case Report: A 72‐year old man with known congestive failure was admitted to the ICU with encephalopathy. Twelve hours prior to admission he had erroneously ingested a large amount of propylene glycol (PG). The laboratory revealed high anion gap (anion gap = 27 meq/l) acidosis (arterial pH = 7.16) and an increased osmolal gap. Toxicological analysis revealed a low serum propylene glycol level. Biochemical analysis indicated that very high amounts of D‐lactic acid (up to 110 mmol/l), but not of the usual type of L‐lactic acid, were responsible for the metabolic acidosis. Hemodialysis was initiated and associated with a decline of both the acidosis and D‐lactic acid levels. The patient regained conciousness. Conclusion: Ingestion of massive doses of propylene glycol, previously not reported as a cause of D‐lactic acidosis, should be added to the differential diagnosis of this rare condition.

Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment

Renal magnesium (Mg(2+)) and sodium (Na(+)) loss are well-known side effects of cyclosporine (CsA) treatment in humans, but the underlying mechanisms still remain unclear. Recently, it was shown that epidermal growth factor (EGF) stimulates Mg(2+) reabsorption in the distal convoluted tubule (DCT) via TRPM6 (Thébault S, Alexander RT, Tiel Groenestege WM, Hoenderop JG, Bindels RJ. J Am Soc Nephrol 20: 78-85, 2009). In the DCT, the final adjustment of renal sodium excretion is regulated by the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC), which is activated by the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to gain more insight into the molecular mechanisms of CsA-induced hypomagnesemia and hyponatremia. Therefore, the renal expression of TRPM6, TRPM7, EGF, EGF receptor, claudin-16, claudin-19, and the NCC, and the effect of the RAAS on NCC expression, were analyzed in vivo in a rat model of CsA nephrotoxicity. Also, the effect of EGF administration on these parameters was studied. CsA significantly decreased the renal expression of TRPM6, TRPM7, NCC, and EGF, but not that of claudin-16 and claudin-19. Serum aldosterone was significantly lower in CsA-treated rats. In control rats treated with EGF, an increased renal expression of TRPM6 together with a decreased fractional excretion of Mg(2+) (FE Mg(2+)) was demonstrated. EGF did not show this beneficial effect on TRPM6 and FE Mg(2+) in CsA-treated rats. These data suggest that CsA treatment affects Mg(2+) homeostasis via the downregulation of TRPM6 in the DCT. Furthermore, CsA downregulates the NCC in the DCT, associated with an inactivation of the RAAS, resulting in renal sodium loss.

HEMOPERFUSION-HEMODIALYSIS INEFFECTIVE FOR PARAQUAT REMOVAL IN LIFE-THREATENING POISONING

We report on a patient treated with hemoperfusion-hemodialysis (HP-HD) for severe paraquat poisoning. This procedure was adopted since the combination of adsorption and dialysis may improve overall drug removal. On admission blood paraquat was 15.8 micrograms/ml. He received conventional treatment and combined HP-HD which started within 3 hours after ingestion of the chemical and lasted 5 hours. Blood samples were obtained during and after HP-HD. The samples during HP-HD were taken before the charcoal column, between the charcoal column and the artificial kidney and after the artificial kidney. Blood clearances of paraquat were 116 +/- 32 ml/min (n=6) for the charcoal column (HP), 90 +/- 54 ml/min (n=6) for the artificial kidney (HD) and 151 +/- 37 ml/min (n=6) for the combined systems (HP-HD). After HP-HD a limited rebound of blood paraquat level was seen. One day after admission renal and hepatic failure had developed, and the patient died after 5 days. Tissue paraquat levels (microgram/g wet tissue) were: skeletal muscle 9.4, pancreas 6.0, prostate 5.6, thyroid 4.2, lungs 4.0, bone marrow 4.0, kidney 3.1, spleen 2.9, adrenal 2.9, heart 2.8, liver 2.3, stomach and testis below 1.0. Measurements of blood levels demonstrated the efficient clearances of paraquat with HP-HD from the central (plasma) compartment. However, the present results confirmed those previously reported which suggest that the efficiency of short HP-HD in treating severe paraquat poisoning is questionable since paraquat levels in the peripheral (tissue) compartment remain elevated.

Impact of a standardized nurse observation protocol including MEWS after Intensive Care Unit discharge

BACKGROUND Analysis of in-hospital mortality after serious adverse events (SAEs) in our hospital showed the need for more frequent observation in medical and surgical wards. We hypothesized that the incidence of SAEs could be decreased by introducing a standard nurse observation protocol. AIM To investigate the effect of a standard nurse observation protocol implementing the Modified Early Warning Score (MEWS) and a color graphic observation chart. METHODS Pre- and post-intervention study by analysis of patients records for a 5-day period after Intensive Care Unit (ICU) discharge to 14 medical and surgical wards before (n=530) and after (n=509) the intervention. RESULTS For the total study population the mean Patient Observation Frequency Per Nursing Shift (POFPNS) during the 5-day period after ICU discharge increased from .9993 (95% C.I. .9637-1.0350) in the pre-intervention period to 1.0732 (95% C.I. 1.0362-1.1101) (p=.005) in the post-intervention period. There was an increased risk of a SAE in patients with MEWS 4 or higher in the present nursing shift (HR 8.25; 95% C.I. 2.88-23.62) and the previous nursing shift (HR 12.83;95% C.I. 4.45-36.99). There was an absolute risk reduction for SAEs within 120h after ICU discharge of 2.2% (95% C.I. -0.4-4.67%) from 5.7% to 3.5%. CONCLUSION The intervention had a positive impact on the observation frequency. MEWS had a predictive value for SAEs in patients after ICU discharge. The drop in SAEs was substantial but did not reach statistical significance.

The TRPM6/EGF Pathway Is Downregulated in a Rat Model of Cisplatin Nephrotoxicity

Cisplatin-induced hypomagnesemia is described in humans and rats, but the underlying mechanisms are still unclear. Recent studies have shown that epidermal growth factor (EGF) stimulates Mg2+ re-absorption in the distal convoluted tubule via the Mg2+ channel TRPM6. This study investigates the role of TRPM Mg2+ channels, claudines, and EGF in the Mg2+ homeostasis in a rat model of cisplatin-induced nephrotoxicity. Wistar rats were given 2.5 mg/kg cisplatin per week for 3 weeks and were euthanized 4 or 9 weeks after the first administration. The cisplatin treatment significantly increased the fractional excretion of Mg2+. Real-time RT-PCR and/or Western blots were performed to assess the renal expression TRPM6, TRPM7, claudin-16, claudin-19, EGF, EGF receptor (EGFR) and EGFR-pathway components. The renal mRNA expression of TRPM6 and EGF showed a significant decrease after cisplatin treatment, while the TRPM7, claudin-16 and EGFR expressions remained stable. The claudin-19 mRNA expression was significantly upregulated after cisplatin treatment. Western blotting confirmed the mRNA expression data for the claudins, but an showed upregulation of EGFR only at week 9. The role of the EGFR pathway, involving Pi3-AKT-Rac1, in cisplatin-induced nephropathy, could not be substantiated in further detail. This study shows that cisplatin treatment results in EGF and TRPM6 downregulation in the rat kidney, causing renal Mg2+ loss. Our results are in line with the hypothesis that EGF influences the renal expression or activation of TRPM6 and plays a significant role in Mg2+ loss in medication-induced nephropathy.

Immunogenicity and safety of an investigational AS02v-adjuvanted hepatitis B vaccine in patients with renal insufficiency who failed to respond or to maintain antibody levels after prior vaccination: results of two open, randomized, comparative trials

An investigational AS02(v)-adjuvanted hepatitis B (HB-AS02) was compared with a licensed conventional recombinant hepatitis B vaccine (HBVAXPRO™; Sanofi Pasteur MSD, Lyon, France) in pre-dialysis, peritoneal dialysis and hemodialysis patients aged ≥18 years who had failed either to respond to prior vaccination with a conventional hepatitis B vaccine (Study A; n=251) or to maintain protective antibody concentrations after prior hepatitis B vaccination (Study B; n=181). These were open, randomized, comparative trials. Mean (range) age was 65.9 (31-92) and 64.6 (29-92) years in the two studies, respectively. In Study A, two doses of HB-AS02 given one month apart were found to be superior to two doses of the licensed vaccine in terms of seroprotection rate (76.9% versus 37.6%) and anti-HBs geometric mean antibody concentration (GMC; 139.3 versus 6.9mIU/ml), with antibody concentrations ≥100mIU/ml in 61.1% and 15.4% of subjects in the two groups, respectively. In Study B, one month after administration of a single booster dose, seroprotection rates were 89.0% in the HB-AS02 group and 90.8% in the licensed vaccine group, 81.3% and 60.9% of subjects had antibody concentrations ≥100mIU/ml, and anti-HBs GMCs were 1726.8 and 189.5mIU/ml. HB-AS02 was found to be more reactogenic than the licensed vaccine. In summary, the investigational HB-AS02 vaccine induced higher seroprotection rates and anti-HBs GMCs than a licensed conventional hepatitis B vaccine in uremic patients who had failed to respond or to maintain protective antibody titers after prior hepatitis B vaccination.