Unexpected effect of haemodialysis on salivary hepatocyte growth factor

Nephrology Dialysis Transplantation, Dec 2005

Magdalena Wilczynska-Borawska, Jacek Borawski, Oksana Kovalchuk, Lech Chyczewski, Michal Mysliwiec, Wanda Stokowska

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Unexpected effect of haemodialysis on salivary hepatocyte growth factor

Nephrol Dial Transplant Unexpected effect of haemodialysis on salivary hepatocyte growth factor 1Department of Intensive Care Email: 0 Joost Rutten1 1 0 2Department of Clinical, Pharmacology, 3Department of Internal Medicine, Erasmus Medical Center , Rotterdam , The Netherlands 1 Bart van den Berg1 , Teun van Gelder2, Jan van Saase3 in chronic users as well as in acute overdoses [1]. The haemodynamic and neurological side effects in particular can result in significant morbidity and mortality [2]. Haemoperfusion with a charcoal filter is an established and efficient technique for removal of theophylline [3]. However, oral activated charcoal can also be very effective in lowering serum levels of theophylline, as we experienced while treating a patient with an overdose. Case. A 22-year-old female was brought to the Emergency Department 6 h after ingestion of 20 g of sustainedrelease theophylline in a suicide attempt. She had not used theophylline before. The patient complained of nausea and experienced palpitations. Further medical history was insignificant. Laboratory investigation revealed a hypokalaemia (2.4 mmol/l) and a theophylline serum level of 105 mg/l. After admission to the intensive care unit, she was sedated, intubated and mechanically ventilated in order to administer charcoal by gastric tube as severe nausea and vomiting were unresponsive to anti-emetics. The charcoal was given in three doses, in a total dose of 150 g. To accelerate enteral passage, magnesium sulfate was given by nasogastric tube until charcoal was seen in the stool 2 h later. One hour after admission, the patient experienced severe hypotension and possible epileptic activity, treated with colloids, inotropes and pentobarbital, respectively. Due to technical difficulties, there was a significant delay of 6.5 h in the start of haemoperfusion since the first measured theophylline serum level. During this time, the patient received only oral activated charcoal and the serum theophylline level dropped from 105 to 48 mg/l. Additional clearance by haemoperfusion induced a drop to 24 mg/l; at that time, haemoperfusion was stopped. The following day, sedatives were stopped and the endotracheal tube removed; she made a full recovery. - Discussion. Oral activated charcoal is a well-established therapy for treatment of theophylline intoxication [ 4 ]. The effects of ingested charcoal are multiple: in addition to decreasing gut absorption, the ingested charcoal results in transluminal drug clearance from the systemic circulation [ 4,5 ]. The only contra-indications for the use of oral activated charcoal are ileus or co-ingestion of caustics. Magnesium sulfate was given because cathartics can reduce the risk of bowel obstruction [5]. Cathartics also decrease the transit time of charcoal, thereby preventing reabsorption of theophylline. Intractable vomiting is one of the major reasons for failure of oral activated charcoal therapy. Besides respiratory failure, intractable vomiting can in itself be an indication for sedation and ventilatory support. In this case, oral activated charcoal was a very effective way to remove theophylline, resulting in a >50% reduction in the theophylline serum level. 2. Shannon M. Life threatening events after theophylline overdose, a 10-year prospective analysis. Arch Intern Med 1999; 159: 989–994 3. Gaudreault P, Guay J. Theophylline poisoning, pharmacological considerations and clinical management. Med Toxicol 1986; 1: 169–191 4. Cooling DS. Theophylline toxicity. J Emerg Med 1993; 11: 415–425 5. Shannon M. Predictors of major toxicity after theophylline overdose. Ann Intern Med 1993; 119: 1161–1167 doi:10.1093/ndt/gfi050 Sir, Periodontal disease causing premature tooth loss is common and aggressive in younger and still dentulous patients undergoing maintenance haemodialysis (HD) [ 1 ]. Recent studies showed that hepatocyte growth factor (HGF), a pluripotential, ubiquitous and mostly regenerative cytokine, is strongly involved in the pathogenesis and progression of periodontitis in the general population [ 2 ]. In brief, HGF excessively stimulates the growth of gingival epithelial cells into the periodontal pockets and thus impairs proper regeneration of deep collagenous structures of the periodontium [ 2 ]. Recently, we showed that both unfractionated heparin and low-molecular-weight heparin enoxaparin caused a marked up-regulation of plasma HGF [ 3 ]. The increase amounted to 1300% from baseline after 10 min of HD and to 400% after 180 min, mostly due to HGF release from glysosaminoglycans present on the endothelial surface and within the extracellular matrix. Therefore we hypothesized that HGF released in such striking amounts into circulating blood could penetrate into the periodontium during 4–5 h of thrice weekly HD treatment and propagate periodontal disease. We studied 26 clinically stable patients [aged 51±12 years; 7 females; dialysis for a median of 27 months (range, 2–206 months)] who underwent bicarbonate HD sessions and were anticoagulated with enoxaparin (mean dose, 0.64±0.15 mg/kg). HD session duration was 4–5 h. Each subject had at least two or more teeth which exhibited periodontitis but were not indicated for extraction in minimum one teeth-sextant, according to the WHO recommendations on the performance of periodontal studies [ 4 ]. Before the morning HD session, the patients remained fasting; then a minimum of 5 ml of unstimulated whole saliva was collected by the spit-out method into sterile vessels after 10 min oral rinsing with distilled water. Subjects were asked not to eat and drink during the last 3 h of the HD treatment. Then saliva was collected in the same way during the last hour of the HD session. The samples were kept on melting ice for no longer than 1 h; subsequently they were centrifuged at 3800 rpm for 10 min. The supernatant (middle 1/3) was collected and stored at 70 C until assay with an established immunoenzymatic HGF kit, as described previously [ 3 ]. Median pre-dialysis saliva HGF level was 1.06 (0.02–9.65) ng/ml, while for the ‘last hour’ samples we found a median value of 0.68 (0–8.72) ng/ml. The remarkable 30% decrease in salivary HGF concentration nearly reached the level of statistical significance (Wilcoxon’s P ¼ 0.055). No reciprocal relations between the above HGF values, their per-dialytic change, enoxaparin dose or HD session duration were found. In conclusion, we saw that salivary HGF concentration normalized during HD sessions. Our working hypothesis turned out to be apparently incorrect. The specific and important quest for the cause behind periodontal disease epidemics in maintenance HD patients has just begun and should be pursued. 1Department of Magdalena Wilczynska-Borawska1 Stomatology and Periodontics Jacek Borawski2 2Department of Nephrology Oksana Kovalchuk3 and Transplantology Lech Chyczewski3 with Dialysis Unit Michal Mysliwiec2 3Department of Clinical Wanda Stokowska1 Molecular Biology Medical University Bialystok Poland Email: The long-term effect of serum magnesium on cyclosporin A toxicity Sir, We read with great interest the study by Holzmacher et al. [ 1 ], suggesting that low serum magnesium (Mg) levels caused a more rapid decline in allograft function and higher rates of allograft loss in patients with chronic cyclosporin A (CsA) toxicity. We would like to underline several points in this study: (1) We were surprised by the dose of CsA reported in this paper, as it seems quite high at the time of biopsy, the mean 3.9±0.6 years and 4.3±0.7 years after transplantation, the mean dose of CsA 7.5±2.5 and 8.2±3.6 mg/kg/d for low Mg and the normal Mg groups, respectively, leading to high CsA levels for both groups. Such a high dose of CsA can induce chronic allograft nephropathy due to chronic CsA toxicity. (2) The authors also reported that although the adjusted relative risk (RR) of graft loss was 35% higher in the low Mg in comparison to the normal Mg group, the RR was noted to be 0.65. By definiton, RR is a measure of how much a particular risk factor (patients with low Mg) influences the risk of a specified outcome (kidney failure/death). In this study by Holzmacher et al., according to an RR of 0.65, the low Mg group should have had lower death/kidney failure in comparison to the normal Mg group, as seen in Figure 2, bottom panel. In addition, the confidence interval for the RR was 0.4–1.4. It is clear that the confidence interval contains the value 1.0 and this is evidence that the RR is not statistically significant. (3) The median level of CCR2 for the normal Mg group was not given and the mean level was given. Conflict of Interest statement. None declared. 1Department of Nephrology 2Biostatistic Ankara University School of Medicine Ankara Turkey Email: To haemodialysis and back: saving a kidney graft by treatment of an arteriovenous fistula Sir, With an incidence of around 16%, arteriovenous fistula (AVF) is a frequent complication of percutaneous renal biopsy (PRB) after kidney transplantation [ 1 ]. In only 0–5% of cases, however, an AVF causes clinical signs, such as systolic–diastolic murmur in the area of the graft, haematuria or hypertension [ 1–3 ]. A more serious consequence of AVF is a decline in renal function caused by shunting of part of the blood flow directly through the AVF into the venous system, bypassing the glomerular vessels. This leads to a shortage in circulation at the glomerular level in the flow area behind the AVF. The perfusion outside the flow area of the AVF will also be reduced since a substantial part of the blood flow in this region will be shunted towards the affected flow area. Due to this diminished blood flow the affected flow area will activate the renin–angiotensin system causing hypertension and sodium-retention [ 1,4,5 ]. Recently a 36-year-old male with end-stage renal failure due to type 1 diabetes received a simultaneous pancreas– kidney transplant in our clinic. Due to limited improvement of renal function (Figure 1) in total three PRBs were performed during follow-up, all taken from the upper pole. The first two biopsies showed signs compatible with cyclosporine and tacrolimus toxicity, respectively, but cessation of these drugs did not improve renal function. After the second PRB a systolic–diastolic murmur was heard above the graft and presence of an AVF was suspected. Colourcoded Doppler sonography (CCDS), however, did not support this diagnosis. Forty-five days after transplantation the patient had to return to haemodialysis and a third PRB was performed, showing signs of focal tubular necrosis. 1. Craig RG , Spittle MA , Levin NW . Importance of periodontal disease in the kidney patient . Blood Purif 2002 ; 20 : 113 - 119 2. Ohnishi T , Daikuhara Y. Hepatocyte growth factor/scatter factor in development, inflammation and carcinogenesis: its expression and role in oral tissue . Arch Oral Biol 2003 ; 48 : 797 - 804 3. Borawski J , Naumnik B , Mysliwiec M. Activation of hepatocyte growth factor/activin A/follistatin system during hemodialysis: role of heparin . Kidney Int 2003 ; 64 : 2229 - 2237 4. Oral Health Surveys. Basic Methods. 4th edn. World Health Organization. Geneva 1997

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Magdalena Wilczynska-Borawska, Jacek Borawski, Oksana Kovalchuk, Lech Chyczewski, Michal Mysliwiec, Wanda Stokowska. Unexpected effect of haemodialysis on salivary hepatocyte growth factor, Nephrology Dialysis Transplantation, 2005, 2869-2870, DOI: 10.1093/ndt/gfi129