Creatinine reabsorption by the aged kidney

Aim  The handling of renal creatinine in human beings has classically been described as the result of two particular physiological processes: glomerular filtration and proximal tubular secretion. However, there are particular physiological situations in which tubular creatinine reabsorption has been documented, such as in the case of healthy newborns and premature babies. We performed a prospective study in order to evaluate if there is tubular creatinine reabsorption in healthy elderly people. Patients and method   We studied prospectively nine healthy volunteers, four of them young (20–33 years old) and the remaining five, old (65–73 years old). Since creatinine is secreted in the proximal tubules, and its secretion can be completely blocked by cimetidine administration, a creatinine clearance with cimetidine reliably represents the glomerular filtration rate. Therefore, if the ratio creatinine clearance (Ccr)/creatinine clearance with cimetidine (CcrWC) is higher than one, this would indicate net creatinine secretion, whereas a ratio lower than one would indicate a net renal creatinine tubular reabsorption; a ratio equal to one indicates creatinine filtration. Finally, the Ccr, CcrWC, and Ccr/CcrWC ratios were compared between the young and old group. Statistical tests  Mann-Whitney and Wilcoxon tests were used. Results  As expected, creatinine clearance in the elderly was significantly lower than in the young [Ccr: 74.4 ml/min (47.9–100.9) (old) vs. 153.8 ml/min (108.3–199.2) (young), p = 0.014]. Similarly, the creatinine clearance with cimetidine (CcrWC) was significantly lower in the elderly compared to the young [CcrWC: 81.8 ml/min (69.2–94.5) (old) vs. 122.5 ml/min (82.6–162.4) (young), p = 0.028]. The ratio of Ccr/CcrWC was 0.9 in the elderly vs. 1.26 in the young (p = 0.014), indicating net creatinine reabsorption in the elderly and net creatinine secretion in the young. Conclusion   Our findings indicate that there seems to be a net reabsorption of creatinine in the renal tubules of healthy old persons.     

Anticonvulsant and neuroprotective effects of the novel calcium antagonist NP04634 on kainic acid‐induced seizures in rats

Kainic acid (KA)‐induced status epilepticus (SE) is a well‐characterized model of excitotoxic neuronal injury. Excitotoxicity results from activation of specific glutamate receptors, with resultant elevation of intracellular Ca²⁺. The CA1 and CA3 subregions of the hippocampus are especially vulnerable to KA, and this pattern of neuronal injury resembles that occurring in patients with temporal lobe epilepsy. Calcium plays an essential role in excitotoxicity, and accordingly calcium channel inhibitors have been shown to have protective effects in various experimental models of epilepsy and brain injury. Moreover, they also potentiate the antiseizure efficacy of conventional antiepileptic drugs. This study was undertaken to determine whether NP04634, a novel compound, reported as a non‐L‐type voltage‐sensitive calcium channel (VSCC) inhibitor, could prevent the entrance in SE and the neuronal loss evoked by intraperitoneal injection of KA. Our results show that intragastrical administration of NP04634 reduced the percentage of rats that entered SE after KA injection, increased the latency of SE entry, and significantly reduced the mortality of rats that entered SE. Also, NP04634 prevented the loss of hippocampal CA1 and CA3 pyramidal neurons and reduced the gliosis induced by KA. These results point to a potential anticonvulsant and neuroprotective role for NP04634. © 2009 Wiley‐Liss, Inc.     

Intrajejunal levodopa infusion in Parkinson's disease: A pilot multicenter study of effects on nonmotor symptoms and quality of life

Switching from oral medications to continuous infusion of levodopa/carbidopa gel reduces motor complications in advanced Parkinson's disease (PD), but effects on nonmotor symptoms (NMSs) are unknown. In this prospective open‐label observational study, we report the effects of intrajejunal levodopa/carbidopa gel infusion on NMS in PD based on standard assessments utilizing the nonmotor symptoms scale (NMSS) along with the unified Parkinson's disease rating scale (UPDRS 3 motor and 4 complications) and quality of life (QoL) using the Parkinson's disease questionnaire (PDQ‐8). Twenty‐two advanced PD patients (mean age 58.6 years, duration of disease 15.3 years) were followed for 6 months. A statistically significant beneficial effect was shown in six of the nine domains of the NMSS: cardiovascular, sleep/fatigue, attention/memory, gastrointestinal, urinary, and miscellaneous (including pain and dribbling) and for the total score of this scale (NMSST) paralleling improvement of motor symptoms (UPDRS 3 motor and 4 complications in “best on” state) and dyskinesias/motor fluctuations. In addition, significant improvements were found using the Parkinson's disease sleep scale (PDSS) and the PDQ‐8 (QoL). The improvement in PDQ‐8 scores correlated highly significantly with the changes in NMSST, whereas a moderately strong correlation was observed with UPDRS changes. This is the first demonstration that a levodopa‐based continuous dopaminergic stimulation is beneficial for NMS and health‐related quality of life in PD in addition to the reduction of motor fluctuations and dyskinesias. © 2009 Movement Disorder Society     

Outcome of Subclinical Antibody-Mediated Rejection in Kidney Transplant Recipients with Preformed Donor-Specific Antibodies

This study describes clinical relevance of subclinical antibody-mediated rejection (SAMR) in a cohort of 54 DSA-positive kidney transplant recipients receiving a deceased donor. In 3 months screening biopsies, 31.1% of patients met the criteria of SAMR. A total of 48.9% had an incomplete form of SAMR (g+/ptc+/C4d-negative) whereas 20% had no humoral lesions. Patients with SAMR at 3 months had at 1 year: a higher C4d score, ptc score, and arteriosclerosis score, higher rate of IFTA (100% vs. 33.3%, p < 0.01) and a higher rate of transplant glomerulopathy (43% vs. 0%, p = 0.02) compared to patients without 3-month SAMR. Patients with SAMR at 3 months exhibited at 1 year a higher class II MFImax-DSA and a lower mGFR compared to patients without SAMR (39.2 ± 13.9 vs. 61.9 ± 19.2 mL/min/1.73 m² respectively, p < 0.01). The group of patients with C4d-negative SAMR at 3 months developed more ptc and IFTA lesions, and lower GFR at 1 year in comparison to biopsies without humoral lesions. SAMR is a frequent entity in KTR with preexisting DSAs and promotes subsequent GFR impairment and development of chronic AMR. C4d-negative SAMR patients displayed an intermediate course between the no-SAMR group and the C4d+ SAMR group. Screening biopsies may be useful to recognize patients more likely to develop SAMR.     

Epidermal growth factor in clinical practice – a review of its biological actions,clinical indications and safety implications

Chemotaxis, mitogenesis, motogenesis and cytoprotection are common cellular events involved in both tumourigenesis and tissue repair, which appear amplified upon growth factors exposure. Epidermal growth factor (EGF) promotes these events in epithelial and mesenchymal cells through the binding to a specific tyrosine kinase receptor. In experimental oncology settings, EGF does not initiate malignant transformation but exhibits ‘tumour promotion’. These observations have raised doubts on the clinical use of EGF despite solid demonstrations of efficacy in experimental conditions and clinical trials. The results of a Pubmed and Bioline investigation on EGF clinical uses and preclinical safety data are presented here. EGF topical administration has been used since 1989 to enhance the healing process of a variety of peripheral tissues wounds (16 clinical reports), as well as its intravenous, oral and rectal administration for gastrointestinal damages (11 clinical reports). EGF therapeutic efficacy and excellent tolerability seem demonstrated. Lack of long‐term adverse effects is highlighted in those studies with 6, 12 and 24 months of patients follow‐up. Although post‐treatment follow‐up may fall short for malignant growth, there are no reports on evidences linking EGF clinical use with cancer. A multicentre, nationwide survey in Cuba, 15 years after randomly using silver sulphadiazine with EGF or not in burn victims yielded that cancer incidence was comparable between EGF‐treated and control subjects and that such incidence rate does not differ from the age‐matched national incidence for those 15‐year period. All the animal species subjected to long‐term EGF systemic administration exhibit dose‐dependent and reversible epithelial organs hyperplasia with no changes in cells phenotypic differentiation. Histotypic pre‐malignant markers were not identified. The results emerged from co‐carcinogenesis studies and from transgenic mice over‐expressing EGF are conflicting and indicate that EGF overexposure, either innate or postnatal, may not be sufficient to transform cells. The ability of EGF to heal injured tissues in life‐threatening scenarios or to assist in preventing physical and social disability advocates for its clinical use under a rational medical risk/benefit balance.     

Intralesional administration of epidermal growth factor‐based formulation (Heberprot‐P) in chronic diabetic foot ulcer: treatment up to complete wound closure

Previous studies have shown that an epidermal growth factor‐based formulation (Heberprot‐P) can enhance granulation of high‐grade diabetic foot ulcers (DFU). The aim of this study was to explore the clinical effects of this administration up to complete wound closure. A pilot study in 20 diabetic patients with full‐thickness lower extremity ulcers of more than 4 weeks of evolution was performed. Mean ulcer size was 16·3 ± 21·3 cm². Intralesional injections of 75 μg of Heberprot‐P three times per week were given up to complete wound healing. Full granulation response was achieved in all 20 patients in 23·6 ± 3·8 days. Complete wound closure was obtained in 17 (85%) cases in 44·3 ± 8·9 days. Amputation was not necessary in any case and only one relapse was notified. The most frequent adverse events were tremors, chills, pain and ardour at site of administration and local infection. The therapeutic scheme of intralesional Heberprot‐P administration up to complete closure can be safe and suitable to improve the therapeutic goal in terms of healing of chronic DFU.     

Awakenings change results of nighttime ambulatory blood pressure monitoring

OBJECTIVE: Investigate the effect of distinguishing nighttime and sleep on nocturnal blood pressure results in ambulatory blood pressure monitoring. METHODS: We recruited 36 patients, 29 men, with suspected obstructive sleep apnea/hypopnea syndrome attending a sleep clinic for diagnostic polysomnography and who agreed to wear a Spacelabs 90207 ambulatory blood pressure monitor during polysomnography. Their mean age was 45+/-11 years; body mass index (BMI), 30.8+/-5.4 kg/m; apnea-hypopnea index, 35+/-29 AH/h; 13 had a history of hypertension. A microphone attached to the ambulatory blood pressure monitor recorded its sounds in the polygraph and allowed us to classify each ambulatory blood pressure monitoring measurement as being made in electrographically-determined wake (e-wake) or sleep state (e-sleep). RESULTS: Patients were asleep during (mean+/-SD) 61+/-24% (range 0-100%) of the 14+/-1 nighttime blood pressure measurements. Systolic and diastolic ambulatory blood pressure monitoring readings were significantly higher during e-wake (121+/-12/73+/-9 mmHg) than during total nighttime (119+/-11/70+/-8 mmHg) and e-sleep (116+/-13/68+/-9 mmHg). On the basis of nighttime measurements, 22 patients (61%) had nocturnal hypertension. On the basis of measurements made during e-sleep, nocturnal hypertension was diagnosed in 12 patients (33%; chi2=5.54; P=0.018). A multiple linear regression model showed that the percentage of measurements made in e-sleep was the only variable that significantly explained the difference between nighttime and e-sleep blood pressure figures, when controlling for sex, age, BMI, apnea-hypopnea index, and lowest SaO2. CONCLUSION: During ambulatory blood pressure monitoring, nighttime blood pressure readings are higher than during e-sleep and this changes dipping and nocturnal hypertension classification.     

Myelofibrosis with myeloid metaplasia in a patient with relapsed Hodgkin's lymphoma who underwent autologous hematopoietic stem cell transplantation

Second malignancies after autologous haematopoietic stem-cell transplantation (AHSCT) are well-known long-term complications. We present a case of a 24-year-old male with relapsed Hodgkin lymphoma (HL) with no involvement of his bone marrow who underwent AHSCT. Four years later he developed mild anaemia and a computed tomography showed an enlarged spleen. As his anaemia worsened, a bone marrow was performed. There was no evidence of HL but intense reticular and collagen fibrosis with hypocellularity was detected. Cytogenetic studies could not obtain cells in metaphase in two occasions. PCR for V617F JAK2 mutation was positive. Until now, with 7 years of follow up from his diagnosis of myelofibrosis with myeloid metaplasia (MMM) he did not require specific treatment besides from red cell transfusions when anaemia worsened during a pneumocistis carinii infection. We present this case, because MMM is a infrequent second neoplasm after AHSCT. Revising the literature we could not find any case like this reported previously.