Functional independence in patients with chronic kidney disease being treated with haemodialysis¹

PURPOSE: This study has described and analysed the functional independence of the patients served in the haemodialysis services of a countryside town in the State of São Paulo, Brazil, using the Functional Independence Measure (FIM). METHOD: The population considered was that of 214 patients being treated with haemodialysis, assessed in 2011, by means of a social, demographic and clinical report, a Mini-Mental State Examination (MMSE) and also the FIM. RESULTS: The mean age of the population under study was 58.01 years, while the mean FIM point score was 118.38 points, showing a level of complete or modified independence within this population. Even though the level of dependence found has been low, this can be highlighted, within the locomotion domain, in the activity of going up and down stairs (10.28%). Age, complications arising from haemodialysis, and comorbidities show a negative correlation with FIM. CONCLUSION: Awareness of the level of functional independence of the patients being subjected to treatment with haemodialysis is essential in order to back up intervention for the improvement of nursing assistance provided to this population.

RET haplotype, not linked to the C620R activating mutation, associated with Hirschsprung disease in a novel MEN2 family

Hirschsprung disease is a congenital form of aganglionic megacolon that results from cristopathy. Hirschsprung disease usually occurs as a sporadic disease, although it may be associated with several inherited conditions, such as multiple endocrine neoplasia type 2. The rearranged during transfection (RET) proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease. The prevalence of Hirschsprung disease in multiple endocrine neoplasia type 2 cases was recently determined to be 7.5% and the cooccurrence of Hirschsprung disease and multiple endocrine neoplasia type 2 has been reported in at least 22 families so far. It was initially thought that Hirschsprung disease could be due to disturbances in apoptosis or due to a tendency of the mutated RET receptor to be retained in the Golgi apparatus. Presently, there is strong evidence favoring the hypothesis that specific inactivating haplotypes play a key role in the fetal development of congenital megacolon/Hirschsprung disease. In the present study, we report the genetic findings in a novel family with multiple endocrine neoplasia type 2: a specific RET haplotype was documented in patients with Hirschsprung disease associated with medullary thyroid carcinoma, but it was absent in patients with only medullary thyroid carcinoma. Despite the limited number of cases, the present data favor the hypothesis that specific haplotypes not linked to RET germline mutations are the genetic causes of Hirschsprung disease.

Unilateral giant renal angiomyolipoma and pulmonary lymphangioleiomyomatosis

Angiomyolipomas (AMLs) are mesenchymal neoplasms, named so because of the complex tissue composition represented by variable proportions of mature adipose tissue, smooth muscle cells, and dysmorphic blood vessels. Although AMLs may rise in different sites of the body, they are mostly observed in the kidney and liver. In the case of renal AMLs, they are described in two types: isolated AMLs and AMLs associated with tuberous sclerosis (TS). While most cases of AMLs are found incidentally during imaging examinations and are asymptomatic, others may reach huge proportions causing symptoms. Pulmonary lymphangioleiomyomatosis (LAM) is a rare benign disease characterized by cystic changes in the pulmonary parenchyma and smooth muscle proliferation, leading to a mixed picture of interstitial and obstructive disease. AML and LAM constitute major features of tuberous sclerosis complex (TSC), a multisystem autosomal dominant tumor-suppressor gene complex diagnosis. The authors report the case of a young female patient who presented a huge abdominal tumor, which at computed tomography (CT) show a fat predominance. The tumor displaced the right kidney and remaining abdominal viscera to the left. Chest CT also disclosed pulmonary lesions compatible with lymphangioleiomyomatosis. Because of sudden abdominal pain accompanied by a fall in the hemoglobin level, the patient underwent an urgent laparotomy. The excised tumor was shown to be a giant renal AML with signs of bleeding in its interior. The authors call attention to the diagnosis of AML and the huge proportions that the tumor can reach, as well as for ruling out the TSC diagnosis, once it may impose genetic counseling implications.

Renal GLUT1 reduction depends on angiotensin-converting enzyme inhibition in diabetic hypertensive rats

Aims: Angiotensin-converting enzyme (ACE) inhibitors are used in diabetic kidney disease to reduce systemic/intra-glomerular pressure. The objective of this study was to investigate whether reducing blood pressure (BP) could modulate renal glucose transporter expression, and urinary markers of diabetic nephropathy in diabetic hypertensive rats treated with ramipril or amlodipine. Main methods: Diabetes was induced in spontaneously-hypertensive rats (~210 g) by streptozotocin (50 mg/kg). Thirty days later, animals received ramipril 15 μg/kg/day (R, n =10), or amlodipine 10 mg/kg/day (A, n= 8,) or water (C, n = 10) by gavage. After 30-day treatment, body weight, glycaemia, urinary albumin and TGF-β1 (enzyme-linked immunosorbent assay) and BP (tail-cuff pressure method) were evaluated. Kidneys were removed for evaluation of renal cortex glucose transporters (Western blotting) and renal tissue ACE activity (fluorometric assay). Key findings: After treatments, body weight (p = 0.77) and glycaemia (p = 0.22) were similar among the groups. Systolic BP was similarly reduced (p < 0.001) in A and R vs. C (172.4 ± 3.2; 186.7 ± 3.7 and 202.2 ± 4.3 mm Hg; respectively). ACE activity (C: 0.903 ± 0.086; A: 0.654 ± 0.025, and R: 0.389 ± 0.057 mU/mg), albuminuria (C: 264.8 ± 15.4; A: 140.8 ± 13.5 and R: 102.8 ± 6.7 mg/24 h), and renal cortex GLUT1 content (C: 46.81 ± 4.54; A: 40.30 ± 5.39 and R: 26.89 ± 0.79 AU) decreased only in R (p < 0.001, p < 0.05 and p < 0.001; respectively). Significance:We concluded that the blockade of the renin–angiotensin systemwith ramipril reduced earlymarkers of diabetic nephropathy, a phenomenon that cannot be specifically related to decreased BP levels.

Mercury-induced autoimmunity : Genetics and immunoregulation

The existence of immune self-tolerance allows the immune system to mount responses against infectious agents, but not against self-molecular constitutes. Although self-tolerance is a robust phenomenon, in some individuals as well as in experimental models, the self-tolerance breaks down and as a result, a self-destructive autoimmune disease emerges. The underlying mechanisms for the development of autoimmune diseases are not known, but genetic, environmental and immunological factors are suggested to be involved. In this thesis, we used murine mercury-induced autoimmunity to test this suggestion. In susceptible mice mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of IgG1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. In contrast, in resistant DBA/2 (H-2d) mice, none of these characteristics develop after exposure to mercury. By crossing and backcrossing mercury-resistant DBA/2 mice to mercury susceptible strains, we found that the resistance was inherited as a dominant trait in F1 hybrids and that one gene or a cluster of genes located in the H-2 loci determined the resistance to ANolA production, whereas resistance to the other characteristics was found to be controlled by two or three non-H-2 genes. We further put forward the “cryptic peptide hypothesis” to investigate whether mercury and another xenobiotic metal use similar pathway(s) to induce the H-2 linked production of ANolA. We found that while mercury stimulated ANolA synthesis in all H-2 susceptible (H-2s, H-2q and H-2f) mouse strains, silver induced only ANolA responses in H-2s and H-2q mice, but not in H-2f mice. Further studies showed that the resistance to silver-induced ANolA production in H-2f mice was inherited as a dominant trait. We next tested the proposition that mercury induces more adverse immunological effects in mouse strains, which are genetically prone to develop autoimmune diseases, using tight-skin 1 mice, an animal model for human Scleroderma. It was found that in this strain, mercury induced a strong immune activation with autoimmune characteristics, but did not accelerate the development of dermal fibrosis, a characteristic in Tsk/1 mice. Finally we addressed the Th1/Th2 cross-regulation paradigm by examining if a Th1-type of response could interact with a Th2-type of response if simultaneous induced in susceptible mice. Our findings demonstrated that mercury-induced autoimmunity (Th2-type) and collagen-induced arthritis (CIA) (Th1-type) can interact in a synergistic, antagonistic or additive fashion, depending on at which stage of CIA mercury is administered.

Central autonomic control in spontaneously hypertensive rats: a study on phasic phenomena during rapid-eye-movement sleep

The cardiovascular regulation undergoes wide changes in the different states of sleepwake cycle. In particular, the relationship between spontaneous fluctuations in heart period and arterial pressure clearly shows differences between the two sleep states. In non rapid-eye-movement sleep, heart rhythm is under prevalent baroreflex control, whereas in rapid-eye-movement sleep central autonomic commands prevail (Zoccoli et al., 2001). Moreover, during rapid-eye-movement sleep the cardiovascular variables show wide fluctuations around their mean value. In particular, during rapid-eyemovement sleep, the arterial pressure shows phasic hypertensive events which are superimposed upon the tonic level of arterial pressure. These phasic increases in arterial pressure are accompanied by an increase in heart rate (Sei & Morita, 1996; Silvani et al., 2005). Thus, rapid-eye-movement sleep may represent an “autonomic stress test” for the cardiovascular system, able to unmask pathological patterns of cardiovascular regulation (Verrier et al. 2005), but this hypothesis has never been tested experimentally. The aim of this study was to investigate whether rapid-eye-movement sleep may reveal derangements in central autonomic cardiovascular control in an experimental model of essential hypertension. The study was performed in Spontaneously Hypertensive Rats, which represent the most widely used model of essential hypertension, and allow full control of genetic and environmental confounding factors. In particular, we analyzed the cardiovascular, electroencephalogram, and electromyogram changes associated with phasic hypertensive events during rapid-eyemovement sleep in Spontaneously Hypertensive Rats and in their genetic Wistar Kyoto control strain. Moreover, we studied also a group of Spontaneously Hypertensive Rats made phenotypically normotensive by means of a chronic treatment with an angiotensin converting enzyme inhibitor, the Enalapril maleate, from the age of four weeks to the end of the experiment. All rats were implanted with electrodes for electroencephalographic and electromyographic recordings and with an arterial catheter for arterial pressure measurement. After six days for postoperative recovery, the rats were studied for five days, at an age of ten weeks.The study indicated that the peak of mean arterial pressure increase during the phasic hypertensive events in rapid-eye-movement sleep did not differ significantly between Spontaneously Hypertensive Rats and Wistar Kyoto rats, while on the other hand Spontaneously Hypertensive Rats showed a reduced increase in the frequency of theta rhythm and a reduced tachicardia with respect to Wistar Kyoto rats. The same pattern of changes in mean arterial pressure, heart period, and theta frequency was observed between Spontaneously Hypertensive Rats and Spontaneously Hypertensive Rats treated with Enalapril maleate. Spontaneously Hypertensive Rats do not differ from Wistar Kyoto rats only in terms of arterial hypertension, but also due to multiple unknown genetic differences. Spontaneously Hypertensive Rats were developed by selective breeding of Wistar Kyoto rats based only on the level of arterial pressure. However, in this process, multiple genes possibly unrelated to hypertension may have been selected together with the genetic determinants of hypertension (Carley et al., 2000). This study indicated that Spontaneously Hypertensive Rats differ from Wistar Kyoto rats, but not from Spontaneously Hypertensive Rats treated with Enalapril maleate, in terms of arterial pH and theta frequency. This feature may be due to genetic determinants unrelated to hypertension. In sharp contrast, the persistence of differences in the peak of heart period decrease and the peak of theta frequency increase during phasic hypertensive events between Spontaneously Hypertensive Rats and Spontaneously Hypertensive Rats treated with Enalapril maleate demonstrates that the observed reduction in central autonomic control of the cardiovascular system in Spontaneously Hypertensive Rats is not an irreversible consequence of inherited genetic determinants. Rather, the comparison between Spontaneously Hypertensive Rats and Spontaneously Hypertensive Rats treated with Enalapril maleate indicates that the observed differences in central autonomic control are the result of the hypertension per se. This work supports the view that the study of cardiovascular regulation in sleep provides fundamental insight on the pathophysiology of hypertension, and may thus contribute to the understanding of this disease, which is a major health problem in European countries (Wolf-Maier et al., 2003) with its burden of cardiac, vascular, and renal complications.

The cardio-renal axis. Non ST-segment elevation myocardial infarction risk stratification according to renal dysfunction

Background: Chronic kidney disease (CKD) is one of the strongest risk factor for myocardial infarction (MI) and mortality. The aim of this study was to assess the association between renal dysfunction severity, short-term outcomes and the use of in-hospital evidence-based therapies among patients with non–ST-segment elevation myocardial infarction (NSTEMI). Methods: We examined data on 320 patients presenting with NSTEMI to Maggiore’s Emergency Department from 1st Jan 2010 to 31st December 2011. The study patients were classified into two groups according to their baseline glomerular filtration rate (GFR): renal dysfunction (RD) (GFR<60) and non-RD (GFR≥60 ml/min). Patients were then classified into four groups according to their CKD stage (GFR≥60, GFR 59-30, GFR 29-15, GFR <15). Results: Of the 320 patients, 155 (48,4%) had a GFR<60 ml/min at baseline. Compared with patients with a GFR≥60 ml/min, this group was, more likely to be female, to have hypertension, a previous myocardial infarction, stroke or TIA, had higher levels of uric acid and C-reactive protein. They were less likely to receive immediate (first 24 hours) evidence-based therapies. The GFR of RD patients treated appropriately increases on average by 5.5 ml/min/1.73 m2. The length of stay (mean, SD) increased with increasing CKD stage, respectively 5,3 (4,1), 7.0 (6.1), 7.8 (7.0), 9.2 (5.8) (global p <.0001). Females had on average a longer hospitalization than males, regardless of RD. In hospital mortality was higher in RD group (3,25%). Conclusions: The in-hospital mortality not was statically difference among the patients with a GFR value ≥60 ml/min, and patients with a GFR value <60 ml/min. The length of stay increased with increasing CKD stages. Despite patients with RD have more comorbidities then without RD less frequently receive guideline –recommended therapy. The GFR of RD patients treated appropriately improves during hospitalization, but not a level as we expected.

Renal insufficiency is independently associated with a distal distribution pattern of symptomatic lower-limb atherosclerosis

Objectives The purpose of this study was to assess the impact of renal insufficiency (RI) on the distribution pattern of peripheral arterial disease (PAD). We hypothesised that RI is associated with a distally accentuated involvement of the peripheral arterial tree. Design This is a retrospective analysis. Materials and Methods Analysis was based on a consecutive series of 2709 patients with chronic PAD of atherosclerotic origin undergoing primary endovascular treatment of lower-extremity arteries. Atherosclerotic pattern was grouped into femoropopliteal (n = 2085) and infragenicular (n = 892) disease according to target lesions treated while using iliac disease (n = 1133) as reference. Univariable and multivariable multinomial regression analyses were performed to assess relation with RI. Results are shown as relative risk ratio (RRRs) with 95% confidence intervals (95% CIs). A p < 0.05 was considered statistically significant. RI was defined as glomerular filtration rate (GFR) < 60 ml min−1 1.73 m−2. Results Presence of RI was an independent risk factor for a centrifugal lesion pattern (RRR 1.48, 95% CI: 1.17–1.86, p = 0.001). Moreover, a decrease in GFR by 10 ml min−1 1.73 m−2 was associated with an RRR of 1.08 for below-the-knee arterial disease (95% CI: 1.03–1.13, p = 0.003). Conclusion Presence and severity of RI are independent predictors of a distal obstructive pattern in patients with symptomatic PAD.

Variable Na(v)1.5 protein expression from the wild-type allele correlates with the penetrance of cardiac conduction disease in the Scn5a(+/-) mouse model

BACKGROUND: Loss-of-function mutations in SCN5A, the gene encoding Na(v)1.5 Na+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a(+/-) mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A. METHODOLOGY/PRINCIPAL FINDINGS: Based on ECG, 10-week-old Scn5a(+/-) mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS< or = 18 ms; QRS in wild-type littermates: 10-18 ms). Phenotypic difference persisted with aging. At 10 weeks, the Na+ channel blocker ajmaline prolonged QRS interval similarly in both groups of Scn5a(+/-) mice. In contrast, in old mice (>53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a(+/-) mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A-mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a(+/-) mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a(+/-) mice had similar Na(v)1.5 mRNA but higher Na(v)1.5 protein expression, and moderately larger I(Na) current than severely affected Scn5a(+/-) mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a(+/-) mice than in mildly affected ones. CONCLUSIONS: Scn5a(+/-) mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a(+/-) mice, phenotype severity correlates with wild-type Na(v)1.5 protein expression.

Gout in pediatric renal transplant recipients

Clinical gout has rarely been described after pediatric renal transplantation (RTx), although asymptomatic hyperuricemia is common in these patients. We describe three male pediatric patients who presented with gouty arthritis 7-8.5 years following RTx. Since receiving allopurinol, all patients had been free of gouty symptoms. To prevent severe bone marrow depletion, the dosage of azathioprine, an immunosupressant drug, was reduced by 50% to prevent interaction with allopurinol. Because atypical presentation of gout can occur, a high index of suspicion is needed to allow appropriate diagnosis of this disease in patients with skeletal pain after RTx.

Long-term safety of intramuscular gene transfer of non-viral FGF1 for peripheral artery disease

Peripheral artery disease is a progressive disease. Primary ischemic leg symptoms are muscle fatigue, discomfort or pain during ambulation, known as intermittent claudication. The most severe manifestation of peripheral artery disease is critical limb ischemia (CLI). The long-term safety of gene therapy in peripheral artery disease remains unclear. This four center peripheral artery disease registry was designed to evaluate the long-term safety of the intramuscular non-viral fibroblast growth factor-1 (NV1FGF), a plasmid-based angiogenic gene for local expression of fibroblast growth factor-1 versus placebo in patients with peripheral artery disease who had been included in five different phase I and II trials. Here we report a 3-year follow-up in patients suffering from CLI or intermittent claudication. There were 93 evaluable patients, 72 of them in Fontaine stage IV (47 NV1FGF versus 25 placebo) and 21 patients in Fontaine stage IIb peripheral artery disease (15 NV1FGF versus 6 placebo). Safety parameters included rates of non-fatal myocardial infarction (MI), stroke, death, cancer, retinopathy and renal dysfunction. At 3 years, in 93 patients included this registry, there was no increase in retinopathy or renal dysfunction associated with delivery of this angiogenic factor. There was also no difference in the number of strokes, MI or deaths, respectively, for NV1FGF versus placebo. In the CLI group, new cancer occurred in two patients in the NV1FGF group. Conclusions that can be drawn from this relatively small patient group are limited because of the number of patients followed and can only be restricted to safety. Yet, data presented may be valuable concerning rates in cancer, retinopathy, MI or strokes following angiogenesis gene therapy in the absence of any long-term data in angiogenesis gene therapy. It may take several years until data from larger patient populations will become available.

Cardiovascular surgery in Marfan syndrome: implications of new molecular concepts in thoracic aortic disease

Acute dissection and rupture of aortic aneurysms comprise for 1-2% of all deaths in industrialized countries. Dilation of the aorta is caused by a multitude of mechanisms including inherited connective tissue disorders such as Marfan syndrome (MFS). MFS is one of the most common inherited connective tissue disorders affecting 1 in 5000 individuals. Although the phenotype of MFS can be quite variable, aneurysmal dilation of the aortic root and consecutive acute aortic dissection is the leading cause of death in this patient population. Over the past years it has been shown that a comprehensive understanding of this disorder provides greater understanding of vascular wall biology and identifies pathways relevant to aortic aneurysms and dissection in general. The current review discusses the surgical management of patients with MFS with a special emphasis on indications for surgery in this complex group of patients.

Pseudomyotonia, a muscle function disorder associated with an inherited ATP2A1 (SERCA1) defect in a Dutch Improved Red and White cross-breed calf

A Dutch Improved Red and White cross-breed heifer calf was evaluated for a muscular disorder resulting in exercise induced muscle stiffness. Clinical findings included generalized exercise-induced muscle spasms with normal response to muscle percussion. Electromyography showed no myotonic discharges, thus ruling out myotonia. Whereas histological examination of muscle tissue was unremarkable, Ca(2+)-ATPase activity of sarcoplasmatic reticulum membranes (SERCA1) was markedly decreased compared to control animals. Mutation analysis revealed the presence of a missense mutation in the ATP2A1 gene encoding the SERCA1 protein (p.Arg559Cys). The present case presents similarities to human Brody's disease, but also to pseudomyotonia and congenital muscular dystonia previously described in different cattle breeds.

Quantitative assessment of urea generation and elimination in healthy dogs and in dogs with chronic kidney disease

BACKGROUND: Kinetic assessment of urea, the main end product of protein metabolism, could serve to assess protein catabolism in dogs with chronic kidney disease (CKD). Protein malnutrition and catabolism are poorly documented in CKD and they often are neglected clinically because of a lack of appropriate evaluation tools. HYPOTHESIS: Generation and excretion of urea are altered in dogs with CKD. ANIMALS: Nine dogs with spontaneous CKD (IRIS stages 2-4) and 5 healthy research dogs. METHODS: Endogenous renal clearance (Clrenal) of urea and creatinine was measured first. Exogenous plasma clearance (Clplasma, total body clearance) of the 2 markers then was determined by an IV infusion of urea (250-1,000 mg/kg over 20 minutes) and an IV bolus of creatinine (40 mg/kg). Extrarenal clearance (Clextra) was defined as the difference between Clplasma)and Clrenal. Endogenous urea generation was computed assuming steady-state conditions. RESULTS: Median Clrenal and Clextra of urea were 2.17 and 0.21 mL/min/kg in healthy dogs and 0.37 and 0.28 mL/min/kg in CKD dogs. The proportion of urea cleared by extrarenal route was markedly higher in dogs with glomerular filtration rate<1 mL/kg/min than in normal dogs, reaching up to 85% of the total clearance. A comparable pattern was observed for creatinine excretion, except in 1 dog, Clextra remained<20% of Clplasma. CONCLUSION: Extrarenal pathways of urea excretion are predominant in dogs with advanced CKD and justify exploring adjunctive therapies based on enteric nitrogen excretion in dogs. A trend toward increased urea generation may indicate increased catabolism in advanced CKD.

Gain of chromosome 8q is associated with metastases and poor survival of patients with clear cell renal cell carcinoma

The aim of this study was to evaluate the prevalence of chromosome 8q gain in clear cell renal cell carcinoma (CCRCC) and to correlate the findings with tumor phenotype and disease-specific survival (DSS).