[A case of acute renal failure secondary to late-onset McArdle's disease]. / Un caso di insufficienza renale acuta secondaria a malattia di McArdle ad esordio tardivo.

INTRODUCTION: Mc Ardles disease, also known as Type V glycogen storage disease, is a rare deficiency of the enzyme glycogen phosphorylase in muscle cells, inherited as an autosomal recessive trait. In the absence of this enzyme, muscles cannot break down glycogen during exercise, so in patients affected by McArdles disease even moderate physical activity produces cramps, pain and fatigue. Anaerobic activity leads to severe fixed contractures and rhabdomyolisis with myoglobinuria and raised serum creatine-kinase, which, in turn, can lead to acute renal failure. Disease onset is usually in early childhood, although diagnosis is often not made until the second or third decade. CASE REPORT: We present the case of a 68-year-old man who presented to the Emergency Room with fatigue, vertigo, diarrhea and oliguria. The patient underwent five daily hemodialysis sessions, diuresis reappeared and there was progressive recovery of renal function. The patient described episodes of fatigue and muscular pain occurring since childhood: the positive personal history, together with persistently raised CPK levels in the absence of any infective or toxic cause of myositis, led us to suspect the presence of this rare metabolic disease, which was subsequently confirmed by muscle biopsy. CONCLUSION: To date, there is no specific treatment for type V glycogenosis, although a diet rich in protein and saccarose, vitamin B6 supplementation and creatine administration are generally recommended. Moderate physical activity can help manage symptoms by improving exercise tolerance and blood supply to the muscles, ensuring provision of glucose and free fatty acids for the muscle fibers.

Potassium-based dilutional method to measure hemodialysis access recirculation.

BACKGROUND: Assessment of access recirculation (AR) is crucial to dialysis efficiency and there is thus a need for a method yielding a highly accurate, fast, easy and economical measurement that can be applied in any busy dialysis clinic. Non-urea based dilutional methods are more accurate than urea based methods and avoid problems with cardiopulmonary recirculation, but they require expensive specialized devices, which limit their applicability. METHODS: We developed a simple dilutional method of AR which does not require any specific device, based on the determination of serum potassium [K+] in two samples. Briefly, a basal sample is drawn at the time of needle insertion (basal [K+]); needles are connected to blood lines and blood flow rate is quickly increased to 300 ml/mm; a second sample (arterial [K+]) is drawn from the arterial line port within 5 to 10 seconds, to avoid errors due to cardiopulmonary recirculation of the normal saline entering the blood stream. At this time, if recirculation is present, part of the normal saline will enter the arterial line and dilute the serum [K+]. The AR formula is: AR (%) = 100 x [1 - arterial K+/basal K+]. We compared our method with the two-needle urea and ultrasound velocity dilution methods. RESULTS: AR values by the ultrasound method > 10% were hypothesized as gold standard for AR, against which values obtained with the potassium method were compared. The potassium based method showed: sensitivity (100%,); specificity (95%); predictive value, positive (91%); predictive value, negative (100%). In addition, the potassium based method appears to be more reliable than the two-needle urea based method. CONCLUSION: Our method, similar to other dilutional methods, is not influenced by cardiopulmonary recirculation or veno-venous disequilibrium and is fast and accurate. Moreover it is very simple, economical, and can easily be performed in any dialysis unit.

Severe preeclampsia in antithrombin III deficiency with no history of venous thromboembolism.

Complications of pregnancy, such as preeclampsia, placental abruption, fetal growth retardation, still-birth and fetal death are associated with an increased frequency of pro-thrombotic abnormalities. We describe a case of severe preeclampsia and multiple placental infarctions in a 28-year-old woman at 31 weeks' gestation. Despite a negative personal history for venous thromboembolism, coagulation screening for thrombophilia detected an isolated antithrombin III deficiency. In view of the high prevalence of pro-thrombotic complications, laboratory screening for thrombophilia would be advantageous in women with complicated pregnancies, to ensure adequate management in high-risk situations, as suggested by larger-scale clinical investigations.

The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin.

BACKGROUND: Iron deficiency (ID) is the main cause of hyporesponsiveness to erythropoietin in haemodialysis patients and its detection is of value since it is easily corrected by intravenous iron. Markers of iron supply to the erythron, including erythrocyte zinc protoporphyrin (Er-ZPP), percentage of hypochromic erythrocytes (Hypo), reticulocyte haemoglobin content (CHr) and soluble transferrin receptor (sTfR), may be more accurate predictors of ID than ferritin (Fer) and transferrin saturation (TSat), but relative diagnostic power and best threshold values are not yet established. METHODS: In 125 haemodialysis patients on maintenance erythropoietin, the diagnostic power of the above parameters was evaluated by ROC curve, multivariate regression, and stepwise discriminant analyses. Diagnosis of ID was based on haemoglobin response to intravenous iron (992 mg as sodium ferric gluconate complex over an 8-week period). RESULTS: Fifty-one patients were considered iron deficient (haemoglobin increase by 1.9+/-0.5 g/dl) and 74 as iron replete (haemoglobin increase by 0.4+/-0.3 g/dl). ROC curve analysis showed that all tests had discriminative ability with the following hierarchy: Hypo (area under curve W=0.930, efficiency 89.6% at cut-off >6%), CHr (W=0.798, efficiency 78.4% at cut-off < or =29 pg), sTfR (W=0.783, efficiency 72.4% at cut-off >1.5 mg/l), Er-ZPP (W=0.773, efficiency 73.0% at cut-off >52 micromol/mol haem), TSat (W=0.758, efficiency 70.4% at cut-off <19%) and ferritin (W=0.633, efficiency 64.0% at cut-off <50 ng/ml). Stepwise discriminant analysis identified Hypo as the only variable with independent diagnostic value, able to classify 87.2% of patients correctly. Additional tests did not substantially improve diagnostic efficiency of Hypo >6% alone. CONCLUSIONS: In haemodialysis patients on maintenance erythropoietin, Hypo >6% is the best currently available marker to identify those who will improve their response after intravenous iron. Cost-effectiveness suggests that this parameter should be a first-line tool to monitor iron requirements in clinical practice.

Identification of the gene for oral-facial-digital type I syndrome.

Oral-facial-digital type 1 syndrome (OFD1 [MIM 311200]) is transmitted as an X-linked dominant condition with lethality in males and is characterized by malformations of the face, oral cavity, and digits, and by a highly variable expressivity even within the same family. Malformation of the brain and polycystic kidneys are commonly associated with this disorder. The locus for OFD1 was mapped by linkage analysis to a 12-Mb interval, flanked by markers DXS85 and DXS7105 in the Xp22 region. To identify the gene responsible for this syndrome, we analyzed several transcripts mapping to the region and found mutations in OFD1 (formerly named "Cxorf5/71-7a"), encoding a protein containing coiled-coil alpha-helical domains. Seven patients with OFD1, including three with familial and four with sporadic cases, were analyzed. Analysis of the familial cases revealed a missense mutation, a 19-bp deletion, and a single base-pair deletion leading to a frameshift. In the sporadic cases, we found a missense (de novo), a nonsense, a splice, and a frameshift mutation. RNA in situ studies on mouse embryo tissue sections show that Ofd1 is developmentally regulated and is expressed in all tissues affected in OFD1 syndrome. The involvement of OFD1 in oral-facial-digital type I syndrome demonstrates an important role of this gene in human development.

Detection of two different nonsense mutations in exon 44 of the PKD1 gene in two unrelated Italian families with severe autosomal dominant polycystic kidney disease.

Sixty-seven Italian patients with autosomal dominant polycystic kidney disease (ADPKD) were screened for mutations in the PKD1 gene. We used PCR, heteroduplex and single-strand conformation polymorphism DNA analysis, and automated DNA sequencing for exons 35, 36, 38, 44 and 45. We detected abnormal heteroduplexes in affected individuals from two unrelated families with clinically severe ADPKD phenotype. These changes were absent in other, unaffected members, as well as in the probands of the other families studied. DNA sequencing revealed in both cases different C to T transitions in exon 44, which created premature stop codons. Both mutations altered restriction sites, and the abnormal patterns were observed in all the affected family members. RT-PCR performed on lymphocyte mRNA showed that both the mutant and the normal transcript are represented. To our knowledge these are the first nonsense mutations described in the PKD1 gene.

Increased susceptibility of LDL to in vitro oxidation in patients on maintenance hemodialysis: effects of fish oil and vitamin E administration.

Oxidized low-density lipoproteins (LDL) play an important role in the pathogenesis of atherosclerosis. An increased sensitivity of red blood cell membranes to lipid peroxidation has been previously demonstrated in patients with chronic renal failure, suggesting that the antioxidant defence of lipoproteins might be impaired. Fish oil supplementation has been proposed in dialysis patients, but it is still unclear if the positive effects of fish oil depend only on its polyunsaturated fatty acid content or on other factors, such as the usually added antioxidants. Moreover, the increased concentration of highly peroxidable n-3 polyunsaturated fatty acids induced by fish oil in LDL particles could favour LDL oxidation and possibly the development of atherosclerosis. The present study was designed to evaluate the susceptibility of LDL to in vitro oxidation (lag phase) and the rate of lipid peroxidation (propagation phase) by fluorescence development during copper exposure in 14 hemodialysis patients. A further aim was to compare the effects on lipid metabolism and LDL oxidation of fish oil supplementation (20 ml containing vitamin E 20 IU as antioxidant) for 30 days and of vitamin E administration (50 IU) for another 30 days. The length of the lag phase and vitamin E concentration were significantly reduced (p < 0.01) in hemodialysis patients and increased significantly (p < 0.01) after administration of both fish oil and vitamin E. Fish oil supplementation also reduced plasma lipids significantly (p < 0.01) and increased the propagation phase (p < 0.01). Our results demonstrate that the susceptibility of LDL to oxidation is enhanced in hemodialysis patients, suggesting a possible relationship between excessive LDL peroxidation and accelerated atherosclerosis. The increased susceptibility of LDL to in vitro oxidation can be explained, at least partially, by a reduced LDL vitamin E concentration. Since fish oil increased the lag phase to the same extent as vitamin E supplementation, the positive effect of fish oil could be partly explained by its antioxidant content.

A novel nonsense mutation in the PKD1 gene (C3817T) is associated with autosomal dominant polycystic kidney disease (ADPKD) in a large three-generation Italian family.

We have looked for disease-causing mutations in the PKD1 gene in 20 unrelated ADPKD probands from northern Italy, all members of families in which our previous studies had indicated linkage to PKD1. Using PCR with primer pairs located in the 3' unique region of the gene and heteroduplex DNA analysis, we have detected novel aberrant bands in five affected individuals from the same family, which were absent in 13 other unaffected family members. Cloning and automated DNA sequencing revealed a C to T transition at nucleotide position 3817 of the published cDNA sequence, which created a premature stop codon. The mutation destroyed a MspA1I restriction site, and the abnormal restriction pattern was observed on genomic DNA from all the affected family members. RT-PCR and restriction analysis performed on peripheral white blood cell mRNA showed that in the affected members, both the mutant and the normal transcript are represented. This mutation was not found in the probands of the other families studied. To our knowledge, this is the first nonsense mutation described in the PKD1 gene.

Gene linkage analysis and DNA based detection of autosomal dominant polycystic kidney disease (ADPKD) in a newborn infant. Case report.

Bilateral polycystic kidneys were detected by ultrasound at 23 weeks gestation in a male fetus. Bilateral renal cysts were subsequently also found in the asymptomatic propositus' mother and grandmother, suggesting the diagnosis of autosomal dominant polycystic kidney disease (ADPKD). The renal ultrasonograms showed cortical cysts with normal or decreased-sized kidneys. Renal function was normal. Seven available members of the family were genotyped for flanking DNA markers tightly linked to the PKD1 gene on chromosome 16p, and for a polymorphism close to a second putative disease gene (PKD2) on chromosome 2. The genetic linkage approach allowed us to detect with a high degree of accuracy the ADPKD1 at risk chromosome in the three patients, as well as in a 28-year-old unaffected female. This report illustrates the feasibility and the usefulness of recent molecular genetic strategies for diagnostic purposes in ADPKD, especially when clinical and radiological data are atypical. Furthermore, it also confirms that early or very early onset forms of the disease are not uncommon, and should be considered in the differential diagnosis of childhood cystic disease.

Low platelet glutathione peroxidase activity and serum selenium concentration in patients with chronic renal failure: relations to dialysis treatments, diet and cardiovascular complications.

1. Selenium status was investigated in patients with chronic renal failure, with special regard to its relations to the dialysis treatments, dietary habits and clinical signs of atherosclerosis. 2. Serum selenium concentration and platelet glutathione peroxidase activity were measured in 45 patients with chronic renal failure subdivided into three groups according to the type of treatment: 15 non-dialysed, 15 on haemodialysis, 15 on continuous ambulatory peritoneal dialysis. A 7-day diet history was carried out in all patients. Seventeen of the patients with chronic renal failure had clinically overt cardiovascular disease. Forty-five age-matched healthy subjects were considered as controls. 3. Both serum selenium concentration and platelet glutathione peroxidase were significantly reduced in all patients with chronic renal failure compared with control subjects; a direct and significant correlation was found between the two parameters. No differences in selenium status were observed among the non-dialysed, haemodialysis and continuous ambulatory peritoneal dialysis groups. No correlation between total calorie or protein intakes and selenium indices were observed. The chronic renal failure patients with cardiovascular complications showed a further significant reduction in both serum selenium concentration and platelet glutathione peroxidase activity as compared with the patients without cardiovascular complications; these two groups were similar with respect to the other well-known cardiovascular risk factors (age, smoking, plasma lipids, hypertension, body mass index). 4. It is concluded that a low selenium concentration is present in chronic renal failure, which is independent of dialysis and is accompanied by biological repercussion in terms of reduced platelet glutathione peroxidase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Molecular genetic diagnosis of autosomal dominant polycystic kidney disease in a newborn with bilateral cystic kidneys detected prenatally and multiple skeletal malformations.

We report a case of an unusual prenatal presentation of polycystic kidneys associated with multiple skeletal limb defects, including polydactyly, syndactyly, bilateral agenesis of the tibia, and club foot. The ultrasonographic picture was consistent with a diagnosis of polycystic kidney disease, either the adult onset autosomal dominant type (ADPKD) or the early onset autosomal recessive form (ARPKD). However, there was a positive family history for ADPKD. Linkage analysis was performed in 10 family members, of whom four were affected, using six flanking DNA markers tightly linked to the PKD1 locus on chromosome 16p, and one marker linked to the putative PKD2 locus on chromosome 2p. Lod score determinations indicated that the affected gene in the family is most likely PKD1. The patient inherited the disease linked haplotype from his affected mother.

Linkage analysis for the diagnosis of autosomal dominant polycystic kidney disease, and for the determination of genetic heterogeneity in Italian families.

Sixty-eight individuals from six Italian families in which autosomal dominant polycystic kidney disease (ADPKD) is segregating, were typed in DNA polymorphisms linked to the PKD1 locus on chromosome 16. A total of ten probes were used: 3' HVR, HMJ1, EKMDA, GGG1, 26-6, VK5B, 218EP6, 24.1, CRI090, and 41.1. Zmax was 4.502 at theta = 0.082 between ADPKD and 3'HVR, and 4.382, 1.947, and 1.576 between ADPKD and GGG1, 26.6, and 218EP6, respectively, at theta = 0.0. No clear evidence of genetic heterogeneity was found. Multipoint analyses were consistent with linkage to PKD1. Twenty-nine diagnoses and 16 exclusions made by ultrasonography were confirmed by genotype determinations; in two clinically uncertain cases, DNA analysis predicted one individual as being affected and the other unaffected.

Systemic hemodynamic pattern in primary hyperparathyroidism and its changes after parathyroidectomy.

Twelve patients (7 men and 5 women) with an average age of 53 years (range 37-69) were hospitalized for renal stones and found to have primary hyperparathyroidism. Five were hypertensive and 7 normotensive. The systemic hemodynamics, plasma renin activity and glomerular filtration rate were evaluated before and at least 6 months after removal of a parathyroid adenoma. After surgery the mean intra-arterial blood pressure fell in almost all patients, due to some reduction in the peripheral vascular resistance index with no change in the cardiac index. However, the hemodynamic variations were not uniform in all patients. No change was seen in plasma renin activity and glomerular filtration rate. A positive correlation between the percent change in mean arterial pressure and percent decrease in total serum calcium was found. The results obtained indicate that it is likely that hypercalcemia plays some role both in patients with high and those with normal blood pressure. The systemic hemodynamic changes after parathyroidectomy indicate that the fall in peripheral vascular resistance could have a certain influence.

Systemic and renal hemodynamic changes after two-month treatment with enalapril in patients with essential hypertension.

Twelve essential hypertensive patients with normal renal function were treated once daily with a new angiotensin converting enzyme inhibitor, enalapril maleate, for about two months. In all patients, the drug-induced changes in blood pressure (BP), systemic and renal hemodynamics, plasma renin activity (PRA), and urine aldosterone (UA) were evaluated. Mean arterial pressure was significantly lowered. No significant changes in cardiac index, heart rate, and stroke index were observed, while peripheral vascular resistance index was significantly decreased. Plasma and blood volumes were not significantly altered. The effects on renal hemodynamics consisted of a significant increase in renal plasma flow (RPF), a decrease in renal vascular resistance, and no change in glomerular filtration rate (GFR). UA excretion was significantly reduced during enalapril therapy. The drug was well tolerated, and no side effects were observed. In summary, enalapril is able to reduce blood pressure through a vasodilatatory effect without change in cardiac output. It increases renal blood flow with no change in glomerular filtration rate.