Insufficient protection by Neisseria meningitidis vaccination alone during eculizumab therapy

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Clinical presentation and long-term follow-up of dopamine beta hydroxylase deficiency

Dopamine beta hydroxylase (DBH) deficiency is an extremely rare autosomal recessive disorder with severe orthostatic hypotension, that can be treated with L-threo-3,4-dihydroxyphenylserine (L-DOPS). We aimed to summarize clinical, biochemical, and genetic data of all world-wide reported patients with DBH-deficiency, and to present detailed new data on long-term follow-up of a relatively large Dutch cohort. We retrospectively describe 10 patients from a Dutch cohort and 15 additional patients from the literature. We identified 25 patients (15 females) from 20 families. Ten patients were diagnosed in the Netherlands. Duration of follow-up of Dutch patients ranged from 1 to 21 years (median 13 years). All patients had severe orthostatic hypotension. Severely decreased or absent (nor)epinephrine, and increased dopamine plasma concentrations were found in 24/25 patients. Impaired kidney function and anemia were present in all Dutch patients, hypomagnesaemia in 5 out of 10. Clinically, all patients responded very well to L-DOPS, with marked reduction of orthostatic complaints. However, orthostatic hypotension remained present, and kidney function, anemia, and hypomagnesaemia only partially improved. Plasma norepinephrine increased and became detectable, while epinephrine remained undetectable in most patients. We confirm the core clinical characteristics of DBH-deficiency and the pathognomonic profile of catecholamines in body fluids. Impaired renal function, anemia, and hypomagnesaemia can be part of the clinical presentation. The subjective response to L-DOPS treatment is excellent and sustained, although the neurotransmitter profile in plasma does not normalize completely. Furthermore, orthostatic hypotension as well as renal function, anemia, and hypomagnesaemia improve only partially

Human and animal fertility studies in cystinosis reveal signs of obstructive azoospermia, an altered blood-testis barrier and a subtherapeutic effect of cysteamine in testis

Cystinosis is an inherited metabolic disorder caused by autosomal recessive mutations in the CTNS gene leading to lysosomal cystine accumulation. The disease primarily affects the kidneys followed by extra-renal organ involvement later in life. Azoospermia is one of the unclarified complications which are not improved by cysteamine, which is the only available disease-modifying treatment. We aimed at unraveling the origin of azoospermia in cysteamine-treated cystinosis by confirming or excluding an obstructive factor, and investigating the effect of cysteamine on fertility in the Ctns−/− mouse model compared with wild type. Azoospermia was present in the vast majority of infantile type cystinosis patients. While spermatogenesis was intact, an enlarged caput epididymis and reduced levels of seminal markers for obstruction neutral α-glucosidase (NAG) and extracellular matrix protein 1 (ECM1) pointed towards an epididymal obstruction. Histopathological examination in human and mouse testis revealed a disturbed blood-testis barrier characterized by an altered zonula occludens-1 (ZO-1) protein expression. Animal studies ruled out a negative effect of cysteamine on fertility, but showed that cystine accumulation in the testis is irresponsive to regular cysteamine treatment. We conclude that the azoospermia in infantile cystinosis is due to an obstruction related to epididymal dysfunction, irrespective of the severity of an evolving primary hypogonadism. Regular cysteamine treatment does not affect fertility but has subtherapeutic effects on cystine accumulation in testis

Interactions of Shiga-like toxin with human peripheral blood monocytes

The cytotoxic effect of Shiga-like toxin (Stx; produced by certain Escherichia coli strains) plays a central role in typical hemolytic uremic syndrome (HUS). It damages the renal endothelium by inhibiting the cellular protein synthesis. Also, the monocyte has a specific receptor for Stx but is not sensitive for the cytotoxic effect. In this work, monocytes were studied as a potential transporter for Stx to the renal endothelium. Coincubation of isolated human monocytes loaded with Stx and target cells (vero cells and human umbilical vascular endothelial cells) were performed. Transfer was determined by measuring the protein synthesis of target cells and by flow cytometry. Furthermore, the effect of a temperature shift on loaded monocytes was investigated. Stx-loaded monocytes reduced the protein synthesis of target cells. After adding an antibody against Stx, incomplete recovery occurred. Also, adding only the supernatant of coincubation was followed by protein synthesis inhibition. Stx detached from its receptor on the monocyte after a change in temperature, and no release was detected without this temperature shift. Although the monocyte plays an important role in the pathogenesis of HUS, it has no role in the transfer of Stx

Novel conditionally immortalized human proximal tubule cell line expressing functional influx and efflux transporters

Reabsorption of filtered solutes from the glomerular filtrate and excretion of waste products and xenobiotics are the main functions of the renal proximal tubular (PT) epithelium. A human PT cell line expressing a range of functional transporters would help to augment current knowledge in renal physiology and pharmacology. We have established and characterized a conditionally immortalized PT epithelial cell line (ciPTEC) obtained by transfecting and subcloning cells exfoliated in the urine of a healthy volunteer. The PT origin of this line has been confirmed morphologically and by the expression of aminopeptidase N, zona occludens 1, aquaporin 1, dipeptidyl peptidase IV and multidrug resistance protein 4 together with alkaline phosphatase activity. ciPTEC assembles in a tight monolayer with limited diffusion of inulin-fluorescein-isothiocyanate. Concentration and time-dependent reabsorption of albumin via endocytosis has been demonstrated, together with sodium-dependent phosphate uptake. The expression and activity of apical efflux transporter p-glycoprotein and of baso-lateral influx transporter organic cation transporter 2 have been shown in ciPTEC. This established human ciPTEC expressing multiple endogenous organic ion transporters mimicking renal reabsorption and excretion represents a powerful tool for future in vitro transport studies in pharmacology and physiology

Hyporeninemic hypoaldosteronism in RMND1-related mitochondrial disease

Background: RMND1 is a nuclear gene needed for proper function of mitochondria. A pathogenic gene will cause multiple oxidative phosphorylation defects. A renal phenotype consisting of hyponatremia, hyperkalemia, and acidosis is frequently reported, previously considered to be due to aldosterone insensitivity. Methods: Clinical features and pathophysiology of three patients will be reported. DNA of these patients was subjected to exome screening. Results: In the first family, one pathogenic heterozygous and one highly probable heterozygous mutation were detected. In the second family, a homozygous pathogenic mutation was present. The electrolyte disbalance was not due to aldosterone insensitivity but to low plasma aldosterone concentration, a consequence of low plasma renin activity. This disbalance can be treated. In all three patients, the kidney function declined. In the first family, both children suffered from an unexplained arterial thrombosis with dire consequences. Conclusions: Hyporeninemic hypoaldosteronism is the mechanism causing the electrolyte disbalance reported in patients with RMND1 mutations, and can be treated.</p

Urinary excretion of polyols and sugars in children with chronic kidney disease

The urinary concentrations of monosaccharides and polyols are used for diagnosing inborn errors of metabolism and renal tubular disorders. Reference values are age-related and depend on the method of detection. However, the influence of the renal function is often still neglected. In this study we examined the urinary excretion of monosaccharides and polyols in children with various degrees of chronic kidney disease (CKD), but with no known metabolic or renal tubular disorders.status: publishe

Hyporeninemic hypoaldosteronism in RMND1-related mitochondrial disease

Background: RMND1 is a nuclear gene needed for proper function of mitochondria. A pathogenic gene will cause multiple oxidative phosphorylation defects. A renal phenotype consisting of hyponatremia, hyperkalemia, and acidosis is frequently reported, previously considered to be due to aldosterone insensitivity. Methods: Clinical features and pathophysiology of three patients will be reported. DNA of these patients was subjected to exome screening. Results: In the first family, one pathogenic heterozygous and one highly probable heterozygous mutation were detected. In the second family, a homozygous pathogenic mutation was present. The electrolyte disbalance was not due to aldosterone insensitivity but to low plasma aldosterone concentration, a consequence of low plasma renin activity. This disbalance can be treated. In all three patients, the kidney function declined. In the first family, both children suffered from an unexplained arterial thrombosis with dire consequences. Conclusions: Hyporeninemic hypoaldosteronism is the mechanism causing the electrolyte disbalance reported in patients with RMND1 mutations, and can be treated.</p