W. Van Biesen

Posttransplantation Hypomagnesemia and Its Relation with Immunosuppression as Predictors of New-Onset Diabetes after Transplantation

New‐onset diabetes after transplantation (NODAT) is a frequent complication and has an impact on patient and graft survival. Hypomagnesemia is common in both renal transplant recipients and in diabetics. This study examines the relationship between hypomagnesemia, NODAT and the type of immunosuppression in renal transplant recipients.

Questioning the Pathogenic Role of the GLA p.Ala143Thr “Mutation” in Fabry Disease: Implications for Screening Studies and ERT

Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by quantitative or qualitative defects in the lysosomal enzyme alfa-Galactosidase A (aGAL A), ultimately resulting in vital organ dysfunction. Mainly the kidneys, the heart, and the central nervous system are involved. While the classical phenotype of Fabry disease is readily recognizable, screening studies have identified clinical variants. Here, we report the phenotype associated with the GLA p.Ala143Thr (c.427G>A) mutation in 12 patients aged 42-83 years. None of the patients had classical Fabry signs or symptoms as angiokeratoma, hypohidrosis, acroparesthesia, or cornea verticillata. Possible Fabry manifestations were renal failure (5/12), stroke (7/12), and left ventricular hypertrophy (5/12), but these were not necessarily attributable to the p.Ala143Thr mutation, as a cardiac biopsy in one female and left ventricular hypertrophy and kidney biopsies in two males with renal failure and microalbuminuria lacked Gb-3 deposits. The literature data on this mutation as well as data collected in the Fabry Outcome Survey (FOS) database confirm these findings. The association of renal failure, stroke, and left ventricular hypertrophy with this mutation could be the result of selection bias, as most patients were detected in screening studies.We conclude that care should be taken with attribution of vital organ dysfunction to GLA sequence alterations. In case of the p.Ala143Thr mutation, and possibly also other mutations associated with an attenuated phenotype, diagnostic tools such as biopsy and imaging should critically evaluate the relation of end-organ failure with Fabry disease, as this has important consequences for enzyme replacement therapy.

Advantages of New Hemodialysis Membranes and Equipment

Chronic kidney disease is characterized by the progressive retention of a number of compounds, several of which have the potential to cause cardiovascular damage. Many of these are difficult to remove by standard dialysis strategies. Removal of the larger middle molecules (mostly larger peptidic compounds) can be obtained by increasing dialyzer pore size and/or by applying convective strategies. For protein-bound solutes, convection (essentially hemodiafiltration) positively affects removal. The HEMO study demonstrated outcome superiority for the large-pore high-flux hemodialysis membranes in a number of subgroup analyses. Likewise, the Membrane Permeability Outcome study showed outcome superiority for high flux in patients with serum albumin <4 g/dl, the group for which the study had originally been designed. Apart from a small controlled trial, data suggesting superiority for convective strategies are all observational.

The Role of the International Society of Nephrology/Renal Disaster Relief Task Force in the Rescue of Renal Disaster Victims

Disasters are a major cause of distress and material as well as corporal damage. Next to direct trauma, the crush syndrome inducing multiorgan problems as a consequence of muscle compression and the release of muscular contents into the bloodstream is the most important cause of death; this is to a large extent related to the induction of severe acute kidney injury, for which dialysis is a life-saving therapy. The practical means (both hardware and personnel) to do so are, however, often lacking in disaster conditions. The Renal Disaster Relief Task Force (RDRTF) offered support for renal problems in the aftermath of several disasters, e.g. the Marmara earthquake (1999) in Turkey, the Bam earthquake (2003) in Iran, and the Kashmir earthquake (2005) in Pakistan. A preconceived intervention plan is followed with adaptations according to local conditions. Material and personnel are dispatched to the disaster areas. These interventions have been life-saving for a substantial number of victims. The current article describes the structure and approach of the RDRTF.

The Impact of the Pre-Transplant Renal Replacement Modality on Outcome After Cadaveric Kidney Transplantation: The Ghent Experience

For suitable patients, renal transplantation is still the most preferable renal replacement modality, offering the best outcome in terms of survival and quality of life [Meier-Kriesche, H.U. et al: Semin Dial 2005;18:499-504]. The shorter the period on dialysis, the better the outcome after transplantation seems to be [Meier-Kriesche, H.U. et al: Transplantation 2002;74: 1377-1381]. However, for most patients, a pre-emptive transplantation is not an option by lack of a suitable organ. Therefore, most people have to undergo hemodialysis or peritoneal dialysis (PD) while awaiting a donor kidney. There is evidence that PD positively impacts on the outcome after transplantation [Van Loo, A.A. et al: J Am Soc Nephrol 1998;9:473-481], an effect that could be attributed to a more stable fluid homeostasis, but also to an independent effect of biocompatibility of the dialysis membrane [Van Biesen, W. et al: Transplantation 2000;69:508-514], which is by definition better in PD. Based on these findings, since 1999, all hemodialysis patients at the university of Ghent are dialyzed on a low complement activating dialyzer, and dialysis and especially ultrafiltration in the 24 h preceding the transplantation are avoided as much as possible. A recent re-analysis of the data of the outcome of our transplant program showed that this approach resulted in a reduction of delayed graft function in the hemodialysis patients, allowing to reach an outcome level comparable to that of the PD patients. However, the long-term patient survival still is slightly superior in the PD patients.

The paradox of bardoxolone methyl: a call for every witness on the stand?

People with type 2 diabetes and chronic kidney disease (CKD) remain an extremely vulnerable population with increased cardiovascular morbidity, mortality and mounting societal costs. As such, any effort to improve their dismal outcome is heavily supported. Yet, most drugs fail to replicate the promising signals of early experiments in humans in large and methodologically sound trials. As a recent example, an independent data and safety committee advised the termination of a phase 3 trial due to excessive cardiovascular disease and especially heart failure in patients allocated to the antioxidant synthetic triterpenoid bardoxolone methyl versus placebo. We evaluate the reasons why this outcome in hindsight was possibly not totally unexpected and develop a mechanistic model that shows that the consistent drop in serum magnesium concentration in patients exposed to bardoxolone methyl might have contributed to the development of heart failure. As such, this trial, despite its negative outcome, might provide additional pieces of the puzzle enabling us to get a better grip on diseases that share increased inflammation and oxidative stress, such as type 2 diabetes, metabolic syndrome, heart failure and CKD.

Development and validation of an ultra-high performance liquid chromatography-tandem mass spectrometry method to measure creatinine in human urine.

Despite decades of creatinine measurement in biological fluids using a large variety of analytical methods, an accurate determination of this compound remains challenging. Especially with the novel trend to assess biomarkers on large sample sets preserved in biobanks, a simple and fast method that could cope with both a high sample throughput and a low volume of sample is still of interest. In answer to these challenges, a fast and accurate ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to measure creatinine in small volumes of human urine. In this method, urine samples are simply diluted with a basic mobile phase and injected directly under positive electrospray ionization (ESI) conditions, without further purification steps. The combination of an important diluting factor (10(4) times) due to the use of a very sensitive triple quadrupole mass spectrometer (XEVO TQ) and the addition of creatinine-d3 as internal standard completely eliminates matrix effects coming from the urine. The method was validated in-house in 2012 according to the EMA guideline on bioanalytical method validation using Certified Reference samples from the German External Quality Assessment Scheme (G-Equas) proficiency test. All obtained results for accuracy and recovery are within the authorized tolerance ranges defined by G-Equas. The method is linear between 0 and 5 g/L, with LOD and LOQ of 5 × 10(-3) g/L and 10(-2) g/L, respectively. The repeatability (CV(r) = 1.03-2.07%) and intra-laboratory reproducibility (CV(RW) = 1.97-2.40%) satisfy the EMA 2012 guideline. The validated method was firstly applied to perform the German G-Equas proficiency test rounds 51 and 53, in 2013 and 2014, respectively. The obtained results were again all within the accepted tolerance ranges and very close to the reference values defined by the organizers of the proficiency test scheme, demonstrating an excellent accuracy of the developed method. The method was finally applied to measure the creatinine concentration in 210 urine samples, coming from 190 patients with a chronic kidney disease (CKD) and 20 healthy subjects. The obtained creatinine concentrations (ranging from 0.12 g/L up to 3.84 g/L) were compared, by means of a Passing Bablok regression, with the creatinine contents obtained for the same samples measured using a traditional compensated Jaffé method. The UHPLC-MS/MS method described in this paper can be used to normalize the concentration of biomarkers in urine for the extent of dilution.

Evaluation of the Peritoneal Membrane Function by Three Letter Word Acronyms: PET,PDC®, SPA, PD-Adequest, POL: What to Do?

This paper describes and reviews different methods to evaluate the peritoneal transport capacity. This evaluation is important because it will influence the preferred treatment regimen, and will also be a tool for longitudinal follow up both in the individual patient as in patient groups.

What is the difference between prerenal and renal acute kidney injury

Abstract This paper discusses the somewhat artificial distinction between the traditional classification of acute kidney injury in prerenal AKI and established acute tubular necrosis. The primary focus in the setting of a rising SCr should not be assigning the diagnosis of “prerenal” or “renal” AKI but should be determining where the dysfunction lies on the spectrum between purely “functional” and completely structural kidney damage. The new definitions and classification systems of AKI are summarised and the approach to the patient with acute rising serum creatinine and/or acute decline in urinary output is described. The role of the recently introduced novel biomarkers is discussed but it is believed that these biomarkers have not yet proven to be more discriminative in the differential diagnosis between “pure prerenal AKI” and established acute tubular necrosis, beyond a careful clinical evaluation of the patient and the use of the more “traditional” blood and urine parameters.

INTERNAL MEDICINE, RENAL ANAEMIA, AND ERYTHROPOIESIS-STIMULATING AGENTS (ESAS)

The connection between hypoxaemia and red blood cell (RBC) production was already known at the end of the 19th century. In 1883, Miescher (1) observed an increase in his own haemoglobin (Hb) concentration and red cell count when entering a sanatorium in Arosa (Swiss Alps). He realized that this increase occurred in response to reduced oxygen availability. The fascinating history of the development of erythropoietin (EPO) has been summarized by Denker (2) and more recently by Nanagaku and Eckardt (3). Erslev (4) elegantly demonstrated that plasma from anaemic rabbits contained a factor capable of stimulating RBS production and predicted its therapeutic potential. The human EPO gene was cloned in 1983, and this enabled the expression of the mature glycoprotein hormone from Chinese hamster ovary cells and the mass production of recombinant human erythropoietin (rhEPO – called epoietin in the literature) to be available for clinical use (5;6). The fi rst successful clinical treatments with EPO in haemodialysis (HD) patients were reported in 1986-1987 (7;8). As might be expected with a genetic copy of the endogenous protein, EPO is highly effective in stimulating erythropoiesis, particularly in chronic renal failure, and has very low immunogenicity (see below). Over the last years, novel erythropoiesis-stimulating agents (ESAs) have been developed (see below).