Steven Van Laecke

New-onset diabetes after renal transplantation: risk assessment and management.

New-onset diabetes after transplantation (NODAT) is a serious and frequent metabolic complication after renal transplantation. This entity is currently well defined since the publication of the International Consensus Guidelines in 2003. Here, we review the factors contributing to the risk of NODAT and the strategies related to modifiable factors, with emphasis on practical issues. Recognizing these factors may help clinicians to evaluate prospectively appropriate prevention strategies to minimize the risk of NODAT.nnOver the past 50 years, the concept of NODAT has evolved in terms of name and definition. Before 2003, de novo diabetes that developed after transplantation was described in various terms, most frequently “posttransplantation diabetes mellitus,” and suffered from a lack of consensus regarding its definition. The most commonly used clinical definition was the requirement of insulin for a minimum period posttransplantation (often 30 days). This definition, however, identified only the most severe cases, leaving out the majority of patients with glucose metabolism disorders. International Consensus Guidelines on NODAT were published in 2003. They recommended that the diagnosis of NODAT should be based on the American Diabetes Association (ADA) criteria for type 2 diabetes published in 2003 (1,2). Since then, a follow-up report from the International Expert Committee further lowered the inferior limit of fasting plasma glucose (FPG) (100 mg/dL) that corresponds to impaired fasting glucose (IFG), based on epidemiologic predictive data (3). In addition, since 2009, the International Expert Committee recommended the use of a standardized A1C assay for diabetes diagnosis (A1C level ≥6.5%), a position that has been endorsed by ADA in 2010 (4). The Expert Committee stated that A1C assay cannot be used in conditions that change red cell turnover. This is the case of end-stage renal disease (ESRD) patients and newly transplanted kidney patients. For instance, the posttransplant period is frequently associated …

Nocardia Infection in Solid Organ Transplant Recipients: A Multicenter European Case-control Study

BACKGROUNDnNocardiosis is a rare, life-threatening opportunistic infection, affecting 0.04% to 3.5% of patients after solid organ transplant (SOT). The aim of this study was to identify risk factors for Nocardia infection after SOT and to describe the presentation of nocardiosis in these patients.nnnMETHODSnWe performed a retrospective case-control study of adult patients diagnosed with nocardiosis after SOT between 2000 and 2014 in 36 European (France, Belgium, Switzerland, the Netherlands, Spain) centers. Two control subjects per case were matched by institution, transplant date, and transplanted organ. A multivariable analysis was performed using conditional logistic regression to identify risk factors for nocardiosis.nnnRESULTSnOne hundred and seventeen cases of nocardiosis and 234 control patients were included. Nocardiosis occurred at a median of 17.5 (range, 2-244) months after transplant. In multivariable analysis, high calcineurin inhibitor trough levels in the month before diagnosis (odds ratio [OR], 6.11; 95% confidence interval [CI], 2.58-14.51), use of tacrolimus (OR, 2.65; 95% CI, 1.17-6.00) and corticosteroid dose (OR, 1.12; 95% CI, 1.03-1.22) at the time of diagnosis, patient age (OR, 1.04; 95% CI, 1.02-1.07), and length of stay in the intensive care unit after SOT (OR, 1.04; 95% CI, 1.00-1.09) were independently associated with development of nocardiosis; low-dose cotrimoxazole prophylaxis was not found to prevent nocardiosis. Nocardia farcinica was more frequently associated with brain, skin, and subcutaneous tissue infections than were other Nocardia species. Among the 30 cases with central nervous system nocardiosis, 13 (43.3%) had no neurological symptoms.nnnCONCLUSIONSnWe identified 5 risk factors for nocardiosis after SOT. Low-dose cotrimoxazole was not found to prevent Nocardia infection. These findings may help improve management of transplant recipients.

The effect of magnesium supplements on early post-transplantation glucose metabolism: a randomized controlled trial

Post‐transplantation hypomagnesemia is common and predicts diabetes. Magnesium improves glycemic control in diabetics and insulin sensitivity in insulin resistant subjects. We aimed to assess the effectiveness of oral magnesium for improving glycemic control and insulin sensitivity at 3 months post‐transplantation. We conducted a single‐center, open‐label, randomized parallel group study. We included adults with serum magnesium <1.7 mg/dl within 2 weeks after kidney transplantation. We randomized participants to 450 mg magnesium oxide up to three times daily or no treatment. The primary endpoint was the mean difference in fasting glycemia. Secondary endpoints were the mean difference in area under the curve (AUC) of glucose during an oral glucose tolerance test and insulin resistance measured by Homeostasis Model of Assessment‐Insulin Resistance (HOMA‐IR). Analyses were on intention‐to‐treat basis. In patients randomized to magnesium oxide (N = 27) versus no treatment (N = 27), fasting glycemia on average was 11.5 mg/dl lower (95% CI 1.7 to 21.3; P = 0.02). There was no difference between the two groups neither for 2 h AUC, where the mean value was 1164 mg/dl/min (95% CI −1884 to 4284; P = 0.45) lower in the treatment group nor for HOMA‐IR. Magnesium supplements modestly improved fasting glycemia without effect on insulin resistance. Higher baseline glycemia among patients in the control group may have driven the positive outcome (ClinicalTrials.gov number: NCT01889576).

Severe hypertension with renal thrombotic microangiopathy: what happened to the usual suspect?

Patients with atypical hemolytic uremic syndrome (aHUS) and malignant hypertension can both present with concomitant hypertension and thrombotic microangiopathy (TMA), rendering policy decisions complex. Timmermans etxa0al. report that patients withxa0severe hypertension and renal TMA might have unrecognized aHUS with underlying complement abnormalities. Based on this, they assert that all patients presenting with severe hypertension and renal TMAxa0should be evaluated for aHUS. It remains uncertain whether thisxa0holds equally true for patients with malignant hypertension andxa0renal TMA.

Effect of Magnesium Supplements on Insulin Secretion After Kidney Transplantation: A Randomized Controlled Trial

BACKGROUND Hypomagnesemia is associated with a disturbed glucose metabolism. Insulin hypo-secretion predicts diabetes in the general population and in transplant recipients. We aimed to assess whether magnesium improves insulin secretion and glycemic control after transplantation in prevalent hypomagnesemic kidney transplant recipients. MATERIAL AND METHODS We conducted an open-label, randomized, parallel-group study. Eligible participants were adults more than 4 months after kidney transplantation on tacrolimus with persisting serum magnesium concentrations <1.8 mg/dL randomized to magnesium oxide supplementation up to a maximum of 3 times 450 mg daily (N=26) or no supplements (N=26). Insulin secretion was assessed by OGTT-derived, first-phase insulin secretion (FPIR). The primary endpoint was the mean difference in FPIR between baseline and 6 months after randomization. Secondary endpoints were differences in HbA1c and insulin resistance, measured by HOMA. Dietary magnesium was assessed by a food-frequency questionnaire. All analyses were done on an intention-to-treat basis. RESULTS Magnesium with a mean daily dose of 688±237mg in the treatment group failed to lead to significant differences between the 2 groups in FPIR, fasting glucose, HbA1c, or HOMA-IR. Persisting hypomagnesemia was very common and associated with more insulin hypo-secretion, glucose intolerance, and lower dietary magnesium intake (142±56 versus 202±90 mg; p=0.015) as compared to patients with a rise in serum magnesium over 6 months. CONCLUSIONS Magnesium supplementation does not improve insulin secretion in stable hypomagnesemic kidney transplant recipients on tacrolimus. Persisting hypomagnesemia is associated with impaired glucose tolerance, insulin hypo-secretion, and dietary factors.

Pitfalls and opportunities in multidisciplinary research about nocturia in adults

Objectives: Describe current shortcomings in clinical research on the treatment of nocturia in adults, and suggest new directions for future studies in this field. Methods: A literature search was conducted using the keywords ‘nocturia,’ ‘nocturnal polyuria,’ ‘sleep,’ and ‘hypertension.’ Results: Nocturia, or waking up at night to void, is a highly prevalent and bothersome lower urinary tract symptom (LUTS) affecting up to 40% of adults. Since the majority of patients are diagnosed with nocturnal polyuria (NP) as one of the underlying causes, it is not surprising that the effect of treatments for overactive bladder (OAB) and bladder outlet obstruction (BOO) are disappointing with regard to nocturia. Therefore, we suggest to conduct studies in which nocturic patients are treated according to the underlying pathophysiology: (1) antimuscarinics or β3-agonists for OAB symptoms, (2) α-blockers or 5α-reductase inhibitors in men with BOO caused by enlarged prostates, (3) desmopressin or diuretics for NP, (4) continuous positive airway pressure in nocturic patients with obstructive sleep apnea, and (5) all its combinations in case of combined pathophysiology. Not only the effect on treatment efficacy or side effects needs to be assessed, but also the impact on related comorbidities such as sleep disorders, hypertension, and endocrine functions such as blood glucose regulation. Conclusion: Future research needs to subtype nocturic patients in order to adapt treatment according to the underlying cause.

Cardiovascular disease after transplantation: an emerging role of the immune system

Cardiovascular disease (CVD) after transplantation remains a major concern. Little is known about what drives the increased cardiovascular risk in transplant recipients apart from traditional risk factors. The immune system is involved in the pathogenesis of hypertension, atherosclerosis, and coronary artery disease in the general population. Recently, inhibition of interleukin 1 − β by canakinumab versus placebo decreased the incidence of cardiovascular events. Emerging evidence points to a role of adaptive cellular immunity in the development of CVD. Especially, expansion of pro‐inflammatory and antiapoptotic cytotoxic CD4+CD28null T cells is closely associated with incident CVD in various study populations including transplant recipients. The association of cytomegalovirus exposure with increased cardiovascular mortality might be explained by its capacity to upregulate these cytotoxic cells. Also, humoral immunity seems to be relevant for cardiovascular outcome in transplant recipients. Panel‐reactive antibodies at baseline and donor‐specific antibodies are independently associated with poor cardiovascular outcome after kidney transplantation. Cardiovascular effects of immunosuppressive drugs and statins do not only imply indirect positive or negative effects on traditional cardiovascular risk factors but also intrinsic immunological effects. How immunosuppressive drugs modify atherosclerosis largely remains elusive.

The clinical significance of epitope mismatch load in kidney transplantation: A multicentre study

Since the advent of kidney transplantation a key strategy for maximising graft survival by avoiding allorecognition has been to minimise HLA mismatching between donor and recipient. As HLA antibodies are now recognised as being specific for epitopes and donor-recipient HLA mismatch at the amino acid level can now be determined, HLA epitope mismatch load could be a better predictor for dnDSA development than classical HLA antigen mismatch calculation. This hypothesis has been investigated by other studies and the aim of our multicentre study was to confirm this observation in our population. Two algorithms, HLAMatchmaker and PIRCHE-II, were used to determine the HLA epitope mismatch load between donor and recipient. We have shown a significant association between the number of HLA epitope mismatches and the development of dnDSA and we have confirmed the earlier observations.

Deleting Death and Dialysis: Conservative Care of Cardio-Vascular Risk and Kidney Function Loss in Chronic Kidney Disease (CKD)

The uremic syndrome, which is the clinical expression of chronic kidney disease (CKD), is a complex amalgam of accelerated aging and organ dysfunctions, whereby cardio-vascular disease plays a capital role. In this narrative review, we offer a summary of the current conservative (medical) treatment options for cardio-vascular and overall morbidity and mortality risk in CKD. Since the progression of CKD is also associated with a higher cardio-vascular risk, we summarize the interventions that may prevent the progression of CKD as well. We pay attention to established therapies, as well as to novel promising options. Approaches that have been considered are not limited to pharmacological approaches but take into account lifestyle measures and diet as well. We took as many randomized controlled hard endpoint outcome trials as possible into account, although observational studies and post hoc analyses were included where appropriate. We also considered health economic aspects. Based on this information, we constructed comprehensive tables summarizing the available therapeutic options and the number and kind of studies (controlled or not, contradictory outcomes or not) with regard to each approach. Our review underscores the scarcity of well-designed large controlled trials in CKD. Nevertheless, based on the controlled and observational data, a therapeutic algorithm can be developed for this complex and multifactorial condition. It is likely that interventions should be aimed at targeting several modifiable factors simultaneously.

Intravenous immunoglobulins modify relapsing membranous glomerulonephritis after kidney transplantation: a case report

Abstract Objectives: Recurrence of membranous glomerulonephritis after transplant is common and is an important cause of loss of renal graft. This case supports the effect of immunoglobulins in the treatment of this disease after transplantation. It is the first report in the literature with a follow-up of more than 10 years and because of the sustained effect of the immunoglobulins, it strengthens the idea that this can alter long-term outcome. Methods: Single case study and search of the literature. Results: A female transplant recipient, who had an early histologically proven relapse of an idiopathic membranous glomerulonephritis and who was, before transplantation, refractory to various immunosuppressive agents. This relapsing disease has now been stable for over 10 years of intravenous immunoglobulins treatment in conjunction with belatacept and low doses of corticosteroids after gradual withdrawal of mycophenolate mofetil. This report supports the finding that immunoglobulins could influence the course of a relapse of membranous glomerulonephritis after transplantation. Conclusion: This case illustrates that immunoglobulins had long-lasting effects on the renal transplant although the glomerulonephritis had been resistant to other lines of therapy before transplant. We advocate that the use of immunoglobulins as a rescue therapy in refractory idiopathic membranous glomerulonephritis should be further investigated. Presently, existing evidence only comes from retrospective data and non-randomized trials.