DPP4 Inhibitor-Induced Bullous Pemphigoid in Patients with Diabetes and Chronic Kidney Disease: Clinical Case Series.

INTRODUCTION: Dipeptidyl peptidase-4 (DPP4) inhibitors (gliptins) are commonly prescribed for glucose control in patients with advanced chronic kidney disease (CKD) in whom other oral glucose-lowering agents are contraindicated. In the past few years, new reports of drug-induced bullous pemphigoid associated with DPP4 inhibitors have emerged. However, there is not enough information about the renal function of the patients with DPP4 inhibitor-induced bullous pemphigoid, and it remains unknown whether the risk of this complication is increased among patients with CKD. CASE REPORTS: Five patients with stage 3b-5 CKD received a diagnosis of DPP4 inhibitor-associated bullous pemphigoid in our institution within a period of 17 months (between December 2018 and May 2020). All patients in the current series were male. Skin biopsies were performed in all patients. Three cases were secondary to vildagliptin, and 2 cases were attributed to linagliptin. In each of these patients, treatment consisted of permanent discontinuation of the DPP4 inhibitor and administration of corticosteroids. CONCLUSION: We report here the first single-center experience of DPP4 inhibitor-induced bullous pemphigoid in patients with CKD. Our case series highlights the importance of considering bullous pemphigoid in patients with CKD taking DPP4 inhibitors presenting with bullous or pruritic cutaneous lesions. By calling attention to this important complication, we hope to minimize the delay in diagnosing DPP4 inhibitor-induced bullous pemphigoid among patients with CKD.

Validation of the International IgA Nephropathy Prediction Tool in the Greek Registry of IgA Nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is among the commonest glomerulonephritides in Greece and an important cause of end-stage kidney disease (ESKD) with an insidious chronic course. Thus, the recently published International IgAN prediction tool could potentially provide valuable risk stratification and guide the appropriate treatment module. This study aimed to externally validate this prediction tool using a patient cohort from the IgAN registry of the Greek Society of Nephrology. METHODS: We validated the predictive performance of the two full models (with or without race) derived from the International IgAN Prediction Tool study in the Greek Society of Nephrology registry of patients with IgAN using external validation of survival prediction models (Royston and Altman). The discrimination and calibration of the models were tested using the C-statistics and stratified analysis, coefficient of determination ( R D 2 ) for model fit, and the regression coefficient of the linear predictor (ßPI), respectively. RESULTS: The study included 264 patients with a median age of 39 (30-51) years where 65.2% are men. All patients were of Caucasian origin. The 5-year risk of the primary outcome (50% reduction in estimated glomerular filtration rate or ESKD) was 8%. The R D 2 for the full models with and without race when applied to our cohort was 39 and 35%, respectively, and both were higher than the reported R D 2 for the models applied to the original validation cohorts (26.3, 25.3, and 35.3%, respectively). Harrel's C statistic for the full model with race was 0.71, and for the model without race was 0.70. Renal survival curves in the subgroups (<16th, ~16 to <50th, ~50 to <84th, and >84th percentiles of linear predictor) showed adequate separation. However, the calibration proved not to be acceptable for both the models, and the risk probability was overestimated by the model. CONCLUSIONS: The two full models with or without race were shown to accurately distinguish the highest and higher risk patients from patients with low and intermediate risk for disease progression in the Greek registry of IgAN.

IgA nephropathy in Greece: data from the registry of the Hellenic Society of Nephrology.

BACKGROUND: Natural history, predisposing factors to an unfavourable outcome and the effect of various therapeutic regimens were evaluated in a cohort of 457 patients with immunoglobulin A nephropathy (IgAN) and follow-up of at least 12 months. METHODS: Patients with normal renal function and proteinuria <1 g/24 h as well as those with serum creatinine (SCr) >2.5 mg/dL and/or severe glomerulosclerosis received no treatment. Patients with normal or impaired renal function and proteinuria >1 g/24 h for >6 months received daily oral prednisolone or a 3-day course of intravenous (IV) methylprednisolone followed by oral prednisolone per os every other day or a combination of prednisolone and azathioprine. The clinical outcome was estimated using the primary endpoints of end-stage renal disease and/or doubling of baseline SCr. RESULTS: The overall 10-year renal survival was 90.8%, while end-stage renal disease and doubling of baseline SCr developed in 9.2% and 14.7% of patients, respectively. Risk factors related to the primary endpoints were elevated baseline SCr, arterial hypertension, persistent proteinuria >0.5 g/24 h and severity of tubulointerstial fibrosis. There was no difference in the clinical outcome of patients treated by the two regimens of corticosteroids; nevertheless, remission of proteinuria was more frequent in patients who received IV methylprednisolone (P = 0.000). The combination of prednisolone with azathioprine was not superior to IV methylprednisolone followed by oral prednisolone. Side effects related to immunossuppressive drugs were observed in 12.8% of patients. CONCLUSION: The clinical outcome of patients with IgAN was related to the severity of clinical and histological involvement. The addition of azathioprine to a corticosteroid-based regimen for IgAN does not improve renal outcome.

Dapagliflozin as a cause of acute tubular necrosis with heavy consequences: a case report.

A 50-year-old man with type II diabetes, hypertension and dyslipidemia, presented with non-oliguric acute kidney injury (AKI) and anemia. Renal biopsy showed acute tubular necrosis (ATN) with extensive cytoplasmic vacuolization and areas of tubulitis. These findings were ultimately attributed to dapagliflozin, which he started 3 months earlier due to poor glycemic control. ATN with similar microscopic findings has been described with larger doses of dapagliflozin in non-clinical trials. Our patient was started on dialysis and remained dialysis-dependent for 4 weeks while his renal function improved gradually thereafter. Sixteen months after initial presentation he is being followed as an outpatient with chronic kidney disease (CKD) stage 3a. Dapagliflozin belongs to a novel class of antidiabetic drugs for which clinical trials show great beneficial effects on cardiovascular outcomes and glycemic control and as with many new drugs, their safety profile is being constantly revised. We report the first biopsy-proven ATN caused by dapagliflozin. Great caution together with continuous monitoring of renal function is advised when implementing SGLT-2 inhibitors in clinical practice.

Magnesium retards the progress of the arterial calcifications in hemodialysis patients: a pilot study.

BACKGROUND: The aim of the study was to evaluate the impact of magnesium (Mg) on the evolution of arterial calcifications in hemodialysis patients. PATIENTS AND METHODS: Seventy-two stable hemodialysis patients were randomly allocated to two groups: 36 administered a regimen containing magnesium carbonate plus calcium acetate as a phosphate binder (Mg group), while the rest 36 received calcium acetate alone (Ca group). The presence and the progression of arterial calcifications were evaluated in plain X-rays using a simple vascular calcification score. The duration of the follow-up period was 12 months. RESULTS: Thirty-two patients of the Mg group and 27 of the Ca group completed the study. The mean time average values of the biochemical laboratories did not differ between the two groups, except serum Mg: 2.83 + 0.38 in the Mg group versus 2.52 + 0.27 mg/dl in the Ca group, p = 0.001. In 9/32 (28.12 %) patients of the Mg group and in 12/27 (44.44 %) patients of the Ca group, the arterial calcifications were worsened, p = 0.276. Moreover, in 4/32 (15.6 %) patients of the Mg group and in 0/27 (0 %) patients of the Ca group, they were improved, p = 0.040. The multivariate logistic regression analysis revealed that serum magnesium was an independent predictor for no progression of the arterial calcifications, p = 0.047. CONCLUSIONS: Magnesium probably retards the arterial calcifications in hemodialysis patients. Further clinical studies are needed to clarify whether magnesium provides cardiovascular protection to this group of patients.

Low serum testosterone, arterial stiffness and mortality in male haemodialysis patients.

BACKGROUND: In the general population, accumulating data support a link between low testosterone levels and mortality by all causes, but especially by cardiovascular disease (CVD). Also, accelerated arterial stiffness has been recognized as an important cardiovascular risk factor. Here, we explored the association between testosterone levels and risk of death in male haemodialysis (HD) patients, whose arterial system is characterized by generalized stiffening. METHODS: In this three-centre prospective observational study, 111 male HD patients after completion of baseline assessment, including measurement of male sex hormones and pulse wave velocity (PWV), were followed up for CVD and all-cause mortality. RESULTS: Of the 111 patients studied, 54 were found with and 57 without testosterone deficiency, defined as testosterone levels <8 nmol/L. During a median follow-up period of 37 months, 49 deaths occurred, 28 (57%) of which were caused by CVD. Testosterone deficiency patients had increased CVD and all-cause mortality {crude hazard ratio: 3.14 [95% confidence interval (CI), 1.21-8.16] and 3.09 (95% CI, 1.53-6.25), respectively}, even after adjustment for age, body mass index, serum albumin and C-reactive protein, prevalent CVD and HD vintage. The association of testosterone with CVD mortality, but not with all-cause mortality, was lost after adjusting for PWV, an index of arterial stiffness. Testosterone levels were inversely related to PWV (r = -0.441; P < 0.001). CONCLUSION: We showed that testosterone deficiency in male HD patients is associated with increased CVD and all-cause mortality and that increased arterial stiffness may be a possible mechanism explaining this association.

Development and validation of a high-performance liquid chromatography method for the evaluation of niflumic acid cross-reactivity of two commercial immunoassays for cannabinoids in urine.

Niflumic acid is a nonsteroidal, anti-inflammatory drug widely prescribed in Greece. We recently noticed that this drug cross-reacts for cannabinoids in a kinetic interaction of microparticles in a solution (KIMS) immunoassay method but does not in an enzyme multiplied immunoassay technique (EMIT) immunoassay method. The objective of the study was to develop and validate a high-performance liquid chromatographic method in order to evaluate niflumic acid cross-reactivity in two commercial immunoassays for cannabinoids in urine, both in niflumic acid standards as well as in urine specimens obtained from subjects receiving niflumic acid. Urine niflumic acid standards were prepared in drug-free urine at 13 concentrations ranging from 1.25 to 1000 microg/mL. The standards gave presumptive positive cannabinoids results when analyzed by the KIMS immunoassay method when the concentration was above 2.5 microg/mL. None of the prepared standards gave a false-positive cannabinoid result when analyzed by the EMIT immunoassay method. By applying a 50 ng/mL cutoff for cannabinoids in these assays, all 55 urine specimens collected from the 5 subjects who participated gave negative results by the EMIT and false-positive results by the KIMS immunoassay method. It is concluded that KIMS is more prone to cross-reactions by niflumic acid compared to EMIT. Therefore, all positive screening tests for cannabinoids obtained by KIMS should be confirmed by another technique.

Development and validation of an HPLC method for the determination of seven penicillin antibiotics in veterinary drugs and bovine blood plasma.

Herein a quantitative method for the determination of seven penicillins in bovine plasma and veterinary drugs has been developed. Amoxicillin (AMO), ampicillin (AMP), penicillin G (PENG), penicillin V (PENV), oxacillin (OXA), cloxacillin (CLO) and dicloxacillin (DICLO) were separated on a Perfectsil ODS-2 (250 x 4 mm, 5 microm) column, using gradient elution, with a mobile phase of 0.1% v/v TFA and ACN-methanol (90:10 v/v). PDA detection was used at 240 nm. Penicillins were isolated from bovine plasma by SPE on Lichrolut RP-18 cartridges with mean recoveries from 85.7 to 113.5%. Colchicine (3 ng/microL) was used as an internal standard. The developed method was validated in terms of selectivity, linearity, accuracy, precision, stability and sensitivity. Repeatability (n = 5) and between-day precision (n = 5) revealed RSD < 12%. The detection limits in the bovine plasma were estimated as 18 ng for AMO and AMP, 25 for PENG, PENV and OXA, 3 ng for CLO and 12 ng for DICLO. Spiked plasma samples were stable for 1 wk, except for AMP and CLO, which were stable for 3 wk and OXA for 4 wk. AMO, PENG and PENV were stable for two freeze-thaw cycles, OXA, CLO and DICLO for four, while AMP only for one.

Sleep disturbance in haemodialysis patients is closely related to depression.

OBJECTIVE: To investigate the relationship between depression and disturbed sleep in haemodialysis patients (HP), and its relative contribution in the development of reported sleep problems. METHOD: A total of 101 patients suffering from end-stage renal disease (ESRD) were assessed through the Athens Insomnia Scale (AIS) for potential sleep problems. Anxiety and depression were evaluated with the Hospital Anxiety and Depression Scale (HADS), and their health-related quality of life and functional status were assessed through the Short Form-36 questionnaire (SF-36). Socio-demographic, anthropometric and clinical data along with a series of biochemical measures were also collected. RESULTS: Multiple logistic regression analysis showed that the independent predictors associated with insomnia in ESRD patients were female sex (OR=7.58) and depression as measured by the HADS (OR=2.59). CONCLUSION: Incorporating a standard assessment and eventually treatment of depressive symptoms into the care provided to haemodialysis patients might improve psychological well-being, insomnia and quality of life, and, consequently, reduce mortality risk in this population.

Magnesium carbonate for phosphate control in patients on hemodialysis. A randomized controlled trial.

BACKGROUND: Magnesium salts bind dietary phosphorus, but their use in renal patients is limited due to their potential for causing side effects. The aim of this study was to evaluate the efficacy and safety of magnesium carbonate (MgCO(3)) as a phosphate-binder in hemodialysis patients. METHODS: Forty-six stable hemodialysis patients were randomly allocated to receive either MgCO(3) (n=25) or calcium carbonate (CaCO(3)), (n=21) for 6 months. The concentration of Mg in the dialysate bath was 0.30 mmol/l in the MgCO(3) group and 0.48 mmol/l in the CaCO(3) group. RESULTS: Only two of 25 patients (8%) discontinued ingestion of MgCO(3) due to complications: one (4%) because of persistent diarrhea, and the other (4%) because of recurrent hypermagnesemia. In the MgCO(3) and CaCO(3) groups, respectively, time-averaged (months 1-6) serum concentrations were: phosphate (P), 5.47 vs. 5.29 mg/dl, P=ns; Ca, 9.13 vs. 9.60 mg/dl, P<0.001; Ca x P product, 50.35 vs. 50.70 (mg/dl)(2), P=ns; Mg, 2.57 vs. 2.41 mg/dl, P=ns; intact parathyroid hormone (iPTH), 285 vs. 235 pg/ml, P<0.01. At month 6, iPTH levels did not differ between groups: 251 vs. 212 pg/ml, P=ns. At month 6 the percentages of patients with serum levels of phosphate, Ca x P product and iPTH that fell within the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines were similar in both groups, whereas more patients in the MgCO(3) group (17/23; 73.91%) than in the CaCO(3) group (5/20, 25%) had serum Ca levels that fell within these guidelines, with the difference being significant at P<0.01. CONCLUSION: Our study shows that MgCO(3) administered for a period of 6 months is an effective and inexpensive agent to control serum phosphate levels in hemodialysis patients. The administration of MgCO(3) in combination with a low dialysate Mg concentration avoids the risk of severe hypermagnesemia.

Intra- and extracellular magnesium levels and atheromatosis in haemodialysis patients.

Traditional risk factors do not adequately explain the high prevalence of cardiovascular disease in patients with chronic renal insufficiency. Currently, there is a lot of evidence that hypomagnesaemia may play a significant role in the pathogenesis of cardiovascular diseases in general population. The aim of this study was to test the hypothesis that magnesium status in haemodialysis patients is related to the degree of atheromatosis of carotid arteries, as assessed by B-mode ultrasound. Intima-media thickness of both common carotids was assessed by B-mode ultrasound in 93 stable chronic haemodialysis patients and in 182 age- and sex-matched healthy controls. Intracellular magnesium as well as serum magnesium levels were obtained in the haemodialysis patients. Intracellular magnesium was estimated by determination of this ion in isolated peripheral lymphocytes. Haemodialysis patients had also a significantly higher mean common carotid intima-media thickness than controls (0.87+/-0.16 vs 0.76+/-0.13 mm, p < 0.001). Multivariate analysis revealed that in haemodialysis patients both serum magnesium and intracellular magnesium were negatively associated with common carotid intima-media thickness (p = 0.001 and p = 0.003 respectively). Significant associations between the age of the haemodialysis patients, the existence of diabetes mellitus as well as the serum calcium x serum phosphate product with common carotid intima-media thickness of haemodialysis patients were also observed. A strong negative association of both extracellular and intracellular magnesium with common carotid intima-media thickness exists in haemodialysis patients. The above finding suggests that magnesium may play an important protective role in the development and/or acceleration of arterial atherosclerosis in patients with chronic renal insufficiency.