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.

Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece.

Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3/COL4A4 (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis.

Impact of Adverse Drug Reactions in Patients with End Stage Renal Disease in Greece.

BACKGROUND: Patients with end-stage renal disease (ESRD) require specialized therapeutic interventions. The decreased renal function that modulates the physiology and presence of comorbidities is often associated with variations in the pharmacological response, thus increasing the risk of adverse drug events or reactions (ADE/ADRs) from co-administered drugs. METHODS: A cross-sectional study to record comorbidities, drug-drug interactions (DDIs), ADE/ADRs in patients with chronic kidney disease of stage five in Greece. The study enrolled 60 patients of mean age 64.8 ± 12.9 years, undergoing hemodialysis three times a week. Demographic and social factors, comorbidities, laboratory test data, medication regimens, DDIs and the reporting of ADE/ADRs were analyzed. RESULTS: Cardiovascular diseases and diabetes were the main comorbidities. In total, 50 different DDIs of various clinical significance were identified. CNS, GI-track, and musculoskeletal-system-related ADE/ADRs were most often reported by patients. ADE/ADRs as clinical outcome from DDIs were associated in 64% of the total identified DDIs. There was a positive trend between number of medications, ADE/ADRs report and DDIs. CONCLUSIONS: The impact of ADE/ADRs in ESRD patients should be always considered. Guidelines as well as continuous training in the context of evidence-based clinical practice by healthcare personnel on therapy administration and prevention of adverse events are important.

Immunosuppressive regimens based on Cyclophospamide or Calcineurin inhibitors: Comparison of their effect in the long term outcome of Primary Membranous Nephropathy.

INTRODUCTION: Management of the Primary Membranous Nephropathy (PMN) usually involves administration of immunosuppressives. Cyclophosphamide (Cyclo) and Calcineurin Inhibitors (CNIs) are both widely used but only limited data exist to compare their efficacy in long term follow-up. AIM: The aim of the present study was to estimate and compare long term effects of Cyclo and CNIs in patients with PMN. PATIENTS-METHODS: Clinical data, histologic findings and long term outcome were retrospectively studied. The response to treatment and rate of relapse was compared between patients treated with CNIs or Cyclo based immunosuppressive regimens. RESULTS: Twenty three centers participated in the study, with 752 PMN patients (Mean age 53.4(14-87) yrs, M/F 467/285), followed for 10.1±5.7 years. All patients were initially treated with Renin Angiotensin Aldosterone System inhibitors (RAASi) for at least 6 months. Based on their response and tolerance to initial treatment, patients were divided into 3 groups, group I with spontaneous remission, who had no further treatment, group II, continued on RAASi only, and group III on RAASi+immunosuppression. Immunosuppressive regimes were mainly based on CNIs or Cyclo. Frequent relapses and failure to treatment were more common between patients who had started on CNIs (n = 381) compared to those initially treated with Cyclo (n = 110), relapse rate: 25.2% vs. 6.4%, p<0.0001, and no response rate: 22.5% vs. 13.6%, p = 0.04, respectively. CONCLUSIONS: Long term follow up showed that administration of Cyclo in PMN is followed by better preservation of renal function, increased response rate and less frequent relapses, compared to CNIs.

Histological grading in primary membranous nephropathy is essential for clinical management and predicts outcome of patients.

AIMS: Diagnosis of primary membranous nephropathy (PMN) is mainly based on immunofluorescence/immunohistochemistry findings. However, assessment of specific features on optical microscopy can help to estimate the severity of the disease, guide treatment and predict the response. The aim of this study was to identify, classify and grade the precise histological findings in PMN to predict renal function outcome and guide treatment. METHODS AND RESULTS: Histological parameters, including focal segmental sclerosis (FSGS), tubular atrophy (TA), interstitial fibrosis (IF) and vascular hyalinosis (VH), were re-evaluated in 752 patients with PMN. Their predictive value was estimated separately, and also in a combination score (FSTIV) graded from 0 to 4. Finally, the impact of histology was assessed in the response to immunosuppressive treatment. Mean age of patients was 53.3 (15-85) years and most presented with nephrotic syndrome. FSGS was present in 32% and VH in 51% of the patients, while TA and IF were graded as stage ≥1 in 52% and 51.4%, respectively. The follow-up period was 122.3 (112-376) months. FSGS, TA and IF and VH were associated with impaired renal function at diagnosis (P = 0.02, P < 0.0001, P = 0.001 and P = 0.02, respectively) and at the end of follow-up (P = 0.004, P < 0.0001, P < 0.0001 and P = 0.04, respectively). In multiple regression and binary logistic analysis, the presence of FSGS and degree of TA were the most significant parameters predicting renal function outcome, defined either by eGFR (end), FSGS (r = 0.6, P < 0.0001) and TA (r = 0.6, P < 0.0001), or by the endpoint of >50% eGFR reduction, FSGS (P = 0.001) and TA (P = 0.02). Also, patients presented with FSGS, IF, VH and/or with FSTIV > 1 could benefit from immunosuppression, regardless of clinical presentation. CONCLUSIONS: The presence and degree of four histological indices, FSGS, VH, TA and IF, assessed separately or in combination, and FSTIV score not only predict renal function outcome after long-term follow-up, but can also help in the choice of appropriate treatment. Decisions concerning immunosuppressive treatment can be guided by pathology regardless of clinical findings.

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.

Epidemiology and burden of systemic lupus erythematosus in a Southern European population: data from the community-based lupus registry of Crete, Greece.

OBJECTIVES: Several population-based studies on systemic lupus erythematosus (SLE) have been reported, yet community-based, individual-case validated, comprehensive reports are missing. We studied the SLE epidemiology and burden on the island of Crete during 1999-2013. METHODS: Multisource case-finding included patients ≥15 years old. Cases were ascertained by the ACR 1997, SLICC 2012 criteria and rheumatologist diagnosis, and validated through synthesis of medical charts, administrative and patient-generated data. RESULTS: Overall age-adjusted/sex-adjusted incidence was 7.4 (95% CI 6.8 to 7.9) per 100 000 persons/year, with stabilising trends in women but increasing in men, and average (±SD) age of diagnosis at 43 (±15) years. Adjusted and crude prevalence (December 2013) was 123.4 (113.9 to 132.9) and 143 (133 to 154)/105 (165/105 in urban vs 123/105 in rural regions, p<0.001), respectively. Age-adjusted/sex-adjusted nephritis incidence was 0.6 (0.4 to 0.8) with stable trends, whereas that of neuropsychiatric SLE was 0.5 (0.4 to 0.7) per 100 000 persons/year and increasing. Although half of prevalent cases had mild manifestations, 30.5% developed organ damage after 7.2 (±6.6) years of disease duration, with the neuropsychiatric domain most frequently afflicted, and 4.4% of patients with nephritis developed end-stage renal disease. The ACR 1997 and SLICC 2012 classification criteria showed high concordance (87%), yet physician-based diagnosis occurred earlier than criteria-based in about 20% of cases. CONCLUSIONS: By the use of a comprehensive methodology, we describe the full spectrum of SLE from the community to tertiary care, with almost half of the cases having mild disease, yet with significant damage accrual. SLE is not rare, affects predominantly middle-aged women and is increasingly recognised in men. Neuropsychiatric disease is an emerging frontier in lupus prevention and care.

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.

Prolactin levels, endothelial dysfunction, and the risk of cardiovascular events and mortality in patients with CKD.

BACKGROUND AND OBJECTIVES: Both prolactin clearance and production are altered in CKD. In nonrenal populations, emerging evidence suggests that prolactin participates in the atherosclerotic process. Given the elevated cardiovascular risk of CKD, this study examined links between prolactinemia, vascular derangements, and outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This observational study was conducted in two cohorts: one with 457 nondialyzed CKD patients (mean age 52±12 years; 229 men) with measurements of flow-mediated dilation (FMD) and carotid intima-media thickness and one with 173 hemodialysis patients (65±12 years; 111 men) with measurements of pulse wave velocity (PWV). Patients were followed for cardiovascular events (n=146, nondialyzed cohort) or death (n=79, hemodialysis cohort). RESULTS: Prolactin levels increased along with reduced kidney function. Prolactin significantly and independently contributed to explain the variance of both FMD (in nondialyzed patients) and PWV (in hemodialysis patients), but not intima-media thickness. In Cox analyses, the risk of cardiovascular events in nondialyzed patients increased by 27% (hazard ratio [HR], 1.27; 95% confidence interval [95% CI], 1.17-1.38) for each 10 ng/ml increment of prolactin. Similarly, the risk for all-cause and cardiovascular mortality in hemodialysis patients increased by 12% (HR, 1.12; 95% CI, 1.06-1.17) and 15% (HR, 1.15; 95% CI, 1.08-1.21), respectively. This was true after multivariate adjustment for confounders and after adjustment within the purported causal pathway (FMD or PWV). CONCLUSIONS: Prolactin levels directly associated with endothelial dysfunction/stiffness and with increased risk of cardiovascular events and mortality in two independent cohorts of CKD 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.

Beneficial effects of magnesium in chronic renal failure: a foe no longer.

Magnesium plays a critical role in cellular physiology in humans, regulating many fundamental functions. In the general population its deficiency is associated with many disorders, the most significant being cardiovascular diseases. The role of magnesium in many aspects of end-stage renal disease (ESRD) may be also very important, although this has not been explored in depth. The most significant of these roles are use of magnesium salts as phosphate binders and its ability to inhibit the development or progression of vascular calcification. Moreover, serum magnesium suppresses parathyroid hormone excretion, whereas high magnesium dialysate may result in intradialytic hemodynamic stability. Data provided by recent studies on these issues have promoted promising renewed interest in the role of magnesium in ESRD and its possible favorable therapeutic application in these patients. Further large studies are needed to establish its efficacy and safety, and, probably, to re-evaluate its appropriate concentration in hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) fluids.

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.

Prostate-specific antigen in hemodialysis patients and the influence of dialysis in its levels.

The determination of prostate-specific antigen (PSA) is a useful tool in the diagnosis and follow-up of prostate cancer in males, but its diagnostic validity is uncertain in hemodialysis patients. We prospectively evaluated PSA in male hemodialysis patients as well as the influence of a single dialytic session on its levels. We measured pre- and postdialysis total PSA (tPSA) in 63 hemodialysis patients (mean age 68.44 +/- 11.16 years, range 33-86 years) who had received dialysis with low flux membranes as well as in 729 normal subjects (mean age 63.22 +/- 16.85 years, range 28-92 years). We also measured pre- and postdialysis hematocrit (Hct) in patients in order to estimate the degree of hemoconcentration after the dialysis session. If any of the examined patients or subjects had abnormal tPSA levels then free PSA (fPSA) and the f/tPSA ratio were additionally measured. Patients had lower levels of tPSA compared with those of the subjects (2.41 +/- 4.06 vs. 3.76 +/- 7.16 ng/ml, p < 0.05) while both of the two groups had near equal prevalence of individuals with abnormal values of tPSA or f/tPSA ratio (patients 12.69 and 7.93%, subjects 11.01 and 7.11%, respectively; nonsignificant. Dialysis resulted in a 9.48% increase in mean tPSA levels (2.41 +/- 4.06 vs. 2.69 +/- 4.06 ng/ml, nonsignificant) and in a 10.09% increase in mean Hct; the correlation between these increases was significant (r = 0.79, p < 0.001). In conclusion, our male hemodialysis patients had lower PSA levels compared with the general population, while both groups of individuals had a similar prevalence of abnormal values of tPSA and f/tPSA ratio. Dialysis with low flux membranes does not eliminate PSA and its postdialysis increase is due to hemoconcentration.