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.

Case Report: Spherocytic Hemolytic Anemia after Envenomation by Long-Nosed Viper (Vipera ammodytes).

Snakebite envenoming is a major health issue in many parts of the world, especially in rural areas. Vipera ammodytes is the commonest cause of snakebite in Greece. We report our experience with a patient bitten by such a snake, who developed massive intravascular hemolysis characterized by a spherocytic rather than microangiopathic hemolytic picture. This case illustrates the potential of snakebite envenoming to cause spherocytic hemolytic anemia associated with hemoglobinuria and acute renal failure, and represents the first report of V. ammodytes in this context. Another important point is that antivenom was rapidly effective in reversing spherocytic hemolytic anemia, even though several hours had elapsed since the bite.

Glomerular expression of matrix metalloproteinases in systemic lupus erythematosus in association with activity index and renal function.

PURPOSE: The aim of this study was to examine the expression of matrix metalloproteinases (MMPs) MMP-1, MMP-2, MMP-3, MMP-9, and their specific tissue inhibitor TIMP-1 in kidney biopsies of patients with lupus nephritis (LN) and to investigate the relationship between MMPs, activity index, and renal function at the time of kidney biopsy. METHODS: We performed immunohistochemistry with monoclonal antibodies against MMP-1, MMP-2, MMP-3, MMP-9, and TIMP-1 in 58 kidney-biopsy specimens with LN (according to the 2004 ISN/RPS classification) and eight specimens from normal kidney tissue. We used clinical data of 36 patients at the time of kidney biopsy to evaluate the association between MMPs expression and renal function. RESULTS: We found increased MMP-1, MMP-2, and MMP-3 expression in LN glomeruli and a significant correlation with the activity features, with higher activity index score and worse renal function (p < .001). In particular, we have noticed a significant correlation of MMP-1 with leukocyte influx (OR:16.5 95%CI 4.3-62.5 p < .001), and MMP-3 with glomerular hypercellularity (OR:18.6 95%CI 4.8-72.8 p < .001). Moreover, we found a strong correlation of MMP-2 expression with fibrinoid necrosis and cellular crescents formation (OR:17.1 95%CI 4.3-67.7 p < .001). CONCLUSIONS: MMP expression in renal biopsy of patients with LN is increased and directly related to a highly active inflammatory response. Moreover, stronger MMP expression is associated with higher activity index and a more profound renal dysfunction.

Haemodialysis and haemodiafiltration lead to similar changes in vascular stiffness during treatment.

BACKGROUND: Haemodiafiltration (HDF) has been reported to cause less hypotension than haemodialysis (HD). We hypothesized that HDF causes less change in vascular tone, thereby reducing hypotension. METHODS: Aortic pulse wave velocity (PWVao) was measured in 284 patients, during a single dialysis session using cooled dialysate (117 HD, 177 HDF). Patient groups were matched for age, sex and cardiovascular comorbidity. RESULTS: Systolic blood pressure (SBP) declined from 144 ± 26 to 133 ± 26 after 20 minutes, and to 131 ± 26 mmHg post HD, and for HDF from 152 ± 26 to 143 ± 27 after 20 minutes, then to 138 ± 27 mmHg post HDF. Net Ultrafiltration rates to achieve weight loss were similar; HD 0.13 ± 0.06 vs HDF 0.12 ± 0.05 mL/kg/min. PWVao did not change after 20 minutes HD 0.42(-0.7 to 1.3), HDF 0.5 (-0.6 to 1.8) or at the end of the session: HD -0.39 (1.5 to 1.2), HDF -0.41(-2.0 to 1.3) m/s. Aortic augmentation index (AiAxo), assessment of vascular tone fell significantly with both HD; 20 minutes by 6.2 (-2.5 to 14), end 5.6 (-6.7 to 13.9), and HDF 20 min by 4.2 (-2.5 to 10), end 7.8 (-0.8 to 19.3), with no difference between HD and HDF. The ultrafiltration rate correlated with % change in aortic SBP (r = 0.28 p = 0.004), but not with changes in PWVao or augmentation indices. CONCLUSIONS: Blood pressure declined during both HD and HDF treatments, as did augmentation indices, unrelated to weight loss, suggesting a reduction in vascular stiffness occurs independently of treatment modality. We did not observe an advantage for HDF.

Changes in Vascular Tone Occur Early During Hemodialysis Treatments Independently of Volume Reduction.

Hypotension commonly occurs during hemodialysis (HD). Hypotension can result from an absolute reduction in plasma volume following excessive ultrafiltration or from a reduction in vascular tone. We hypothesized that changes in vascular tone could occur during dialysis. Aortic pulse wave velocity (aPWV) was measured in 197 HD patients, mean age 63.3 ± 16.6 years, 62% male, 49% diabetic, during a single HD session. aPWV did not change (9.6 ± 2.2 vs. 9.6 ± 2.2 m/s) with HD. Systolic blood pressure (SBP) declined from 151 ± 31 to 147 ± 32 after 20 min and to 140 ± 36 mm Hg on completion of HD (P < 0.05), with an ultrafiltration volume of 2.2 ± 0.9 L over a 3.9 ± 0.4 h HD session. Aortic SBP declined from 154 ± 32 to 146 ± 29 after 20 min and 143 ± 35 at the end of HD, P < 0.001. Aortic augmentation index (Aortic Aix) decreased from 65% (52-79%) to 36.7% (23.3-52.9%) by 20 min and to 34.3 (15.1-49.1%) on completion of HD (P < 0.05), and brachial augmentation index (brachial Aix) from 5.7% (-25.2 to 27.5%) to -1.9% (-2.2 to 30.1%) and -6.6% (-44 to 22.7%), respectively, P < 0.05. Diastolic reflection area (DRA) increased from 36.7 (27.9-46.3) to 40.4 (32.2-51) after 20 min and 47.1 (34.2-60.5) on completion of HD, P < 0.05. We report changes in arterial tone within 20 min of starting HD, when minimal ultrafiltration has occurred, suggesting that volume changes may not be the only predisposing cause of intradialytic hypotension. The combination of a fall in SBP and a rise in DRA would suggest a reduction in coronary blood flow in keeping with reports of "myocardial stunning" during HD.

Glomerular expression of matrix metalloproteinases in AL-amyloidosis and association with renal function at the time of kidney biopsy.

BACKGROUND: Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of various renal diseases, however, there are limited data regarding their role in renal AL-amyloidosis. In the present study, we evaluated the glomerular expression of MMPs in renal-biopsy specimens containing AL-amyloid deposits. We also examined the association of MMPs with renal function at the time of diagnostic renal biopsy. METHODS: We performed immunohistochemistry with monoclonal antibodies against MMP-1, MMP-2, MMP-3, MMP-9, and TIMP-1 in 19 kidney-biopsy specimens with AL-amyloidosis and 8 specimens from normal kidney tissue. We used clinical data of the patients at the time of kidney biopsy to evaluate the association between MMP expression and renal function. RESULTS: We found increased MMP-1 and MMP-3 expression within the amyloid deposits and adjacent tissues in > 50% of the amyloid-positive biopsies, whereas MMP-1 and MMP-3 were negative in control samples. In contrast, we found no significant glomerular MMP-2 and TIMP-1 expression in amyloid-containing or normal kidneys. MMP-9 expression was found in the glomerular basement membrane equally in AL-amyloidosis and control specimens. The presence of MMP-1 and MMP-3 in the glomeruli of patients with AL-amyloidosis correlated with worse renal function at the time of kidney biopsy. CONCLUSION: The findings of this study show increased glomerular expression of MMP-1 and MMP-3 in patients with AL-amyloidosis which is associated with worse renal function at the time of the kidney biopsy. Our results suggest an important role for MMP-1 and MMP-3 in the pathogenesis of renal damage in AL-amyloidosis.

Early tumor-cell gene expression changes may predict the response to first-line bortezomib-based therapy in patients with newly diagnosed multiple myeloma.

PURPOSE: Maximizing the response rate to first-line therapy in patients with multiple myeloma (MM) is important because it leads to improved outcome. Gene-expression studies have identified prognostic gene sets in patients receiving bortezomib-based therapy. Comparison of the lists of genes derived from two gene-expression-based models (GEP70, GEP80) showed that they overlap in three genes, namely PSMD4, BIRC5, and KIAA1754. An unanswered question is whether early gene-expression changes can be used as predictors of the response to first-line bortezomib. In this study we aimed to examine the predictive value of gene expression changes for the depth of response after bortezomib-based therapy in newly diagnosed MM. METHODS: We prospectively assessed the relation between early PSMD4, BIRC5, and KIAA1754 gene expression changes (before therapy and one week later) and the response rate after bortezomib-based therapy in 25 patients with newly diagnosed MM. Gene expression was studied by RT-PCR on CD138-selected plasma cells, and changes were recorded as upregulation, downregulation, or unchanged. RESULTS: Whereas baseline prognostic factors including genetic lesions and stage were not predictive of the response rate, we found that early BIRC5 and KIAA1754 gene-expression changes were significantly associated with the depth of response to bortezomib (p=0.001 and p<0.001, respectively). PSMD4 was not predictive of the depth of response. KIAA1754 upregulation was linked to complete remission (CR) or very good partial remission (VGPR). BIRC5 upregulation was linked to stable disease (SD) or progressive disease (PD). We also observed that BIRC5 upregulation was associated with worse progression-free survival (PFS). CONCLUSIONS: Our results suggest that BIRC5 and KIAA1754 gene-expression changes may predict the response to bortezomib-based therapy. These data may have relevance for the stratification and early adaptation of first-line treatment in patients with newly diagnosed MM.

Treatment with haemodiafiltration stabilises vascular stiffness (measured by aortic pulse wave velocity) compared to haemodialysis.

BACKGROUND/AIMS: Cerebrovascular diseases such as stroke are increased in dialysis patients, and haemodiafiltration has been reported to reduce cerebrovascular mortality compared to haemodialysis. We wished to determine whether haemodiafiltration improves arterial stiffness. METHODS: We audited aortic pulse wave velocity (PWV) measurements 6 months apart in 3 cohorts of patients: 69 treated with haemodialysis, 78 who converted from haemodialysis to haemodiafiltration and 142 treated with haemodiafiltration. RESULTS: Cohorts were well matched for age (means ± SD: haemodialysis 64 ± 15 years vs. haemodialysis to haemodiafiltration 64 ± 17 years vs. haemodiafiltration 67 ± 16 years), sex (male 65 vs. 59 vs. 63%), diabetes (45 vs. 56.4 vs. 44%) and body mass index (26 ± 6 vs. 26 ± 5 vs. 26 ± 5), respectively. Systolic blood pressure did not differ over time (haemodialysis 143 ± 25 vs. 146 ± 27 mm Hg, haemodialysis to haemodiafiltration 153 ± 26 vs. 154 ± 25 mm Hg, haemodiafiltration 149 ± 31 vs. 148 ± 30 mm Hg) or between groups. Aortic PWV significantly increased in the haemodialysis group (9.5 ± 1.9 vs. 10.2 ± 2.2 m/s, p < 0.01) and haemodialysis to haemodiafiltration group (9.4 ± 1.9 vs. 10.1 ± 2.2 m/s, p < 0.01), but did not change with haemodiafiltration (9.9 ± 2.1 vs. 10.1 ± 2.2 m/s). CONCLUSIONS: Aortic PWV, a measure of vascular stiffness, stabilised with haemodiafiltration. Our preliminary findings require further investigation to determine how haemodiafiltration may potentially improve vascular stiffness.

Does hemodiafiltration reduce vascular stiffness measured by aortic pulse wave velocity compared with high-flux hemodialysis?

Hemodialfiltration (HDF) has been reported to reduce the frequency of intradialytic hypotension compared with hemodialysis (HD). We wished to determine whether HDF resulted in improvement of arterial stiffness compared with HD. We reviewed peripheral blood pressure and pulse wave velocity measurements in a cross-sectional analysis of stable HDF and HD outpatients. One hundred forty-one HDF patients were matched to 148 HD patients in terms of age, sex, prevalence of diabetes, peripheral blood pressure, and body mass. Pulse wave velocity was not different between the HD and HDF cohorts (median 9.1 [8.0-10.7] m/s vs. 9.7 [8.5-11.6] m/s). Similarly, there were no differences in central aortic pressure (149.2 ± 30.9 mmHg vs. 151.9 ± 35.2 mmHg), or aortic (39 [25.1-51.2]% vs. 38.6 [25.8-51.4]%) and brachial (3.8 [-24.3 to 26.9]% vs. 3 [-22.4 to 27.1]%) augmentation indices, respectively. Pulse wave velocity did not differ between adult patients treated by HD and HDF, and similarly, there were no differences in central aortic pressure, aortic or brachial augmentation indices, and cardiac diastolic perfusion. Our study suggests that HDF does not appear to offer any benefit over HD in terms of vascular stiffness.

Do higher dialysate calcium concentrations increase vascular stiffness in haemodialysis patients as measured by aortic pulse wave velocity?

BACKGROUND: Haemodialysis patients have an increased prevalence of hypertension and risk of cardiovascular mortality and stroke. Higher dialysate calcium concentrations have been reported to cause both an acute and chronic increase in arterial stiffness. We therefore looked at changes in arterial stiffness in established haemodialysis patients to determine whether there was a threshold effect of dialysate calcium concentration linked to change in arterial stiffness. METHODS: We performed pulse wave velocity measurements six months apart in patients dialysing with calcium concentrations of 1.0, 1.25, 1.35 and ≥1.5 mmol/l. RESULTS: 289 patients, 62.2% male, mean age 65.5 ± 15.7 years, weight body mass index 25.8 ± 5.4 kg/m2 ,47.9% diabetic were studied. Systolic blood pressure (SBP) was 148.4 ± 28.6 mmHg and diastolic blood pressure (DBP) 80.2 ± 15.5 mmHg. Mean pulse wave velocity increased over time (9.66 ± 2.0 vs 10.13 ± 2.16 m/s; p < 0.001), but there was no change in aortic augmentation index (38.7 ± 16.3 vs 39.8 ± 15.6%) or central aortic pressure (149.6 ± 33.3 vs 150.4 ± 31.9 mmHg).Pulse wave velocity did not differ between the four groups either at start or end of the study, but increased both in the groups dialysing with a calcium concentration of 1.0 mmol/l (9.64 ± 1.94 vs 10.45 ± 1.98 m/s, p = 0.0028) and also with 1.35 mmol/l (9.75 ± 1.96 vs 10.21 ± 2.18 m/s, p = 0.02). CONCLUSIONS: Pulse wave velocity increased over the six months study. As pulse wave velocity increased in the group dialysing using the lowest dialysate calcium, it is likely that factors, other than simple net calcium influx and efflux during dialysis according to dialysate calcium concentration are involved with vascular stiffening.

Primary renal MALT lymphoma presenting with cryoglobulinaemia.

Primary renal lymphoma is a rare clinicopathologic entity that typically presents as renal mass or renal impairment with enlarged kidneys. We describe the case of a 66-year-old woman who presented with type II mixed cryoglobulinaemic vasculitis as the first manifestation of underlying low-grade primary renal lymphoma.

Sclerosing peritonitis presenting 2 years after renal transplantation in a former CAPD patient.

Sclerosing peritonitis (SP) is a rare but serious complication of peritoneal dialysis (PD), characterized by a fibrous peritoneal thickening. The etiology of this condition remains unknown but is likely to be multifactorial. Patients with SP almost invariably develop ultrafiltration and clearance failure. Although a number of pharmacologic drug treatment options have been tried with various results, surgical treatment and cessation of PD are almost always necessary and transfer to hemodialysis is the only practical option. Despite some evidence supporting the recovery of gastrointestinal function after renal transplantation in such patients, SP may very rarely appear much later after the cessation of PD and even after renal transplantation. We report an interesting case of a former PD patient who 2 years after renal transplantation presented with abdominal discomfort, vomiting, and malnutrition due to SP. Despite the initial conservative treatment, the symptoms persisted and a surgical treatment was decided upon. After that the patient recovered with no further complications. Although the appearance of SP after renal transplantation is extremely rare, it must be included in the differential diagnosis of every case of unexplained malnutrition and abdominal obstruction in a patient with a PD history.

High levels of serum angiogenic growth factors in patients with AL amyloidosis: comparisons with normal individuals and multiple myeloma patients.

Serum levels of five angiogenic cytokines were evaluated in 82 patients with primary systemic amyloidosis (AL). Angiopoietin-1, vascular endothelial growth factor, basic fibroblast growth factor and angiogenin were higher in AL patients than in controls (n = 35) and newly-diagnosed, symptomatic, myeloma patients (n = 35). Angiopoetin-1/Angiopoetin-2 ratio was lower in AL compared to controls but higher than in myeloma patients. Angiopoetin-2 correlated with cardiac dysfunction indices; however, none of the angiogenic growth factors was prognostically significant. The increased angiogenic cytokine levels observed in AL seem to represent either a toxic effect of amyloid fibrils or light chains, or a compensatory response to organ dysfunction.

Syndrome of inappropriate secretion of antidiuretic hormone associated with imatinib.

OBJECTIVE: To describe a patient with Bcr-abl(+) acute lymphoblastic leukemia who developed the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) while being treated with high-dose imatinib. CASE SUMMARY: A 29-year-old woman was diagnosed with Bcr-abl(+) acute lymphoblastic leukemia, and treatment was initiated with chemotherapy and imatinib 800 mg daily. Following imatinib initiation, a gradual decrease in serum sodium level was noticed. Prolonged aplasia and neutropenic fever prompted discontinuation of therapy for 4 weeks. Following the patient's recovery, complete remission was achieved and monotherapy with imatinib 800 mg daily was restarted; however, hyponatremia recurred a few days later. The clinical findings and laboratory workup were compatible with the diagnosis of SIADH, which was attributed to high-dose imatinib. Fluid restriction and imatinib dosage reduction (to 600 mg/day) restored sodium levels. According to the Naranjo probability scale, this adverse reaction was probably associated with imatinib. DISCUSSION: Imatinib emerged as the first tyrosine kinase inhibitor to enter everyday clinical practice for the treatment of Ph(+) leukemias. Due to its molecular specificity, imatinib lacks the broad cytotoxicity of conventional chemotherapy. Inhibition of kinases in normal tissues accounts for many of imatinib's adverse reactions. To our knowledge, this is the first reported case of imatinib-induced SIADH. CONCLUSIONS: We recommend monitoring for SIADH if a patient receiving high-dose imatinib develops hyponatremia.