Elevated checkpoint inhibitor expression and Treg cell number in autosomal dominant polycystic kidney disease and their correlation with disease parameters and hypertension.

Autosomal dominant polycystic kidney disease (ADPKD) has cancer-like pathophysiology. In this study, we aimed to investigate the phenotype of peripheral blood (PB) T cell subsets and immune checkpoint inhibitor expression of ADPKD patients across different chronic kidney disease (CKD) stages. Seventy-two patients with ADPKD and twenty-three healthy controls were included in the study. The patients were grouped into five different CKD stages, according to glomerular filtration rate (GFR). PB mononuclear cells were isolated and T cell subsets and cytokine production were examined by flow cytometry. CRP levels, height-adjusted total kidney volume (htTKV), rate of hypertension (HT) differed significantly across different GFR stages in ADPKD. T cell phenotyping revealed significantly elevated CD3+ T cells, CD4+, CD8+, double-negative, and double-positive subsets and significantly elevated IFN-γ and TNF-α producing subsets of CD4+, CD8+ cells. The expression of checkpoint inhibitors CTLA-4, PD-1, and TIGIT by T cell subsets was also increased to various extent. Additionally, Treg cell numbers and suppressive markers CTLA-4, PD-1, and TIGIT were significantly elevated in ADPKD patients' PB. Treg CTLA4 expression and CD4CD8DP T cell frequency in patients with HT were significantly higher. Lastly, HT and increased htTKV and higher frequency of PD1+ CD8SP were found to be risk factors for rapid disease progression. Our data provide the first detailed analyses of checkpoint inhibitor expression by PB T cell subsets during stages of ADPKD, and that a higher frequency of PD1+ CD8SP cells is associated with rapid disease progression.

Peritoneal dialysis patient selection from a comorbidity perspective.

Despite many medical and socioeconomic advantages, peritoneal dialysis (PD) is an underutilized dialysis modality that in most countries is used by only 5%-20% of dialysis patients, while the vast majority are treated with in-center hemodialysis. Several factors may explain this paradox, such as lack of experience and infrastructure for training and monitoring of PD patients, organizational issues, overcapacity of hemodialysis facilities, and lack of economic incentives for dialysis centers to use PD instead of HD. In addition, medical conditions that are perceived (rightly or wrongly) as contraindications to PD represent barriers for the use of PD because of their purported potential negative impact on clinical outcomes in patients starting PD. While there are few absolute contraindications to PD, high age, comorbidities such as diabetes mellitus, obesity, polycystic kidney disease, heart failure, and previous history of abdominal surgery and renal allograft failure, may be seen (rightly or wrongly) as relative contraindications and thus barriers to initiation of PD. In this brief review, we discuss how the presence of these conditions may influence the strategy of selecting patients for PD, focusing on measures that can be taken to overcome potential problems.

Demographic, clinical and laboratory characteristics of rapidly progressive glomerulonephritis in Turkey: Turkish Society of Nephrology-Glomerular Diseases (TSN-GOLD) Working Group.

BACKGROUND: In our study, diagnostic and demographic characteristics of patients diagnosed with RPGN by biopsy, clinical and laboratory findings in our country were investigated. METHODS: Data were obtained from the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) Working Group database. Demographic characteristics, indications for biopsy, diagnosis of the glomerular diseases, comorbidities, laboratory and biopsy findings of all patients were recorded. According to their types, RPGN patients were classified as type 1 (anti-GBM related), type 2 (immuncomplex related) and type 3 (pauci-immune). RESULTS: Of 3875 patients, 200 patients with RPGN (mean age 47.9 ± 16.7 years) were included in the study which constitutes 5.2% of the total glomerulonephritis database. Renal biopsy was performed in 147 (73.5%) patients due to nephritic syndrome. ANCA positivity was found in 121 (60.5%) patients. Type 1 RPGN was detected in 11 (5.5%), type 2 RPGN in 42 (21%) and type 3 RPGN in 147 (73.5%) patients. Median serum creatinine was 3.4 (1.9-5.7) mg/dl, glomerular filtration rate was 18 (10-37) ml/min/1.73m2 and proteinuria 2100 (1229-3526) mg/day. The number of crescentic glomeruli ratio was ratio 52.7%. It was observed that urea and creatinine increased and calcium and hemoglobin decreased with increasing crescentic glomerular ratio. CONCLUSIONS: Our data are generally compatible with the literature. Advanced chronic histopathological findings were prominent in the biopsy of 21 patients. Early biopsy should be performed to confirm the diagnosis of RPGN and to avoid unnecessary intensive immunosuppressive therapy. In addition to the treatments applied, detailed data, including patient and renal survival, are needed.

Soluble vascular endothelial growth factor receptor-1 as a novel marker of arteriovenous fistula stenosis in hemodialysis patients.

INTRODUCTION: Arteriovenous fistula (AVF) stenosis is one of the most important clinical problems in hemodialysis patients. The histopathological findings of neointimal hyperplasia and impaired angiogenesis have been well established in stenotic AVFs. Soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) has been implicated in pathological angiogenesis. Thus, we aimed to investigate the association between sVEGFR-1 and AVF stenosis in hemodialysis patients. METHODS: This prospective cohort study included 70 patients with end-stage renal disease. Forty-five patients were included in the final analysis, and the median follow-up period was 36 months. Venous stenosis was detected by physical examination and documented by fistulography. Blood samples were analyzed a day before the fistula operation, and serum levels of sVEGFR-1 were measured. FINDINGS: The median sVEGFR-1 level was higher in the stenosis group than in the nonstenosis group (17 pg/mL [89.5%] vs. 5 pg/mL [19.2%], respectively; P < 0.001]. According to body mass index (BMI) categories, obese patients (BMI > 30 kg/m2 ) had the shortest stenosis-free survival (20 months [9.35-30.65]). Multivariate Cox analysis showed that sVEGFR-1, serum creatinine, and parathyroid hormone levels were associated with AVF stenosis risk. Kaplan-Meier survival curves showed that patients with less than the median value of sVEGFR-1 (<6093.07 pg/mL) had longer cumulative stenosis-free survival than patients with sVEGFR-1 levels above the median value (P < 0.001). DISCUSSION: Increased levels of sVEGFR-1 and obesity were found to be associated with AVF stenosis in hemodialysis patients.

Hypoxia-inducible factors in arteriovenous fistula maturation: A prospective cohort study.

BACKGROUND: Neointimal hyperplasia is the main cause of arteriovenous fistula (AVF) failure. Hypoxia-inducible factors (HIFs) factors are associated with neointimal hyperplasia. Thus, we investigated the association between HIF-2 alpha (HIF-2α) and AVF maturation in end-stage kidney disease (ESKD) patients. METHODS: This prospective cohort study was conducted in 21 voluntary healthy subjects and 50 patients with ESKD who were eligible for AVF creation. Inclusion criteria were being ESKD patients without a history of AVF surgery and dialysis. Eight patients excluded from the study due to having unavailable veins six patients were excluded due to acute thrombosis after surgery. One patient lost to follow-up. A total of 35 patients were included in final analysis. The blood samples were collected a day before the AVF surgery for biochemical parameters and HIF-2α measurement. HIF-2α levels were measured by the ELISA method. RESULTS: Compared with healthy subjects, ESKD patients had a significantly higher level of HIF-2α. [1.3 (1.0-1.9) vs 2.2 (1.6-3.0)] (P = .002). Patients were divided into two groups after the evaluation of AVF maturation, as the mature group (n = 19) and the failure group (n = 16). Serum HIF-2α level was 1.7 (1.1-1.8) in the mature group; however, it was 3.1 (2.8-3.3 in failure group (P < .001). Multiple logistic regression analyses showed that HIF-2α independently predicted AVF maturation. The ROC curve analysis showed that HIF-2α > 2.65 predicted AVF maturation failure with the 87% sensitivity and 94% specificity [AUC:0.947, 95% CI (0.815-0.994), P < .001]. CONCLUSIONS: HIF-2-α levels were higher in ESKD patients than healthy subjects. HIF-2-α could be a marker of AVF maturation failure.

Successful treatment of tubulointerstitial nephritis in immunoglobulin G4-related disease with rituximab: A case report.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated condition that consisted of disorders that share particular clinical, serologic and pathologic properties. The common presentation of disease includes tumor-like swelling of involved organs and the histopathological findings are a lymphoplasmacytic infiltrate enriched with IgG4-positive plasma cells, and a variable degree of fibrosis that has a characteristic "storiform" pattern in biopsy specimens of tumor-like masses. Major presentations of this disease, which often affects more than one organ, include autoimmune pancreatitis, salivary gland disease (sialadenitis), orbital disease and retroperitoneal fibrosis. The steroid treatment is essential for the treatment of the disease however, other immunosuppressive drugs including cyclophosphamide or rituximab could be an option in resistant cases. CASE SUMMARY: Herein, we reported a 34-year-old woman whom previously had diagnosed with asthma, rheumatoid arthritis and Sjögren's syndrome (SS) referred our nephrology department due to acute kidney failure development at the last rheumatology visit. After kidney biopsy she has been diagnosed with IgG4-RD and tubuluointerstitial nephritis. She had been accepted resistant to steroid, mycophenolate mofetil, methotrexate and azathioprine therapies due to receiving in last two years. She refused to receive cyclophosphamide due to potential gonadotoxicity of the drug. Thus, rituximab therapy was considered. She received 1000 mg infusion, 15 d apart and 6 mo later it has been administered same protocol. After one year from the last rituximab dose serum creatinine decreased from 4.4 mg/dL to 1.6 mg/dL, erythrocyte sedimentation rate decreased from 109 mm/h to 13 mm/h [reference range (RR) 0-20], and C-reactive protein decreased from 55.6 mg/L to 5 mg/L (RR 0-6). All pathologic lymph nodes and masses were also disappeared. CONCLUSION: Patients with IgG4-RD usually misdiagnosed with rheumatologic diseases including systemic lupus erythematous or SS and also they were screened for the presence of malignancy. Rituximab could be an important treatment option in cases with steroid resistant tubulointerstitial nephritis in IgG4-RD.

Systemic Succinate, Hypoxia-Inducible Factor-1 Alpha, and IL-1ß Gene Expression in Autosomal Dominant Polycystic Kidney Disease with and without Hypertension.

BACKGROUND AND OBJECTIVES: Cyst pressure induces renin-angiotensin-aldosterone system activation and kidney hypoxia in autosomal dominant polycystic kidney disease (ADPKD). Lipopolysaccharide-induced Toll-like receptor activation causes metabolic disturbances that are triggered by increased succinate levels and hypoxia inducible factors, which results in inflammation via IL-1ß activation. Since we aimed to investigate the role of both inflammation and hypoxia in the clinical course of ADPKD, via succinate levels from sera samples, HIF-1α gene expression from whole blood and urine samples and IL-1ßgene expression from whole blood were measured. METHODS: One hundred ADPKD patients and 100 matched healthy controls were enrolled to this cross-sectional study. Twenty-four-hour ambulatory blood pressure monitoring was conducted in all participants. Blood, serum, and urine samples were taken after 12-h fasting for the measurement of biochemical parameters and succinate levels. Whole blood and urine samples were used for HIF-1α and IL-1ß geneexpression by using quantitative real-time PCR. RESULTS: There were significant differences in whole blood HIF-1α, IL-1ß geneexpression, and serumsuccinate levels between the ADPKD patients and the control subjects. Whole blood HIF-1αgene expression, IL-1ß geneexpression, and serumsuccinate levels were also significantly different in ADPKD patients with hypertension in comparison with normotensive ones (p < 0.05). Serum succinate levels and blood IL-1ß geneexpression were increased in ADPKD patients with high levels of HIF-1α geneexpression (p = 0.018 and p = 0.029, respectively). CONCLUSIONS: Increased age,low eGFR, and HIF-1α and IL-1ß geneexpressions were also independently associated with hypertension in ADPKD patients. Inflammation and hypoxia are both relevant factors that might be associated with hypertension in ADPKD.

Brown tumor of the thoracic spine presenting with paraplegia in a patient with peritoneal dialysis.

Secondary and tertiary hyperparathyroidism is an important problem of chronic kidney disease. Brown tumor is a benign, unusual, reactive lesion as a result of disturbed bone remodeling, from long-standing increase in parathyroid hormone level. Brown tumors may cause morbidity due to pressure symptoms on neural structures and spontaneous bone fractures. Herein, we presented a peritoneal dialysis patient with tertiary hyperparathyroidism under calcand calcitriol treatment for 4 years due to refusing of the parathyroidectomy operation. She admitted to hospital for sudden onset back pain with difficulty in gait and walking, and imaging studies showed an expansile mass lesion in the thoracic spine. She was operated for mass and diagnosed with brown tumor. After operation, she lost the ability of walking than become paraplegic and she underwent rehabilitation program. Preventive measures including calcitriol and cinacalcet may cause a modest decrease in parathyroid hormone levels but it should be remembered for the development of bone complications such as brown tumor formation in patients with moderate elevated PTH levels, especially those with tertiary hyperparathyroidism. Parathyroidectomy should be performed without delay in these cases.

Acute renal infarction in Turkey: a review of 121 cases.

PURPOSE: Renal infarction is a clinical condition which is caused by renal artery occlusion and leads to permanent renal parenchymal damage. In the literature, there are generally case reports on this subject, and few studies that include a large group of patients. Therefore, we aimed to present the data of a large group of patients who were diagnosed with acute renal infarction in our country in this retrospective study. METHODS: The data of patients who were diagnosed with acute renal infarction according to clinical and radiological findings in Turkey in the last 3 years were examined. For this purpose, we contacted with more than 40 centers in 7 regions and obtained support from clinically responsible persons. Demographic data of patients, laboratory data at the time of diagnosis, tests performed for etiologic evaluation, given medications, and patients' clinical status during follow-up were obtained from databases and statistical analysis was performed. RESULTS: One-hundred and twenty-one patients were included in the study. The mean age was 53 ± 1.4 (19-91) years. Seventy-one (58.7%) patients were male, 18 (14.9%) had diabetes, 53 (43.8%) had hypertension, 36 (30%) had atrial fibrillation (AF), and 6 had a history of lupus + antiphospholipid syndrome (APS). Forty-five patients had right renal infarction, 50 patients had left renal infarction, and 26 (21.5%) patients had bilateral renal infarction. The examinations for the ethiologies revealed that, 36 patients had thromboemboli due to atrial fibrillation, 10 patients had genetic anomalies leading to thrombosis, 9 patients had trauma, 6 patients had lupus + APS, 2 patients had hematologic diseases, and 1 patient had a substance abuse problem. Fifty-seven (57%) patients had unknown. The mean follow-up period was 14 ± 2 months. The mean creatinine and glomerular filtration rate (GFR) values at 3 months were found to be 1.65 ± 0.16 mg/dl and 62 ± 3 ml/min, respectively. The final mean creatinine and GFR values were found to be 1.69 ± 0.16 mg/dl and 62 ± 3 ml/min, respectively. CONCLUSIONS: Our study is the second largest series published on renal infarction in the literature. More detailed studies are needed to determine the etiological causes of acute renal infarction occurring in patients.

Clinical problems in hemodialysis patients with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disease characterized by massive enlargement of fluid-filled cysts in the kidney. Due to its genetic pattern, the disease differs from other CKD. ADPKD is a multi-system, progressive disorder which is frequently complicated with hypertension, cardiovascular events and cerebrovascular disease. Thus, there are many clinical problems specific to ADPKD. In this article, we reviewed these clinical problems and their management in ADPKD with hemodialysis patients.

Cutaneous ulcerations caused by Paecilomyces variotii in a renal transplant recipient.

Skin infections caused by Paecilomyces species have been rarely described in patients with solid organ transplantation. Cutaneous manifestations are highly variable and include erythematous macules, nodules, pustules, and vesicular and necrotic lesions. The diagnosis of these infections is generally made by examination of a skin biopsy. Management of these fungal infections is difficult due to the immunocompromised state of the patients. Moreover, antifungal therapy and immunosuppressive drug interactions should be considered during treatment management. Herein, we reported a case of cellulitis caused by Paecilomyces variotii in a 56-year-old man who had undergone a kidney transplantation. Erythematous macular and nodular lesions on the left hand and left foot appeared first; within 2 months the skin lesions became ulcerated, hemorrhagic, and progressively painful and the patient was admitted to our hospital. The diagnosis was made by skin biopsy and tissue culture. The skin lesions resolved by the sixth week of the treatment with voriconazole.

Long-Term Protective Effect of N-Acetylcysteine against Amikacin-Induced Ototoxicity in End-Stage Renal Disease: A Randomized Trial.

BACKGROUND: The aim of the study is to evaluate the long-term protective effect of N-acetylcysteine (NAC), an antioxidant agent, against aminoglycoside (AG)-induced ototoxicity. METHODS: A total of 40 patients receiving continuous ambulatory peritoneal dialysis (CAPD) and having their first peritonitis attacks and planned to be treated with AGs were enrolled in the study. They were randomized into 2 groups: 1 group received additional NAC and the other did not. All patients underwent hearing tests with pure tone audiometry (PTA) after the diagnosis, at 1 month and 12 months and at the same time the tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were measured. RESULTS: Patients taking NAC had better hearing test results in both ears at 1 month except 2,000 Hz for the left ear, which wasn't significantly different between the 2 groups. Although patients taking NAC had generally better PTA results at 12 months, differences between the 2 groups were not statistically significant. Baseline IL-6 level was significantly higher in the NAC group than the control group. Both TNF-α and IL-6 levels at 1 month were significantly lower in the NAC group than in the control group. On the other hand, there was no significant difference between the 2 groups in terms of TNF-α and IL-6 levels at 12 months. CONCLUSIONS: The results of the current study showed that NAC, a potent anti-inflamatory drug, may be otoprotective, but that the effect is not long-lasting.

Unicentric Castleman's disease associated with end stage renal disease caused by amyloidosis.

Castleman's disease (CD), also known as angiofolicular lymph node hyperplasia, is a rare heterogenous group of lymphoproliferative disorders. Histologically, it can be classified as hyaline vascular type, plasma cell type, or mixed type. Clinically two different subtypes of the CD are present: Unicentric and multicentric. Unicentric CD is generally asymptomatic and associated with hyaline vascular type, and its diagnoses depend on the localized lymphadenopathy on examination or imaging studies. However, multicentric CD presents with generalized lymphadenopathy and systemic symptoms including malaise, fever, night sweats, weight loss, and it is associated with the plasma cell type and mix type. Herein, we report a patient with unicentric CD of the plasma cell type without systemic symptoms, who developed end stage renal failure caused by amyloidosis 6 years after onset of CD.

Vasopressin-related copeptin is a novel predictor of early endothelial dysfunction in patients with adult polycystic kidney disease.

BACKGROUND: In this study, we examined the relative usefulness of serum copeptin levels as a surrogate marker of vasopressin (AVP) in adult polycystic kidney disease (ADPKD) by correlating it with baseline and longitudinal changes in markers of both renal function and common CVD manifestations (hypertensive vascular disease, atherosclerosis and endothelial dysfunction) that accompany the progression of this disease. METHODS: We studied a cohort of young and otherwise healthy ADPKD patients (n = 235) and measured cardiovascular function using flow-mediation dilatation (FMD), carotid intima media thickness (cIMT) and pulse wave velocity (PWV), as well as serum copeptin (commercial ELISA, a stable marker of AVP activity). The same analyses were carried out at baseline and after 3 years of follow-up. RESULTS: At baseline, median eGFR was 69 mL/min./1.73 m2, mean FMD 6.9 ± 0.9%, cIMT 0.7 ± 0.1 mm, and PWV 8.1 ± 1.2 m/s. At follow-up, equivalent values were 65 (44-75) mL/min./1.73 m2, 5.8 ± 0.9%, 0.8 ± 0.1 mm. and 8.2 ± 1.3 m/s. with all changes statistically significant. Plasma copeptin also rose from 0.62 ± 0.12 to 0.94 ± 0.19 ng/mL and this change correlated with ΔeGFR (-0.33, p < 0.001), ΔFMD (0.599, p < 0.001), ΔcIMT (0.562, p < 0.001) and ΔPWV (0.27, p < 0.001) also after linear regression modeling to correct for confounders. Finally, ROC analysis was done for a high baseline copeptin with ΔeGFR [cut-off:≤59], ΔFMD [cut-off: ≤7.08], ΔcIMT [cut-off:>0.76], and ΔPWV [cut-off:≤7.80]. CONCLUSIONS: Vascular dysfunction as reflected by FMD and cIMT, but not PWV or an altered cardiac geometry, precede most other signs of disease in ADPKD but is predicted by elevated levels of the circulating AVP-marker copeptin.

Drug Induced Lupus Erythematosus Due to Capecitabine and Bevacizumab Treatment Presenting with Prolonged Thrombocytopenia.

Drug induced lupus erythematosus (DLE) is a syndrome that is formed by lupus-like symptoms and laboratory characteristics. Capecitabine is an orally administered tumor-selective fluoropyrimidine that acts as a prodrug of 5-Fluorouracil and bevacizumab is an antivascular endothelial growth factor (anti-VEGF) antibody, both are used for the treatment of patients with colorectal cancer. Herein we report the first case of DILE in a 68-year-old woman who presented with arthralgia, myalgia and prolonged thrombocytopenia after receiving capecitabine and bevacizumab combination treatment as palliative treatment for metastatic colon cancer. Platelet-levels were increased and joint complaints disappeared in the first week of hydroxychloroquine and methylprednisolone treatment after chemotherapy had been discontinued. In conclusion, physicians should be alert to the possibility of DILE in patients presenting with thrombocytopenia under a capecitabine and bevacizumab chemotherapy regimen.

Carpal tunnel release surgery and venous hypertension in early hemodialysis patients without amyloid deposits.

AIM: Carpal tunnel syndrome (CTS) is one of the frequent problems of the patients who underwent hemodialysis (HD). The role of venous hypertension due to arteriovenous fistula (AVF) has not been clarified completely; therefore, we aimed to investigate the role of venous hypertension due to AVF in hemodialysis patients who had CTS. PATIENTS AND METHODS: We included 12 patients who had been receiving HD treatment for less than 8 years and the newly diagnosed CTS patients with the same arm of AVF. All patients were diagnosed clinically and the results were confirmed by both nerve conduction studies and electromyography. Open carpal tunnel release surgery was performed on all of them. Venous pressure was measured in all patients before and after two weeks of surgery. RESULTS: There were significant differences before and after the surgery with regard to pressures (P > 0.05). After the surgery, all carpal ligament specimens of the patients were not stained with Congo red for the presence of amyloid deposition. CONCLUSION: Increased venous pressure on the same arm with AVF could be responsible for CTS in hemodialysis patients. Carpal tunnel release surgery is the main treatment of this disease by reducing the compression on the nerve.

Unusual clinical presentation of ethylene glycol poisoning: unilateral facial nerve paralysis.

Ethylene glycol (EG) may be consumed accidentally or intentionally, usually in the form of antifreeze products or as an ethanol substitute. EG is metabolized to toxic metabolites. These metabolites cause metabolic acidosis with increased anion gap, renal failure, oxaluria, damage to the central nervous system and cranial nerves, and cardiovascular instability. Early initiation of treatment can reduce the mortality and morbidity but different clinical presentations can cause delayed diagnosis and poor prognosis. Herein, we report a case with the atypical presentation of facial paralysis, hematuria, and kidney failure due to EG poisoning which progressed to end stage renal failure and permanent right peripheral facial nerve palsy.

Mesangial proliferative glomerulonephritis in familial Mediterranean fever patient with E148Q mutation: the first case report.

Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease characterized by recurrent attacks of fever, usually accompanied by sterile polyserositis. Although amyloidosis is the most common renal involvement, non-amyloid renal lesions, such as glomerulonephritis, have been described in patients with FMF. In this report, we present the first case of an FMF patient with heterozygous mutation of E148Q, mesangial proliferative glomerulonephritis, and no amyloidosis. While the association of mutation E148Q with renal involvement is still obscure, colchicine treatment is useful in mesangial proliferative glomerulonephritis with FMF.