Galip Guz

Current perspectives on familial Mediterranean fever.

Purpose of review The gene responsible for familial Mediterranean Fever (FMF), MEditerranean FeVer (MEFV), was identified two decades ago; however, only recent studies have shed light on its pathogenesis. This review focuses on recent studies that have led us to more fully understand FMF pathogenesis. Recent findings The vast majority of FMF-associated mutations are located in the B30.2 (SPRY) domain, which functions as a ligand binding or a signal transduction domain, at the carboxy terminus of the protein. As a result, B30.2 mutations may lead to postponed apoptosis and inflammation due to the reduced ability of pyrin to control interleukin-1β (IL-1β) activation. Development of AA amyloidosis is rare in FMF patients without amyloidogenic single nucleotide polymorphisms (SNPs) (713T allele) of the SAA1 gene. High macrophage inflammatory protein-1α levels during FMF attacks might be responsible for the enhancement of T-cell mediated immunity in FMF. IL-1β-511 (C/T), IL-1β+3953 (C/T) and IL-1Ra VNTR polymorphisms were not associated with the development of amyloid in FMF patients. Summary Future studies should focus on defining the impact of MEFV and other mutations on the pathological course of FMF, and to understand the exact pathophysiology of those patients who are unresponsive to colchicine, which may help to develop novel therapeutic options for the management and improvement of prognosis.

Alterations in ocular surface and corneal thickness in relation to metabolic control in patients with chronic renal failure

Aim:  Ocular surface changes and ocular symptoms may be encountered in patients with chronic renal failure (CRF) undergoing haemodialysis. The ocular surface changes and its relationship with metabolic control in CRF patients were aimed to be emphasized in this study.

STOBADINE PROTECTS RAT KIDNEY AGAINST ISCHAEMIA/REPERFUSION INJURY

1 Ischaemia–reperfusion (I/R) injury, one of the main causes of acute renal failure, still needs satisfactory treatment for routine clinical application. Stobadine, a novel synthetic pyridoindole anti‐oxidant, has the ability to reduce tissue injury induced by mechanisms involving reactive oxygen species during I/R. The aim of the present study was to determine the effects of stobadine on renal I/R injury. 2 Forty male Wistar rats were randomly divided into four groups as follows: sham, I/R, stobadine treated and I/R + stobadine treated. Stobadine (2 mg/kg, i.v.) was given intravenously to two groups of rats. The stobadine‐treated group was treated with stobadine following sham operation before the abdominal wall was closed, whereas the I/R + stobadine group received stobadine at the beginning of reperfusion. Renal I/R was achieved by occluding the renal arteries bilaterally for 40 min, followed by 6 h reperfusion. Immediately thereafter, blood was drawn and tissue samples were harvested to assess: (i) serum levels of blood urea nitrogen and creatinine; (ii) serum and/or tissue levels of malondialdehyde (MDA), glutathione (GSH), glucose 6‐phosphate dehydrogenase (G‐6PD), 6‐phosphogluconate dehydrogenase (6‐PGD), glutathione reductase (GR) and glutathione peroxidase (GPx); (iii) renal morphology; and (iv) immunohistochemical staining for P‐selectin. 3 Stobadine was able to significantly attenuate the renal dysfunction as a result of renal I/R injury. Iscahemia–reperfusion resulted in a significant increase in serum and kidney MDA levels and a decrease in serum and kidney GSH. Stobadine treatment at the beginning of reperfusion attenuated both the increased MDA levels and decreased GSH secondary to I/R injury. In addition, the decreased G‐6PD activity observed after I/R was significantly attenuated by stobadine treatment. Stobadine did not alter 6‐PGD activity after I/R. Neither GR nor GPx activity was significantly changed in the I/R alone or the I/R + stobadine groups compared with the sham group. In addition, stobadine decreased the morphological deterioration and high P‐selectin immunoreactivity secondary to renal I/R injury. 4 A pyridoindole anti‐oxidant, stobadine exerts a renal protective effect in renal I/R injury, which is probably due to its radical‐scavenging and anti‐oxidant activities.

The effect of taurine on renal ischemia/reperfusion injury

Summary.Ischemia-reperfusion (I/R) injury is one of the most common causes of renal dysfunction. Taurine is an endogenous antioxidant and a membrane-stabilizing, intracellular, free beta-amino acid. It has been demonstrated to have protective effects against I/R injuries to tissues other than kidney. The aim of this study was to determine whether taurine has a beneficial role in renal I/R injury. Forty Wistar-Albino rats were allocated into four groups as follows: sham, taurine, I/R, and I/R + taurine. Taurine 7.5 mg/kg was given intra-peritoneally to rats in the groups taurine and I/R + taurine. Renal I/R was achieved by occluding the renal arteries bilaterally for 40 min, followed by 6 h of reperfusion. Immediately thereafter, blood was drawn and tissue samples were harvested to measure 1) serum levels of BUN and creatinine; 2) serum and/or tissue levels of malondialdehyde (MDA), glutathione (GSH), glucose 6-phosphate dehydrogenase (G-6PD), 6-phosphogluconate dehydrogenase (6-PGD) and glutathione reductase (GSH-red); 3) renal morphology; and 4) immunohistochemical staining for P-selectin. Taurine administration reduced I/R-induced increases in serum BUN and creatinine, and serum and tissue MDA levels (p < 0.05). Additionally, taurine lessened the reductions in serum and tissue glutathione levels secondary to I/R (p < 0.05). Taurine also attenuated histopathologic evidence of renal injury, and reduced I/R-induced P-selectin immunoreactivity (p < 0.05). Overall, then, taurine administration appears to reduce the injurious effects of I/R on kidney.

The Relationship between the MEFV Genotype, Clinical Features, and Cytokine-Inflammatory Activities in Patients with Familial Mediterranean Fever

Familial Mediterranean Fever (FMF) is an autosomal recessive disease characterized by periodic attacks of fever and polyserositis. The effects of the MEFV genotype differences on clinical picture and inflammatory activity have not been well documented. The aim of this study was to investigate levels of conventional inflammation markers, procalcitonin, interleukin levels, TNF-alpha, and C5a levels in patients with FMF who had different MEFV genotypes and compare them with those of healthy subjects. The study consisted of 41 patients with FMF (F/M: 23/18), and 31 healthy subjects (F/M: 18/13). Tests were performed during the attack-free period. White-blood cell count, CRP and IL-8 levels were higher in patients with FMF than in healthy subjects (p < 0.05) and also higher in M680I carriers than in the patients with M694V allele carriers. However, ESR, fibrinogen, procalcitonin, IL-6, C5a, TNF-alpha, and IgD levels were not significantly different between patients and healthy subjects (p > 0.05). Arthralgia or arthritis was significantly higher in M694V carriers than in non-M694V carriers (p < 0.05). It is concluded that the clinical features and inflammatory-cytokine activities were higher in patients with FMF during the attack-free period than in healthy subjects, and the different genotype might be related to different clinical pictures.

A Comparative Study of the Effects of Hemin and Bilirubin on Bilateral Renal Ischemia Reperfusion Injury

Background/Aims: The aim of this study was to determine the effects of hemin, a heme oxygenase-1 inducer, and bilirubin on renal ischemia-reperfusion (I-R) injury. Methods: 40 Wistar-Albino rats were allocated into six groups as follows: sham (S), bilirubin (B), hemin (H), ischemia/reperfusion (IR), IR + bilirubin (IRB) and IR + hemin (IRH). Conjugated bilirubin (20 mg·kg–1 i.v.) was given to rats in groups B and IRB, and hemin (50 mg·kg–1 i.p.) was given to rats in groups H and IRH just prior to reperfusion. Renal I-R was achieved by occluding the renal arteries bilaterally for 50 min. Following 6 h of reperfusion, blood was drawn to study BUN, creatinine and bilirubin, and tissue samples were harvested to determine the renal malonyldialdehyde and heme oxygenase-1 levels, and for histopathologic grading. Results: BUN, creatinine and malonyldialdehyde levels in group IRH were similar to controls whereas the results of groups IR and IRB were significantly higher (p < 0.01). There was a grade 2 damage in all I-R groups. Conclusion: This study showed the preventive effect of hemin on renal ischemia reperfusion injury. Administration of exogenous bilirubin did not prevent the I-R injury.

Peritonitis due to Lactococcus lactis in a CAPD patient

Lactococcus lactis is a Gram-positive bacterium, commonly used in the dairy industry. Although Lactococcus lactis is known to be non-pathogenic for humans, it can cause infection in immunocompromized patients. We report a case of peritonitis due to L. lactis in a continuous ambulatory peritoneal dialysis patient, which is the second reported case in the literature.

Gastric Emptying in Patients on Renal Replacement Therapy

In addition to gastrointestinal tract symptoms such as nausea, vomiting, and loss of appetite, impaired gastric emptying time (GET) may be related to nutritional parameters and nutritional status of patients on renal replacement therapy (RRT). Patients on RRT are affected by several factors such as uremic toxins, the presence of dialysate in the peritoneal cavity, and the drugs used against renal allograft rejection. In this study, we investigated the gastric emptying time and its relationship with biochemical and nutritional parameters in patients on RRT: those on hemodialysis and peritoneal dialysis, and renal transplantation patients. Seventy‐five patients, 44 on hemodialysis, 16 on peritoneal dialysis, and 15 renal transplant patients, were included in the study. They were examined for gastric emptying time using a radioisotopic method. The results were compared with the GET of healthy subjects. Each group of patients was evaluated in terms of hemoglobin, hematocrit, blood urea nitrogen (BUN), creatinine, blood glucose, total protein, albumin, serum lipids, parathyroid hormone (PTH) and body mass index and biceps and triceps skinfold. The mean GET of patients on RRT was significantly longer than the mean GET of healthy subjects (87.8 ± 23.4 vs. 55 ± 18 min, p < 0.05). The mean GET of each therapy subgroups was significantly longer than the healthy subjects (the mean GET was 85.1 ± 22.4 min for hemodialysis, 87.7 ± 31.8 min for peritoneal dialysis, and 94.6 ± 16.7 min for renal transplant patients, respectively, p < 0.05). On the other hand, the differences in the mean GET between the three therapy subgroups were not statistically significant (p > 0.05). In addition, time on replacement therapy inversely and blood glucose positively correlated with GET in renal transplant patients. In conclusion, GET was longer in patients on all three RRT modalities than in healthy subjects. GET was not significantly different in dialysis patients and renal transplant patients.

Association of the Angiotensinogen M235T and APO E Gene Polymorphisms in Turkish Type 2 Diabetic Patients with and without Nephropathy

Background: Diabetic nephropathy (DN) is a leading cause of diabetes-related morbidity and mortality. The aim of this study was to evaluate the relationship of AGT M235T and apoprotein E (APO E) gene polymorphism with DN in Turkish patients of Type 2 diabetes, and to compare genotype and allele distributions among DN patients, non-DN patients, and healthy controls. Methods: AGT M235T and APO E genotype and allele analysis were performed in 111 DN patients, 108 non-DN patients, 106 healthy control subjects for APO E genotype, and 100 for AGT M235T genotype polymorphism. APO E and AGT M235T genotype were determined by RFLP-PCR. Results: The frequencies of APO E ε2/3, ε 3/3, ε 3/4 genotypes were 22.7%, 60%, 60%, respectively, among DN patients and 6.6%, 80%, 10.4%, respectively (p < 0.001), in the non-DN patients. The frequencies of AGT M235T MM, MT, TT genotypes among the same groups were 17%, 46%, 37% and 21%, 63%, 16%, respectively (p < 0.02). Having the ε2/3 genotype and TT genotype increased the risk for DN nephropathy [4.8-fold (95% CI: 1.94–11.67), 2.9-fold (95% CI: 1.27–6.69), respectively]. Conclusion: Our study has shown that AGT M235T TT genotype and APO E ε 2/3 genotype may be linked to a risk for DN among Turkish population.

Sunitinib- and Sorafenib-Induced Nephrotic Syndrome in a Patient with Gastrointestinal Stromal Tumor

Objective TO report a case of nephrotic syndrome (NS) induced by both sunitinib and sorafenib therapy. Case Summary A 61-year-old woman with metastatic gastrointestinal stromal tumor (GIST) presented with NS and hypertension following therapy with sunitinib 400 mg/day. Because of grade 3 toxicity, the drug was discontinued. After sunitinib discontinuation, NS and hypertension resolved. However, NS recurred on rechallenge. A similar picture developed following therapy with sorafenib 800 mg/day. A renal biopsy revealed a focal segmental glomerulosclerosis (FSGS). A few months after sorafenib cessation, resolution of NS and hypertension was again achieved. Discussion Several cases of NS have been reported among patients receiving sunitinib and sorafenib. However, renal histopathologic data were obtained in only a few patients. Although biopsy-proven cases of FSGS associated with sunitinib have been reported, this is, to our knowledge, the first reported case of biopsy-proven FSGS associated with sorafenib. The Naranjo probability scale indicated probable causality for NS developing with sorafenib, and definite causality with sunitinib. The clinical and histopathologic findings have led us to agree with the class effect proposal that all antiangiogenic drugs share a similar toxicity profile. Evidence supporting this hypothesis includes worsening of hypertension and proteinuria by both drugs, with full recovery occurring within a few months after cessation of the drugs, which favors the role of vascular endothelial growth factor receptor inhibition in FSGS development. Conclusions The clinical adverse spectrum of antiangiogenic drugs may be broader than initially observed because of a lack of renal biopsy data and routine screening for proteinuria. It can be speculated that proteinuria, as well as hypertension, is a class effect of all antiangiogenic drugs.