Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis.

Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies.

P2X(7) receptor at the heart of disease.

Purinergic signaling is a crucial component of disease whose pathophysiological basis is now well established. This review focuses on P2X(7), a unique bifunctional purinoreceptor that either opens a non selective cation channel or forms a large, cytolytic pore depending on agonist application and leading to membrane blebbing and to cell death either by necrosis or apoptosis.Activation of P2X(7) receptor has been shown to stimulate the release of multiple proinflammatory cytokines by activated macrophages, with the IL-1b to be the most extensively studied among them. These findings were verified by the use of knockout P2X(7) ((-/-)) mice.Update information coming from all fields of research implicate this receptor at the very heart of diseases such as rheumatoid arthritis, multiple sclerosis, depression, Alzheimer disease, and to kidney damage, in renal fibrosis and experimental nephritis.Clinical studies are currently underway with the newly developed selective antagonists for P2X(7) receptor, the results of which are eagerly anticipated. These studies together with data from in-vivo experiments with the P2X(7) knockout mice and in-vitro experiments will shed light in this exciting area.

Brain dead donor kidneys are immunologically active: is intervention justified?

The improvement in the field of kidney transplantation, during the last decades, has brought kindey transplantation to the top of patient preference as the best kidney replacement therapy. The use of marginal kidney grafts, which are highly immunogenic has become common practice because of lack of kidney donors. Inflammatory activity in the kidneys after brain death is an ongoing phenomenon. The inappropriate treatment of brain dead donor may result to primary non function (PNF) of the graft, delayed graft function (DGF) or to long term graft dysfunction and shortened graft survival. Therefore correct handling of the brain dead donor is of paramount importance. The impact of various pharmacologic agents (catecholamines, glucocorticoids, carbamylated recombinant human erythropoietin, recombinant soluble P-selectin glycoprotein ligant, heme oxygenase-1, carbon monoxide, and mycophenolate mofetil) on the immunogenicity of brain dead donor kidneys is discussed.

Renal fibrosis.

Tubulointerstitial renal fibrosis, characterized as a progressive detrimental connective tissue deposition on the kidney parenchyma, appears to be a harmful process leading inevitably to renal function deterioration, independently of the primary renal disease which causes the original kidney injury. Epithelial to Mesenchymal Transition (EMT) of tubular epithelial cells which are transformed to mesenchymal fibroblasts migrating to adjacent interstitial parenchyma constitutes the principal mechanism of renal fibrosis along with local and circulating cells. Proteinuria as well as hypoxia is included among the main mechanisms of EMT stimulation. TGFbeta-1 through the SMAD pathway is considered as the main modulator regulating the EMT molecular mechanism, probably in cooperation with hypoxia inducible factors. Hepatocyte Growth Factor (HGF) and Bone Morphogenetic Factor-7 (BMF-7) are inhibitory to EMT molecules which could prevent in experimental and clinical level the catastrophic process of interstitial fibrosis. Interesting data emerge indicating that HGF and BMF-7 administration prevents the peritoneal fibrosis of mesothelial cells.

Use of everolimus in de novo renal recipients: initial experience in the Greek population.

Although everolimus has proven to be as clinically efficacious as mycophenolate mofetil (MMF), there are reports that proliferation signal inhibitors are associated with poor tolerability. This study reported the experience of a Greek transplant center using either everolimus or MMF in de novo renal transplant recipients. In this retrospective study, a cohort of 40 patients who received everolimus after renal transplant was matched for 10 descriptive parameters with a cohort of another 40 patients who received MMF. The primary endpoint was renal function measured by creatinine and its clearance as well as wound dehiscence and opportunistic infections. The mean creatinine clearance at month 3 was 61.03 +/- 16.99 mL/min versus 60.99 +/- 8.03 for living related recipients on everolimus versus MMF, respectively. The mean creatinine clearance at month 3 was 71.24 +/- 12.61 and 62.61 +/- 20.24 mL/min for cadaveric recipients on everolimus versus MMF, respectively. In addition, the incidence of wound dehiscence was 33.34% versus 3.92% and the incidence of cytomegalovirus infection, 8.33% versus 17.64% for the same two groups, respectively.

Outcomes of kidney transplantation in Greek and Albanian patients: a single centre experience.

BACKGROUND AND AIM: It has been reported that racial and ethnic (genetic make up), as well as socioeconomic differences may affect the results of kidney transplantation. Socioeconomic factors are quite difficult to differentiate from genetic factors. It is not surprising that a group with poorer access to health care, less private insurance and less income does less well with serious medical problems. The aim of this study was to compare the outcomes of kidney transplantations in Greek (G) and Albanian (A) patients. PATIENTS AND METHODS: Twenty nine transplanted patients of Albanian ancestry were matched with 29 Greek patients retrospectively. Their mean age was 34 (G) and 31 (A) years, there were 21 men and 8 women in each group (G, A) and they received 26 kidneys from living related donors and 3 kidneys from cadaveric donors respectively. Arterial blood pressure (ABP), body weight (BW), serum creatinine, serum total protein and albumin, total cholesterol, HDL-cholesterol and triglycerides, 24 hour proteinuria were measured on 7th, 15th postoperative day, 1st , 3rd , 6th month and 1st year after transplant. BMI was calculated before and 1 year after transplantation and acute rejection episodes were recorded too. Methylprednizolone (MP), cyclosporine (CsA) dose /kg BW were calculated at baseline, 1, 3, 6, 12 months after transplant. Cumulative patient and graft survival at 1 and 5 years were calculated too. RESULTS: Patient survival at 1 and 5 years was 100% / 93.1% and 100% /93.1% respectively (p: NS). Graft survival at 1 and 5 years was 100% / 93.10% and 93.75% / 86.45% respectively (p: NS). BW (but not BMI) and total cholesterol levels in Greek patients were higher compared to those of Albanian patients during the 1st post transplant year (p: 0.044 and p: 0.021 respectively). MP dose in A patients was higher during the first year (p: 0.05). CONCLUSION: Patients and graft survival do not present difference between G and A patients. There is significant difference on cholesterol profile between G and A patients. A larger number of transplants are possibly needed to allow us to draw firm conclusions.

Cardio-renal anemia syndrome.

The interaction between chronic heart failure, chronic kidney insufficiency and anemia, form a vicious cycle, termed as the cardio-renal anemia syndrome. The interaction between these three conditions causes deterioration of the cardiac and renal function and increases anemia. Each of the three can cause or be caused by the others.We herein analyze and speculate the mechanisms involved in the pathophysiology of this new syndrome highlighting the main points of interest that seem to expand upon more than one specialty. The cardio-renal anemia syndrome is emerging in the area of clinical investigation with progressively elevated significance. Additionaly we report the data related to anemia treatment as part of therapeutic perspective concerning the management of patients manifesting the profile of this syndrome.

Interventional nephrology: a new subspecialty of nephrology.

Interventional Nephrology is a new and emerging subspecialty of Nephrology that mainly deals with ultrasonography of kidneys and ultrasound-guided renal biopsy, insertion of peritoneal dialysis catheters, tunneled dialysis catheters as a vascular access for patients undergoing hemodialysis as well as percutaneous endovascular procedures performed to manage dysfunction of arteriovenous fistulas or grafts in end stage renal disease patients. Traditionally, these procedures have been delegated to a variety of specialists with resultant delays in diagnosis and initiation of therapy. To avoid the delays nephrologists have taken the initiative to perform these procedures themselves. Indeed, recent data have emphasized that nephrologists can safely and successfully perform these procedures with excellent results. The success of nephrologist's role in Interventional Nephrology insures the ideal management of renal patients with effectiveness, safety and lower cost for Public Health System. Certainly nephrologists must have adequate training and develop the necessary skills in the new fields as a prerequisite for the success of the concept.

Antihypertensive agents and renal transplantation.

Advances in the field of kidney transplantation have led to a significant increase in the life of renal allograft with 1-year graft survival rates of 93% to 99%. This increase in early graft survival has made it possible to observe the long-term morbidities that accompany renal transplantation. Studies correlating the reduction of arterial blood pressure with patient and graft survival as well as the risk of cardiovascular disease do not exist. The recommendations come from the general population and from comparative studies of hypertensive and normotensive kidney graft recipients. It is known that in the general population hypertension is a risk factor for chronic kidney disease but at the same time a risk factor for death, ischaemic heart disease, chronic heart failure and left ventricular hypertrophy. We must always have in mind that there are many similarities between a kidney graft recipient and a patient with chronic kidney disease. Renal transplant recipients represent a patient population with a very high risk for development of cardiovascular disease which has been identified as the leading cause of death in these patients. Of 18,482 deaths among renal allograft recipients, 38% had functioning renal allografts. Successful renal transplantation (Rt) can result in partial regression of left ventricular hypertrophy (LVH) if it is associated with hypertension (HTN) remission or if HTN is controlled by medications. Frequently post transplant HTN is associated with failure of LVH to regress. Transplant clinicians must choose antihypertensive agents that will provide their patients with maximum benefit from renal allograft and cardiovascular perspective. The target must always be long term patient and graft survival and acceptable quality of life. The antihypertensive drugs usually used after kidney transplantation are diuretics, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and beta-blockers. Most emphasis is given lately to ACEIs/ARBs and beta-blockers because of their cardioprotecive effect.

Leptin as a cardiovascular risk factor.

The role of leptin in humans is not yet precisely established. Nevertheless there is increasing evidence revealing that this molecule is involved in the pathogenesis of atherosclerosis as an independent risk factor. From another point of view, however, leptin is already related to known traditional risk factors for accelerated atherogenesis, like obesity. We herein provide the experimental and clinical data concerning the association between leptin and atherosclerotic disease. Vascular stiffness and calcification, immune response regulation, fibrinolysis, and oxidative stress, are the main fields to be investigated in relation to leptin in the present study. Additionally the description of the main characteristics of leptin and its receptors is included in the introduction of this article, whereas in the end the main clinical data suggesting that this molecule represents an interesting risk factor for atherosclerotic disease are provided.

Rhabdomyolysis updated.

Rhabdomyolysis constitutes a common cause of acute renal failure and presents paramount interest. A large variety of causes with different pathogenetic mechanisms can involve skeletal muscles resulting in rhabdomyolysis with or without acute renal failure. Crush syndrome, one of the most common causes of rhabdomyolysis presents increased clinical interest, particularly in areas often involved by earthquakes, such as Greece and Turkey. Drug abusers are another sensitive group of young patients prone to rhabdomyolysis, which attracts the clinical interest of a variety of medical specialties. We herein review the evidence extracted from updated literature concerning the data related to pathogenetic mechanisms and pathophysiology as well as the management of this interesting syndrome.

Quality of life survey and palliative care in lung cancer patients.

Aim. In patients with advanced and/or inoperable bronchial tumors, methods of palliative care such as radiotherapy, chemotherapy, brachytherapy and cryotherapy, singly and/or in combination, aiming at extending the survival time and improving the quality of life, were examined. Methods. One hundred and sixty three (163) patients, with mean age 67.9 yrs (range 22-25) and a male/female ratio at 1.34/1, treated between 2000-2004 were studied. Eighty one (81) patients receiving only cryotherapy presented a two-year survival rate at 19.3%, whilst eighty three (83) patients treated with radiotherapy or brachytherapy and/or chemotherapy showed a two-year survival rate at 25%. Sixty-five percent (65%) of patients only cryotreated had improvement in at least one or more Karnofsky and WHO indices. Results. Eighty percent (80%) of patients who received cryotherapy accompanied with supplementary palliative treatment showed amelioration of their clinical status. Conclusion. It seems that for patients with advanced or inoperable lung tumors, cryotherapy associated with additional palliative care may influence the survival time and improve their quality of life.

Hemolytic uremic syndrome after renal transplantation.

Hemolytic Uremic Syndrome after kidney transplantation affects an increasing number of patients. It is characterized as recurrent and de novo. Older age at onset of HUS, shorter mean interval between HUS and transplantation or ESRD, living related donor and treatment with CNI have been associated with an increased risk of recurrence. Patients who lost the first transplant because of HUS recurrence should not receive a second transplant. The outcome of recurring HUS after transplantation is worse in familial forms leading invariably to graft loss and for this reason doctors should discourage the use of living related donors in this setting. De novo HUS is not a rare complication after kidney transplantation and may be associated with infection, CNI or mTOR inhibitor toxicity, antibody use (OKT3), or acute vascular rejection. The clinical picture is obscure and treatment rests on removal of inciting factor with or without plasma exchange/FFP infusion.

Combined treatment of hypercholesterolemia of renal transplant allograft recipients with fluvastatin and gemfibrozil.

The aim of this study was to investigate the safety and efficacy of combined treatment with fluvastatin (F) and gemfibrozil (G) in hypercholesterolemic renal transplant recipients (RTR). Ten hypercholesterolemic (total cholesterol [TC] > 220 mg/dl) RTR (7 men) with mean age 44 years (range 25-56 years) who remained hypercholesterolemic after 3 months of treatment (period A) with fluvastatin (40 mg/d) continued taking the same dose of F plus G (600 mg/dl) for another 3-month period (B). Serum total cholesterol, high density lipoprotein cholesterol (HDL-C), LDL cholesterol (LDL-C), triglyceride, serum creatinine (creatinine phosphokinase (CPK), serum glutamic-oxaloacetic transaminase (SGOT), and serum glutamate pyruvate transaminase (SGPT) were measured before treatment and at the end of periods A and B. Mean TC levels were 360.30 +/- 62.42 mg/dl, 324.10 +/- 100.53 mg/dl, 270.80 +/- 67.77 mg/dl; mean LDL-C levels were 259.33 +/- 71.43 mg/dl, 219.60 +/- 81.31 mg/dl, 189.70 +/- 65.51 mg/dl; mean HDL-C levels were 37.10 +/- 11.68 mg/dl, 39.80 +/- 13.21 mg/dl, 41.00 +/- 12.94 mg/dl; mean triglyceride levels were 354.60 +/- 183.29 mg/dl, 349.30 +/- 242.94 mg/dl, 207.00 +/- 85.35 mg/dl before treatment and at the end of periods A and B, respectively. There was a statistically significant fall of serum TC (P = 0.002), LDL-C (P = 0.016), and triglyceride (P = 0.029) levels at the end of periods A and B. Kidney and liver function did not change. F and G combined treatment is safe and useful in patients who do not respond satisfactorily to monotherapy with F. Gemfibrozil augments the effect of F on TC, LDL-C, and triglyceride levels.