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.

Glomerular filtration rate estimation in patients with type 2 diabetes: creatinine- or cystatin C-based equations?

AIMS/HYPOTHESIS: It is argued that GFR estimation (eGFR) using cystatin C-based equations (eGFRcys) is superior to that using creatinine-based equations (eGFRcre). We investigated whether eGFRcys are superior to eGFRcre in patients with type 2 diabetes. METHODS: GFR was measured in 448 type 2 diabetic patients using (51)Cr-EDTA-measured GFR (mGFR) as the reference standard. Bias, precision and accuracy of eGFRcys and eGFRcre were compared. RESULTS: The most accurate eGFRcre equation (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]), which produced the highest proportion of estimates that were within 30% and 10% of the reference standard (80.7% and 38.0% of samples, respectively) had a bias of 7.1 and precision of 12.0 ml min(-1) 1.73 m(-2). The calibrated eGFRcys with the highest accuracy (Tan-C), which produced the highest proportion of estimates that were within 30% (78.8%) and within 10% (39.0%) of the reference standard had a bias of -3.5 and precision of 18.0 ml min(-1) 1.73 m(-2). Moreover, the areas under the receiver operating curve were higher with eGFRcre (CKD-EPI and Modification of Diet in Renal Disease [MDRD]) than with eGFRcys for the diagnosis of mild (mGFR <90 ml min(-1) 1.73 m(-2)) and moderate (mGFR <60 ml min(-1) 1.73 m(-2)) chronic kidney disease. In patients with mGFR ≥90 ml min(-1) 1.73 m(-2), CKD-EPI was the least biased, the most precise and the most accurate equation. CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes, eGFRcys do not currently provide better eGFR than eGFRcre. At present, compared with eGFRcys, eGFRcre are better at predicting the stage of chronic kidney disease. In addition, CKD-EPI seems to be the best equation for eGFR in patients with normal renal function.

Adaptation and validation of the Kidney Disease Quality of Life-Short Form questionnaire in the Greek language.

AIM: The aim of this study was to examine the validity, reproducibility and internal consistency of a Greek translation of the Kidney Disease Quality of Life-Short Form (KDQOL-SF) questionnaire. METHODS: The KDQOL-SF questionnaire was translated from English to Greek and was administered in 240 randomly selected patients undergoing hemodialysis in six Renal Units in Greece. The instrument's validity was tested by examining the association between patient's KDQOL-SF scores and comorbidity assessed with the Index of Coexistent Disease. Reproducibility was examined by readministering the questionnaire in 50 randomly selected patients within 1 month. Internal consistency was assessed by estimating Cronbach's alpha coefficient. RESULTS: Patients were divided into two groups according to the severity of comorbidity assessed with the Index of Coexistent Disease. Those with less comorbid conditions had significantly higher scores in most components of the KDQOL-SF questionnaire, confirming its validity. The correlation coefficients between the two administrations of the instrument ranged from 0.88 to 0.98 for each of the main components, which was above the desired level of 0.85. Cronbach's alpha coefficient ranged from 0.91 to 0.92 for the various components, values well above the minimum desired 0.70 level. CONCLUSIONS: The present study shows that the Greek version of the KDQOL-SF questionnaire has high validity, reproducibility and internal consistency. Production of validated translations of the KDQOL-SF questionnaire in various languages will help promote health-related quality of life of end-stage renal disease patients all over the world.

Effects of exercise training during hemodialysis on cardiac baroreflex sensitivity.

BACKGROUND: Arterial baroreflex sensitivity (BRS) evaluation has been increasingly used as an index of cardiac autonomic control. Cardiac autonomic dysfunction leading to depressed BRS has been associated with an increased risk of ventricular arrhythmias and sudden death in patients with chronic kidney disease (CKD) on hemodialysis (HD). AIM: The purpose of this study was to investigate the effects of an exercise training program during hemodialysis on BRS in CKD patients. PATIENTS AND METHODS: 43 HD patients participated in the study. They were randomly assigned into either a 7-month exercise training program during HD (Group A: n=22 patients) or a sedentary control group (Group B: n=21 patients). Additionally, 20 sex- and age-matched sedentary individuals comprised a healthy control group (Group C). All patients at the beginning and the end of the study underwent a tilt test for evaluation of BRS and an exercise testing with spiroergometric study for cardiorespiratory capacity estimation. The level of Hb, medications and the HD procedure remained stable during the study. RESULTS: At baseline BRS was found to be reduced by 51.5% (p<0.05) and baroreflex effectiveness index (BEI) by 36.4% (p<0.05) in Group A compared with Group C. Initially, all HD patients had also significantly lower exercise time and VO2 peak than the healthy subjects. After training, Group A showed a significant improvement in BRS by 23.0% (p<0.05), in BEI by 27.0% (p<0.05), in event and ramp count by 35.0% (p<0.05) and 29.0% (p<0.05), respectively as well as in VO2 peak by 22.4% (p<0.05) and in exercise time by 40.9% (p<0.05). Significant correlations were found between BRS and METs (r=0.476, p<0.05), BRS and VO2 peak (r=0.443, p<0.05), BEI and METs (r = 0.492, p<0.05), BEI and VO2 peak (r=0.467, p<0.05), event count and VO2 peak (r=0.715, p<0.01), event count and exercise time (r=0.799, p<0.01), in Group A at the end of the study. CONCLUSIONS: Our results indicate that HD patients had considerably reduced cardiorespiratory capacity and impaired cardiac BRS compared to healthy sedentary individuals. Importantly, exercise training during HD yielded a marked increase of the indices representing baroreflex activity in association to the improvement of their functional capacity.

Cost-effectiveness of losartan in diabetic nephropathy: a Greek perspective.

BACKGROUND: Diabetic nephropathy is the primary cause of end-stage renal disease (ESRD), which involves substantial economic burden. The primary objective of this study was to estimate the potential effect of losartan on the costs associated with ESRD in patients with diabetic nephropathy in a Greek setting. A secondary aim was to approximate the direct health care cost of renal replacement therapy (RRT) in Greece. METHODS: A cost-effectiveness analysis was performed to compare losartan with placebo in patients with type 2 diabetes and nephropathy. Clinical data were derived from the RENAAL study. All costs were calculated from the perspective of the Greek social insurance system, in 2003 euros. Future costs were discounted at 3%. The time horizon was 3.5 years. Extensive sensitivity analyses were performed. RESULTS: The reduction in the number of ESRD days over 3.5 years in patients treated with losartan reduced ESRD-related costs by 3,056.54 euros, resulting in net cost savings of 1,665.43 euros per patient. Net cost savings increase thereafter, increasing to 2,686.48 euros per patient over a period of 4.0 years. The results were robust under a wide range of plausible assumptions. The weighted mean daily cost of RRT was estimated at 90.97 euros per patient. The total economic burden of RRT for the year 2003 has been estimated at 304.773 million euros. CONCLUSIONS: This study demonstrated that treatment of patients with diabetic nephropathy in Greece with losartan is cost-effective, as it leads to important savings for the social insurance system by slowing the progression to ESRD.

Thrombotic thrombocytopenic purpura associated with rapidly progressive lupus nephritis: report of two cases.

There are a few reported cases in the literature of thrombotic thrombocytopenic purpura (TTP), associated with systemic lupus erythematosus (SLE). We describe two cases of TTP which have been presented during rapidly progressive lupus nephritis, with grand-mal seizures, thrombocytopenia and microangiopathic hemolytic anemia. Both cases were treated with hemodialysis, plasma exchange, corticosteroids, cyclophosphamide and intravenous gamma-globulin. In both cases the TTP was improved but not the renal function. Further experience is needed to determine whether intensive and prompt treatment with plasma exchange, corticosteroids and chemotherapy leads to a favorable outcome, in cases of TTP associated with SLE.

Renal hemodynamics in hypertensive renal allograft recipients: effects of calcium antagonists and ACE inhibitors.

Hypertension present in more than 50% of successfully renal transplanted patients and its prevalence has slightly increased since the introduction of cyclosporine A. Twenty patients, 9 women and 11 men aged from 30 to 58 years, with stable cadaveric renal allograft function and moderate to severe hypertension, were included in the study. Renal artery graft stenosis causing hypertension were excluded. All patients were given triple drug immunosuppressive treatment with methylprednisolone, azathioprine and cyclosporine A (CsA) and their hypertension was treated with a nifedipine dose of 20 mg twice daily. To evaluate the effect of ACE inhibitors on renal hemodynamics and hypertension, a 4 mg/daily dose of perindopril was added to the above regimen for two months. Effective renal plasma flow (ERPF) decreased from 208 +/- 54 to 168 +/- 61 ml/min and renal vascular resistance (RVR) increased from 75 +/- 12 to 88 +/- 17 mm Hg/ml/min (P < 0.05 and P < 0.01, respectively). Mean blood pressure was significantly (P < 0.001) reduced by the combination of both agents in comparison to the blood pressure control by monotherapy with nifedipine. It is suggested that the combination of both antihypertensive agents was more effective than monotherapy with nifedipine in controlling blood pressure, but less favorable on the renal hemodynamic response in hypertensive renal transplant patients who were maintained on CsA.

The response of muscle interstitial F2-isoprostane (8-ISO-PGF2alpha) during dynamic muscle contractions in humans.

8-Iso-prostaglandin F2alpha (8-iso-PGF2alpha) is a characteristic F2-isoprostane which is produced in humans via a free radical-catalysed lipid peroxidation mechanism of arachidonic acid, independent of the cycloxygenase pathway. The measurement of the plasma levels of 8-iso-PGF2alpha was shown to be the most reliable biochemical index of oxidant stress status in the human body. However, there is no reference in literature of local muscle interstitial 8-iso-PGF2alpha production during dynamic muscle contractions. The aim of the present study was to evaluate the response of 8-iso-PGF2alpha during intensive exercise with a cycle ergometer. Two microdialysis probes with CMA-60 microdialysis catheters were inserted into the vastus lateralis muscle of the right leg of six healthy male volunteers. After insertion, these microdialysis probes were attached to a perfusion pump that perfused ringer acetate solution at a rate of 0.3 microl/min. The dialysate fluid samples were collected: (a) during a 30 min rest period and (b) during a 30 min period of dynamic exercise with a cycle ergometer at 150 Watts. Our measurements showed that the levels of 8-iso-PGF2alpha in the interstitial fluid (IF) of the vastus lateralis muscle increase significantly during exercise (from 113.5 +/- 30.2 to 329.9 +/- 69.8 pg/ml, P = 0.05). In conclusion, dynamic muscle exercise produces a local increase of the IF levels of 8-iso-PGF2alpha due to local peroxidation injury of the contractive muscle. The microdialysis method is widely applied, easily repeated and it could contribute in evaluating the local lipid muscle peroxidation during intensive exercise.

Outcomes of long-term exercise training in dialysis patients: comparison of two training programs.

BACKGROUND: Exercise training has been shown to improve the low functional capacity and quality of life in dialysis (HD) patients. However, there are no data about the outcome of long-term exercise training and, also, the adherence of HD patients in such long-term renal rehabilitation programs. Therefore, the aim of this study was to evaluate the effects of 2 modes of long-term physical training on HD patients' physical fitness, perception of health and overall life situation. PATIENTS AND METHODS: Forty-eight HD patients, free of any other systemic disease, who followed 2 modes of exercise training for 4 years, were studied. Half of them (group A) were randomly assigned to participate in a supervised outpatient exercise training program (3/weekly) on the non-dialysis days, while the other half (group B) followed a training program with stationary bicycles during their HD sessions (3/weekly). The measured domains of physical fitness and well-being every year were: aerobic capacity, as estimated from a modified Bruce treadmill exercise test and spiroergometric study, the patients' perception of health, the overall life situation and the employment status. RESULTS: During the 4-year study, there were 8 drop-outs in group A and 5 in B. No adverse effects of the exercise programs were reported. The 1 year of exercise training resulted in 38% in group A (16 patients, who remained in the study) and 31% in group B (18 patients) improvement of exercise time, and a 47% increase in group A of peak oxygen consumption (VO2peak) and a 36% in group B in comparison to baseline value. After 3 additional years of training, significant improvements were also noted in exercise time (by 53% in group A and by 43% in B) and VO2peak (by 70% in group A and by 50% in group B), as well as in other gas exchange variables in comparison to baseline values. However, the improvements in group A were more pronounced than in B. Interestingly, the gains in exercise capacity were more enhanced in the first year of training in both groups. After 4-year training, significantly more patients in both groups perceived their health and overall life situation as well, compared to baseline. In addition, perception of improved health was higher in group A. The increase in the proportion of patients working was also higher in group A than B after the 4-year training. CONCLUSION: HD patients can adhere to long-term physical training programs on the non-dialysis days, as well as during hemodialysis with considerable improvements in physical fitness and health. Although training out of HD seems to result in better outcomes, the drop out rate was higher.

Isolated C3 deposition in patients without systemic disease.

Deposition of C3 without immunoglobulins ("isolated C3") was found in 9.8% of 540 renal biopsies performed between 1976 and 1982. Thirty-two of these samples were from patients with systemic diseases (16), well defined forms of glomerulonephritis (9), other renal diseases (4) or renal allografts (4). The remaining 22 patients are described. Five had nephrotic syndrome, three of them with minimal changes on light microscopy and good response to corticosteroids. We were left with a group of 17 patients who presented with gross (4) or microscopic (12) hematuria or asymptomatic proteinuria (1) whose biopsies showed mesangial proliferation or/and hyperplasia and who followed a benign course over the mean 3 years of follow-up, with the exception of one whose renal function is declining. This clinicopathological picture is similar to that described in two previous publications suggesting that "Isolated C3 mesangial proliferative nephritis" is a recognizable sub-group within the spectrum of glomerulonephritis.

Hypertension in chronic hemodialysis patients: current view on pathophysiology and treatment.

BACKGROUND: Hypertension accounts for 65 - 85% of patients beginning dialysis, and dialysis alone controls hypertension in over 50% of patients. PATIENT AND METHODS: We have surveyed the status of BP control in 113 hemodialysis patients, 66 men and 47 women, aged 59 +/- 13 years old, with a mean duration on hemodialysis 42 +/- 44 months. The following measurements were recorded: predialysis mean arterial pressure (pre-MAP), post-dialysis MAP (post-MAP), percentage of change in MAP, pre-dialysis weight, post-dialysis weight, fluid removed by ultrafiltration during each dialysis session, interdialytic weight gain and excess weight over the desirable dry weight. RESULTS: Our results showed a hypertension prevalence of 59% (hypertension defined as pre-MAP +/- 110 mmHg). MAP was not different between men and women, and only 4.5% of patients had isolated systolic hypertension. All hypertensive patients were on treatment with antihypertensives. Reduction in post-MAP by > or = 5% (controlled by ultrafiltration) was found in 68.5% of hypertensive and in 87.5% of normotensive patients. Age, primary renal disease, time on dialysis and adequacy of dialysis were not correlated with pre-MAP. Excess volume and interdialytic weight gain were found to correlate with pre-MAP (p = 0.03). Also, the weekly dosage of EPO had a significant correlation with pre-MAP (p = 0.03). No differences were found among four classes of antihypertensive drugs regarding the BP control. Patients with hypertension requiring one drug achieved a significantly (p < 0.05) lower pre-MAP than the group of patients receiving three or more drugs. In conclusion, hemodialysis population shows high prevalence of hypertension, resistant to antihypertensive treatment. CONCLUSION: Current methods of hemodialysis are not effective in controlling BP. This implies that more insight into the role of excess volume and vasomotor systems in the pathogenesis of dialysis hypertension is warranted.

Effective treatment of secondary hyperparathyroidism in hemodialysis patients by titration of intravenous calcitriol dosage.

AIM: Effective treatment of secondary hyperparathyroidism (HPTH) with intravenous (i.v.) administration of calcitriol in hemodialysis patients. PATIENTS AND METHODS: The current study evaluates the use of i.v. calcitriol dosing in relation to the severity of the HPTH in 35 hemodialysis patients with serum phosphate < 6.5 mg/dl. Arbitrarily, patients with plasma IPTH levels (intact PTH) between 288 and 576 pg/ml (288 pg/ml = four-fold the upper normal limit) were given initially 1 microg i.v. calcitriol at the end of each dialysis (group A, n = 15). Patients with IPTH between 577 and 864 pg/ml received 2 microg i.v. calcitriol (group B, n = 10) and patients with IPTH more than 865 pg/ml were given 3 - 4 microg i.v. calcitriol (group C, n = 10). As IPTH levels decreased, the dose of i.v. calcitriol was also decreased gradually. Patients were followed-up for 4 months after the end of calcitriol treatment. RESULTS: During the i.v. calcitriol treatment period, the observed plasma IPTH concentrations compared with the baseline values were significantly lower (p < 0.01 for A and B group and p < 0.05 for C group) from the sixth month onwards in group A and C and from the third month onwards in group B. At the 12th month of follow-up, all patients being off i.v. calcitriol treatment for four months, a sharp and significant increase (p < 0.01 for group A and B and p < 0.05 for group C) of plasma IPTH was recorded in all three groups of patients. Alkaline phosphatase was also gradually decreased in all studied groups. Serum Ca and P remained unchanged in most patients. CONCLUSION: In conclusion, the study presented here demonstrates that the titration of i.v. calcitriol dosage according to the severity of HPTH is an effective and safe treatment of HPTH in chronic hemodialysis patients. It also shows that parathyroidectomy could be avoided in the majority of patients with severe HPTH, if an appropriate dose of calcitriol not aggravating hyperphosphatemia is administered.

Effect of sympathetic and plasma renin activity on hemodialysis hypertension.

BACKGROUND: The reasons for poor control of blood pressure in hemodialysis (HD) patients are not clear, while patients have achieved their desirable dry weight and excess weight are not different between the hypertensive and normotensive patients. A link between sympathetic activity and HD hypertension could be an alternative explanation. PATIENTS AND METHODS: We studied the effect of sympathetic and plasma renin-aldosterone activity of 10 hypertensive patients, 5 men and 5 women, aged from 30 to 60 years. The results were compared to those of another 10 normotensive hemodialysis patients. Blood samples were taken before HD and at the end of a 4-hour HD session for plasma aldosterone (ALDO), renin activity (PRA), adrenaline and noradrenaline determination. One month dialysis records, which includes 13 dialysis sessions and 26 blood pressure readings for each patient were used, for pre-dialysis and post dialysis mean arterial blood pressure (MAP) measurement. RESULTS: Pre-dialysis plasma adrenaline was 124.12 +/- 12.93 pg/ml vs. 121.12 +/- 14.71 pg/ml and plasma noradrenaline was 260.88 +/- 140.86 pg/ml vs. 138.11 +/- 122 +/- 32 pg/ml for hypertensive and normotensive patients, respectively. Post-dialysis plasma adrenaline and noradrenaline levels were 119.37 +/- 8.81 pg/ml vs. 120.62 +/- 15.35 pg/ml and 210.44 +/- 126.71 pg/ml vs. 94.88 +/- 64.05 pg/ml for hypertensive and normotensive patients, respectively. Pre-dialysis PRA was 8.70 +/- 6.37 ng/ml/h vs. 2.77 +/- 1.8 ng/ml/h and plasma ALDO was 457.07 +/- 245.54 pg/ml vs. 197.74 +/- 87.46 pg/ml for hypertensive and normotensive patients, respectively. Pre-MAP was 109.76 +/- 5.21 mmHg vs. 99.28 +/- 7.13 mmHg and post-MAP was 107.22 +/- 6.74 mmHg, vs. 91.61 +/- 7.27 mmHg for hypertensive and normotensive patients, respectively. Plasma ALDO and fluid volume removed by ultrafiltration were found to be significantly correlated (p < 0.05). PRA and plasma adrenaline-noradrenaline levels were not correlated with MAP or body weight alterations. CONCLUSIONS: It is suggested that sympathetic activity, as it was expressed by plasma catecholamine alterations, is not associated with hemodialysis hypertension.

Management of moderate to severe hypertension and proteinuria by nifedipine retard and perindopril after renal transplantation.

Clinical studies of treatment with angiotensin converting enzyme (ACE) inhibitors in patients with glomerular disease have shown the clinical efficacy of these agents. Fifteen renal transplant hypertensive and proteinuric patients on triple drug treatment with cyclosporin (CSA), azathioprine and methylprednisolone entered the therapeutic protocol of this study. All patients followed up last year had stable graft function (serum creatinine less than 2 mg/dl). Hypertension was treated by nifedipine retard and occasionally by furosemide. Patients with a renal artery graft stenosis, at least as judged by technetium-scan imaging were excluded. In order to evaluate the possible role of ACE inhibitors on hypertension and proteinuria, perindopril 4 mg/daily was added for two months to the above regimen. Two patients, who showed a reversible deterioration of renal function during treatment and three who did not comply to the therapeutic protocol were excluded. Systolic and diastolic blood pressure as well as 24 h urine protein was found to be significantly (p < 0.01) reduced at the end of the two-month combined treatment with perindopril and nifedipine retard in comparison to the result of monotherapy with nifedipine retard. GFR and ERPF showed no significant difference (NS) between the two modes of treatment. It is suggested that the combined treatment with nifedipine retard and perindopril is more effective than the monotherapy with nifedipine retard in the management of moderate to severe post-transplant hypertension and proteinuria of renal transplant patients.

Stenting of central venous stenoses and occlusions to maintain hemodialysis vascular access.

BACKGROUND/AIMS: The aim of the study was to evaluate the efficacy of stenting for the treatment of central arm vein obstructions in hemodialysis patients in order to maintain hemodialysis from the affected side. METHODS: Fifteen self-expanding (8) and balloon expandable (7) stainless steel stents were implanted in 10 hemodialysis patients for the treatment of symptomatic central arm vein obstructions. Thirteen lesions were treated: 6 subclavian, 4 innominate and 3 restenoses. RESULTS: Stent deployment was successful in all cases leading to resolution of symptoms by correcting the underlying cause of venous hypertension. Follow-up from 3 months to 4 years revealed four deaths from unrelated causes, three restenoses at 1, 3, 4 months and one occlusion at 6 months respectively for a cumulative primary one-year and two-year patency rate of 70%. CONCLUSION: Stenting of subclavian and innominate venous stenoses and occlusions effectively corrected the underlying lesions responsible for disturbed hemodynamics and, in most cases, prolonged available hemodialysis access from the affected side.

ProCol vascular bioprosthesis for vascular access: midterm results.

BACKGROUND/AIMS: This study aimed to evaluate the safety and efficacy of the ProCol vascular bioprostheses as vascular access (VA) material, especially in patients with a history of prior failed access. METHODS: During a 20-month period, 25 arteriovenous (AV) bovine vein grafts were placed in 24 hemodialysis (HD) patients for VA. All patients presented with failed autologous access sites. RESULTS: Graft placement was successful in all patients with no procedure-related complications. Follow-up from 6-26 months gave primary 6-month, 12-month and 24-month patency rates of, respectively, 90%, 80% and 70%. Graft characteristics in cannulation and hemostasis were very satisfying. CONCLUSION: Our midterm results demonstrated that the ProCol vascular bioprosthesis was a promising material for VA with good patency and low complication rates.

Matrix metalloproteinases, atherosclerosis, proteinuria and kidney disease: Linkage-based approaches.

Matrix metalloproteinases (MMPs) are important enzymes of extracellular matrix (ECM) degradation for creating the cellular environments required during development and morphogenesis. MMPs, collectively called matrixins, regulate also the biological activity of non matrix substrates such as cytokines, chemokines, receptors, growth factors and cell adhesion molecules. Enzymatic activity is regulated at multiple levels. Endogenous specific inhibitors of metalloproteinases (TIMPs) participate in controlling the local activities of MMPs in tissues. The pathological effects of MMPs and TIMPs are involved in cardiovascular disease (CVD) processes, including atherosclerosis and in a number of renal pathophysiologic alterations, both acute and chronic, linking them to acute kidney injury, glomerulosclerosis and tubulointerstitial fibrosis. This review presents an overview of the place of MMPs in atherosclerosis, proteinuria and kidney disease as a subject of considerable interest, given the differentiated and ambiguous role of MMPs in the progression of these diseases.

Network-centric Analysis of Genetic Predisposition in Diabetic Nephropathy.

Diabetic nephropathy is a serious, long-term complication of diabetes and the leading cause of end-stage renal disease throughout the world. Although this disease is progressively imposing a heavier burden on the health care system, in many aspects it remains poorly understood. In addition to environmental influences, there is abundant evidence in support of genetic susceptibility to microvascular complications of nephropathy in diabetic patients. Familial clustering of phenotypes such as end-stage renal disease, albuminuria and kidney disease have been reported in large scale population studies throughout the world demonstrating strong contribution of inherited factors. Recent genome-wide linkage scans identified several chromosomal regions that are likely to contain diabetic nephropathy susceptibility genes, and association analyses have evaluated positional candidate genes under linkage peaks. In this review we have extracted from the literature the most promising candidate genes thought to confer susceptibility to diabetic nephropathy and mapped them to affected pathways by using network-centric analysis. Several of the top susceptibility genes have been identified as network hubs and bottlenecks suggesting that they might be important agents in the onset of diabetic nephropathy.