Regulatory T cells and minimal change nephropathy: in the midst of a complex network.

Minimal change nephrosis (MCN) is an important cause of morbidity in children. In spite of successful therapies having been developed in the last three decades, most aspects related to pathogenesis still remain poorly defined. Evolution in basic immunology and results deriving from animal models of the disease suggest a complex interaction of factors and cells starting from activation of innate immunity and continuing with antigen presentation. Oxidants, CD80 and CD40/CD40L have probably a relevant role at the start. Studies in animal models and in human beings also suggest the possibility that the same molecules (i.e. CD80, CD40) are expressed by podocytes under inflammatory stimuli, representing a direct potential mechanism for proteinuria. B and T cells could play a relevant role this contest. Implication of B cells is suggested indirectly by studies utilizing anti-CD20 monoclonal antibodies as the main therapy. The role of regulatory T cells (Tregs ) is supported mainly by results in animal models of nephrotic syndrome (i.e. adriamycin, puromycin, lipopolysaccharide), showing a protective effect of direct Treg infusion or stimulation by interleukin 2 (IL-2). Limited studies have also shown reduced amounts of circulating Tregs in patients with active MCN cells. The route from bench to bedside would be reduced if results from animal models were confirmed in human pathology. The expansion of Tregs with recombinant IL-2 and new anti-CD20 monoclonal antibodies is the beginning. Blocking antigen-presenting cells with cytotoxic T lymphocyte antigen (CTLA-4)-Ig fusion molecules inhibiting CD80 and/or with blockers of CD40-CD40 ligand interaction represent potential new approaches. The hope is that evolution in therapies of MCN could fill a gap lasting 30 years.

Survival in dialysis patients is different between patients with diabetes as primary renal disease and patients with diabetes as a co-morbid condition.

AIMS/HYPOTHESIS: A previous study in Dutch dialysis patients showed no survival difference between patients with diabetes as primary renal disease and those with diabetes as a co-morbid condition. As this was not in line with our hypothesis, we aimed to verify these results in a larger international cohort of dialysis patients. METHODS: For the present prospective study, we used data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry. Incident dialysis patients with data on co-morbidities (n = 15,419) were monitored until kidney transplantation, death or end of the study period (5 years). Cox regression was performed to compare survival for patients with diabetes as primary renal disease, patients with diabetes as a co-morbid condition and non-diabetic patients. RESULTS: Of the study population, 3,624 patients (24%) had diabetes as primary renal disease and 1,193 (11%) had diabetes as a co-morbid condition whereas the majority had no diabetes (n = 10,602). During follow-up, 7,584 (49%) patients died. In both groups of diabetic patients mortality was higher compared with the non-diabetic patients. Mortality was higher in patients with diabetes as primary renal disease than in patients with diabetes as a co-morbid condition, adjusted for age, sex, country and malignancy (HR 1.20, 95% CI 1.10, 1.30). An analysis stratified by dialysis modality yielded similar results. CONCLUSIONS/INTERPRETATION: Overall mortality was significantly higher in patients with diabetes as primary renal disease compared with those with diabetes as a co-morbid condition. This suggests that survival in diabetic dialysis patients is affected by the extent to which diabetes has induced organ damage.

Mortality due to pulmonary embolism, myocardial infarction, and stroke among incident dialysis patients.

BACKGROUND: It is has been suggested that dialysis patients have lower mortality rates for pulmonary embolism than the general population, because of platelet dysfunction and bleeding tendency. However, there is limited information whether dialysis is indeed associated with a decreased mortality risk from pulmonary embolism. OBJECTIVE: The aim of our study was to evaluate whether mortality rate ratios for pulmonary embolism were lower than for myocardial infarction and stroke in dialysis patients compared with the general population. METHODS: Cardiovascular causes of death for 130,439 incident dialysis patients registered in the ERA-EDTA Registry were compared with the cardiovascular causes of death for the European general population. RESULTS: The age- and sex-standardized mortality rate (SMR) from pulmonary embolism was 12.2 (95% CI 10.2-14.6) times higher in dialysis patients than in the general population. The SMRs in dialysis patients compared with the general population were 11.0 (95% CI 10.6-11.4) for myocardial infarction, 8.4 (95% CI 8.0-8.8) for stroke, and 8.3 (95% CI 8.0-8.5) for other cardiovascular diseases. In dialysis patients, primary kidney disease due to diabetes was associated with an increased mortality risk due to pulmonary embolism (HR 1.9; 95% CI 1.0-3.8), myocardial infarction (HR 4.1; 95% CI 3.4-4.9), stroke (HR 3.5; 95% CI 2.8-4.4), and other cardiovascular causes of death (HR 3.4; 95% CI 2.9-3.9) compared with patients with polycystic kidney disease. CONCLUSIONS: Dialysis patients were found to have an unexpected highly increased mortality rate for pulmonary embolism and increased mortality rates for myocardial infarction and stroke.

Urotensin II is an inverse predictor of death and fatal cardiovascular events in chronic kidney disease.

Urotensin II (UTN), a cyclic vasoactive peptide expressed in multiple organs, had higher plasma levels that was previously shown to predict longer survival in dialysis patients. We sought to determine if this association exists in earlier stages of chronic kidney disease (CKD) by studying a cohort of 122 incident clinically stable pre-dialysis patients. Linear models were used to determine associations of UTN with baseline characteristics such as renal function and traditional and nontraditional cardiovascular risk factors. We used Cox regression analysis to model time-to-death as a function of UTN and the same variables for adjustment including a time-varying covariate that indicated progression to end-stage renal disease. No correlation was found between baseline glomerular filtration rate and plasma UTN. In adjusted analysis, UTN correlated directly with serum albumin and, inversely, with history of previous coronary events. During a mean follow-up of 41 months, 43 patients died - 29 from cardiovascular events. After adjusting for potential confounding factors, increased UTN predicted lower risk of death from all-cause and cardiovascular causes. In patients with moderate-to-severe CKD, plasma UTN was found to be an inverse predictor of overall and cardiovascular mortality.

The native arteriovenous fistula in 2007. Surveillance and monitoring.

In the past 5 years, some clinical trials have questioned the value of surveillance in managing vascular accesses. Although prolongation of access life span is an important end point, reduction of thrombotic events reduces patient risks resulting from loss of access patency. Most of the available evidence suggests that detection of stenosis and prevention of thrombosis is valuable. When a test indicates the likely presence of a stenosis, then venography or fistulography should be used to definitively establish the presence and degree of the stenosis. In most but not all cases, angioplasty should be performed if the stenosis is greater than 50% by diameter. The value of routine use of any surveillance technique for detecting anatomic stenosis alone, without concomitant functional assessment by measurement of access flow, venous pressure, recirculation or other physiologic parameters, has not been established. Stenotic lesions should not be repaired merely because they are present. If such correction is performed, then intraprocedural or periprocedural measurement of access flow (QA) or intra-access pressure should be conducted to demonstrate a functional improvement with a successful percutaneous transluminal angioplasty.

The native arteriovenous fistula in 2007. Research needs.

Several research questions are open in the field of vascular access for hemodialysis. The present paper reviews both prognostic issues, such as the identification of factors for patient stratification before access insertion, and intervention questions, such as comparison of the advantages and disadvantages of different surgical solutions, the effects of different medications on vascular pathology, the different cannulation practices to prevent vessel wall lesions and technologies for early diagnosis of access dysfunction. Given that the quality of the available literature in nephrology is often suboptimal, nephrologists need to pay special attention to methodology issues before embarking on expensive multicenter studies.

[Antihypertensive agents for the prevention of chronic kidney disease progression: guideline from the Italian Society of Nephrology]. / Farmaci antipertensivi per la prevenzione della progressione delle nefropatie croniche: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of the use of antihypertensive agents to prevent chronic kidney disease progression (CKD) is presented. METHODS: SR of RCT and RCT on antihypertensive agents used to prevent CKD progression were identified referring to a Cochrane Library and Renal Health Library search (2005 update). RESULTS: Seven SR and 26 further RCT were found addressing this intervention issue. Methodological quality of available RCT was suboptimal according to current methodological standards. Angiotensin converting enzyme inhibitors (ACE-I) are associated with significant effects on the prevention of CKD progression in non-diabetic and diabetic patients (evidence from SR). Angiotensin receptor blockers (ARB) are as effective as ACE-I in delaying CKD progression in diabetic and non-diabetic patients (evidence from SR). Dihydropyridine and non-dihydropyridine calcium antagonists have not been found to significantly affect proteinuria and CKD progression (evidence from SR). Combination therapy with ACE-I and ARB is associated with a significant reduction in the risk of CKD progression and proteinuria, but long term data are only available in patients with non-diabetic nephropathy (evidence from RCT). CONCLUSION: Available evidence of renal protection suggest that ACE-I and ARB should be recommended in CKD patients (diabetic and non-diabetic nephropathy). Further studies are necessary to test the effectiveness of other antihypertensive agents or combination therapy.

[Erythropoietins and haemoglobin targets to prevent the progression of chronic kidney disease: guideline from the Italian Society of Nephrology]. / Utilizzo di eritropoietina e targets di emoglobina e progressione del danno renale: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of Systematic Reviews (SR) of Randomized Trials (RCT) or RCT data only. The present guideline reports evidence of the use of Erythropoietins (EPO) and/or optimal haemoglobin (Hgb) targets to delay Chronic Kidney Disease (CKD) progression. METHODS: SR of RCT and RCT on EPO and different Hgb targets in CKD (pre-dialysis) were identified searching in the Cochrane Library and Renal Health Library (2005 update). Quality of SR and RCT was assessed according to current methodological standards. RESULTS: Two SR (15 RCT) and 5 further RCT were found addressing the intervention issue. No significant evidence supporting the use of EPO compared with placebo/no treatment to prevent or delay CKD progression was found (evidence from SR). Progression rates do not appear to be affected by Hgb targets (evidence from SR). Methodological quality of included RCT was suboptimal. In diabetic patients not receiving renin-angiotensin-system inhibitors, early EPO treatment (when Hgb ≥9 g/dL) with target Hgb ≥13 g/dL as compared to delayed treatment initiation (Hgb < 9 g/dL) is associated with reduced risk of disease progression, end-stage renal disease and death (evidence from RCT). CONCLUSION: In CKD patients not undergoing dialysis current evidence does not support the hypothesis that EPO treatment or optimal Hgb targets reduce the progression rate of the disease. Further studies are necessary to test this hypothesis in selected patient populations.

[Use of statins for preventing cardiovascular and renal outcomes in patients with chronic kidney disease excluding dialysis: guideline from the Italian Society of Nephrology]. / Statine per la prevenzione della progressione del danno renale: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of the efficacy of statins in chronic kidney disease patients (CKD, non-dialysis patients) is presented. METHODS: SR of RCT and RCT on statins in CKD (non-dialysis) patients were identified referring to a Cochrane Library and Renal Health Library search (2005 update). Quality of SR and RCT was assessed according to current methodological standards. RESULTS: Three SR and 36 RCT were found addressing this intervention issue. Methodological quality of the relevant RCT was suboptimal. There is no enough evidence to suggest that statins are associated with a significant reduction in the risk of serum creatinine doubling or of end-stage renal disease in CKD patients (evidence from SR and RCT). Statins compared to placebo or no treatment are associated with significant improvements in proteinuria (evidence from SR). Statins are also associated with significant reduction in the risk of cardiovascular events and mortality in CKD patients (evidence from SR and RCT) and in renal transplant recipients (evidence from RCT), and no significant increases in the risk of rhabdomyolysis and hepatotoxicity in CKD patients. CONCLUSION: Available evidence supports the hypothesis that statins should be recommended in CKD patients (non-dialysis patients) on the basis of significant evidence of cardiac and renal protection and no evidence of significant harms. Further studies are necessary to test this hypothesis in selected patient populations.

[Confounding and interaction in multiple regression]. / Confondimento e interazione nella regressione multipla.

In multiple regression the effect of an input (independent) variable on a continuous output (dependent or response) variable can be adjusted for the effect of confounding and modifying variables. This adjustment is useful to obtain either an unbiased estimate of the true association between an exposure and an outcome or to predict the outcome for given inputs after removing the influence of other factors. These factors are defined as confounders if they are associated with the exposure and are independent risk factors for the outcome, without being intermediates on the biological pathway between exposure and outcome. An interaction between exposure and another independent variable is present when the exposure-disease relationship varies across different values of this variable. Multivariable regression modeling removes the association between the confounder and the outcome eliminating the necessary condition for confounding. An interaction term can be also incorporated into the model to quantify any potential modifying effect.

[P value and confidence intervals: reporting and interpreting the result of a clinical study]. / Guida al corretto uso della P e degli Intervalli di Confidenza nella lettura e presentazione dei risultati di uno studio clinico.

The main purpose of statistics in the analysis of clinical and epidemiological studies is to summarize data and information, as well as assess variability, trying to distinguish between chance findings and results that may be replicated upon repetition. Statistical analyses only convey the effect of chance element in data (random error). Statistics cannot control non-sampling errors concerning study design, conduct and methods adopted. At the end of the study, a result is defined statistically significant if the observed difference in the outcome variable is too large to be attributed to chance. A small P value provides evidence against the null hypothesis (of no effect), since data have been observed that would be unlikely if the null hypothesis was true. However, confidence intervals estimate separate the two data dimensions (strength of the relation between exposure and disease, and precision with which the relation is measured), and add to the hypothesis testing useful information for finding interpretation and further research.

How to improve dialysis adequacy in patients with vascular access problems.

Blood flow rate is a critical factor in the achievement of an adequate dialysis dose. The aim of this review is to evaluate the possibility of optimizing dialysis dose in terms of Kt/V in patients with reduced vascular access (VA) flow rate, considering effective blood flow (Qb eff), recirculation, access flow and hemodialyzer. In patients where the achievement of adequate blood flow rates are difficult to obtain and no surgical revision is necessary, to avoid under dialysis the increase in the treatment time should be the first choice solution. If such a solution is difficult for various reasons, a forced partial blood flow recirculation, especially in central venous catheters (CVCs) with reversed lines can be useful, on condition that the dialysis session is prolonged. The possibility of increasing the efficiency of dialysis through an increase in filter clearance has to be considered. Monitoring arterial pre-pump pressure (P asp) and optimizing ratio P asp/Qb eff during hemodialysis (HD) is one possible solution to improve blood flow rates, but it is necessary to educate and involve the staff. Recent developments in a new class of highly effective hemodialyzer due to dialysate distribution, has opened up interesting opportunities in terms of dialysis adequacy in patients with reduced VA flow rate.

[Clinical relevance of study results]. / Rilevanza dei risultati di uno studio clinico.

The critical appraisal process of available evidence includes the evaluation of clinical importance of the study findings. This should coincide with the minimum worthwhile effect expected by the investigators in the study design and planning. In hard outcome studies it can be quantified by the absolute risk difference between groups and its reciprocal, known as number needed to treat to avoid one adverse event, or benefit (NNTB). The number needed to treat to produce harmful consequences of treatment (NNTH) should also be taken into account. Finally these effect measures, like risks and incidence proportions, are usually rough estimates of the true effects, due to non-complete follow-up of the observations under study. Underlying assumptions and design issues are especially important to assess the clinical relevance of any results.

[Statistical models and multivariable analysis]. / Concetti di modello statistico e analisi multi-variabile.

Most clinical research can be simplified as an investigation of an input/output relationship. The inputs are called explanatory (independent) variables or predictors and are thought to be related to the outcome, or response (independent) variable. This relationship is usually complicated by other factors related to both the input and the output (presence of confounding) and can vary according to the levels of the other variables (presence of interaction). This input/output relationship is usually described by statistical models that include a fit part and a residual component or difference between the data and the fit. The most popular models are the general linear models, which can be considered the paradigm of all models used in multi-variable analyzes.

[Introduction of the general linear models]. / Introduzione ai modelli lineari generali.

General linear models can be considered the paradigm of all models used in clinical epidemiology. In these models, the independent variables combine in linear fashion to predict the values of the variable response. Since no model predicts the variable response perfectly, an error term is incorporated into the model to acknowledge what remains to be explained after getting a fit to the data. When this error term is normally distributed with constant variance, the linear models are reasonably appropriate to describe the input/output relationship of interest.

[Control of calcium and phosphate metabolism and prevention of vascular calcifications in uremic patients]. / Controllo del metabolismo calcio-fosforico e prevenzione delle calcificazioni vascolari nel paziente uremico.

Vascular calcifications are more frequent in dialysis patients than in the general population or in patients with cardiovascular disease (CVD) and normal renal function. The reasons for this high incidence are multiple; they include traditional factors such as hypertension, diabetes, dyslipidemia, and specific factors such as sodium overload, hyperomocysteinemia, chronic inflammation and oxidative stress, as well as mineral metabolism disturbances. Specifically, hyperphosphatemia and the elevated calcium (Ca) x phosphate product have been associated with an increased risk for the development of vascular calcification and death. Treatment with Ca salts can induce hypercalcemia, increased Ca x phosphate product and Ca overload. Sevelamer substitution for Ca salts has been documented to attenuate the progression of coronary artery and aortic calcification. A possible mechanism explaining this observation could be ongoing Ca loading related to oral Ca ingestion. Treatment with Ca salts could induce Ca overload, particularly in patients dialyzed against a high dialysate Ca (>1.5 mmol/L) solution, which is known to determine a positive dialysis balance. Conversely, an overall negative Ca balance can result from low Ca dialysate use (1.25 mmol/L) when the patients do not receive Ca supplements or vitamin D metabolites. Maintaining normal Ca and phosphate balances remains a primary goal in the management of dialysis patients. Control of hyperphopshataemia should be achieved either using Ca and aluminum-free phosphate binders, such as sevelamer, or Ca salts, alone or in combination, provided that a daily oral elemental Ca intake of 1.5 g is not exceeded.

[Disturbances of mineral metabolism and vascular calcifications in dialysis patients (review)]. / Alterazioni del metabolismo calcio-fosforico e calcificazioni vascolari nei pazienti in dialisi.

Vascular calcifications are more frequent in dialysis patients than in the general population or in patients with cardiovascular disease and normal renal function. The reasons for this high incidence are multiple. They include traditional factors such as hypertension, diabetes, dyslipidaemia, and specific factors such as sodium overload, hyperomocysteinaemia, chronic inflammation, oxidative stress as well as disturbance of mineral metabolism. Specifically, hyperphosphataemia and the elevated calcium (Ca) x phosphate product have been associated with an increased risk for development of vascular calcification and death. Even though a causal relationship between the use of Ca- containing phosphate binders and the development of vascular calcifications has not been documented, treatment with Ca salts can induce hypercalcaemia, increased Ca x phosphate product, and Ca overload. A net intestinal Ca absorption of 180-500 mg has been documented in uraemic patients after a meal containing 1200 mg of Ca. Thus, treatment with Ca salts may induce Ca overload when a patient is dialyszed against a high dialysate Ca (> 1.5 mmol/L) solution, which is known to determine a positive dialysis balance. On the contrary, an overall negative Ca balance can result from the use of a low Ca dialysate (1.25 mmol/L) when the patients do not receive Ca supplements or vitamin D metabolites. Maintaining a normal Ca and phosphate balance remains one of the primary goals in the management of dialysis patients. Control of hyperphopshataemia should be obtained using either Ca and aluminium- free phosphate binders, such as sevelamer, or Ca salts, while avoiding a daily oral elemental Ca intake > 1.5 g.

[Effect of an ambulatory program devoted to chronic renal insufficiency on the reduction of mobidity and hospitalization among patients at the beginning of dialysis treatment]. / Effetto dell'ambulatorio dedicato all'insufficienza renale cronica sulla riduzione della morbilità e dell'ospedalizzazione nei pazienti che iniziano il trattamento dialitico.

BACKGROUND: Late nephrological referral of end-stage renal disease (ESRD) patients is associated with increased risk of emergent dialysis start and poor complications control. However, the relative contribution of pre-dialysis care organization is unknown. METHODS: All 175 consecutive patients who started chronic dialysis for ESRD at our Institution from 1.1.99 to 30.6.02 were grouped as follows: referred ? 3 months before dialysis, (A, n=50); followed by non-dedicated specialists (B, n=74) or by pre-dialysis educational program personnel (PEP, n=51). We examined the first six months of hospitalization, uraemic complications control, type of dialysis initiation, and first dialysis modality. RESULTS: There was no difference in baseline characteristics and comorbidities among groups. PEP patients had higher creatinine clearance, haemoglobin, calcemia and BMI at initiation. They also made greater use of ACE-inhibitors and were more likely to have a planned start and choose peritoneal dialysis. Emergent starts were 50% (A 100%, B 45%, PEP 4%, p<0.001). Mean pre-dialysis hospitalization (due to in-patient emergency dialysis onset for unplanned starts and planned for access insertion for elective out-patient starts) was shorter among PEP patients (7days-PEP, 17days-B, 30days-A). Logistic regression confirmed the predictive role of PEP for emergent start (AOR 0.03, 0.001 to 0.101, p<0.001) even excluding late referrals (AOR 0.1, 0.033 to 0.306, p<0.001), independently of baseline characteristics and comorbidities. CONCLUSIONS: Pre-dialysis follow-up by dedicated personnel was more effective than traditional specialist care in reducing morbidity and health care resources utilization in patients starting dialysis.