Battista Fabio Viola

Genome-wide association study identifies susceptibility loci for IgA nephropathy

We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10−26 and 4.84 × 10−9 and minor allele odds ratios of 0.63–0.80). These five loci explain 4–7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.

IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22–23

End-stage renal disease (ESRD) is a major public health problem, affecting 1 in 1,000 individuals and with an annual death rate of 20% despite dialysis treatment. IgA nephropathy (IgAN) is the most common form of glomerulonephritis, a principal cause of ESRD worldwide; it affects up to 1.3% of the population and its pathogenesis is unknown. Kidneys of people with IgAN show deposits of IgA-containing immune complexes with proliferation of the glomerular mesangium (Fig. 1). Typical clinical features include onset before age 40 with haematuria and proteinuria (blood and protein in the urine), and episodes of gross haematuria following mucosal infections are common; 30% of patients develop progressive renal failure. Although not generally considered a hereditary disease, striking ethnic variation in prevalence and familial clustering, along with subclinical renal abnormalities among relatives of IgAN cases, have suggested a heretofore undefined genetic component. By genome-wide analysis of linkage in 30 multiplex IgAN kindreds, we demonstrate linkage of IgAN to 6q22–23 under a dominant model of transmission with incomplete penetrance, with a lod score of 5.6 and 60% of kindreds linked. These findings for the first time indicate the existence of a locus with large effect on development of IgAN and identify the chromosomal location of this disease gene.

The Challenge of Diagnosing Atheroembolic Renal Disease: Clinical Features and Prognostic Factors

Background— Atheroembolic renal disease (AERD) is caused by showers of cholesterol crystals released by eroded atherosclerotic plaques. Embolization may occur spontaneously or after angiographic/surgical procedures. We sought to determine clinical features and prognostic factors of AERD. Methods and Results— Incident cases of AERD were enrolled at multiple sites and followed up from diagnosis until dialysis and death. Diagnosis was based on clinical suspicion, confirmed by histology or ophthalmoscopy for all spontaneous forms and for most iatrogenic cases. Cox regression was used to model time to dialysis and death as a function of baseline characteristics, AERD presentation (acute/subacute versus chronic renal function decline), and extrarenal manifestations. Three hundred fifty-four subjects were followed up for an average of 2 years. They tended to be male (83%) and elderly (60% >70 years) and to have cardiovascular diseases (90%) and abnormal renal function at baseline (83%). AERD occurred spontaneously in 23.5% of the cases. During the study, 116 patients required dialysis, and 102 died. Baseline comorbidities, ie, reduced renal function, presence of diabetes, history of heart failure, acute/subacute presentation, and gastrointestinal tract involvement, were significant predictors of event occurrence. The risk of dialysis and death was 50% lower among those receiving statins. Conclusions— Clinical features of AERD are identifiable. These make diagnosis possible in most cases. Prognosis is influenced by disease type and severity.

Renal Apolipoprotein A-I Amyloidosis: A Rare and Usually Ignored Cause of Hereditary Tubulointerstitial Nephritis

Apolipoprotein A-I amyloidosis is a rare, late-onset, autosomal dominant condition characterized by systemic deposition of amyloid in tissues, the major clinical problems being related to renal, hepatic, and cardiac involvement. Described is the clinical and histologic picture of renal involvement as a result of apolipoprotein A-I amyloidosis in five families of Italian ancestry. In all of the affected family members, the disease was caused by the Leu75Pro heterozygous mutation in exon 4 of apolipoprotein A-I gene, as demonstrated by direct sequencing and RFLP analysis. Immunohistochemistry confirmed that amyloid deposits were specifically stained with an anti-apolipoprotein A-I antibody. The clinical phenotype was mainly characterized by a variable combination of kidney and liver disturbance. The occurrence of renal involvement seemed to be almost universal, although its severity varied greatly ranging from subclinical organ damage to overt, slowly progressive renal dysfunction. The renal presentation was consistent with a tubulointerstitial disease, as suggested by the findings of defective urine-concentrating capacity, moderate polyuria, negative urinalysis, and mild tubular proteinuria. Histology confirmed tubulointerstitial nephritis. Surprising, amyloid was restricted to nonglomerular regions and limited to the renal medulla. This location of apolipoprotein A-I amyloid differs sharply from other systemic amyloidoses that are mainly characterized by glomerular and vascular deposits. The tubulointerstitial nephritis as a result of hereditary apolipoprotein A-I amyloidosis is a rare disease and a challenging diagnosis to recognize. Patients who present with familial tubulointerstitial nephritis associated with liver disease require a high index of suspicion for apolipoprotein A-I amyloidosis.

Familial clustering of IgA nephropathy: Further evidence in an Italian population

Several lines of evidence suggest that genetic factors have an important role in the pathogenesis of immunoglobulin A (IgA) nephropathy. We report the prevalence of familial IgA nephropathy in a referral center in northern Italy and present the data on HLA genotypes in the families identified. Twenty-six of 185 patients (14%) with IgA nephropathy investigated in Brescia, Italy, were related to at least one other patient with the disease. Restriction fragment length polymorphism (RFLP) analysis of HLA-DR beta and HLA-DQ alpha and beta genes, as well as polymerase chain reaction-based oligonucleotide typing, was performed in family members. The 26 patients with IgA nephropathy belonged to 10 families. Familial relationships between the patients varied greatly, ranging from parent-child to sib-pair to more distant familial relationships. No common nephrotoxic factor was identified in the families. The intervals separating the apparent onset of disease in relatives with IgA nephropathy varied from 8 months to 13 years. In patients with a family history of IgA nephropathy, there was an increased incidence of HLA-DRB1*08 compared with those with sporadic IgA nephropathy. The study shows that a significant number of the patients with IgA nephropathy followed up in Brescia had a family history of disease. The fact that the Italian population, an ethnic group not previously examined, also presents an increased familial susceptibility to IgA nephropathy suggests that familial predisposition is a very common finding for IgA nephropathy. Thus, clinicians should become aware that IgA nephropathy may aggregate within families in a substantial number of cases. In addition, this subgroup of patients with IgA nephropathy offers an ideal opportunity to elucidate the molecular genetics of this disease.

Long-term Effects of Arteriovenous Fistula Closure on Echocardiographic Functional and Structural Findings in Hemodialysis Patients: A Prospective Study

BACKGROUND The arteriovenous fistula (AVF) provides an effective vascular access for hemodialysis; however, the associated hemodynamic effects may alter cardiac structure and function. The objective of this study is to evaluate the effect of AVF closure on functional and structural echocardiographic findings. STUDY DESIGN Prospective observational study. SETTING & PARTICIPANTS In a single center between 2003 and 2006, we enrolled 25 consecutive hemodialysis patients with AVF malfunction who underwent AVF closure and conversion to a tunneled central venous catheter because of exhaustion of alternative vascular sites and 36 matched controls with a well-functioning AVF. PREDICTOR AVF closure. OUTCOMES & MEASUREMENTS Outcomes were changes in findings on echocardiograms obtained before and 6 months after AVF closure for patients in the AVF-closure group and at baseline and 6 months later for controls. Echocardiographic measurements included left ventricular (LV) internal diastolic diameter, interventricular septum thickness, diastolic posterior wall thickness, LV mass (LVM), LVM index (LVMi), and LV ejection fraction (LVEF). Dialysis modality and scheme were unchanged. RESULTS In the AVF-closure group, LVM decreased from 225 +/- 55 to 206 +/- 51 g (P < 0.001) and LVMi decreased from 135 +/- 40 to 123 +/- 35 g/m(2) (P < 0.001). LV internal diastolic diameter, interventricular septum thickness, and diastolic posterior wall thickness decreased significantly, whereas LVEF increased from 56% +/- 7% to 59% +/- 6% (P < 0.001). No significant changes were observed in controls. In patients with AVF closure, LV morphologic characteristics showed a decrease in both eccentric and concentric hypertrophy in favor of normalization or a pattern of concentric remodeling. No significant changes were observed in controls. LIMITATIONS Use of matched rather than randomized controls. CONCLUSIONS Closure of an AVF determines a significant decrease in LV internal diastolic diameter, interventricular septum thickness, and diastolic posterior wall thickness. This is associated with significant improvement in LVEF, a significant decrease in LVM and LVMi, and a more favorable shift of cardiac geometry toward normality.

Low-protein diets for chronic kidney disease patients: the Italian experience

BackgroundNutritional treatment has always represented a major feature of CKD management. Over the decades, the use of nutritional treatment in CKD patients has been marked by several goals. The first of these include the attainment of metabolic and fluid control together with the prevention and correction of signs, symptoms and complications of advanced CKD. The aim of this first stage is the prevention of malnutrition and a delay in the commencement of dialysis. Subsequently, nutritional manipulations have also been applied in association with other therapeutic interventions in an attempt to control several cardiovascular risk factors associated with CKD and to improve the patients overall outcome. Over time and in reference to multiple aims, the modalities of nutritional treatment have been focused not only on protein intake but also on other nutrients.DiscussionThis paper describes the pathophysiological basis and rationale of nutritional treatment in CKD and also provides a report on extensive experience in the field of renal diets in Italy, with special attention given to approaches in clinical practice and management.SummaryItalian nephrologists have a longstanding tradition in implementing low protein diets in the treatment of CKD patients, with the principle objective of alleviating uremic symptoms, improving nutritional status and also a possibility of slowing down the progression of CKD or delaying the start of dialysis. A renewed interest in this field is based on the aim of implementing a wider nutritional therapy other than only reducing the protein intake, paying careful attention to factors such as energy intake, the quality of proteins and phosphate and sodium intakes, making today’s low-protein diet program much more ambitious than previous. The motivation was the reduction in progression of renal insufficiency through reduction of proteinuria, a better control of blood pressure values and also through correction of metabolic acidosis. One major goal of the flexible and innovative Italian approach to the low-protein diet in CKD patients is the improvement of patient adherence, a crucial factor in the successful implementation of a low-protein diet program.

Cost-benefit analysis of supplemented very low-protein diet versus dialysis in elderly CKD5 patients

BACKGROUND Dialysis increases patient life expectancy but is associated with clinically severe and costly complications. Health and economic benefits could derive from postponing dialysis with a supplemented very low-protein diet (sVLPD). METHODS An economic evaluation was conducted to compare benefits and costs of sVLPD versus dialysis in elderly CKD5 patients. Data from 57 patients aged >or=70 years, with glomerular filtration rate (GFR) 5-7 mL/min, previously participating in a clinical trial demonstrating non-inferior mortality and morbidity of starting sVLPD compared to dialysis treatment, were analysed: 30 patients were randomized to dialysis and 27 to sVLPD. A cost-benefit analysis was conducted, in the perspective of the National Health Service (NHS). Direct medical and non-medical benefits and costs occurring in 3.2 mean years of follow-up were quantified: time free from dialysis, cost of dialysis treatment, hospitalization, drugs, laboratory/instrumental tests, medical visits and travel and energy consumption to receive dialysis. Prices/tariffs valid in 2007 were used, with an annual discount rate of 5% applied to benefits and costs occurring after the first year. Sensitivity analyses were conducted to identify how estimates could vary in different contexts of applications. Results are reported as net benefit, expressed as mean euro/patient (patient-year). RESULTS The opportunity to safely postpone initiation of dialysis of 1 year/patient on average translated into an economic benefit to the NHS, corresponding to 21 180 euro/patient in the first, 6500 euro/patient in the second and 682 euro/patient in the third year of treatment, with a significant net benefit in favour of sVLPD even in a worst-case hypothesis. CONCLUSION The initiation of sVLPD in elderly CKD5 subjects is a safe and beneficial strategy for these patients and allows them to gain economic resources that can be allocated to further health care investments.

Blood volume changes during three different profiles of dialysate sodium variation with similar intradialytic sodium balances in chronic hemodialyzed patients

The aim of this study was to evaluate the effects on blood volume (BV) preservation of three different profiles of dialysate sodium variation with similar intradialytic sodium balances. Ten uremic patients aged 50 +/- 11 years receiving regular bicarbonate hemodialysis for 49 +/- 57 months were studied. Each patient underwent three hemodialysis treatments with different modalities of dialysate sodium profiles: constant sodium hemodialysis (CHD), high-low sodium hemodialysis (H-LHD), and low-high sodium hemodialysis (L-HHD). In CHD, the dialysate sodium concentration was 141 mEq/L and did not change during treatment. In H-LHD and L-HHD, the dialysate sodium concentration at the start of dialysis was 160 mEq/L and 133 mEq/L, respectively, and remained constant for 60 minutes. At this time, a single-step break point of variation of dialysate sodium concentration occurred. The dialysate sodium concentration changed according to a model aimed to keep identical the amount of dialysate sodium exchanged in the three different dialysis procedures. The duration of hemodialysis, the blood flow rate, the dialysate flow rate, and the dialysis membrane were the same for all three different hemodialysis modalities. The ultrafiltration rate was kept constant during treatment. Total dialysate collection and intradialytic sodium balance were calculated for each hemodialysis session. Blood pressure and heart rate were monitored at 10-minute intervals; percent reductions of BV (%R-BV) were continuously monitored by an online optical reflection method (Hemoscan; Hospal-Dasco, Medolla, Italy). The results have shown a lower intradialytic %R-BV with H-LHD compared with L-HHD and CHD. No differences in total ultrafiltration rate, systolic and diastolic blood pressures, and heart rate were observed among the three different dialysis procedures. The total dialysate sodium collected and the intradialytic sodium balances were very similar among the three different dialysis procedures, confirming the accuracy of the precision of the sodium model used. The H-LHD sodium profile may be a useful tool in the prevention of excessive %R-BV and of dialysis intolerance episodes.

Very low-protein diet plus ketoacids in chronic kidney disease and risk of death during end-stage renal disease: a historical cohort controlled study

BACKGROUND Very low-protein intake during chronic kidney disease (CKD) improves metabolic disorders and may delay dialysis start without compromising nutritional status, but concerns have been raised on a possible negative effect on survival during dialysis. This study aimed at evaluating whether a very low-protein diet during CKD is associated with a greater risk of death while on dialysis treatment. METHODS This is an historical, cohort, controlled study, enrolling patients at dialysis start previously treated in a tertiary nephrology clinic with a very low-protein diet supplemented with amino acids and ketoacids (s-VLPD group, n = 184) or without s-VLPD [tertiary nephrology care (TNC) group, n = 334] and unselected patients [control (CON) group, n = 9.092]. The major outcome was survival rate during end-stage renal disease associated to s-VLPD treatment during CKD. The propensity score methods and Cox regression model were used to match groups at the start of dialysis to perform survival analysis and estimate adjusted hazard ratio (HR). RESULTS In s-VLPD, TNC and CON groups, average age was 67.5, 66.0 and 66.3 years, respectively (P = 0.521) and male prevalence was 55, 55 and 62%, respectively (P = 0.004). Diabetes prevalence differed in the three groups (P < 0.001), being 18, 17 and 31% in s-VLPD, CON and TNC, respectively. A different prevalence of cardiovascular (CV) disease was found (P < 0.001), being similar in TNC and CON (31 and 25%) and higher in s-VLPD (41%). Median follow-up during renal replacement therapy (RRT) was 36, 32 and 36 months in the three groups. Adjusted HR estimated on matched propensity patients was 0.59 (0.45-0.78) for s-VLPD versus CON. Subgroup analysis showed a lower mortality risk in s-VLPD versus matched-CON in younger patients (<70 years) and those without CV disease. No significant difference in HRs was found between s-VLPD and TNC. CONCLUSION s-VLPD during CKD does not increase mortality in the subsequent RRT period.