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The current implementation into nephrology clinical practice of guidelines on treatment of cardiovascular (CV) risk factors in chronic kidney disease (CKD) is unknown. We designed a cross-sectional analysis to evaluate the prevalence and treatment of eight modifiable CV risk factors in 1058 predialysis CKD patients (stage 3: n =486; stage 4: n =430, stage 5: n =142) followed for at least 1 year in 26 Italian renal clinics. The median nephrology follow-up was 37 months (range: 12–391 months). From stages 3 to 5, hypertension was the main complication (89, 87, and 87%), whereas smoking, high calcium-phosphate product and malnutrition were uncommon. The prevalence of proteinuria (25, 38, and 58%), anemia (16, 32, and 51%) and left ventricular hypertrophy (51, 55, and 64%) significantly increased, while hypercholesterolemia was less frequent in stage 5 (49%) than in stages 4 and 3 (59%). The vast majority of patients received multidrug antihypertensive therapy including inhibitors of renin–angiotensin system; conversely, diuretic treatment was consistently inadequate for both frequency and dose despite scarce implementation of low salt diet (19%). Statins were not prescribed in most hypercholesterolemics (78%), and epoietin treatment was largely overlooked in anemics (78%). The adjusted risk for having a higher number of uncontrolled risk factors rose in the presence of diabetes (odds ratio 1.29, 95% confidence interval 1.00–1.66), history of CV disease (odds ratio 1.48, 95% confidence interval 1.15–1.90) and CKD stages 4 and 5 (odds ratio 1.75, 95% confidence interval 1.37–2.22 and odds ratio 2.85, 95% confidence interval 2.01–4.04, respectively). In the tertiary care of CKD, treatment of hypertension is largely inadequate, whereas therapy of anemia and dyslipidemia is frequently omitted. The risk of not achieving therapeutic targets is higher in patients with diabetes, CV disease and more advanced CKD.

To define whether age modifies the prognosis of patients with chronic kidney disease (CKD) on nephrology care, we prospectively followed patients with CKD who have been receiving nephrology care in a clinic for 1 year or more. The incidence of end-stage renal disease (ESRD), defined by the occurrence of dialysis or transplant, or death without ESRD was estimated by a competing-risk approach, and interactions between age and risk factors tested in Cox models over a median follow-up period of 62.4 months. Of 1248 patients with stage III-V CKD, 481 were younger than 65, 410 were between 65 and 75, and 357 were over 75 years old. Within each age class, the mean estimated glomerular filtration rate (eGFR) was 31, 32, and 29 ml/min per 1.73 m2, respectively. There were 394 ESRD events and 353 deaths. The risk of ESRD was higher than the risk of death without ESRD for ages 60 years, and independent of eGFR. The ESRD risk diminished with aging but still prevailed for eGFRs of 25-35 in patients between 65 and 75 years and with an eGFR below 15 in those up to 85 years old. Proteinuria significantly increased the risk of ESRD with advancing age. Surprisingly, the unfavorable effects of cardiovascular disease on ESRD and of diabetes on survival significantly decreased with increasing age. Male gender, higher phosphate, lower body mass index, and hemoglobin were age-independent predictors for ESRD, while cardiovascular disease, lower hemoglobin, higher proteinuria and uric acid, and ESRD also predicted death. Thus, in older patients on nephrology care, the risk of ESRD prevailed over mortality even when eGFR was not severely impaired. Proteinuria increases ESRD risk, while the predictive role of other modifiable risk factors was unchanged compared with younger patients. © 2012 International Society of Nephrology.

Split intein-mediated protein trans-splicing expands AAV transfer capacity, thus overcoming the limited AAV cargo. However, non-mammalian inteins persist as trans-splicing by-products, and this could raise safety concerns for AAV intein clinical applications. In this study, we tested the ability of several degrons to selectively decrease levels of inteins after protein trans-splicing and found that a version of E. coli dihydrofolate reductase, which we have shortened to better fit into the AAV vector, is the most effective. We show that subretinal administration of AAV intein armed with this short degron is both safe and effective in a mouse model of Stargardt disease (STGD1), which is the most common form of inherited macular degeneration in humans. This supports the use of optimized AAV intein for gene therapy of both STGD1 and other conditions that require transfer of large genes., Graphical abstract, Intein-mediated protein trans-splicing (PTS) expands AAV gene transfer capacity. However, non-mammalian inteins persist as trans-splicing by-products. Here, we show that ecDHFR selectively degrades inteins after PTS and that AAV intein vectors armed with this degron are both safe and effective in the retina of a mouse model of genetic blindness.

Gene therapy with adeno-associated viral (AAV) vectors is limited by AAV cargo capacity that prevents their application to the inherited retinal diseases (IRDs), such as Stargardt disease (STGD) or Usher syndrome type IB (USH1B), which are due to mutations in genes larger than 5 kb. Trans-splicing or hybrid dual AAV vectors have been successfully exploited to reconstitute large gene expression in the mouse retina. Here, we tested them in the large cone-enriched pig retina that closely mimics the human retina. We found that dual AAV trans-splicing and hybrid vectors transduce pig photoreceptors, the major cell targets for treatment of IRDs, to levels that were about two- to threefold lower than those obtained with a single AAV vector of normal size. This efficiency is significantly higher than that in mice, and is potentially due to the high levels of dual AAV co-transduction we observe in pigs. We also show that subretinal delivery in pigs of dual AAV trans-splicing and hybrid vectors successfully reconstitute, albeit at variable levels, the expression of the large genes ABCA4 and MYO7A mutated in STGD and USH1B, respectively. Our data support the potential of dual AAV vectors for large gene reconstitution in the cone-enriched pig retina that is a relevant preclinical model.

Retinal gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. However, AAV’s limited cargo capacity prevents its application to therapies of inherited retinal diseases due to mutations of genes over 5 kb, like Stargardt’s disease (STGD) and Usher syndrome type IB (USH1B). Previous methods based on ‘forced’ packaging of large genes into AAV capsids may not be easily translated to the clinic due to the generation of genomes of heterogeneous size which raise safety concerns. Taking advantage of AAV’s ability to concatemerize, we generated dual AAV vectors which reconstitute a large gene by either splicing (trans-splicing), homologous recombination (overlapping), or a combination of the two (hybrid). We found that dual trans-splicing and hybrid vectors transduce efficiently mouse and pig photoreceptors to levels that, albeit lower than those achieved with a single AAV, resulted in significant improvement of the retinal phenotype of mouse models of STGD and USH1B. Thus, dual AAV trans-splicing or hybrid vectors are an attractive strategy for gene therapy of retinal diseases that require delivery of large genes.

Summary Retinitis pigmentosa (RP) is a group of progressive retinal degenerations of mostly monogenic inheritance, which cause blindness in about 1:3,500 individuals worldwide. Heterozygous variants in the rhodopsin (RHO) gene are the most common cause of autosomal dominant RP (adRP). Among these, missense variants at C-terminal proline 347, such as p.Pro347Ser, cause severe adRP recurrently in European affected individuals. Here, for the first time, we use CRISPR/Cas9 to selectively target the p.Pro347Ser variant while preserving the wild-type RHO allele in vitro and in a mouse model of adRP. Detailed in vitro, genomic, and biochemical characterization of the rhodopsin C-terminal editing demonstrates a safe downregulation of p.Pro347Ser expression leading to partial recovery of photoreceptor function in a transgenic mouse model treated with adeno-associated viral vectors. This study supports the safety and efficacy of CRISPR/Cas9-mediated allele-specific editing and paves the way for a permanent and precise correction of heterozygous variants in dominantly inherited retinal diseases.

Background The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. Methods TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50–75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2–3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15–45 mg) or a sulfonylurea (5–15 mg glibenclamide, 2–6 mg glimepiride, or 30–120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. Findings Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74–1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p

Background. Non-anaemic haemodialysis (HD) patients are potentially more prone to the adverse effects of ultrafiltration-induced haemoconcentration. No study, however, has assessed the effects of dialytic session on haemoglobin (Hb) levels in these patients. Methods. The levels of Hb and total protein before, at the end (T0) and up to 120 min (T120) after the third HD session of the week were compared in non-anaemic (Hb >13 g/dl, n ¼ 14, NOR) and anaemic (Hb ¼ 11–12 g/dl, n ¼ 18, LOW) HD patients. Results. The intradialytic weight loss was similar in the two groups (4.0 ± 0.9 and 4.1 ± 0.9% body weight). During the treatment, Hb levels increased to the same extent in both groups (from 14.4 ± 1.2 to 16.3 ± 1.9 g/dl in NOR, and from 11.4 ± 0.8 to 12.7 ± 0.9 g/dl in LOW) in the presence, presumably, of a smaller plasma volume in NOR, whereas the increment of total protein was greater in NOR (from 7.1 ± 0.2 to 9.6 ± 0.5 g/dl) than in LOW (from 7.3 ± 0.6 to 8.7 ± 0.8 g/dl) (P < 0.0001). At T120, the Hb decline in NOR was almost double that measured in LOW (� 9.2 ± 3.0 vs � 4.7 ± 2.4%, P < 0.001). Consequently, Hb concentration did not differ from the pre-dialytic value in NOR (P ¼ 0.10), but persisted higher in LOW (P < 0.005). The extent of the postdialytic decrement of Hb was inversely related to the total protein values at T0 (r ¼� 0.547, P ¼ 0.0012). Conclusions. This study indicates that in NOR: (i) the extent of intradialytic increment of Hb is limited by a greater intradialytic plasma refilling; (ii) the greater plasma refilling persists after the end of dialysis, with the restoration of pre-dialytic Hb levels within the initial 2 h; and (iii) the force driving this phenomenon resides mainly in the larger changes of total protein concentration.

Supplemented very low protein diet ameliorates responsiveness to erythropoietin in chronic renal failure.BackgroundThe aim of this study was to evaluate the relationship between uremic state and erythropoiesis in patients with predialytic chronic renal failure (CRF).MethodsWe monitored for 2years the erythropoietin (EPO) requirement in patients with advanced CRF (creatinine clearance ≤25mL/min), randomized to either low protein diet (LPD) group (0.6g/kg body weight/day, N = 10) or very low protein diet (VLPD) group (0.3g/kg body weight/day, N = 10) supplemented with a mixture of ketoanalogs and essential amino acids, both kept at target hemoglobin levels.ResultsThe achieved protein intake after 6months was 0.79 ± 0.02g/kg body weight/day and 0.50 ± 0.02g/kg body weight/day in LPD and VLPD, respectively; such a difference was maintained up to the end of follow up. The final hemoglobin values did not differ from the basal values in either group (11.5 ± 0.2g/dL and 11.5 ± 0.3g/dL). EPO dose, that was similar at baseline (62.4 ± 9.6 UI/kg body weight/week and 61.8 ± 8.8 UI/kg body weight/week subcutaneously), remained unchanged in LPD but progressively decreased in VLPD down to the final value of 41.2 ± 7.0 UI/kg body weight/week (P < 0.0001 vs. basal and LPD). VLPD was associated with a decrease of urinary excretion and serum levels of urea nitrogen and phosphate; however, EPO requirement was not correlated with the changes of these parameters. On the contrary, the variation of EPO dose directly correlated with the modification of parathyroid hormone (PTH) levels, that diminished from 229 ± 55pg/mL to 118 ± 16pg/mL (P < 0.0001) in VLPD and did not change in LPD.ConclusionIn patients with advanced CRF, an effective decrease of protein intake of 0.3g/kg body weight/day induces a reduction of about 35% of the EPO dose required to maintain the target hemoglobin levels. This effect appears dependent on the correction of a moderate secondary hyperparathyroidism.

Maximal suppression of renin-angiotensin system in nonproliferative glomerulonephritis. Background Elimination of residual proteinuria is the novel target in renoprotrection; nevertheless, whether a greater suppression of renin-angiotensin system (RAS) effectively improves the antiproteinuric response in patients with moderate proteinuria remains ill-defined. Methods We evaluated the effects of maximizing RAS suppression on quantitative and qualitative proteinuria in ten patients with stable nonnephrotic proteinuria (2.55 ± 0.94 g/24 hours) due to primary nonproliferative glomerulonephritis (NPGN), and normal values of creatinine clearance (103 ± 17 mL/min). The study was divided in three consecutive phases: ( 1 ) four subsequent 1-month periods of ramipril at the dose of 2.5, 5.0, 10, and 20 mg/day; ( 2 ) 2 months of ramipril 20 mg/day + irbesartan 300 mg/day; and ( 3 ) 2 months of irbesartan 300 mg/day alone. Results Maximizing RAS suppression was not coupled with any major effect on renal function and blood pressure; conversely, a significant decrement in hemoglobin levels, of 0.8 g/dL on average, was observed during up-titration of ramipril dose. The 2.5 mg dose of ramipril significantly decreased proteinuria by 29%. Similar changes were detected after irbesartan alone (-28%). The antiproteinuric effect was not improved either by the higher ramipril doses (-30% after the 20 mg dose) or after combined treatment (-33%). The reduction of proteinuria led to amelioration of the markers of tubular damage, as testified by the significant decrement of α 1 microglobulin (α 1 m) excretion and of the tubular component of proteinuria at sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Conclusion In nonnephrotic NPGN patients, standard doses of either ramipril or irbesartan lead to significant reduction of residual proteinuria and amelioration of the qualitative features suggestive of tubular damage. The enhancement of RAS suppression up to the maximal degree does not improve the antiproteinuric response and is coupled with a decrement of hemoglobin levels.

The body composition in overweight and obese hemodialyzed patients (HD) remains ill-defined. This study evaluates in HD patients the influence of body size, as indicated by body mass index (BMI, kg/m(2)), on body composition by measuring bioimpedance analysis (BIA)-derived variables (phase angle (PA), fat-free mass (FFM) and body cell mass (BCM).We studied 50 Caucasian patients (mean age 62.8+/-9.2 y) on standard bicarbonate hemodialysis for at least 12 months who regularly achieved dry weight in post-HD, received similar dialysis doses and were free from inflammation/infection. Thirty-eight gender- and age-matched healthy subjects were included as controls (CON). Both HD and CON were divided into three groups on the basis of their BMI(kg/m2) 18.5-24.9, normal-weight (NW); 25-29.9, overweight (OW); andor =30, obese (OB). In HD patients, BIA was performed 30 min after the end of dialysis.Seven patients were obese (12%) while 16 were overweight (32%); in CON, 12 were obese (31%) and 12 overweight (31%). BIA-measured extracellular water was comparable in all groups. PA, which was similar in normal-weight HD and CON (6.2+/-0.9 degrees and 6.3+/-0.8 degrees ), decreased in OW- and OB-HD patients (5.3+/-1.0 degrees and 5.2+/-0.6 degrees, respectively; P0.05 vs NW-HD) while it was unchanged in OW- and OB-CON (6.1+/-0.8 degrees and 5.9+/-0.5 degrees, P0.05 vs respective HD groups). In OW and OB patients, the lower PA values were coupled with a major reduction of BIA-derived percentage BCM and FFM (P0.05 vs NW-HD, and vs OW- and OB-CON). In patients, PA and BCM correlated with anthropometry-measured FFM. Of note, serum albumin and protein catabolic rate were significantly reduced in OB patients.In overweight and obese HD patients, BIA-derived FFM, BCM and PA are significantly lower with respect to normal-weight patients and BMI-matched controls. These abnormalities of body composition are coupled with reduction of anthropometric measures of lean mass and a decrease of protein intake that, however, becomes significant only in the obese. We therefore suggest that overweight and obese HD patients are at risk of protein malnutrition in spite of excessive energy intake. BIA may be considered as a useful diagnostic tool to detect such a condition early.

Background: Dry weight prescription is commonly based on symptoms induced by inappropriate fluid removal by hemodialysis (HD). Aim of this study was to compare the assessment of volume status by conventional bioelectrical impedance analysis (BIA) and the resistance-reactance (RXc) graph method in HD patients achieving their target dry weight determined on clinical criteria. Methods: We studied 39 HD patients (23 males and 16 females, mean age 52 ± 17 years, dialytic age 41.2 ± 37 months). Dry weight, prescribed according to the standard clinical criteria, was constantly achieved in the last 3 months. Patients symptom-free over the last 3 months were defined as asymptomatic. Patients with either muscular cramps or hypotensive episodes were defined as symptomatic. Thirty-three healthy volunteers (11 males, 22 females, mean age 50 ± 11 years) constituted the control group. Standard, single frequency (50 kHz), tetrapolar, BIA measurements were obtained in controls, and in patients before, every 60 min, and 30 min after one HD session. Total body water (TBW), and extracellular water (ECW) were calculated using conventional BIA regression equations. In both groups, tissue hydration was also assessed by the RXc graph method. Results: On the basis of 95% tolerance interval (mean ± 2 SD) for the ECW (%) calculated in healthy subjects (ECW = 35–44%), HD patients were divided into 3 groups according to their post-HD ECW: 72% normohydrated with ECW 35–44%, 10% overhydrated with ECW >44%, and 18% underhydrated with ECW 2 = 6.9, p = 0.03) where the majority (73%) were classified as underhydrated, while 0 and 27% were classified as over- and normohydrated, respectively. The frequency distribution of the 28 asymptomatic patients also significantly differed between conventional BIA and RXc graph hydration categories (χ2 = 10.8, p = 0.005), since 11, 71 and 18% vs. 0, 43 and 57% of patients were classified as over-, normo-, and underhydrated, respectively. Conclusions: The classification of volume status based on conventional BIA was insensitive to either clinical situation (presence or absence of symptoms). In contrast, the classification based on the RXc graph was consistent with the clinical course in symptomatic patients (73% dehydrated, and 27% normohydrated), while it did not reflect the clinical course in asymptomatic patients, 57% of whom were classified as (already) underhydrated. A longitudinal study will establish the clinical usefulness of RXc graph indications in asymptomatic patients.

BACKGROUND Whether nephrology management improves over time achievement of blood pressure (BP) goal (

Background/Aims: In chronic kidney disease (CKD), no data on resistant hypertension (RH) are so far available despite the high prevalence of uncontrolled hypertension. We evaluated frequency, correlates and prognosis of RH in 300 consecutive incident hypertensive CKD patients in an academic renal clinic. Methods: RH was defined as office blood pressure (BP) ≧130/80 mm Hg despite ≧3 drugs at full dose including a diuretic, or as BP at goal with ≧4 full-dose drugs. Patients were evaluated at referral and after 6 months of nephrology management; thereafter, they were included in a renal survival analysis lasting 37.6 months. Results: On referral, glomerular filtration rate was 41.3 ± 16.6 ml/min/1.73 m2 and BP 148 ± 23/81 ± 12 mm Hg. After 6 months, BP decreased by 8 ± 23/3 ± 12 mm Hg. From referral to month 6, RH detection increased from 26 to 38% due to the significant increment in full-dose antihypertensive medications (from 2.0, IQR 1.0–3.0 to 2.5, IQR 2.0–3.0). Diabetes and proteinuria predicted the incidence of RH at month 6. Presence of RH at month 6 was associated with greater risk of renal death (HR, 1.85, 95% CI, 1.13–3.03), independent of main clinical features and degree of BP control. Conclusion: In CKD, RH is prevalent and associated with decreased renal survival, independent of BP levels.

During hemodialysis, amino acids (AA) are lost in the ultrafiltrate with consequent modification of their plasma profile. The aim of this cross-sectional study was to evaluate intradialytic changes of plasma AA levels during a single session of hemodiafiltration with endogenous reinfusion (HFR) versus acetate-free biofiltration (AFB). 48 patients chronically treated with HFR or AFB were matched 1:1 for age, gender, Kt/V and diabetes. Blood samples were collected at the beginning and the end of dialysis. Baseline plasma levels (µmol/l) of total AA (3,176 ± 722), essential AA (889 ± 221), and branched chain AA (459 ± 140) levels in HFR were similar to those in AFB (3,399 ± 621, 938 ± 277, and 463 ± 71, respectively). Plasma intradialytic AA levels did not change in HFR, while in AFB there was a reduction by about 25%. In conclusion, as compared with AFB, HFR has a sparing effect on AA loss due to the lack of adsorption by cartridge and to their complete reinfusion in blood.

Severe inherited retinal diseases, such as retinitis pigmentosa and Leber congenital amaurosis, are caused by mutations in genes preferentially expressed in photoreceptors. While adeno-associated virus (AAV)-mediated gene transfer can correct retinal pigment epithelium (RPE) defects in animal models, approaches for the correction of photoreceptor-specific diseases are less efficient. We evaluated the ability of novel AAV serotypes (AAV2/7, AAV2/8, AAV2/9, AAV2rh.43, AAV2rh.64R1, and AAV2hu.29R) in combination with constitutive or photoreceptor-specific promoters to improve photoreceptor transduction, a limiting step in photoreceptor rescue. Based on a qualitative analysis, all AAV serotypes tested efficiently transduce the RPE as well as rod and cone photoreceptors after subretinal administration in mice. Interestingly, AAV2/9 efficiently transduces Müller cells. To compare photoreceptor transduction from different AAVs and promoters in both a qualitative and quantitative manner, we designed a strategy based on the use of a bicistronic construct expressing both enhanced green fluorescent protein and luciferase. We found that AAV2/8 and AAV2/7 mediate six- to eightfold higher levels of in vivo photoreceptor transduction than AAV2/5, considered so far the most efficient AAV serotype for photoreceptor targeting. In addition, following subretinal administration of AAV, the rhodopsin promoter allows significantly higher levels of photoreceptor expression than the other ubiquitous or photoreceptor-specific promoters tested. Finally, we show that AAV2/7, AAV2/8, and AAV2/9 outperform AAV2/5 following ex vivo transduction of retinal progenitor cells differentiated into photoreceptors. We conclude that AAV2/7 or AAV2/8 and the rhodopsin promoter provide the highest levels of photoreceptor transduction both in and ex vivo and that this may overcome the limitation to therapeutic success observed so far in models of inherited severe photoreceptor diseases.

The greater antiproteinuric efficacy of converting enzyme inhibitor and angiotensin II receptor blocker combination (CEI+ARB), versus monotherapy with either drug, is not a consistent finding. We evaluated the clinicopathologic predictors of response to CEI+ARB in 43 patients with primary glomerulonephritis (GN), never treated with immunosuppressive drugs, and with persistent proteinuria after CEI alone. Main histological lesions were analyzed by obtaining on 557 glomeruli and 165 arteries formal score of mesangial cellularity, glomerulosclerosis, tubulointerstitial damage, mononuclear cell infiltration, arteriosclerosis, and arteriolar hyalinosis. Duration of CEI and CEI+ARB therapy was similar (4.7+/-2.4 and 5.0+/-1.5 months). Proteinuria (g/day) decreased from 3.5+/-2.9 to 2.4+/-2.3 after CEI, and to 1.5+/-1.3 after CEI+ARB (P

Background In maintenance haemodialysis patients, daily food intake is changeable; however, its relationship with nutritional status is unexplored. This study aimed to evaluate the isolated, long-term effect of daily nutrient intake on nutritional status in haemodialysis patients. Methods We performed a prospective 1-year controlled study in 27 chronic haemodialysis patients, without recognized risk factors for malnutrition. Each day for 1 week, four times in the year, we measured protein nitrogen appearance, and assessed dietary protein (DPI) and energy (DEI) intake from dietary diaries. We compared the nutritional outcome of patients spontaneously reducing nutrient intake below the threshold of 0.8 g/kg body weight/day for DPI and 25 kcal/kg body weight/day for DEI during the week (LOW, n = 8), with controls at adequate nutrient intake (CON, n = 19). An interventional 6-month study was then carried out in LOW to verify the cause-effect relationship. Results All patients showed a day-by-day reduction of whole nutrient intake during interdialytic period, which was mostly relevant in the third interdialytic day (L3). During the 1-year study, even in the presence of adequate dialysis dose and normal inflammatory indexes, body weight (68.0 +/- 5.5 to 65.8 +/- 5.9 kg), serum albumin (3.96 +/- 0.07 to 3.66 +/- 0.06 g/dl) and creatinine (9.2 +/- 1.1 to 8.1 +/- 0.7 mg/dl) significantly decreased in LOW but not in CON. Diaries evidenced in LOW a reduced number of meals at L3 that was explained by the fear of excessive interdialytic weight gain. During the interventional study, daily DPI and DEI increased at L3; this was associated with a significant increment of body weight, and serum albumin and creatinine levels. Conclusions In maintenance haemodialysis patients the persistent, marked reduction of daily nutrient intake, even if limited to a single day of the week, is an independent determinant of reversible impairment of nutritional status.

Maintenance hemodialysis (HD) patients were studied to assess the effect on hemoglobin (Hb) concentration induced by the cyclic variation in hydration status.Forty-nine HD patients were examined in three consecutive HD sessions in a 1-week treatment period. In a subgroup of 23 patients, Hb levels also were investigated during the long interdialytic interval.Hb levels at the end of the long interdialytic interval were significantly lower by 0.5 to 0.6 g/dL (5 to 6 g/L) than those at the end of short intervals. Among all pre-HD and post-HD Hb values, levels measured at the end of short intervals were closest to the mean Hb value of the week, derived from calculation of the area under the curve (12.0 +/- 0.2 g/dL [120 +/- 2 g/L]). Intradialytic Hb increments were different in the three sessions (+1.6 +/- 0.1 g/dL [+16 +/- 1 g/L] after the long interval, +1.1 +/- 0.1 g/dL [+11 +/- 1 g/L] and +1.1 +/- 0.1 g/dL [+11 +/- 1 g/L] after short intervals [P0.001] and proportionate to weight loss [-3.4 +/- 0.1, -2.7 +/- 0.1, and -2.6 +/- 0.1 kg, respectively; P0.001]). Hb level increment and weight loss correlated directly (r = 0.527; P0.0001); each 1 L of ultrafiltration (UF) led to an increase in Hb level of approximately 0.4 g/dL (4 g/L). Plasma refilling accounted for an approximately 45% decrement in the intradialytic increase in Hb level 2 hours post-HD.This study suggests that: (1) the end of the short interdialytic period is the most appropriate timing for anemia assessment, and (2) the remarkable hemodiluting effect of post-HD plasma refilling protects against excessive increments in Hb levels induced by UF.

Indications for renal biopsy are still ill defined. We recently sent a detailed questionnaire to 360 nephrologists in different areas of the world with the aim of providing information on this critical issue by evaluating the replies. The questionnaire was organized in four sections that included questions on renal biopsy indications in patients with normal renal function, renal insufficiency, and a transplanted kidney. In addition, the questions included methods applied to each renal biopsy procedure and to specimen processing. We received 166 replies; North Europe (50 replies), South Europe (47 replies), North America (31 replies), Australia and New Zealand (24 replies), and other countries (14 replies). In patients with normal renal function, primary indications for renal biopsy were microhematuria associated with proteinuria, particularly greater than 1 g/d of protein. In chronic renal insufficiency, kidney dimension was the major parameter considered before renal biopsy, whereas the presence of diabetes or serological abnormalities was not considered critical. In the course of acute renal failure (ARF) of unknown origin, 20% of the respondents would perform renal biopsy in the early stages, 26% after 1 week of nonrecovery, and 40% after 4 weeks. In a transplanted kidney, the majority of nephrologists would perform a renal biopsy in the case of graft failure after surgery, ARF after initial good function, slow progressive deterioration of renal function, and onset of nephrotic proteinuria. The last section provided comprehensive information on the technical aspects of renal biopsy. This survey represents the first attempt to provide a reliable consensus that can be used in developing guidelines on the use of kidney biopsy.

To gain insights into postdialytic rebound of serum phosphate (PDR-P), serum phosphate (P), calcium (Ca), and parathyroid hormone (PTH), levels were compared from the end of treatment (T0) to the subsequent 30 to 120 min and up to 68 hr in uremic patients who underwent with crossover modality a single session of two dialytic treatments characterized by different convective removal: standard hemodialysis (HD) and hemodiafiltration (HDF). In HDF, versus HD, P removal was greater (1171 +/- 90 versus 814 +/- 79 mg; P < 0.05) in the presence of similar predialytic P levels (6.0 +/- 0.2 and 5.9 +/- 0.4 mg/dl) and Kt/V (1.35 +/- 0.06 and 1.34 +/- 0.05); however, the serum P values at T0 did not differ (3.0 +/- 0.2 versus 3.3 +/- 0.2 mg/dl). In HDF, PDR-P was more rapid (30 min versus 90 min) and of a greater extent (at T120: +69 +/- 6% versus +31 +/- 4%; P < 0.0001). The higher P levels were maintained throughout the interdialytic period. Ca x P and PTH changed in parallel. Thereafter, patients were randomized to receive either HD or HDF for 3 mo. During this period, in the presence of similar Kt/V, protein intake, and dose of phospate binder, predialytic serum P levels diminished in HDF (from 5.8 +/- 0.2 to 4.4 +/- 0.3 mg/dl; P < 0.05), but they remained unchanged in HD. A similar pattern of changes was detected in Ca x P. Therefore, PDR-P is likely dependent on the mobilization of phosphate from a deep compartment induced by the intradialytic removal of this solute. Enhancement of convective removal acutely amplifies the entity of the phenomenon but allows a better control of Ca-P homeostasis in the medium term.