Effect of a plasma sodium biofeedback system applied to HFR on the intradialytic cardiovascular stability. Results from a randomized controlled study.

BACKGROUND: Intradialytic hypotension (IDH) is still a major clinical problem for haemodialysis (HD) patients. Haemodiafiltration (HDF) has been shown to be able to reduce the incidence of IDH. METHODS: Fifty patients were enrolled in a prospective, randomized, crossover international study focussed on a variant of traditional HDF, haemofiltration with endogenous reinfusion (HFR). After a 1-month run-in period on HFR, the patients were randomized to two treatments of 2 months duration: HFR (Period A) or HFR-Aequilibrium (Period B), followed by a 1-month HFR wash-out period and then switched to the other treatment. HFR-Aequilibrium (HFR-Aeq) is an evolution of the haemofiltration with endogenous reinfusion (HFR) dialysis therapy, with dialysate sodium concentration and ultrafiltration rate profiles elaborated by an automated procedure. The primary end point was the frequency of IDH. RESULTS: Symptomatic hypotension episodes were significantly lower on HFR-Aeq versus HFR (23 ± 3 versus 31 ± 4% of sessions, respectively, P l= l0.03), as was the per cent of clinical interventions (17 ± 3% of sessions with almost one intervention on HFR-Aeq versus 22 ± 2% on HFR, P <0.01). In a post-hoc analysis, the effect of HFR-Aeq was greater on more unstable patients (35 ± 3% of sessions with hypotension on HFR-Aeq versus 71 ± 3% on HFR, P <0.001). No clinical or biochemical signs of Na/water overload were registered during the treatment with HFR-Aeq. CONCLUSIONS: HFR-Aeq, a profiled dialysis supported by the Natrium sensor for the pre-dialysis Na(+) measure, can significantly reduce the burden of IDH. This could have an important impact in every day dialysis practice.

Effects of efficiency and length of acetate-free biofiltration session on postdialysis solute rebound.

BACKGROUND: Postdialytic rebound (PDR) of plasma solutes is a relevant drawback of intermittent hemodialysis, but its pathophysiological process remains undefined. We assessed the independent effects of efficiency and length of dialytic session on PDR of urea, phosphate, and potassium. METHODS: Uremic patients were evaluated at the beginning and end of dialysis and after 180 minutes in 2 randomized crossover studies. In study 1, we compared the effect of standard versus higher efficiency acetate-free biofiltration (AFB) while maintaining the same duration of 4 hours. In study 2, we compared the effect of 3- versus 5-hour AFB sessions while maintaining similar efficiency. RESULTS: In study 1, greater Kt/V (1.49 +/- 0.20 versus 1.22 +/- 0.15; P < 0.0001) was coupled with significant increases in both absolute removal and PDR of urea and phosphate (PDR of urea, +45% versus +29%; PDR of phosphate, +79% versus +52%), but not of potassium. Similarly, in study 2, shortening the AFB session while maintaining similar absolute removal and Kt/V (1.28 +/- 0.09 versus 1.31 +/- 0.09) significantly increased PDR of urea and phosphate (PDR of urea, +32% versus +19%; PDR of phosphate, +63% versus +36%), but not of potassium. In both studies, greater PDRs of urea and phosphate were associated with estimated greater removal of these solutes per hour. CONCLUSION: The rate of removal of phosphate and urea is a critical determinant of their PDR; conversely, potassium is not influenced by removal rate, likely because of its marked cell compartmentalization.

Renal cystic diseases: a review.

This review aims to assist in the categorization of inherited, developmental, and acquired cystic disease of the kidney as well as to provide a pertinent, up-to-date bibliography. The conditions included are autosomal-dominant polycystic kidney disease, autosomal-recessive polycystic kidney disease, unilateral renal cystic disease (localized cystic disease), renal simple cysts, multicystic dysplastic kidney, pluricystic kidney of the multiple malformation syndromes, juvenile nephronophthisis and medullary cystic disease, medullary sponge kidney, primary glomerulocystic kidney disease, and glomerulocystic kidney associated with several systemic disorders mainly of genetic or chromosomal etiology, cystic kidney in tuberous sclerosis, and in von Hippel-Lindau syndrome, cystic nephroma, cystic variant of congenital mesoblastic nephroma, mixed epithelial stromal tumor of the kidney, renal lymphangioma, pyelocalyceal cyst, peripylic cyst and perinephric pseudocyst, acquired renal cystic disease of long-term dialysis, and cystic renal cell carcinoma and sarcoma. Whereas the gross and histologic appearance of some of these conditions may be diagnostic, clinical and sometimes molecular studies may be necessary to define other types.

The genetic background of uremic secondary hyperparathyroidism.

Many studies have shown how gene mutations and genetic polymorphisms could influence secondary uremic hyperparathyroidism (HPTH), modulating parathyroid (PT) function and hyperplasia. Parathyroid hormone (PTH) gene expression and hormone secretion is regulated mainly by serum calcium, with a post-transcriptional effect, and by vitamin D with a transcriptional effect. PT cells retain the ability to proliferate and to apoptose. Hyperphosphatemia, hypocalcemia and vitamin D deficiency all stimulate PT cell proliferation. In the early stage of chronic uremia, PT proliferation is polyclonal, as in diffuse hyperplasia, whereas nodular hyperplasia growth is monoclonal with an increasingly recognized genetic background. HPTH has been associated with a number of familial diseases, such as multiple endocrine neoplasia-type 1 (MEN1), multiple endocrine neoplasia-type2A (MEN2A), neurofibromatosis type1 (NF1) and HPTH with multiple ossifying jaw fibromas (HPT-JT Syndrome). The genes involved in these diseases have been also investigated in secondary HPTH (sHPTH). Moreover, in sporadic and secondary uremic HPTH, clonal rearrangement and/or oncogene overexpression, gene deletions and tumor suppressor gene inactivation have been reported. However, each condition shows different patterns of genetic abnormalities. Finally, PT function modulation by genetic polymorphisms of vitamin D and calcium receptors and of the PTH gene is reviewed.

Molecular analysis of NPHS2 and ACTN4 genes in a series of 33 Italian patients affected by adult-onset nonfamilial focal segmental glomerulosclerosis.

BACKGROUND: Mutations in the NPHS2 gene, encoding podocin, and in the ACTN4 gene, encoding alpha-actinin-4, have been identified in familial childhood-onset forms of focal and segmental glomerulosclerosis (FSGS). NPHS2 may be also responsible for some sporadic cases. The role of NPHS2 and ACTN4 in the adult sporadic form of the disease is being clarifying. METHODS: Thirty-three adult subjects affected by sporadic FSGS were studied at molecular level. At biopsy, 12 patients had nephrotic syndrome, 5 patients had isolated proteinuria and 16 patients showed proteinuria and hematuria. Glomerular filtration rate (GFR) was in the normal range in 19 subjects and 14 patients had a variable degree of renal failure. Multiplex families presenting with a clear familial inheritance for proteinuria or other congenital nephrotic syndrome were excluded. The whole coding region, all intron/exon boundaries and flanking intronic regions of NPHS2 gene and the exon 8, i.e. hot-spot mutations of the ACTN4 gene, were analyzed in all patients by denaturing high-performance liquid chromatography (DHPLC) to search disease-causing defects. RESULTS: The analysis identified four already described and two new polymorphisms, IVS3-21C>T and IVS3-46C>T, on the NPHS2 gene. Moreover, the R229Q allele was identified in 3/33 patients and in 7/124 controls, accounting for an allelic frequency of 0.045 and 0.028, respectively. The new intronic polymorphism IVS7-54C>T was also found in the exon 8 of the ACTN4 gene. CONCLUSIONS: In this study, we exhaustively analyzed the NPHS2 and the exon 8 of the ACTN4 genes in a series of sporadic 'adult-onset' FSGS patients. No causative mutations were found while the R229Q allele was identified in 3 patients confirming its possible role as a 'disease-associated NPHS2 allele' although its pathogenetic involvement needs to be further clarified. Moreover, the description of new intronic polymorphisms in both genes is reported.

The C677T methylenetetrahydrofolate reductase gene mutation does not influence cardiovascular risk in the dialysis population: results of a multicentre prospective study.

BACKGROUND: Although the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been identified as an independent cardiovascular risk factor (CRF) in the general population and among uraemic subjects, the validity of this association remains controversial. METHODS: To verify this hypothesis, we enrolled all subjects on maintenance dialysis treatment from a specific Italian district. We also enrolled, from the same area, 1307 subject to serve as controls. Genomic DNA was obtained and MTHFR C677T gene polymorphisms were determined. After a baseline evaluation, patients were followed-up for 37+/-13 months, and all cardiovascular events and causes of mortality were recorded. RESULTS: A total of 461 patients (417 on haemodialysis and 44 on peritoneal dialysis) were investigated, and these included patients with and without cardiovascular diseases at baseline. At enrollment, mean age was 58.8+/-15.6 years and dialytic age was 82+/-69 months. Genotype frequencies were not different between controls and uraemics. During the follow-up, the mean mortality rate was 8.81%/year, with cardiovascular events as the most frequent cause of death (n = 68, 56.6%). There was no relationship between the MTHFR genotype and cardiovascular morbidity, overall mortality or cardiovascular mortality. CONCLUSIONS: In end-stage renal disease, MTHFR C677T polymorphisms were not associated with cardiovascular disease or mortality.

Calcitriol increases burst-forming unit-erythroid proliferation in chronic renal failure. A synergistic effect with r-HuEpo.

BACKGROUND: Calcitriol (C) improves anemia in chronic renal failure. This effect may be related to the suppression of iPTH release, or to a direct effect on erythropoiesis. METHODS: Thirty-three patients with chronic renal failure were enrolled; among them, 24 were on chronic hemodialysis and 9 on conservative management. None had other chronic or hematological disease, aluminum levels were below 20 microg/l and DFO testing was negative. The iPTH range was 250-480 pg/l. None were treated with C or r-HuEpo. In vitro study: Samples were drawn for a basal erythroid precursor (burst forming unit-erythroid BFU-E) study: Mononuclear cells were incubated for 14 days with r-HuEpo 3U/ml (A), r-HuEpo 3U/l + C 30 pg (B), r-HuEpo 3U/ml + C 300 pg (C), or r-HuEpo 30 U/ml + C 300 pg (D). In vivo study: After the basal evaluation, 10 patients on chronic dialysis were treated with C (Calcijex-Abbott) 1 microg three times a week, and 4 patients served as controls. BFU-E studies were performed after 1, 2 and 4 months. RESULTS: In vitro, culture B showed increased BFU-E proliferation vs. A (41 +/- 23 vs. 27 +/- 15, p < 0.02); in cultures C and D, proliferation was 61 +/- 31 and 78 +/- 42, respectively, p < 0.01 vs. A. There was no difference among patients with predialysis renal failure and those on dialysis. BFU-E proliferation was inversely related to basal Hb (p < 0.04) and CRP levels (p < 0.05). During the in vivo study, all cultures showed a progressive increase in proliferation without a plateau level (basal, after 1, 2 and 4 months, respectively) In A: 17 +/- 8, 22 +/- 13, 30.9 +/- 14.9, 41.4 +/- 20; in B: 27.3 +/- 15, 35.6 +/- 20, 45.5 +/- 21, 57 +/- 26; in C: 48.2 +/- 20.6, 63.7 +/- 32, 75.7 +/- 37, 83 +/- 40; in D: 72 +/- 24, 91 +/- 42, 106 +/- 42, 110 +/- 42.3 (all p < 0.001). Hb and Hct showed a significant increase (p < 0.03) in the treatment group. The decrease in iPTH was not related to BFU-E proliferation. CONCLUSIONS: In chronic uremia, C has a direct effect on erythroid precursors proliferation, as demonstrated both in vitro and in vivo, with a synergistic effect with r-HuEpo. C may be a useful adjuvant therapy to r-HuEpo treatment.

Intra- and post-dialytic changes of haemoglobin concentrations in non-anaemic haemodialysis patients.

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 = 14, NOR) and anaemic (Hb = 11-12 g/dl, n = 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 = 0.10), but persisted higher in LOW (P < 0.005). The extent of the post-dialytic decrement of Hb was inversely related to the total protein values at T0 (r = -0.547, P = 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.

PAI-1 4G/5G and ACE I/D gene polymorphisms and the occurrence of myocardial infarction in patients on intermittent dialysis.

BACKGROUND: Myocardial infarction (MI) is a leading cause of death, particularly in high-risk settings such as uraemia, in which it is not yet known to what extent genetic factors contribute to the overall risk of MI. We have prospectively evaluated the effect of plasminogen activator inhibitor-1 (PAI-1) 4G/5G and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms on the occurrence of MI in uraemics. METHODS: All patients undergoing intermittent dialysis in an Italian district were enrolled as subjects. From the same area, 1307 individuals served as controls. Genomic DNA was obtained and ACE I/D and PAI-1 4G/5G gene polymorphisms were determined. After a baseline evaluation, patients were followed for 28.8+/-9.8 months. MIs and other causes of death were recorded. RESULTS: A total of 461 patients (417 on haemodialysis and 44 on peritoneal dialysis) were investigated. At entry, their mean age was 58.2+/-16.2 years and dialytic age was 82+/-69 months. Genotype frequencies were not different between controls and uraemics and, in the latter group, between patients with or without cardiovascular diseases at baseline evaluation. During the follow-up, 22 fatal and 16 non-fatal MIs were recorded (mean incidence 1.99 and 1.45%/year, respectively). The adjusted risk of fatal and total MI was related to the presence at entry of a history of MI [hazard ratios (HR) 4.3; 95% confidence interval (CI) 1.5-12.0 and HR 6.8; 95% CI: 3.3-14.0, respectively] and to the PAI-1 4/4 genotype (HR 2.8; 95% CI 1.2-6.9 and HR 2.1; 95% CI 1.1-4.2, respectively). CONCLUSIONS: In end-stage renal disease, PAI-1 4G/5G gene polymorphism may have a significant role in the occurrence of fatal and non-fatal MI.

Effects of ethylene oxide and steam sterilization on dialysis-induced cytokine release by cuprophan membrane.

The effects of sterilization modalities on dialysis-induced cytokine release are still unknown. To investigate these effects, 8 patients on chronic hemodialysis were enrolled for evaluating at different intervals interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) production (pg/ml/106). They were using a 1.3 m2 ethylene oxide (E3) or steam (E3S) sterilized Cuprophan membrane. The patients underwent a basal test with E3 (A1) and 2 following tests after 1 (B1) and 2 (B2) months of E3S treatment, respectively. Finally, the last test was performed 1 month after the switch to E3 (A2). Il-1beta predialysis release by mononuclear cells was 162 +/- 114 pg/ml/106 in A1, 185 +/- 129 pg/ml/106 in B1, and 226 +/- 138 pg/ml/106 in B2, then decreased to 123 +/- 134 in A2 (p < 0.07). Il-1beta postdialysis levels were 234 +/- 238 pg/ml/106 in A1, 429 +/- 285 pg/ml/106 (B1), and 438 +/- 473 pg/ml/106 (B2) with the steam membrane, decreasing to 204 +/- 134 pg/ml/106 in A2 (p < 0.01). TNF-alpha predialysis basal release (A1) was 826 +/- 817 pg/ml/106, 720 +/- 496 in B1, and 1079 +/- 515 pg/ml/106 in B2, and finally 680 +/- 588 pg/ml/106 in A2 (p < 0.03). In postdialysis TNF-alpha levels were 963 +/- 542 pg/ml/106 in A1, 1,226 +/- 541 pg/ml/106, and 1,183 +/- 776 in B1 and B2 respectively, and 388 +/- 297 pg/ml/106 in A2 (p < 0.003). Steam sterilization seems to induce a higher cytokine release by mononuclear cells when a Cuprophan membrane is used. This finding may be related to a less physiologic action of the steam in the case of Cuprophan membranes. Further studies are needed to clarify this hypothesis.