Distinct HLA class II alleles determine antibody response to vaccination with hepatitis B surface antigen.

Major histocompatibility complex (MHC) determinants control antibody production in response to protein antigens. Vaccination with hepatitis B surface antigen (HBsAg) frequently fails in hemodialyzed patients, but the genetic factors that modulate humoral responsiveness are poorly characterized. We studied the distribution of HLA class II alleles in 415 hemodialyzed Caucasian patients who received a full course of HBsAg vaccination, using class II oligotyping after genomic amplification of the DRB1 and DQB1 loci. Phenotype frequencies were compared in 114 non responders (anti-HBs antibodies < or = 10 SI units/liter), 301 responders (anti-HBs antibodies > 10 units/liter) and 471 healthy controls. DRB1*01 (DR1) and DRB1*15 (DR15) frequencies were lower in nonresponders than in responders and controls (DR1, 12.3% vs. 22.9% and 24.8%, respectively; DR15, 14% vs. 22.9% and 25.1%), while DRB1*03 (DR3) and DRB1*14 (DR14) frequencies were higher (DR3, 32.5% vs. 16.6% and 25.3%, respectively; DR14, 9.6% vs. 3% and 6.6%). Overall, 44.5% of DR3 or DR14 patients were nonresponders, compared to 18.1% of DR1 or DR15 patients (P = 0.0001). In conclusion the humoral response to HBsAg vaccine is influenced by class II allelic variants, which differ in their capacity to bind and present peptides to T lymphocytes.

Factors influencing progression of renal failure in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) frequently leads to end-stage renal failure (ESRF) in the sixth decade of life, but considerable heterogeneity exists in the rate of progression of renal failure. The respective contribution of genetic factors and of potentially amendable factors, such as blood pressure control or protein intake limitation, on the rate of progression in ADPKD patients is still debated. To evaluate the role of factors influencing the rate of progression of renal failure in ADPKD, we retrospectively analyzed the annual rate of decline of creatinine clearance (Ccr) in 109 ADPKD patients followed from the time a Ccr value of 30 to 50 mL per min/1.73 m2 was measured until ESRD and need for hemodialysis (Study A), and in 48 undialyzed ADPKD patients followed for at least 4 yr from the time a Ccr value of 50 to 60 mL per min/1.73 m2 was measured (Study B). In Study A, the decline in Ccr (delta Ccr) (mean +/- SE) was 5.8 +/- 0.2 mL per min/1.73 m2 per year in the whole series, and was lower in females than in males (5.0 +/- 0.2 versus 6.4 +/- 0.2, P < 0.001). Accordingly, ESRF was reached at a later age in female patients (55.1 +/- 1.2 versus 50.6 +/- 1.2 yr, P < 0.01). The age at ESRF in male patients was lower when the disease was transmitted by mother than by father (46.3 +/- 1.9 versus 54.1 +/- 1.8 yr, P < 0.01), whereas no significant effect of the gender of the affected parent was apparent in female patients. By regression analysis, there was a positive but weak relationship between delta Ccr and mean arterial pressure (average value during follow-up, 107 +/- 1 mm Hg, r = 0.224, P < 0.05) but not with dietary protein intake (mean value in follow-up, 0.87 +/- 0.03 g/kg per day, r = 0.10, P = 0.33) nor with proteinuria at baseline, which was lower than 0.3 g/day in 104 cases (r = 0.10, P = 0.28). There was a negative relationship between age at ESRF and delta Ccr (r = 0.245, P < 0.05), with a later and slower progression in older subjects. In Study B, the mean decline in renal function during follow-up was 5.3 +/- 0.4 mL/min/1.73 m2 per year, a value close to that observed in Study A. By multiple regression analysis of the overall population (studies A and B combined), only MAP, age and gender were independent predictive factors of delta Ccr but all studied parameters taken together accounted for at best 20% of delta Ccr variation. We conclude that the rate of progression of renal failure in ADPKD patients is mainly determined by gene expression, with female gender and older age associated with a slower progression, whereas blood pressure control, but not protein intake, exerts a limited beneficial influence on the rate of progression in patients with advanced polycystic kidney disease who already have significant renal insufficiency.

Progression rate to end-stage renal failure in non-diabetic kidney diseases: a multivariate analysis of determinant factors.

BACKGROUND: The respective contribution of the type of nephropathy, gender, and proteinuria, and of the potentially alterable factors blood pressure level and daily protein intake on the rate of progression in non-diabetic renal diseases is debated. METHODS: We retrospectively analysed the influence of primary renal disease, gender, urinary protein excretion, mean arterial pressure (MAP), and dietary protein intake on the rate of decline in creatinine clearance (delta Ccr) in 159 adult patients with well-defined nondiabetic kidney diseases. All patients had been followed from a baseline Crr of 40-50 ml/min/1.73 m2 until endstage renal disease and need for dialysis. RESULTS: Mean (+/- SD) delta Ccr (ml/min/1.73 m2/year) was 9.9 +/- 6.5 in 51 patients (45 males) with chronic glomerulonephritis, 6 +/- 2.5 in 50 patients (26 males) with polycystic kidney disease, 5.5 +/- 2.4 in 17 patients (16 males) with hypertensive angionephrosclerosis, and 3.9 +/- 2 in 41 patients (21 males) with chronic tubulointerstitial nephritis. delta Ccr was higher in males than in females (7.5 +/- 5.2 versus 4.8 +/- 2.5; P < 0.001). Linear regression analysis of the whole population disclosed a strong relationship between delta Ccr and proteinuria (r2 = 0.23; P < 0.001), and a weak relationship between delta Ccr and protein intake (r2 = 0.03; P = 0.02), but no relationship between delta Ccr and MAP (r2 = 0.01; P = 0.23). Stepwise multiple regression analysis identified the type of nephropathy, gender, and proteinuria as independent predictive factors of progression; however, these factors together accounted for only 36% of the variation in delta Ccr, suggesting the contribution of other yet unidentified factors. CONCLUSIONS: Primary kidney disease and urinary protein excretion (reflecting the severity of renal disease in individual cases) appear as the major determinants of the rate of progression, with faster progression in males in all types of nephropathy, whereas potentially alterable factors such as blood pressure and protein intake had only a modest influence in the range of values observed in our patients.

Factors affecting progression in advanced chronic renal failure.

In a series of 174 patients with advanced chronic renal failure due to well defined primary nephropathies, we retrospectively studied factors influencing the rate of progression of renal failure. Using multivariate analysis of variance, we examined the role of gender, type of nephropathy, body mass index, age, protein intake quantified from 24-hour urine urea excretion, blood pressure and need for antihypertensive treatment (including a group of patients treated with ACE inhibitors) on the rate of decline of creatinine clearance (Ccr). We found a prominent and independent influence of sex and type of nephropathy, and to a lesser extent of mean arterial pressure and protein intake. Overall, these covariates were significantly correlated with the slope of decline in creatinine clearance (n = 174; r = 0.61; r2 = 0.37; p < 0.001) indicating that nearly 40% of the total variation in the slope could be predicted by these covariates. The influence of blood pressure was more readily apparent in males, and in patients with the opposite extreme values, i.e., chronic tubulointerstitial nephritis (CIN) and hypertensive angionephrosclerosis (ANS). The effect of protein intake was marginal and limited to patients with CIN and chronic glomerulonephritis (CGN). Effect of gender was important with a progression nearly two times faster in males than in females, and was mostly apparent in polycystic kidney disease (PKD) and in CGN. Type of nephropathy was also determinant. The rate of progression was steeper in Alport's syndrome than in CGN and ANS, and in the latter than in PKD and CIN (slope: CIN = PKD < CGN = ANS < Alport).(ABSTRACT TRUNCATED AT 250 WORDS)

Urea rebound and residual renal function in the calculation of Kt/V and protein catabolic rate.

Kt/V-urea and protein catabolic rate (PCR) are used for dialysis prescription and evaluation of protein intake of patients on regular dialysis treatment. The study was undertaken to determine the implication of urea rebound and residual renal function (RRF) on the calculation of Kt/V-urea and PCR for 61 patients. Kt/V-urea and PCR were calculated, implementing or not urea rebound at one hour after the end of dialysis session. Urea and creatinine rebound rate in patients without RRF was significantly higher than in patients with RRF (P < 0.05). In patients without RRF, creatinine generation rate and Kt/V-urea calculated without rebound were significantly higher than calculated with rebound (P < 0.001). On the contrary, calculation of urea generation and PCR is not affected by these parameters. It is concluded that: (1) Rebound rate magnitude of urea and creatinine is dependent on solute molecular weight, RRF and probably on dialysis duration, whereas rebound rate magnitude of phosphorus is not affected, and (2) Rebound should be taken into account in the calculation of Kt/V-urea and creatinine generation rate in patients without RRF, otherwise, they would be overestimated.

HLA genetic heterogeneity of hepatitis B vaccine response in hemodialyzed patients.

Major histocompatibility complex (MHC) determinants are critical to the induction or suppression of immune response and have been shown to control the ability to produce antibodies in response to protein antigen. Hepatitis B vaccine commonly fails among patients with renal failure, but genetic factors that modulate response to this vaccination are not yet characterized. The availability of HLA Class II genotyping by hybridization with specific oligonucleotidic probes, following DNA amplification by the polymerase reaction (PCR), has made the analysis of HLA class II loci a reliable and practical approach. Antibody response to HBs and HLA class II oligotyping were assessed among 203 hemodialyzed patients having received a full course of vaccination. Twenty-two percent (N = 45) produced less than 10 IU (radioimmunoassay) of anti-HBs antibodies following the fourth injection. These nonresponder patients had a significantly decreased frequency of the DR2 haplotype compared to responder patients or to a group of 405 normal controls (8.9% vs. 21.5% and 26.2%, P < 0.01). The frequency of the DR3 haplotype was not increased among subjects with lower response. No significant difference appeared in the responder group. These results argue in favor of the presence of HLA-linked immune response gene(s) controlling humoral response to HBs antigen, rather than in favor of the presence of an immune suppressive gene.

Detrimental effects of late referral in patients with chronic renal failure: a case-control study.

Despite broader indications and easier access to renal replacement therapy during the past decades in Western countries, an unduly high number of patients is still referred to maintenance hemodialysis (HD) at a very advanced stage of chronic renal failure (CRF). To assess whether such late referral induces detrimental effects, we retrospectively compared clinical status and laboratory features in 20 patients who had been referred to us less than one month prior to first HD (late referral, or LR group) and in 20 sex- and age-matched controls who had undergone regular follow-up for at least six months prior to HD (early referral, or ER group). Male to female ratio was 12/8 and age averaged 53.5 years in both groups. Mean (+/- 1 SD) systolic and diastolic blood pressure were higher in LR group than in controls (180 +/- 14/102 +/- 10 vs. 153 +/- 15/86 +/- 7 mm Hg, P < 0.001) and fluid overload with pulmonary edema was present in 13/20 versus 3/20 patients (P < 0.001). Plasma concentrations (mmol/liter) of creatinine (1.12 +/- 0.27 vs 0.97 +/- 0.11, P < 0.01) and phosphate (2.58 +/- 0.47 vs. 1.92 +/- 0.31, P < 0.001) were higher, whereas plasma levels of bicarbonate (14.2 +/- 3.9 vs 22.5 +/- 4.2, P < 0.001) and calcium (1.85 +/- 0.24 vs. 2.27 +/- 0.15, P < 0.001) were lower in LR than in ER group, as were hemoglobin (7.1 +/- 1.1 vs. 9.4 +/- 0.9 g/dl, P < 0.001) and serum albumin levels (35.3 +/- 4.8 vs. 39.7 +/- 3.4, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of blood pressure and antihypertensive treatment on progression of advanced chronic renal failure.

The potential role of blood pressure and antihypertensive treatment on the progression of advanced chronic renal failure was analyzed in 223 adult patients (126 males) with well-defined primary chronic renal diseases (glomerulonephritis, n = 73; angionephrosclerosis, n = 24; interstitial nephritis, n = 61; polycystic kidney disease, n = 52, Alport's syndrome, n = 13). Effect of average mean arterial pressure (MAP) obtained during follow-up, antihypertensive treatment (normotensive, conventional antihypertensive treatment, angiotensin-converting enzyme inhibitors [ACEI]), gender, type of the nephropathy, age, body mass index, and protein intake were analyzed using a multivariate analysis of variance. Mean arterial pressure was significantly and independently correlated with duration (r = -0.40, P < 0.0001) and slope of creatinine clearance (delta Ccr; r = 0.32, P < 0.0001). Mean arterial pressure and antihypertensive treatment could predict 25% of the variation in duration. Gender, type of the nephropathy, and MAP were able to predict 30% of the variation in delta Ccr. When analyzing results by type of nephropathy, MAP was significantly and inversely correlated with duration in glomerulonephritis (r = 0.29, P < 0.05), and positively with delta Ccr in angionephrosclerosis and interstitial nephritis (r = 0.49, P < 0.05 and r = 0.36, P < 0.01, respectively). In each type of nephropathy, conventional antihypertensive treatment and ACEI had grossly similar effects upon duration and slope except. In conclusion, blood pressure level is an important contributor to progression of chronic renal failure but its effect was more evident in angionephrosclerosis and interstitial nephritis at the extreme values of blood pressure distribution.(ABSTRACT TRUNCATED AT 250 WORDS)

Late referral to maintenance dialysis: detrimental consequences.

Thirty per cent of patients who started maintenance haemodialysis at our institution between January 1989 and December 1991 had been referred at a very late stage of their renal disease. To assess the causes and consequences of such late referral we retrospectively compared clinical and laboratory features of 65 patients who had been referred less than 1 month prior to first dialysis (late referral, or LR group) and of 153 patients who had been previously followed-up by us for more than 6 months (early referral, or ER group). Age, sex ratio, and socioeconomic status were similar in the two groups. In the LR group, 38 patients had never been referred to a nephrology unit, whereas 27 had discontinued nephrological surveillance. Fluid overload, severe hypertension, and/or pulmonary oedema was present in 57% of LR versus 15% of ER patients (P < 0.001). Mean (+/- 1 SD) systolic and diastolic blood pressure was greater in the LR than the ER group (173 +/- 19/99 +/- 12 versus 147 +/- 15/84 +/- 8 mmHg, P < 0.001). Mean plasma concentration of creatinine, urea and phosphate was significantly greater, whereas bicarbonate, calcium, haematocrit and albumin were less in the LR than the ER group. Most (88%) LR patients started dialysis in emergency conditions through central vein catheterization. Total hospital stay lasted 34.5 +/- 16.3 days in LR versus 5.8 +/- 3.0 days in ER patients (P < 0.0001), resulting in an excess cost of 0.2 million French francs per LR patient.(ABSTRACT TRUNCATED AT 250 WORDS)

The most suitable calculation of Kt/V-urea: Kt/V = ln(Ci/Cf).

Although various simplified calculation formulae of Kt/V-urea based on urea kinetic modeling have been reported, all the formulae include errors such as post-dialysis urea rebound and urea generation during a dialysis session. In the present study, in order to calculate the precise Kt/V-urea, a formula of Kt/V-urea, taking into account post-dialysis plasma urea rebound and urea generation during a dialysis session (Kt/V-P) was proposed, and compared to other formulae already published, in 49 dialysis patients without residual renal function (26 M and 23 F; mean age, 65 +/- 2 years; mean dialysis duration, 70 +/- 7 mos). The precise post-dialysis plasma urea concentration was significantly higher than the actually measured post-dialysis plasma urea concentration by approximately 12%, and Kt/V-P corresponded to Kt/V-urea = ln(Ci/Cf) with the best correlation in the formulae utilized in the present study, around 1 of Kt/V-urea, which is clinically the most important range. It is concluded that Kt/V-urea = ln(Ci/Cf) is the most suitable formula for the calculation of Kt/V-urea, when post-dialysis plasma urea rebound and urea generation during a dialysis session are taken into account.

Cholangiocellular carcinoma in polycystic kidney and liver disease.

Cholangiocellular carcinoma developed in two uremic patients with polycystic kidney and liver disease, who had been treated with intermittent hemodialysis for one and nine years. In one case, in situ transformation of the liver cyst epithelium into cholangiocellular carcinoma could be demonstrated. The incidence of cholangiocellular carcinoma in patients undergoing long-term dialysis for polycystic kidney and liver disease, however, has yet to be determined.