[Contribution of clinical biology in the etiological exploration and follow-up of urolithiasis]. / Apport de la biologie clinique dans l'exploration étiologique et le suivi de l'urolithiase.

Urolithiasis is a frequent pathology with a constantly increasing prevalence in industrial countries. The relapse frequency is around 50 % with a risk of complications. The laboratory input is essential in the determination of the etiology and in the therapeutic monitoring. The morphoconstitutional analysis of the stone is the most important element. It comprises the examination of the stone with binocular loupes and the simultaneous analysis of its crystalline composition. This can be done by different techniques but infrared spectrophotometry is the most powerful. The chemical analysis should be definitely proscribed. The analysis of crystalluria includes the search, the identification and the counting of crystals in fresh morning urines. It is useful for the diagnosis and for the patient follow-up. Finally, the biochemical analyses in urine and serum, in first line or on the basis of the stone composition, are an important part of the etiological exploration and therapeutic monitoring.

Complement factor H functional assay may help to monitor atypical haemolytic uraemic syndrome: a pilot study.

BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) results from uncontrolled complement system activation. Complement factor H gene mutations are common causes of aHUS. Plasmatherapy, including plasma infusions and/or plasma exchanges, has been tried in this setting with various successes. At present, we lack a specific marker to monitor functional factor H deficiency-related aHUS. METHODS: We report the use of factor H functional assay in three patients with atypical haemolytic uraemic syndrome. This assay is based on the requirement of soluble complement regulators that bind sheep red cells to prevent haemolysis. As factor H is highly abundant in the plasma, its defect results in haemolysis. Factor H activity was also measured among plasma donors. RESULTS: One patient suffered from a plasma-dependent form of atypical haemolytic uraemic syndrome. Plasma exchanges restored higher factor H activity and were associated with a 15-months disease-free period. In the two other patients, one with a failing renal graft and the other on chronic dialysis, a bout of thrombotic microangiopathy was preceded by a drop of haemolytic activity below normal values. Plasma from healthy donors (N=65) showed only minimal variations of Factor H activity (mean activity: 98.3%, SD=4.0). CONCLUSION: These preliminary data suggest that factor H activity could be of interest in both the diagnosis and the treatment by plasmatherapy of factor H-related aHUS.

Pre-terminal renal insufficiency in a patient with enteric hyperoxaluria: effect of medical management on renal function.

Enteric hyperoxaluria causes tubular deposition calcium oxalate crystals and severe chronic interstitial nephritis. We describe a patient with pre-terminal renal failure due to oxalate nephropathy after ileal resection. Increased oral hydration, low oxalate diet, and oral calcium carbonate and potassium citrate supplements resulted in a significant improvement of renal function. During the three-year follow-up, urinary oxalate concentration was repeatedly reduced below the crystallization threshold and serum creatinine decreased from 4.5 to 1.7 mg/dL. This case illustrates the benefit of combining and optimizing dietary and medical management in enteric hyperoxaluria, even in patients with advanced chronic kidney disease.

[Twenty years of research in the field of haemodialysis: the contribution of the Nephrology Department of Erasme Hospital]. / Vingt ans de recherche dans le domaine de l'hémodialyse: la contribution du Service de Néphrologie de l'Hôpital Erasme.

This article summarizes the contribution of the Department of Nephrology, Dialysis, and renal Transplantation to the research in the field of haemodialysis during the last twenty years. The most important contributions are devoted, on the one hand, to the infections and immune defenses of the dialysis patient, on the other hand, to the biocompatibility of the materials used for haemodialysis and to the adverse reactions of the patient to these materials.

[Experimental nephrology unit: overview and research projects]. / Unité de néphrologie expérimentale facultaire: etat des lieux et projets d'avenir.

After a short historical background of the Laboratory, the main research topics--renal toxicology, physiopathology of renal interstitial fibrosis and hormonology--are described in the perspective of a partnership between research clinicians and full time scientists. National as well as international scientific collaborations underline the need of combining expertises, stimulating also the training of youngest colleagues to the experimental approach of their future discipline.

Lipid and apoprotein changes during atorvastatin up-titration in hemodialysis patients with hypercholesterolemia: a placebo-controlled study.

BACKGROUND: Patients with end-stage renal disease commonly present with an atherogenic lipid profile characterized by the accumulation of triglyceride-rich, apoprotein B-containing "remnant" lipoproteins, small dense low-density lipoprotein, and low levels of high-density lipoprotein. They are at increased cardiovascular risk and may benefit from drastic lipid-lowering treatment with atorvastatin, a potent, broadacting lipid regulator. This study aims to assess the effects of atorvastatin on the lipid profile in hemodialysis patients, to determine wether atorvastatin is also effective at lowering lipid levels in this particular high-risk subgroup. METHODS: In this randomized, placebo-controlled, double-blind study in hemodialysis patients with hypercholesterolemia (n = 42, mean total cholesterol 243 +/- 33 mg/dl (6.3 +/- 0.8 mmol/l)), the efficacy of 4-weekly increasing doses of atorvastatin (10 - 40 mg daily) was investigated. Lipids and apoproteins were measured in plasma and isolated lipoprotein fractions. RESULTS: Mean total cholesterol and low-density lipoprotein cholesterol progressively decreased with increasing doses of atorvastatin (total cholesterol -33%, low-density lipoprotein cholesterol -43% after 12 weeks), while high-density lipoprotein cholesterol remained unchanged. Plasma levels of apoprotein B and apoprotein E were also significantly reduced by atorvastatin 10 mg, while up-titration to 20 and 40 mg daily provided additional benefits by lowering triglycerides and apoprotein C-III. At week 12, the fraction of small dense low-density lipoprotein was significantly reduced from 23% - 18%, and apoprotein B-containing intermediate-density lipoproteins were no longer detectable. CONCLUSION: In conclusion, atorvastatin not only treated hypercholesterolemia but also favorably affected the uremic lipid profile in patients on hemodialysis. Atorvastatin 4-weekly dose escalation up to 40 mg daily was well-tolerated. Further prospective studies are needed to evaluate the impact of this improved lipid profile on morbidity and mortality.

[The medico-surgical department of nephrology dialysis and renal transplantation]. / Le département médico-chirurgical de Néphrologie Dialyse et Transplantation Rénale.

The Department of Nephrology of the Hospital Erasme, opened 25 years ago, is now performing, each year, 22,000 hemodialysis sessions, 800 patient-weeks of peritoneal dialysis treatment and 70 renal grafts. Scientific contributions of the department deal with vascular access for hemodialysis, susceptibility to infections of dialyzed patients, parathyroid surgery, biocompatibility of dialysis membranes, predictive factors of renal graft survival, immunosuppression with monoclonal antibodies, experimental studies of graft tolerance and rejection, toxic nephropathies. The most original contributions are related to anaphylactoïd reactions in hemodialysis by association of acrylonitrile membranes with inhibition of the converting enzyme, to advantages and side effects of OKT3 monoclonal antibody and to discovery and study of the Chinese herbs nephropathy.

Factor H mutations in hemolytic uremic syndrome cluster in exons 18-20, a domain important for host cell recognition.

Several recent studies have established an association between abnormalities of complement factor H (FH) and the development of hemolytic uremic syndrome (HUS). To identify the relative importance of mutations in FH as a cause of HUS, we have undertaken mutation screening of the FH gene in 19 familial and 31 sporadic patients with FH. Mutations were found in two familial and three sporadic patients, and these clustered in exons 18-20, a domain important for host recognition. Moreover, this study demonstrates that familial HUS is likely to be a heterogeneous condition.

Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only innocuous agent?

BACKGROUND: Some reports indicate that fibrates can induce renal dysfunction. However, the clinical characteristics of these episodes, and the respective nephrotoxicity of the four main fibrates used-namely, fenofibrate, bezafibrate, ciprofibrate, and gemfibrozil-remain ill defined. METHODS: To better characterize this side-effect, we first reviewed the charts of 27 patients from our institution who developed an impairment of renal function during fibrate therapy. We next analysed the articles (n=24) that contained data on renal function in patients taking fibrates (n=2676). RESULTS: Among our 27 patients, 25 were on fenofibrate therapy, one was taking bezafibrate, and one ciprofibrate. Nineteen were recipients of solid-organ transplants (kidney recipients, n=15; heart or heart-lung recipients, n=4), and eight were non-transplanted patients with some impairment of renal function. Baseline plasma creatinine ranged from 0.9 to 2.9 mg/dl. It increased by a mean of 40% after the start of fibrate therapy. There was a concomitant increase of blood urea values (mean 36%) in most of the patients. Renal function returned to baseline in 18/24 patients after fibrate discontinuation. However, six patients, all transplant recipients, experienced a permanent increase in plasma creatinine. The incidence of fibrate-induced renal dysfunction among our series of kidney transplant recipients was 60%, as it occurred in 15 of the 25 patients who had ever taken fibrates. An increase of mean creatinine values during therapy was described in all papers on fenofibrate (n=7) and bezafibrate (n=8) (range 8-18% and 8-40% respectively), and in three of four papers dealing with ciprofibrate (range 6-16%). No significant renal impairment was described in any of the eight articles reporting data on gemfibrozil therapy. CONCLUSION: Therapy with fenofibrate, bezafibrate, and ciprofibrate may induce renal dysfunction. Gemfibrozil appears to be devoid of this side-effect.

Role of complement and platelet-activating factor in the stimulation of phagocytosis and reactive oxygen species production during haemodialysis.

BACKGROUND: Neutrophil phagocytic functions have been studied extensively in haemodialysis (HD) patients; however, results are contradictory and the mechanisms that modulate phagocytosis and oxidative burst during dialysis are not completely understood. METHODS: The present study investigated neutrophil functions in a selected population of patients before and during clinical dialysis with cuprophane, and polyacrylonitrile (AN69) membranes. We measured phagocytosis of Escherichia coli and intracellular hydrogen peroxide (H2O2) production by flow cytometry in whole blood. RESULTS: Before dialysis, neutrophils from HD patients showed normal phagocytic capability and H2O2 formation. Phagocytosis of FITC-E. coli was significantly stimulated in cuprophane but not AN69-treated patients. Spontaneous and stimulated H2O2 production was enhanced with both cuprophane and AN69 membranes. We then investigated in vitro the role of complement and platelet-activating factor (PAF) in the activation of neutrophils. Incubation of whole blood with C5a increased phagocytosis but not H2O2 production. On the contrary, the addition of synthetic PAF showed a markedly stimulated H2O2 production without increase in phagocytosis. Moreover, during dialysis with formaldehyde-reused cuprophane, complement activation was abolished and phagocytosis was no longer enhanced, while the stimulation of H2O2 production persisted. In addition, we also excluded a particular role of the membrane itself in the activation of neutrophils. CONCLUSION: We demonstrated that in a selected population of HD patients, neutrophils exhibit normal phagocytic capability and normal intracellular H2O2 production. During dialysis, the stimulation of phagocytosis observed with cuprophane is complement dependent, whereas the enhanced H2O2 production observed with both cuprophane and AN69 membranes might be related to PAF production.

Effect of regional citrate anticoagulation on leukopenia, complement activation, and expression of leukocyte surface molecules during hemodialysis with unmodified cellulose membranes.

BACKGROUND: Dialysis with complement-activating membranes is associated with leukopenia, which is related to an increased expression of adhesion molecules on leukocytes. Citrate chelates calcium and has been claimed to attenuate leukopenia. METHODS: In this study, the effects of citrate anticoagulation on leukocyte and granulocyte counts, complement activation, and the expression of CD11b, CD11c, and CD45 on the surface of granulocytes were evaluated during hemodialysis with unmodified cellulose membranes. Standard heparin was compared to citrate in three different schedules: citrate was infused to obtain a concentration of either 7 or 10 mmol/l blood. CaCl(2) was administered into the dialyzer outlet at 8. 25 mmol Ca(2+)/h (citrate 10 mmol/l) or at 11 mmol Ca(2+)/h (citrate 7 and 10 mmol/l) to reconstitute the calcium levels in the blood returning to the patient. RESULTS: The use of citrate at a high concentration (10 mmol/l) was associated with a blunted upregulation of CD11b, both at the inlet and at the outlet bloodline; for CD11c a reduced upregulation was observed on granulocytes harvested from the inlet bloodline. No effects of citrate were observed on leukopenia, granulocytopenia, or complement activation. A positive correlation between the decrease in systemic ionized Ca(2+) concentration and the increase in CD11b and CD11c expression was found. CONCLUSION: Citrate/CaCl(2) administration affects leukocyte adhesion molecule expression in a dose-dependent way; however, no significant effect could be demonstrated on leukopenia and complement activation.

Long-term results of subcutaneous parathyroid grafts in uremic patients.

HYPOTHESIS: Parathyroid glands are normally surrounded (entirely or partially) by fatty tissue. Subcutaneous parathyroid grafts are thus located in a normal environment. Therefore, we postulated that the late results of subcutaneous implantation of parathyroid tissue in uremic patients should be at least as good as those reported for intramuscular grafting. We also challenged the idea that the recurrence rate of renal hyperparathyroidism after surgery depended solely on the type of hyperplasia (diffuse vs nodular) observed in the implanted tissue. DESIGN: A retrospective study of a series of patients without loss to follow-up. SETTING: A university hospital and 9 affiliated dialysis units. PATIENTS AND INTERVENTIONS: Fifty-nine patients (33 women and 26 men) operated on for renal hyperparathyroidism underwent the resection of at least 4 parathyroid glands followed by presternal subcutaneous implantation of parathyroid tissue. They were followed up for 12 to 130 months (median, 38 months). MAIN OUTCOME MEASURES: Failure of treatment, recurrence of disease, and hypoparathyroidism. RESULTS: During the study period, 9 patients had to undergo another operation: 2 (3%) for persistent hyperparathyroidism due to a fifth ectopic gland and 7 (12%) for recurrence of hyperparathyroidism resulting from hypertrophy of the subcutaneous grafts. Four patients received a kidney transplant. The prevalence of hypoparathyroidism (intact parathyroid hormone serum level <1.6 pmol/L with a normal or low serum calcium concentration) was 14% (8 of 59 patients), and the curve representing the distribution of intact parathyroid hormone serum concentrations among operated on patients was shifted to the left when compared with the curve of patients who underwent hemodialysis and who had no indication for parathyroid surgery. In this latter group, the peak of the curve was situated between 1 and 2 times the upper normal limit, while it was in the normal range 12 to 130 months after total parathyroidectomy and subcutaneous parathyroid autotransplantation. No relation was observed between the recurrence rate of the disease and the histological characteristics of the parathyroid grafts. Also, their function was not influenced by the presence or absence of aluminum deposits in bone biopsy specimens that were obtained at the time of cervical exploration. CONCLUSIONS: The late results of total parathyroidectomy and presternal subcutaneous grafting compare favorably with the published data on other surgical techniques proposed for the treatment of renal hyperparathyroidism. The ease with which the hypertrophied grafts are removed when the disease recurs warrants further use of this procedure.

Comparison of cellulose diacetate and polysulfone membranes in the outcome of acute renal failure. A prospective randomized study.

BACKGROUND: Whether the nature of haemodialysis (HD) membranes can influence the outcome of acute renal failure (ARF) remains debatable. Recent studies have suggested that dialysis with bioincompatible unsubstituted cellulosic membranes is associated with a less favourable patient outcome than dialysis with biocompatible synthetic membranes. Since we generally use a modified cellulosic membrane with substantially lower complement- and leukocyte-activating potential than cuprophane, for dialysis of patients with ARF, and because there are no data in the literature regarding the influence of modified cellulosic membranes on the outcome of patients with ARF, we compared the outcome of ARF patients dialysed either with cellulose diacetate or with a synthetic polysulfone membrane. We also investigated the potential role of permeability by comparing membranes with high-flux versus low-flux characteristics. METHODS: This prospective, randomized, single centre study included 159 patients with ARF requiring HD. Patients were stratified according to age, gender, and APACHE II score and then randomized in chronological order to one of three dialysis membranes: low-flux polysulfone, high-flux polysulfone and meltspun cellulose diacetate. RESULTS: Aetiologies of ARF and the prevalence of oliguria were similarly distributed among the three groups. There was no significant difference between the three groups for survival (multivariate Cox's proportional hazards model, P=0.57), time necessary to recover renal function (P=0.82), and number of dialysis sessions required before recovery (P=0.86). Multivariate analysis showed that survival was significantly influenced only by the severity of the disease state (APACHE III score, P<0.0001), but not by the nature of the dialysis membrane (P=0.57) or the presence of oliguria (P=0.24). CONCLUSIONS: Among patients with ARF requiring HD survival and recovery time are not significantly influenced by the use of either meltspun cellulose diacetate or the more biocompatible high-flux or low-flux polysulfone. Dialysis using modified cellulose membranes is just as effective as dialysis using synthetic polysulfone membranes, but at a lower cost. In addition, the flux of the membrane did not influence patient outcome.

Efficacy of oral immunotherapy on respiratory infections in hemodialysis patients: a double-blind, placebo-controlled study.

BACKGROUND: Hemodialysis (HD) patients suffer from several immune defects that make them prone to develop bacterial infections, in particular respiratory tract infections (RTIs). PATIENTS AND METHODS: As previous studies have shown that oral immunotherapy with an immunomodulating bacterial extract (IBE) is effective against RTIs, we decided to test its efficacy and safety in HD patients during a double-blind placebo-controlled prospective study. 40 HD patients with a documented history of RTIs in the previous year were treated for 24 weeks of the endemic season with one capsule daily of IBE (n = 21) or placebo (PL, n = 19). Clinical examinations, measurements of Mac-1 and gp150.95 on circulating phagocytes and routine laboratory evaluations were performed at week 0, 4, 12 and 24. Patients were also examined at each dialysis session allowing an accurate recording of any infectious episode, its treatment and of any untoward effect. RESULTS: During the last period of the study (weeks 13-24), IBE significantly reduced the number of patients with RTIs and consequently of antibiotic treatment courses as compared to PL (p = 0.018), whereas no difference was detected between IBE and PL during periods I (weeks 0-4) and II (weeks 5-12). There was no difference between IBE and PL for other, non respiratory infections. IBE was associated at several time points with an increased expression on phagocytes of adhesion molecules involved in phagocytosis (Mac-1 and gp150.95). However, the expression of these molecules was not predictive for the occurrence of RTI. IBE was on the whole as well tolerated as PL, 7 patients presented side effects (5 IBE, 2 PL, NS) which led to drop-out in 4 cases (3 IBE, 1 PL). No serious side effect was recorded, gastrointestinal upset being the most prevalent type. CONCLUSION: The results of this study indicate that immunomodulation with selected bacterial extracts constitutes a promising approach for the prevention of bacterial airway infections in groups at risk, such as HD patients.

Evaluation of surgical treatment of renal hyperparathyroidism by measuring intact parathormone blood levels on first postoperative day.

Intact parathormone (inPTH) has a short half-life. Its blood level on the first day after total parathyroidectomy and subcutaneous parathyroid implantation (PTX + G) should therefore allow an early diagnosis of missed residual parathyroid tissue. We tested this hypothesis in 72 uremic patients who were followed for 6 to 110 months after operation. Nine were reoperated for recurrence of the disease. Graft removal was successful in four patients who had post-PTX inPTH levels of 16 pg/ml or lower. In five patients, an overlooked parathyroid gland had to be resected. All of them had elevated post-PTX inPTH blood levels ranging from 72 to 791 pg/ml (upper normal limit 55 pg/ml). Three of these patients had presented with hypocalcemia after PTX. We conclude that the inPTH blood concentration on the first day after PTX allows more precise evaluation of the efficacy of the surgical procedure than the postoperative evolution of blood calcium levels. It is also useful for localizing the source of excessive PTH secretion (graft or overlooked gland) when the disease recurs.

[Does the biocompatibility of the hemodialysis membrane influence the prognosis of acute renal insufficiency?]. / La biocompatibilité de la membrane d'hémodialyse influence-t-elle le pronostic de l'insuffisance rénale aiguë?

Several recent publications have suggested that the use of cuprophane in the setting of acute renal failure is associated with a higher mortality (especially from sepsis) and a slower recovery of renal function in the survivors in comparison with more biocompatible membranes. We present here a critical review of these publications and point to several methodological bias that might invalidate their conclusions. However, while waiting further information, we would advocate to abandon the use of cuprophane to dialyze patients with acute renal failure.

Proximal tubular injury in Chinese herbs nephropathy: monitoring by neutral endopeptidase enzymuria.

Neutral endopeptidase (NEP) is a 94 kDa ectoenzyme of the proximal tubule brush border, physiologically released into the urine with apical membrane fragments. As proximal tubular atrophy was a histological hallmark of Chinese herbs nephropathy (CHN), this study firstly determined renal excretion of NEP in healthy control subjects (N = 31), in patients with CHN (N = 26) and in women having consumed Chinese herbs and whose renal function was normal but running the risk of developing CHN (N = 27). Another patient group consisted of female patients with glomerular diseases (N = 12). At the same time, measurements of urinary microproteins (Clara cell protein, retinol binding protein, beta 2-microglobulin and alpha 1-microglobulin) were performed, as indicators of tubular dysfunction. Cell damage was estimated by the excretion of N-acetyl-beta-D-glucosaminidase (NAG). In the control group, the physiological NEP enzymuria was 43.1 micrograms/24 hr (geometric mean). In CHN patients, levels of urinary NEP were significantly decreased in those with moderate renal failure (26.7 micrograms/24 hr; N = 21; P < 0.05) and almost abolished in end-stage renal failure patients (4.35 micrograms/24 hr; N = 5; P < 0.05). In patients at risk as well as in patients with glomerular diseases, urinary NEP levels were not statistically different from those observed in control subjects (40.68 micrograms/24 hr and 48.5 micrograms/24 hr, respectively). Several degrees of tubular dysfunction and injury were noted in patients groups, as attested by increased urinary microproteins and NAG excretions. Considering the data from control and CHN patients, NEP enzymuria positively correlated with individual creatinine clearance values (r = 0.76; P = 0.0001) and negatively correlated with urinary microproteins levels (r = -0.55; P = 0.00001). Finally, NEP was regularly quantitated in the urine of 6 CHN patients for a period ranging from six months to two years and in 19 patients at risk during two years, respectively. In the first group, renal function progressively deteriorated in 3 patients, leading them to renal replacement therapy after 38 to 115 weeks. Stable parameters were observed in the remaining 3 patients. A direct correlation between creatinine clearance and NEP excretion was found longitudinally in each case. In the second group, no significant change of urinary NEP levels was observed (45.9 micrograms/24 hr), in parallel with stable renal function. Taken together, these results indicate that, in CHN patients, NEP enzymuria provides a rapid and noninvasive determination of the degree of structural impairment affecting the proximal tubular population and further reflecting the severity of the renal disease. The interest of this urinary marker in monitoring the progression of other tubulointerstitial diseases remains to be assessed.