Primary glomerulonephritis: an update on renal survival and determinants of progression.

BACKGROUND: Few epidemiological studies have investigated the long-term outcome of primary glomerulonephritis (GN) and its determinants in the decade since angiotensin-converting enzyme inhibitors entered widespread use. AIM: To study several traditional and less traditional risk factors for kidney disease progression in a cohort of patients with primary GN. DESIGN: Retrospective cohort study. METHODS: We included 536 patients with primary GN first diagnosed between 1994 and 2001: 283 IgA nephropathy (IgA), 129 membranous nephropathy (MN), and 124 focal and segmental glomerulosclerosis (FSGS). Adjusted hazard ratios (HR) or dialysis or preemptive transplantation for end-stage renal disease (ESRD) according to various characteristics were estimated with Cox proportional-hazard models. RESULTS: At diagnosis, mean patient age was 43 +/- 17 years, 74% were men, and the mean estimated glomerular filtration rate (eGFR) was 69 +/- 31 mL/mn/1.73m(2). After a mean follow-up of 7-years, 104 patients had started ESRD treatment and 14 had died before reaching ESRD. The 7-year renal survival rate was 69% for FSGS, 88% for MN, and 82% for IgAN (p < 0.01). In patients with FSGS, younger age was associated with a higher risk of ESRD. Baseline proteinuria, diabetes, and haemoglobin (Hb) concentration were strongly associated with shorter time to ESRD independent of baseline eGFR, but gender, hypertension and smoking were not. Adjusted HRs for ESRD were 2.6 [95% confidence interval, 1.2-5.8] for diabetes and 2.4 [1.3-4.5] for the lowest and 1.9 [1.0-3.6] for the intermediate Hb tertiles versus the highest. DISCUSSION: In patients with primary GN, renal survival is clearly lower for FSGS than for IgAN and MN. Independent predictors for progression were baseline diabetes and anaemia, as well as proteinuria, for all GN types, and younger age, for FSGS.

Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes.

Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. There is now convincing evidence that CKD can be detected using simple laboratory tests, and that treatment can prevent or delay complications of decreased kidney function, slow the progression of kidney disease, and reduce the risk of cardiovascular disease (CVD). Translating these advances to simple and applicable public health measures must be adopted as a goal worldwide. Understanding the relationship between CKD and other chronic diseases is important to developing a public health policy to improve outcomes. The 2004 Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on 'Definition and Classification of Chronic Kidney Disease' represented an important endorsement of the Kidney Disease Outcome Quality Initiative definition and classification of CKD by the international community. The 2006 KDIGO Controversies Conference on CKD was convened to consider six major topics: (1) CKD classification, (2) CKD screening and surveillance, (3) public policy for CKD, (4) CVD and CVD risk factors as risk factors for development and progression of CKD, (5) association of CKD with chronic infections, and (6) association of CKD with cancer. This report contains the recommendations from the meeting. It has been reviewed by the conference participants and approved as position statement by the KDIGO Board of Directors. KDIGO will work in collaboration with international and national public health organizations to facilitate implementation of these recommendations.

New insight into solvent-related end-stage renal disease: occupations, products and types of solvents at risk.

OBJECTIVES: It has been shown that all-solvent exposure is associated with the progression of primary glomerulonephritis to end-stage renal disease (ESRD), but little is known about the type of solvents that are high risk. The aim of this study was to investigate the role of solvents by occupation, product and type. METHODS: Using a retrospective cohort design, the authors studied 269 patients with non-end-stage and biopsy-proven primary glomerulonephritis diagnosed between 1994 and 2001 in Paris and its suburbs. Two industrial hygienists evaluated patients' exposures from lifetime occupational histories collected by interview from 2002-4, and using a list of the 30 most common solvents. The studied outcome was ESRD, defined as glomerular filtration rate <15 ml/mn/1.73 m(2) or dialysis. It was recorded during a mean follow-up of five years. Cox models were used to estimate adjusted hazard ratios (HR) of ESRD related to exposures. RESULTS: Eighteen per cent of the patients had ever been exposed to solvents. Those with the highest risk of progression to ESRD were exposed machinery fitters and machine assemblers (HR 4.7, 95% CI 1.2 to 17.4) and plumbers/welders (HR 4.2, 95% CI 1.3 to 13.6), as compared to never exposed patients, as well as those who ever handled printing inks and petroleum products (HR 12.6 (95% CI 1.7 to 94.9) and 3.2 (95% CI 1.4 to 7.2), respectively). Among solvents, the highest risks were found for: toluene/xylene (HR 5.1, 95% CI 1.8 to 14.8), gasoline, fuel and gas-oil (HR 8.6, 95% CI 2.7 to 27.4), and ketones (HR 13.3, 95% CI 1.4 to 123.5). CONCLUSION: This study highlights the potential nephrotoxicity of several solvents. Intervention to promote screening for proteinuria in exposed workers may prevent the progression of glomerulonephritis to ESRD.

Membranous nephropathy and cancer: Epidemiologic evidence and determinants of high-risk cancer association.

The association between membranous nephropathy (MN) and cancer is often mentioned in textbooks but poorly substantiated, and the characteristics of cancer-associated MN are unknown. To address these questions, we studied a cohort of 240 patients with MN, among them 24 had malignancy at the time of renal biopsy or within a year thereafter. The incidence of cancer was significantly higher in these patients than in the general population (standardized incidence ratio 9.8 [5.5-16.2] for men and 12.3 [4.5-26.9] for women). The frequency of malignancy increased with age. At the time of diagnosis, clinical presentation did not differ between the patients with cancer-associated MN and those with idiopathic MN, but smoking was more frequent among patients with cancer. Analysis of renal biopsies revealed that the number of inflammatory cells infiltrating the glomeruli was significantly higher in patients with cancer-associated MN (P = 0.001). The best cutoff value for distinguishing malignancy-related cases from controls was eight cells per glomerulus. Using this threshold led to a diagnosis of cancer-associated MN with a specificity of 75% and a sensitivity of 92%. In patients with cancer-associated MN, there was a strong relationship between reduction of proteinuria and clinical remission of cancer (P < 0.001). In conclusion, our study provides epidemiologic evidence of an excess of cancer risk in patients with MN. It also shows that age, smoking, and the presence of glomerular leukocytic infiltrates strongly increase the likelihood of malignancy in MN patients.

Screening and management of patients with early chronic kidney disease.

Diabetic nephropathy has become the most prevalent cause of end-stage renal disease (ESRD) in many countries. ESRD patients with diabetes have a particularly poor prognosis compared with patients without diabetes. The course of diabetic nephropathy can be modified with early management of the condition and it is important that diabetes patients are screened regularly for early signs of kidney damage. Blood pressure control and use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have been shown to slow the progression of chronic kidney disease. Patients with diabetes are at considerable risk of cardiovascular complications, and modifiable cardiovascular risk factors, such as anaemia and dyslipidaemia, should be treated at an early stage. Correction of anaemia with recombinant human erythropoietin is associated with improvements in quality of life, functional status, and cardiovascular morbidity and mortality, and may slow the progression of renal disease. Abnormalities in calcium and phosphate metabolism and acidosis may also occur in patients with diabetes and nephropathy and these should be monitored regularly. It is important that patients with kidney disease are detected promptly to allow intervention to slow renal disease progression and to treat modifiable cardiovascular risk factors. Improved collaboration between diabetologists and nephrologists will also ensure that patients receive optimal care.

[An exceptional etiology of left ventricular aneurysm: type AA amyloidosis]. / Une cause exceptionnelle d'anévrisme du ventricule gauche: l'amylose de type AA.

Left ventricular aneurysms most often occur in the course of myocardial infarction. In rare cases they can be detected when the coronary network is devoid of any lesions. The aetiology is therefore multiple and dependent on the context. One aetiology seems less exceptional and concerns idiopathic aneurysms encountered in the African population, where the role of a "debilitating condition" such as tuberculosis has been evoked. We report the case history of a young patient from Zaire with a left ventricular aneurysm discovered in association with ganglionic tuberculosis complicated by AA amyloidosis. Histological analysis allowed the aetiological diagnosis to be established. Aneurysmal dilatation of the left ventricle was reported in the presence of amyloid deposits at the intra-myocardial arteriole level, whereas the context suggested a tubercular role. In spite of the difficulty of establishing a precise aetiological diagnosis, there seems to exist a consensus for surgical management.

Contribution of anaemia to progression of renal disease: a debate.

It is hypothesized that anaemia contributes to the progression of renal disease via hypoxia and oxidative stress. These effects may stimulate the production of extracellular matrix by fibroblasts, increasing interstitial fibrosis and leading to tubular destruction. Recombinant human erythropoietin (r-HuEPO, epoetin) has antioxidative and anti-apoptotic properties, though these effects have yet to be demonstrated in renal cells. In theory, epoetin treatment might slow the progression of renal failure, not only by correcting anaemia but also via direct effects on tubular and vascular cell survival. Alternative hypotheses suggest, however, that epoetin could have negative effects on the kidney because of its vasoconstrictive action, which is independent of haemoglobin levels. Retrospective and prospective clinical studies clearly show that epoetin does not accelerate progression of renal disease, provided that blood pressure is well controlled. Some studies suggest that epoetin slows the progression of renal failure, although this remains a controversial issue, as all these studies have methodological limitations. Larger randomized controlled trials and meta-analysis of the existing trials are required to establish whether treatment of anaemia with epoetin can indeed slow the progression of renal disease.

Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets.

The cloning of the so-called 'parathyroid hormone-related protein' (PTHrP) in 1987 was the result of a long quest for the factor which, by mimicking the actions of PTH in bone and kidney, is responsible for the hypercalcemic paraneoplastic syndrome, humoral calcemia of malignancy. PTHrP is distinct from PTH in a number of ways. First, PTHrP is the product of a separate gene. Second, with the exception of a short N-terminal region, the structure of PTHrP is not closely related to that of PTH. Third, in contrast to PTH, PTHrP is a paracrine factor expressed throughout the body. Finally, most of the functions of PTHrP have nothing in common with those of PTH. PTHrP is a poly-hormone which comprises a family of distinct peptide hormones arising from post-translational endoproteolytic cleavage of the initial PTHrP translation products. Mature N-terminal, mid-region and C-terminal secretory forms of PTHrP are thus generated, each of them having their own physiologic functions and probably their own receptors. The type 1 PTHrP receptor, binding both PTH(1-34) and PTHrP(1-36), is the only cloned receptor so far. PTHrP is a PTH-like calciotropic hormone, a myorelaxant, a growth factor and a developmental regulatory molecule. The present review reports recent aspects of PTHrP pharmacology and physiology, including: (a) the identification of new peptides and receptors of the PTH/PTHrP system; (b) the recently discovered nuclear functions of PTHrP and the role of PTHrP as an intracrine regulator of cell growth and cell death; (c) the physiological and developmental actions of PTHrP in the cardiovascular and the renal glomerulo-vascular systems; (d) the role of PTHrP as a regulator of pancreatic beta cell growth and functions, and, (e) the interactions of PTHrP and calcium-sensing receptors for the control of the growth of placental trophoblasts. These new advances have contributed to a better understanding of the pathophysiological role of PTHrP, and will help to identify its therapeutic potential in a number of diseases.

delta Ef1 binds to a far upstream sequence of the mouse pro-alpha 1(I) collagen gene and represses its expression in osteoblasts.

The transcription of type I collagen genes is tightly regulated, but few cis-acting elements have been identified that can modulate the levels of expression of these genes. Generation of transgenic mice harboring various segments of the mouse pro-alpha1(I) collagen promoter led us to suspect that a repressor element was located between -10.5 and -17 kilobase pairs. Stable and transient transfection experiments in ROS17/2.8 osteoblastic cells confirmed the existence of such a repressor element at about -14 kilobase pairs and showed that it consisted in an almost perfect three-time repeat of a 41-base pair sequence. This element, which we named COIN-1, contains three E2-boxes, and a point mutation in at least two of them completely abolished its repressor effect. In gel shift assays, COIN-1 bound a DNA-binding protein named delta EF1/ZEB-1, and mutations that abolished the repressor effect of COIN-1 also suppressed the binding of delta EF1. We also showed that the repressor effect of COIN-1 was not mediated by chromatin compaction. Furthermore, overexpression of delta EF1 in ROS17/2.8 osteoblastic cells enhanced the inhibitory effect of COIN-1 in a dose-dependent manner and repressed the expression of the pro-alpha 1(I) collagen gene. Thus, delta EF1 appears to repress the expression of the mouse pro-alpha 1(I) collagen gene, through its binding to COIN-1.

[How to slow the progression of chronic renal insufficiency]. / Comment ralentir l'évolution de l'insuffisance rénale chronique.

In patients with chronic renal failure, three kinds of treatments can slow the progression of renal insufficiency: optimal control of blood pressure; use of converting enzyme inhibitors; low-protein diet. The MDRD study strongly suggests that blood pressure should not be higher than 130/85 mmHg in patients with chronic renal failure, and than 125/75 mmHg in patients with chronic renal failure and proteinuria above 1 g/d. Converting enzyme inhibitors have been shown to be beneficial to patients with IDDM and either microalbuminuria or overt diabetic nephropathy and to patients with chronic renal failure and proteinuria above 1 g/d. A diet containing less than 1 g/kg/d of proteins should be prescribed to patients with chronic renal failure, and this protein content should be lowered to 0.75 g/kg/d (or to 0.60 g/kg/j in some cases) when creatinine clearance falls below 25 mL/min.

Blocking sp1 transcription factor broadly inhibits extracellular matrix gene expression in vitro and in vivo: implications for the treatment of tissue fibrosis.

Fibrosis is a consequence of injury characterized by accumulation of excess collagen and other extracellular matrix components, resulting in the destruction of normal tissue architecture and loss of function. Sp1 was originally described as a ubiquitous transcription factor. It is involved in the basal expression of extracellular matrix genes and may, therefore, be important in fibrotic processes. To evaluate the effect of Sp1 blockade on the expression of extracellular matrix genes, clones of NIH 3T3 fibroblasts stably transfected with an anti-sense Sp1 expression vector. Simultaneously reduced expression of several extracellular matrix genes as compared with mock-transfected clones was noted using differential hybridization of cDNA microarrays, without significant alteration in cell growth. Transfection of human dermal fibroblasts with several extracellular matrix gene (COL1A1, COL1A2, COL3A1, COL5A2, COL7A1, TIMP-1, and decorin) promoter/reporter constructs demonstrated that anti-sense Sp1-induced reduction of extracellular matrix gene mRNA steady-state levels results from transcriptional repression, consistent with the role of Sp1 as a transcription factor. Decoy Sp1 binding oligonucleotides inhibited COL1A2 promoter activity both in cultured fibroblasts and in vivo, in the skin of transgenic mice, which have integrated a mouse COL1A2 promoter/luciferase reporter gene construct. These results indicate that targeting Sp1 efficiently blocks extracellular matrix gene expression, and suggest that such an approach may represent an interesting therapeutic alternative toward the treatment of fibrotic disorders.

Upper extremity digital subtraction venography with gadoterate meglumine before fistula creation for hemodialysis.

BACKGROUND: The purpose of this study was to evaluate the feasibility, safety, and potential role of gadoterate meglumine (Gd-DOTA) as a contrast agent for upper extremity venography before the creation of an arteriovenous fistula (AVF) for nondialyzed renal insufficiency patients. METHODS: Over a 16-month period, 50 venographies were performed on end-stage renal insufficiency patients, using Gd-DOTA as a contrast agent on a high-resolution digital subtraction angiography system. Three sequences were performed on forearm, arm, and chest at 3 mL/sec for a total of 35 mL of Gd-DOTA. Examinations were reviewed by two radiologists for diagnostic and opacification quality. Tolerance was evaluated on the evolution of serum creatinine levels and occurrence of pain during injection. RESULTS: Good interobserver correlation was obtained in evaluating the feasibility of AVF creation by vein segment (0.64 < kappa < 0.88) and in relationship to opacification quality (0.62 to 0.87). No deterioration in renal function (creatinine level before and after) or pain was observed. Twenty-six patients underwent surgical creation of brachiobasilic (N = 8), brachiocephalic (N = 8), radiocephalic (N = 8), and cubitocephalic (N = 1) fistulas or insertion of a polytetrafluoroethylene (PTFE) graft (N = 1). Seventeen were awaiting AVF or were on peritoneal dialysis. Two died before surgery for reasons unconnected with the venography. CONCLUSIONS: Venography with Gd-DOTA is an effective and safe technique in planning AVFs for renal insufficiency patients.

[Prophylactic prescription of low-molecular-weight heparin in the non-surgical setting: impact of recommendations]. / Prescription préventive des héparines de bas poids moléculaire en milieu non chirurgical: l'impact de recommandations.

OBJECTIVE: Low-molecular-weight heparins (LMWH) had official approval for use for venous thromboembolism prophylaxis only for surgery patients when this survey was conducted, but were nevertheless often used in non-surgery patients. We conducted this "before and after" survey from May 1998 to April 1999 to assess the impact of the recommendations implemented in the beginning of 1999. METHODS: Data on the use of LMWH were collected on three different days within a three week interval in all non-surgery departments at the Tenon hospital before distribution of expert recommendations early in 1999. Published in La Presse Médicale in January 2000, these recommendations issued from an external panel of 43 experts who were contacted to establish a consensus opinion using the Delphi method. Data were again collected on three different days after implementation of the recommendations. Implementation was based on a patient-specific prescription order form requested by the hospital pharmacy for delivery to the department. RESULTS: Data were collected for 121 prescriptions prior to the recommendations and for 158 after. Sex-ratio, mean age and percentage of LMWH prescriptions did not differ significantly between the two periods. There was a lower number of non-appropriate prescriptions after implementation of the recommendations from 54.5% to 35.4% (p = 0.01) with better conformity for recommendation A (high-risk patients) (36% versus 43%, NS) and for recommendation B (= 2 risk situations or = 1 risk situation and = 2 aggravating factors) (10% versus 22%, p = 0.01). Better conformity of LMWH prescriptions in oncology and radiotherapy departments partially explained this general improvement, but the difference remained significant when excluding these two departments (p = 0.04). CONCLUSION: This study shows that physician compliance with recognized expert recommendations can improve their implementation. This procedure is now in general use in the Tenon hospital.