Daniel Cordonnier

Independent and Additive Impact of Blood Pressure Control and Angiotensin II Receptor Blockade on Renal Outcomes in the Irbesartan Diabetic Nephropathy Trial: Clinical Implications and Limitations

Elevated arterial pressure is a major risk factor for progression to ESRD in diabetic nephropathy. However, the component of arterial pressure and level of BP control for optimal renal outcomes are disputed. Data from 1590 hypertensive patients with type 2 diabetes in the Irbesartan Diabetic Nephropathy Trial (IDNT), a randomized, double-blind, placebo-controlled trial performed in 209 clinics worldwide, were examined, and the effects of baseline and mean follow-up systolic BP (SBP) and diastolic BP and the interaction of assigned study medications (irbesartan, amlodipine, and placebo) on progressive renal failure and all-cause mortality were assessed. Other antihypertensive agents were added to achieve predetermined BP goals. Entry criteria included elevated baseline serum creatinine concentration up to 266 micromol/L (3.0 mg/dl) and urine protein excretion >900 mg/d. Baseline BP averaged 159/87 +/- 20/11 mmHg. Median patient follow-up was 2.6 yr. Follow-up achieved SBP most strongly predicted renal outcomes. SBP >149 mmHg was associated with a 2.2-fold increase in the risk for doubling serum creatinine or ESRD compared with SBP <134 mmHg. Progressive lowering of SBP to 120 mmHg was associated with improved renal and patient survival, an effect independent of baseline renal function. Below this threshold, all-cause mortality increased. An additional renoprotective effect of irbesartan, independent of achieved SBP, was observed down to 120 mmHg. There was no correlation between diastolic BP and renal outcomes. We recommend a SBP target between 120 and 130 mmHg, in conjunction with blockade of the renin-angiotensin system, in patients with type 2 diabetic nephropathy.

Beneficial Effect Of One Hla Haplo- Or Semi-identical Transfusion Versus Three Untyped Blood Units On Alloimmunization And Acute Rejection Episodes In First Renal Allograft Recipients

Acute allograft rejection is the major risk factor of renal function decline and graft loss. Beside histocompatibility matches and pharmacological immunosuppression, blood transfusion is empirically used to detect responder subjects and to induce immune tolerance. Alloimmunization associated with blood transfusions readily detected by anti-HLA antibodies could induce acute vascular rejection episodes during the early period after grafting. Our open prospective study was aimed at analyzing the 1 year follow-up of 105 successive first cadaver renal transplant recipients according to the transfusion protocol as assessed by anti-HLA antibody production, acute rejection episodes, and graft survival. Our conventional transfusion protocol involved 3 nonphenotyped blood transfusions set up at least 20 days before grafting in a control cohort (group A) and was compared with a single pretransplant HLA haplo- or semi-identical blood transfusion in a successive group of patients (group B). Our results suggest that both protocols were associated with similar 1-year graft survivals (> 96% in both groups) and number of patients experiencing rejection episodes (20.7% in group A; 9.6% in group B; P NS). HLA haplo- or semi-identical transfusion was significantly beneficial in naive patients without previous alloantigen contact by pregnancy or blood transfusions during dialysis. Naive patients in group B did not develop post-transfusion anti-HLA antibodies compared to naive patients in group A (16.6%; P < 0.001), and they experienced significantly less acute rejection episodes (2.7%) compared to group A naive patients (20.8%; P = 0.02).

High prevalence of hepatitis C virus RNA in the supernatant and the cryoprecipitate of patients with essential and secondary type II mixed cryoglobulinemia

Detection of hepatitis C virus RNA by polymerase chain reaction was performed in 26 patients with type II mixed cryoglobulinemia, and compared with anti-HCV antibody detection. The patients were divided into two groups according to etiology: 15 had essential type II mixed cryoglobulinemia and 11 had secondary type II mixed cryoglobulinemia. In the essential type II mixed cryoglobulinemia group, the prevalence of hepatitis C virus RNA detected by polymerase chain reaction was 60% in the supernatant and 93% in the cryoprecipitate. In the secondary type II mixed cryoglobulinemia group the prevalence of hepatitis C virus RNA was 45% in the supernatant and 55% in the cryoprecipitate. The differences between the two groups were not statistically significant. In both patient groups, detection of hepatitis C virus RNA in the cryoprecipitate was the most sensitive test for hepatitis C virus infection. These results suggest that hepatitis C virus might be involved in the origin of mixed cryoglobulinemia.

Epidemiology, development and treatment of end-stage renal failure in type 2 (non-insulin-dependent) diabetes mellitus. The case of mainland France and of overseas French territories.

SummaryThe prevalence of diabetes mellitus among patients treated for end-stage renal failure by dialysis in France was studied in two stages (UREMIDIAB Study). The first stage consisted of a questionnaire which was mailed to all dialysis centres in mainland France. The response rate was 80.8%, resulting in a study population of 12,903 patients. Of these patients 884 were declared diabetic (6.9%). Later 295 of them were interviewed by seven specially-trained physicians who checked the medical records together with the nephrologist in charge. Plasma C-peptide was measured in almost all of the patients. Effectively, 1.4% were found to have Type 1 diabetes and 5.5%, Type 2. Diabetic nephropathy was found to be the only primary renal diagnosis among 93.9% of Type 1 diabetic patients and 36.8% of Type 2. Of the latter 51.6% had a non-diabetic cause of renal failure. In the second stage a survey was later conducted in 13 of 14 dialysis centres located in the remote overseas French territories. Among 934 patients 1.04% were Type 1 diabetic and 19.67% Type 2 (22.9% altogether). Type 2 diabetic patients treated overseas were essentially non-Caucasians (92.6%). The sex ratio was 0.54 in the overseas territories vs 1.4 in the mainland. We conclude that the prevalence of diabetes among people on dialysis is low in mainland France. But there are striking differences in the prevalence of Type 2 diabetes among dialysis patients in mainland France and its overseas territories. These differences are not related to access to dialysis facilities.

Double Monoclonal Cryoglobulinemia, Glomerulonephritis and Lyphoma

We present a case of monoclonal cryoglobulinemia with double monoclonal component IgA lambda-IgG lambda, without complement activation, membranoproliferative glomerulonephritis (MPGN) with deposits of IgA, IgG and lambda chains and lymphocytic IgA-lambda-chain-secreting lymphoma. This case emphasizes the possibility that double monoclonal cryoglobulins could behave differently compared to type I cryoglobulins, determining a MPGN-like type II cryoglobulins do, but without activating the complement cascade.

Role of ACE Inhibitors in Patients with Diabetes Mellitus

The adjective ‘epidemic’ is now attributed to the rapidly growing number of patients with diabetes mellitus, mainly type 2, and the specific complications linked to this disorder. Provided they are recognised early enough, these different complications can be treated; in some patients the evolutive course of these complications can be slowed or even stopped. Furthermore, some recent observations suggest that specific tissular lesions may be prevented or even reversed.Although glycaemic control is essential, other therapeutic measures that must also be taken include those to control blood pressure and to lower lipid levels. Of the agents available to control the complications of diabetes mellitus, cardiovascular drugs, and particularly ACE inhibitors, have a pre-eminent place. Experimental and epidemiological data suggest that activation of the renin-angiotensin-aldosterone system plays an important role in increasing in the micro- and macrovascular complications in patients with diabetes mellitus. Not only are ACE inhibitors potent antihypertensive agents but there is a growing body of data indicating that also they have a specific ‘organ-protective’ effect. For the same degree of blood pressure control, compared with other antihypertensive agents, ACE inhibitors demonstrate function and tissue protection of considered organs. ACE inhibitors have been reported to improve kidney, heart, and to a lesser extent, eye and peripheral nerve function of patients with diabetes mellitus. These favourable effects are the result of inhibition of both haemodynamic and tissular effects of angiotensin II. Finally, there are a growing number of arguments favouring the use of ACE inhibitors very early in patients with diabetes mellitus.

Microalbuminurie et excrétion urinaire d'albumine: recommandations pour la pratique clinique

Measurement of urinary albumin excretion (UAE) may be done on a morning urinary sample or on a 24 hours-urine sample. Values defining microalbuminuria are: 24 hour-urine sample: 30–300 mg/24 hours; morning urine sample: 20–200 mg/ml or 30–300 mg/g creatinine or 2.5–25 mg/mmol creatinine (men) or 3.5–35 mg/mol (women). Timed urine sample: 20–200 μg/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been shown in humans.

RecommandationMicroalbuminurie et excrétion urinaire d'albumine : recommandations pour la pratique cliniqueMicroalbuminuria and urinary albumin excretion: clinical practice guidelines

Measurement of urinary albumin excretion (UAE) may be done on a morning urinary sample or on a 24 hours-urine sample. Values defining microalbuminuria are: 24 hour-urine sample: 30–300 mg/24 hours; morning urine sample: 20–200 mg/ml or 30–300 mg/g creatinine or 2.5–25 mg/mmol creatinine (men) or 3.5–35 mg/mol (women). Timed urine sample: 20–200 μg/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been shown in humans.

High Fructose‐Fed Rats: A Model of Glomerulosclerosis Involving The Renin‐Angiotensin System and Renal Gelatinases

The use of fructose oral diets as an easy source of sugar substitute could represent at first sight an interesting carbohydrate (CH) intake, especially for diabetic patients, with weak hyperglycemic effect and allegedly reduced secondary insulin secretion. In the long run, metabolic side effects proceed from an inoperant metabolic control by fructose-6-phosphate kinase, induction of glycogen-synthase, and glycerol-3phosphate/VLDL pathways, and may favor the development of progressive insulin resistance, hyperuricemia, and hypertriglyceridemia, which links fructose-rich diets with the clinical dilemma of insulin resistance, systemic hypertension, and vascular renal lesions suspected in human metabolic syndrome X even without established NIDDM.

INTER-REGULATED BALANCE BETWEEN GELATINASES AND TISSUE INHIBITOR (TIMP-1) IN ISOLATED HUMAN GLOMERULI

Leukocyte infiltration inside glomeruli necessitates basement membrane collagen i.v. breakdown and leads to mesangiolysis, cell proliferation and extracellular matrix synthesis during the repair process as observed in the course of acute glomerulonephritis, vasculitis and acute graft rejection. Two matrix metalloproteinases, MMP-2 and MMP-9 gelatinases, are expressed and co-secreted in balance with the tissue inhibitor of metalloproteinases-1 (TIMP-1) by activated neutrophils as well as by glomerular cells and are aimed to control basement membrane collage i.v. deposition. Using a conventional double mesh sieving method, pure populations of glomeruli were isolated from fresh human cortex specimen and maintained in short-term cultures. ELISA, zymography and immunoblotting of conditioned serum-free media revealed glomerular MMP-2, MMP-9 and TIMP-1 secretion and activity while reverse transcription-polymerase chain reaction amplification of cellular RNA demonstrated glomerular transcripts coding for these enzymes and their inhibitor. When purified neutrophils were allowed to adhere onto Transwell apparatus in contact with glomerular suspensions, neutrophil 92 kDa gelatinase seemed apparently inhibited mainly because the production of TIMP-1 was enhanced on both sides of the insert. Glomerular 72 kDa and 92 kDa gelatinases were activated shortly (1 to 6 h) after neutrophils had interacted with glomeruli and furthermore upon activation by inflammatory or vasoactive mediators such as phorbol. Decreased neutrophil MMP-9 activity together with reduced MMP-9 mRNA levels and protracted TIMP-1 transcription and secretion during cell-cell interaction could participate to cell detachment from degraded basement membranes and to increased collagen i.v. deposition leading to glomerulosclerosis after initial glomerular injury by inflammatory cells.