Blockade of the renin-angiotensin system and renal tissue oxygenation as measured with BOLD-MRI in patients with type 2 diabetes

To assess whether blockade of the renin-angiotensin system (RAS), a recognized strategy to prevent the progression of diabetic nephropathy, affects renal tissue oxygenation in type 2 diabetes mellitus (T2DM) patients.

Endovascular stenting of a renal transplant vein

We describe successful endovascular stenting of a high-grade stenosis of a renal transplant vein in a 53-year old patient. Kidney transplantation had been performed due to IgA nephropathy and the patient had become symptomatic two months after uneventful recovery from operation.

Metzincins, including matrix metalloproteinases and meprin, in kidney transplantation

Chronic allograft nephropathy, including chronic rejection, remains one of the major causes of renal allograft failure. Amongst other mediators, metzincins, such as matrix metalloproteinases (MMP), direct extracellular matrix metabolism and cell proliferation. Thus, we hypothesized, that these proteolytic enzymes are differentially regulated in chronic renal transplant rejection in rats and in human renal allograft nephropathy. Our studies demonstrated on the experimental level and in humans an overall up-regulation of MMP, tissue inhibitors of metalloproteinases (TIMP) and related enzymes as a result of rejection processes. Thus, metzincins may represent novel markers and therapeutic targets with respect to renal allograft rejection.

Coxsackie B viruses and the kidney--a neglected topic

Coxsackie B viruses types 1-6 (CVB1-6) occur worldwide and cause a broad spectrum of diseases, including myocarditis and aseptic meningitis. Although renal damage due to CVB has been suspected since the 1950s, these agents are only rarely searched for in today's clinical nephrological practice. Nevertheless, CVB can infect mesangial cells. Furthermore, infections with these viruses lead to a histological picture resembling mesangioproliferative glomerulonephritis and IgA-nephropathy in mice. In the present article, we provide an overview of this largely neglected topic, and of the slowly and steadily increasing evidence suggesting a link between coxsackieviral infections and kidney diseases.

Cost-effectiveness of pharmacogenetic testing to predict treatment response to angiotensin-converting enzyme inhibitor

OBJECTIVE: This study aimed to assess the potential cost-effectiveness of testing patients with nephropathies for the I/D polymorphism before starting angiotensin-converting enzyme (ACE) inhibitor therapy, using a 3-year time horizon and a healthcare perspective. METHODS: We used a combination of a decision analysis and Markov modeling technique to evaluate the potential economic value of this pharmacogenetic test by preventing unfavorable treatment in patients with nephropathies. The estimation of the predictive value of the I/D polymorphism is based on a systematic review showing that DD carriers tend to respond well to ACE inhibitors, while II carriers seem not to benefit adequately from this treatment. Data on the ACE inhibitor effectiveness in nephropathy were derived from the REIN (Ramipril Efficacy in Nephropathy) trial. We calculated the number of patients with end-stage renal disease (ESRD) prevented and the differences in the incremental costs and incremental effect expressed as life-years free of ESRD. A probabilistic sensitivity analysis was conducted to determine the robustness of the results. RESULTS: Compared with unselective treatment, testing patients for their ACE genotype could save 12 patients per 1000 from developing ESRD during the 3 years covered by the model. As the mean net cost savings was euro 356,000 per 1000 patient-years, and 9 life-years free of ESRD were gained, selective treatment seems to be dominant. CONCLUSION: The study suggests that genetic testing of the I/D polymorphism in patients with nephropathy before initiating ACE therapy will most likely be cost-effective, even if the risk for II carriers to develop ESRD when treated with ACE inhibitors is only 1.4% higher than for DD carriers. Further studies, however, are required to corroborate the difference in treatment response between ACE genotypes, before genetic testing can be justified in clinical practice.

Effect of tenofovir on renal glomerular and tubular function

To evaluate tenofovir-related nephropathy, we quantified calculated glomerular filtration rates (GFR) and renal tubular function in 46 tenofovir-treated patients and 25 without tenofovir. We also analysed patients who stopped tenofovir for drug-related nephrotoxicity at our clinic. Tenofovir use combined with non-nucleoside reverse transcriptase inhibitors, but not with protease inhibitors, resulted in a significant increase in calculated GFR. Tenofovir use was associated with significantly lower phosphatemia and a marginally increased fractional excretion of uric acid, but no other signs of tubulopathy.

[Bleeding complication due to accumulation of low-molecular-weight heparin in a patient with renal insufficiency]

We report of a 71-year-old woman with a history of chronic analgesic nephropathy, who underwent coronary angiography. Because of anterior ventricular aneurysm, anticoagulation with nadroparine was installed. Continued ACE-inhibitor and ASA with additional intravenous contrast substance lead to acute tubular necrosis with rapid decline of the renal function. Due to accumulation of the low molecular weight heparin, the patient developed an extensive retroperitoneal haematoma with circulatory shock and temporary anuric kidney failure. Low molecular weight heparins are commonly used during percutaneous coronary interventions. They are as safe and efficient compared to unfractioned heparin. But due to their renal elimination, they have to be monitored by measuring anti-factor Xa-activity if creatinine-clearance is <30 ml/min.

Microalbuminuria in diabetes mellitus: efficacy of a new screening method in comparison with timed overnight urine collection

Diabetic nephropathy and end-stage renal failure are still a major cause of mortality amongst patients with diabetes mellitus (DM). In this study, we evaluated the Clinitek-Microalbumin (CM) screening test strip for the detection of microalbuminuria (MA) in a random morning spot urine in comparison with the quantitative assessment of albuminuria in the timed overnight urine collection ("gold standard"). One hundred thirty-four children, adolescents, and young adults with insulin-dependent DM Type 1 were studied at 222 outpatient visits. Because of urinary tract infection and/or haematuria, the data of 13 visits were excluded. Finally, 165 timed overnight urine were collected in the remaining 209 visits (79% sample per visit rate). Ten (6.1%) patients presented MA of > or =15 microg/min. In comparison however, 200 spot urine could be screened (96% sample/visit rate) yielding a significant increase in compliance and screening rate (P<.001, McNemar test). Furthermore, at 156 occasions, the gold standard and CM could be directly compared. The sensitivity and the specificity for CM in the spot urine (cut-off > or =30 mg albumin/l) were 0.89 [95% confidence interval (CI) 0.56-0.99] and 0.73 (CI 0.66-0.80), respectively. The positive and negative predictive value were 0.17 (CI 0.08-0.30) and 0.99 (CI 0.95-1.00), respectively. Considering CM albumin-to-creatinine ratio, the results were poorer than with the albumin concentration alone. Using CM instead of quantitative assessment of albuminuria is not cost-effective (35 US dollars versus 60 US dollars/patient/year). In conclusion, to exclude MA, the CM used in the random spot urine is reliable and easy to handle, but positive screening results of > or =30 mg albumin/l must be confirmed by analyses in the timed overnight collected urine. Although the screening compliance is improved, in terms of analysing random morning spot urine for MA, we cannot recommend CM in a paediatric diabetic outpatient setting because the specificity is far too low.

[Treatment of hypertension in type 2 diabetes mellitus--2002 update]

Arterial hypertension and diabetes are potent independent risk factors for cardiovascular, cerebral, renal and peripheral (atherosclerotic) vascular disease. The prevalence of hypertension in diabetic individuals is approximately twice that in the non-diabetic population. Diabetic individuals with hypertension have a greater risk of macrovascular and microvascular disease than normotensive diabetic individuals. Hypertension is a major contributor to morbidity and mortality in diabetes, and should be recognized and treated early. Type 2 diabetes and hypertension share certain risk factors such as overweight, visceral obesity, and possibly insulin resistance. Life-style modifications (weight reduction, exercise, limitation of daily alcohol intake, stop smoking) are the foundation of hypertension and diabetes management as the definitive treatment or adjunctive to pharmacological therapy. Additional pharmacological therapy should be initiated when life-style modifications are unsuccessful or hypertension is too severe at the time of diagnosis. All classes of antihypertensive drugs are effective in controlling blood pressure in diabetic patients. For single-agent therapy, ACE-inhibitors, angiotensin receptor blocker, beta-blockers, and diuretics can be recommended. Because of concerns about the lower effectiveness of calcium channel blockers in decreasing coronary events and heart failure and in reducing progression of renal disease in diabetes, it is recommended to use these agents as second-line drugs for patients who cannot tolerate the other preferred classes or who require additional agents to achieve the target blood pressure. The choice depends on the patients specific treatment indications since each of these drugs have potential advantages and disadvantages. In patients with microalbuminuria or clinical nephropathy, both ACE-inhibitors and angiotensin receptor blockers are considered first line therapy for the prevention of and progression of nephropathy. Since treatment is usually life-long, cost effectiveness should be included in treatment evaluation.

[Intensive insulin therapy--is it worth the effort?]

Diabetes mellitus is associated with a number of well-known, specific macro- and microvascular as well as neuropathic complications. The typical and specific association of microvascular and neuropathic complications with diabetes suggests a causal relationship with hyperglycemia or associated metabolic abnormalities. The results of the Diabetes Control and Complications Trial (DCCT) as well as other recent studies have demonstrated that in patients with insulin-dependent diabetes mellitus (IDDM) the incidence of retinopathy, nephropathy and neuropathy can be reduced by intensive treatment. Strategies of intensified insulin therapy and the clinical importance of improved diabetic control are outlined in view of these studies.

Persistent microalbuminuria in adolescents with type I (insulin-dependent) diabetes mellitus is associated to early rather than late puberty. Results of a prospective longitudinal study

Microalbuminuria is generally accepted to be highly predictive of overt diabetic nephropathy which is the leading cause of end-stage renal failure and, consequently, of death in patients with type 1 (insulin-dependent) diabetes mellitus (IDDM). Its early identification and therapy are exceedingly important. We studied prospectively the occurrence of microalbuminuria (MA) in relation to puberty and its pubertal stages in 164 children and adolescent patients (83 girls and 81 boys) with IDDM. Analysing 100 healthy subjects, normal values for albumin excretion (range: 0-10.1 micrograms/min/1.73 m2) according to sex and the different pubertal stages were defined. No significant difference between the groups were noted and, therefore, 20 micrograms/min per 1.73 m2 (3 SD above the mean) was generally defined as cutoff for MA. Of the patients with IDDM studied, 20% (20 females and 12 males) developed persistent MA (22.1-448.2 micrograms/min/1.73 m2) during the study period of 8 years. The first manifestation of persistent MA was in 69% (13 females and 9 males) during stages of early and midpuberty; and in 28% (6 females and 3 males) at a late pubertal stage or at the end of puberty. The only child who developed MA before the onset of puberty (range: 23.5-157.4 micrograms/min/1.73 m2) was found to have dystopic kidney. Therefore, all patients with IDDM should be screened for MA regardless of diabetes duration, sex and level of diabetes control beginning at the very first stage of puberty and neither earlier nor after puberty as suggested by the American Diabetes Association.

[Pancreas transplantation as treatment of diabetes mellitus]

Pancreatic transplantation is able to normalize blood glucose metabolism and achieve normoglycemia in a majority of patients with insulin-dependent diabetes mellitus. Hoping that normoglycemia will favorably influence development of late complications of diabetes, an increasing number of pancreas transplantations has been performed over the last years. However, the need for immunosuppressive therapy with its problems and possible complications confines pancreatic transplantation mainly to three groups of patients: patients who undergo kidney transplantation for diabetic nephropathy, patients who have already undergone kidney transplantation for diabetic nephropathy and, rarely, patients with extreme difficulties with metabolic control. The results of pancreatic transplantation have continuously improved over the last decade, and a limited number of controlled studies is providing some evidence of a favorable effect on late complications.

Transforming growth factor-beta2 upregulates sphingosine kinase-1 activity, which in turn attenuates the fibrotic response to TGF-beta2 by impeding CTGF expression

Transforming growth factor-beta2 (TGF-beta2) stimulates the expression of pro-fibrotic connective tissue growth factor (CTGF) during the course of renal disease. Because sphingosine kinase-1 (SK-1) activity is also upregulated by TGF-beta, we studied its effect on CTGF expression and on the development of renal fibrosis. When TGF-beta2 was added to an immortalized human podocyte cell line we found that it activated the promoter of SK-1, resulting in upregulation of its mRNA and protein expression. Further, depletion of SK-1 by small interfering RNA or its pharmacological inhibition led to accelerated CTGF expression in the podocytes. Over-expression of SK-1 reduced CTGF induction, an effect mediated by intracellular sphingosine-1-phosphate. In vivo, SK-1 expression was also increased in the podocytes of kidney sections of patients with diabetic nephropathy when compared to normal sections of kidney obtained from patients with renal cancer. Similarly, in a mouse model of streptozotocin-induced diabetic nephropathy, SK-1 and CTGF were upregulated in podocytes. In SK-1 deficient mice, exacerbation of disease was detected by increased albuminuria and CTGF expression when compared to wild-type mice. Thus, SK-1 activity has a protective role in the fibrotic process and its deletion or inhibition aggravates fibrotic disease.

Advanced glycation end products regulate extracellular matrix protein and protease expression by human glomerular mesangial cells

Advanced glycation end products (AGEs) may play a role in the pathogenesis of diabetic nephropathy, by modulating extracellular matrix turnover. AGEs are known to activate specific membrane receptors, including the receptor for AGE (RAGE). In the present study, we analyzed the various receptors for AGEs expressed by human mesangial cells and we studied the effects of glycated albumin and of carboxymethyl lysine on matrix protein and remodelling enzyme synthesis. Membrane RAGE expression was confirmed by FACS analysis. Microarray methods, RT-PCR, and Northern blot analysis were used to detect and confirm specific gene induction. Zymographic analysis and ELISA were used to measure the induction of tPA and PAI-1. We show herein that cultured human mesangial cells express AGE receptor type 1, type 2 and type 3 and RAGE. AGEs (200 microg/ml) induced at least a 2-fold increase in mRNA for 10 genes involved in ECM remodelling, including tPA, PAI-1 and TIMP-3. The increase in tPA synthesis was confirmed by fibrin zymography. The stimulation of PAI-1 synthesis was confirmed by ELISA. AGEs increased PAI-1 mRNA through a signalling pathway involving reactive oxygen species, the MAP kinases ERK-1/ERK-2 and the nuclear transcription factor NF-kappaB, but not AP-1. Carboxymethyl lysine (CML, 5 microM), which is a RAGE ligand, also stimulated PAI-1 synthesis by mesangial cells. In addition, a blocking anti-RAGE antibody partially inhibited the AGE-stimulated gene expression and decreased the PAI-1 accumulation induced by AGEs and by CML. Inhibition of AGE receptors or neutralization of the protease inhibitors TIMP-3 and PAI-1 could represent an important new therapeutic strategy for diabetic nephropathy.

Angiotensin I-converting enzyme-gene-polymorphism: relationship to albumin excretion and blood pressure in pediatric patients with type-I-diabetes mellitus

The purpose of this study was the evaluation of a predictive genetic marker for nephropathy and hypertension in patients with type-I-diabetes mellitus (IDDM). The study was performed on 247 pediatric patients with IDDM. The mean age was 15.5 years (range 3.1-29.3), the mean duration of diabetes was 7.6 years (range 0.1-25.7). Age-related blood pressure and nocturnal albumin excretion rate were compared with the insertion/deletion-(I/D) polymorphism of the angiotensin-I converting enzyme gene. The genotype distribution did not differ significantly between IDDM patients (ID 48%, D 28%, I 24%) and the control group (ID 44%, D 37%, I 19%). Neither in the entire group, nor in patients with IDDM for more than 5 years, was a correlation found bet-ween allele distribution and albumin excretion rate. No correlation was found between genotype and blood pressure. When patients with a chronological age above 12 years were analysed separately, the genotype distribution between the groups with normal and elevated blood pressure showed no significant difference. The previously reported association of the I/D-polymorphism with nephropathy could not be confirmed in this study. The development of microalbuminuria, nephropathy and hypertension will be followed in our pediatric patients.