Günter Stein

Relationship Between Disease Activity and Serum Levels of Vitamin D Metabolites and PTH in Rheumatoid Arthritis

Abstract. In several studies on patients with rheumatoid arthritis, an association of bone loss with a persistently high disease activity has been found. The aim of our study was to investigate the relation between disease activity and serum levels of vitamin D metabolites, parathyroid hormone (PTH), and parameters of bone turnover in patients with rheumatoid arthritis. A total of 96 patients (83 women and 13 men) were divided into three groups according to disease activity measured by serum levels of C-reactive protein (CRP). In the whole group, serum levels of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) (P < 0.001) and PTH (P < 0.05) were negatively correlated to disease activity. The urinary excretion of collagen crosslinks—pyridinoline (Pyd) (P < 0.001) and deoxypyridinoline (Dpd) (P < 0.05)—showed a positive correlation with disease activity. The inverse correlation between serum 1,25(OH)2D3 and disease activity was separately evident in patients with (P < 0.001) and without (P < 0.01) glucocorticoid treatment, in pre- (P < 0.01) and postmenopausal (P < 0.001) women, and in men (P < 0.01). 1,25(OH)2D3 and PTH serum levels were positively correlated to serum bone alkaline phosphatase (ALP) (P < 0.01). The results indicate that high disease activity in patients with rheumatoid arthritis is associated with an alteration in vitamin D metabolism and increased bone resorption. The decrease of 1,25(OH)2D3 levels in these patients may contribute to a negative calcium balance and inhibition of bone formation. Furthermore, low levels of 1,25(OH)2D3 as an endogenous immunomodulator suppressing activated T cells and the proliferation of cells may accelerate the arthritic process in rheumatoid arthritis.

On-line haemodiafiltration versus haemodialysis: stable haematocrit with less erythropoietin and improvement of other relevant blood parameters.

Background: Controlled randomised studies to prove improved cardiovascular stability and improved anaemia management during on-line haemodiafiltration (oHDF) are scarce. Methods: 70 patients were treated with both haemodialysis (HD) and oHDF in a cross-over design during 2 × 24 weeks at a dialysis dose of eKt/V≧1.2. Patients randomised into group A started on HD and switched over to oHDF, whereas patients in group B began with oHDF and were treated with HD afterwards. Intradialytic morbid events (IME), such as symptomatic hypotension or muscle cramps, were noted in case of appearance. Blood parameters reflecting anaemic status, phosphate status, lipid metabolism, oxidative stress, and accumulation of advanced glycation end products were recorded either monthly or at the end of each study phase. Results: The mean incidence of IME was 0.15 IME per treatment, and there was no statistical difference between oHDF and HD. A higher haematocrit (oHDF 31.5% vs. HD 30.5%, p < 0.01) at a lower erythropoietin dose (oHDF 4,913 vs. HD 5,492 IU/week, p = 0.02) was found during oHDF, when the sequence of HD and oHDF had not been taken into account. For the study groups, the results were less distinct: in group A, a higher haematocrit (HD 30.4% vs. oHDF 32.0%, p < 0.01) at a comparable erythropoietin dose (HD 5,421 vs. oHDF 5,187 IU/week, ns) was observed during oHDF, whereas in group B an identical haematocrit (oHDF 30.8% vs. HD 30.7%, ns) was achieved at a reduced erythropoietin dose (oHDF 4,622 vs. HD 5,568 IU/week, p < 0.01). During oHDF, lower levels of free and protein-bound pentosidine and of serum phosphate were found. Conclusion: In contrast to other studies, no benefit regarding cardiovascular stability for oHDF was found, but oHDF could well offer a potential benefit regarding anaemia correction, inflammation, oxidative stress, lipid profiles, and calcium-phosphate product.

Serum concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in patients with chronic kidney diseases.

BACKGROUND NO synthesis is inhibited by the dimethylarginine (DMA) ADMA, which accumulates, similar to SDMA, in the plasma of patients suffering from chronic renal failure (CRF). ADMA and possibly SDMA contribute to hypertension and atherosclerosis in patients with chronic renal disease: ADMA inhibits directly eNOS, whereas SDMA competes with the NO precursor arginine for uptake into the cells. METHODS In 26 control persons and 221 patients with kidney diseases of different stage as were CRF, end stage renal disease (ESRD), and patients after renal transplantation (RT), the plasma concentrations of ADMA (c(ADMA)), SDMA (c(SDMA)) and 20 endogenous amino acids (AA) were measured by HPLC and correlated to blood pressure, cardiac events, endothelial dysfunction, and diabetes mellitus. RESULTS Both ADMA (1.04+/-0.04 vs. 0.66+/-0.04 microM) and SDMA (2.69+/-0.12 vs. 0.49+/-0.03 microM) were significantly (p<0.001) elevated in all patients compared to healthy controls, whereas arginine concentration (51.4+/-2.3 vs. 76.0+/-5.2 microM) was decreased in dependence on the degree of kidney disease. In RT patients, SDMA levels were significantly decreased, but c(ADMA) remained enhanced. A strong correlation was found between SDMA and both serum urea and creatinine in CRF and RT patients. A linear correlation was found between ADMA and cholesterol concentrations in RT patients. Hypertension in CRF was accompanied by a further increase in the concentration of DMAs. There was no relation between DMAs and the occurrence of peripheral arterial occlusive disease or cerebrovascular diseases. In patients with cardiac diseases, c(SDMA) was additionally increased only in the CRF group. CONCLUSIONS In patients with chronic kidney disease, c(ADMA) and c(SDMA) are significantly increased but cardiovascular diseases are evidently not correlated to changes in DMA concentrations in this group of patients.

No association of converting enzyme insertion/deletion polymorphism with immunoglobulin A glomerulonephritis☆

It has been recently reported that in type 1 diabetes the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme gene is associated with the presence of diabetic nephropathy. Tissue angiotensin I-converting enzyme is determined by I/D polymorphism, and it has been speculated that in diabetes differences of local angiotensin II availability determine the risk of renal disease. Since angiotensin II is thought to play an important role in the evolution of renal disease in general, we tested whether genotype distribution of the I/D polymorphism is also different in patients with immunoglobulin A-glomerulonephritis (IgA-GN). Furthermore we compared IgA-GN patients with (1) stable renal function or (2) terminal renal failure to investigate a potential role of the I/D polymorphism in the renal prognosis. We examined 122 patients with biopsy-confirmed IgA-GN who had stable renal function and 82 dialysis-dependent or transplanted patients with biopsy-confirmed IgA-GN. Furthermore, in 134 healthy individuals used as controls we analyzed the DNA for normal distribution of genotypes and allele frequencies. The polymorphic region was amplified using polymerase chain reaction with specific primers. Alleles were detected on 2% agarose gels. Genotype distributions and allele frequencies were not significantly different between controls and patients with IgA-GN and stable renal function. Furthermore, no significant difference in genotype distribution was detected between patients with IgA-GN and stable renal function compared with patients with IgA-GN and end-stage renal failure, although a trend for a higher frequency of DD-homozygotes was noted in the latter group (P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Cell‐Free DNA in Urine

Abstract: Intrigued by the rapid clearance of free fetal DNA from the maternal circulation, we have investigated whether this fetal genetic material could be cleared via the kidney. For this purpose, we examined for the presence of Y chromosome‐specific DNA sequences in urine samples obtained from 8 women pregnant with male fetuses. No male‐specific sequences could be detected, despite the use of a very sensitive nested PCR assay nor a highly reproducible real‐time PCR assay. We did, however, detect maternal DNA sequences. To determine if this cell‐free DNA was derived from the kidney or another source, we next examined urine from female kidney transplant patients who had received male kidneys. Y chromosome‐specific sequences were indeed detectable by both nested and real‐time PCR in these samples, thereby confirming a recent report describing urinary DNA microchimerism. Quantitative analysis of serially obtained samples furthermore suggests that transplant‐derived sequences are elevated during periods of graft rejection. These results imply that the measurement of graft‐derived urinary DNA may serve as a new marker for kidney graft tolerance.

Asymmetrical (ADMA) and symmetrical dimethylarginine (SDMA) as potential risk factors for cardiovascular and renal outcome in chronic kidney disease – possible candidates for paradoxical epidemiology?

Summary.Background: Asymmetrical dimethylarginine (ADMA) is an inhibitor of nitric-oxide synthase. It has been linked to atherosclerotic risk in the general population as well as in end-stage renal disease patients (ESRD), whereas symmetrical dimethylarginine (SDMA) is thought to be biological inactive. Prospective data concerning the role of both dimethylarginines are rare in patients with chronic kidney disease.Methods: 200 patients with chronic kidney disease (mean age 57.6 ± 13.0 years, 69 female, 131 male); 82 with chronic renal failure (CRF), 81 on maintenance haemodialysis (HD) and 37 renal transplant recipients (RTR) were prospectively followed for 24 months. ADMA and SDMA were measured by HPLC. The relation of plasma levels of ADMA and SDMA together with conventional risk factors for the cardiovascular and renal outcome was investigated with Cox proportional hazards model.Results: Mean serum levels of SDMA were significantly increased in all groups compared to the control group (P ≤ 0.0005), ADMA was increased only in HD and RTR (P ≤ 0.004). Forty-seven cardiovascular events (CVE) occurred during follow-up, 35 patients died, and 39 patients reached ESRD. Multivariate analysis showed diabetes (RR 3.072, P = 0.01), ESRD (RR 11.915, P < 0.0005), elevated CRP levels (RR 3.916, P < 0.0005) and surprisingly a lower ADMA level (RR 0.271, P = 0.008) as independent risk factors for CVE. Serum creatinine (RR 11.378, P = 0.001), haemoglobin (RR 0.710, P = 0.038 for an increment of 1 mmol/l), and SDMA levels (RR 1.633, P = 0.006, per 1 µmol/l increment) were predictors for the progression to ESRD.Conclusions: Data from a heterogeneous group of patients with chronic kidney disease provide evidence that conventional risk factors seem to play a more important role than elevated serum levels of ADMA or SDMA for cardiovascular events. Increasing serum SDMA concentration seems to play an additive role for the renal outcome besides serum creatinine and haemoglobin levels. Whether ADMA might possibly be a candidate for the phenomenon of “paradoxical epidemiology” in chronic kidney disease needs further investigation.

Vitamin Levels in Chronic Renal Failure and Need for Supplementation

Deficiencies of water-soluble vitamins may occur in uremic patients mainly because of restricted consumption and of loss during chronic hemo- and peritoneal dialysis. Although the daily requirement for most vitamins is not well defined in chronic renal failure supplementation of the vitamins thiamine, riboflavin, pyridoxine, pantothenic acid, niacin and ascorbic acid, the form of one multivitamin preparation without vitamin A as well as folic acid in dialysis patients after each dialysis is recommended. There is no need for vitamin B12, vitamin A and vitamin E.

Anti-C1q antibodies and antiendothelial cell antibodies in systemic lupus erythematosus – relationship with disease activity and renal involvement

The aim of this study was to investigate the relationship between the presence and titre of antibodies against C1q (anti-C1q Ab) and disease activity and renal involvement in patients with systemic lupus erythematosus (SLE). Anti-C1q Ab were measured in 79 patients with SLE (70 women and 9 men; mean age 41.7 years; mean disease duration 8.4 years): 19 patients had active disease with lupus nephritis, 8 active disease without nephritis, 26 inactive disease with nephritis and 26 inactive disease without nephritis. Anti-dsDNA antibodies (EIA and immunofluorescence), antiendothelial cell antibodies (AECA) and complement levels (C3, C4, total haemolytic complement activity) were determined in parallel. Anti-C1q Ab were positive in 49%, anti-dsDNA Ab in 61% and AECA in 19% of the patients, respectively. Significantly higher titres of anti-C1q Ab were found in patients with active disease compared with those with inactive SLE (P < 0.01). Serum levels of anti-C1q Ab showed a positive correlation with anti-dsDNA Ab and SLEDAI score (P < 0.01) and a negative correlation with C3 (P < 0.05), C4 (P < 0.01) and CH50U (P < 0.01). The presence of anti-C1q Ab was not different between patients with or without nephritis. In patients with (P < 0.05) and without nephritis (P < 0.01) the frequency of anti-C1q Ab was significantly higher in active patients compared with inactive patients. Both anti-C1q and anti-ds-DNA Ab were detectable in 74% of patients with active nephritis but only in 30% of all other patients (P=0.001). None of the patients with active nephritis was negative for anti-C1q and anti-dsDNA Ab, whereas 37% of the patients without active nephritis were negative for both antibodies (P < 0.01). Sensitivity, specificity, positive and negative predictive values for active lupus nephritis among SLE patients were 100%, 50%, 51.9% and 100% for anti-dsDNA Ab (EIA) and 74%, 70%, 57% and 89.4% for positive findings of both anti-dsDNA and anti-C1q Ab. The presence and titre of anti-C1q-Ab in SLE are related to disease activity. Absence of anti-dsDNA Ab excludes active nephritis; positive findings of both anti-dsDNA Ab and anti-C1q Ab are of relatively high specificity for active nephritis.

Smelling Renal Dysfunction via Electronic Nose

The human body odor plays an important role in social communication in various situations, like the olfactory identification of partners and relatives as well as in parents–child interactions. In patients with renal dysfunction the compound of sweat and volatile gases is changed because of the limited ability for removing metabolic products from the blood. The regulation of electrolyte composition and acid–base balance are also altered so that the body odor of these patients may be significantly influenced by these disorders. We show the ability of an electronic nose to detect changes in the human body odor in consequence of renal dysfunction by reducing multivariate sensor signals with principal component analysis to its first and second principal odor component (POC). All healthy subjects could clearly be distinguished from patients with renal failure using quadratic discriminant analysis, whereas a correct classification of 95.2% (98.4% using 1st–3rd POC) of patients between end stage renal failure and chronic renal failure was found. This methodology of analyzing human body odor may also provide new approaches for investigating symptoms of renal failure and for diagnosing other diseases of internal or cutaneous origin.

Advanced glycation end products in children with chronic renal failure and type 1 diabetes

Abstract Serum levels of advanced glycation end products (AGEs) are markedly elevated in adults with chronic renal failure (CRF) and diabetes mellitus. Accumulation of AGEs in tissues contributes to the development of long-term complications. Up to now little has been known about the formation of AGEs in childhood. We determined serum levels of the well known AGEs pentosidine and Nɛ-carboxymethyllysine (CML) in children with CRF (n=12), end-stage renal disease (ESRD) (n=9), renal transplantation (n=12), and type 1 diabetes mellitus (n=42) and in healthy children (n=20). Pentosidine was measured by high-performance liquid chromatography (HPLC), CML by a competitive enzyme-linked immunosorbent assay (ELISA) system. Serum levels of pentosidine and CML were significantly higher in the children with CRF and ESRD than in controls (P<0.001), but nearly within the normal range after transplantation. Both AGEs showed a significant negative correlation with creatinine clearance (P<0.001). During a single session of low-flux hemodialysis, total pentosidine and CML levels did not change. Free pentosidine, however, was reduced by 78% (P=0.04). Diabe-tic children showed significantly elevated pentosidine levels (P<0.001) despite normal renal function. We conclude that, similar to adults, increased formation and accumulation of AGEs also exist in children with CRF and type 1 diabetes mellitus. At present the best prevention of AGE-related complications is an early renal transplantation in children with ESRD, as well as a careful metabolic monitoring of diabetics.