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Background: Risk stratification of patients presenting with acute chest pain is crucial for immediate and long-term management. Traditional predictors are suboptimal; therefore inflammatory biomarkers are studied for clinical assessment of patients at risk. Recently, we reported the association of IgM-uria with worse cardiovascular outcome in patients with acute chest pain. In this study, in the same cohort of patients with chest pain, we compared the value of IgM-uria to pro-inflammatory cytokines in predicting the occurrence of subsequent cardiovascular events., Methods: A total of 178 consecutive patients presenting with acute chest pain to the emergency department at the University Hospital of Lund, were recruited. Twenty-seven of 57 patients with acute coronary syndrome (ACS), and 18 of 118 patients with non-specific chest pain at baseline developed a subsequent major cardiovascular event during the 18 months follow-up. Urinary proteins (IgM-uria and Microalbuminuria) and plasma inflammatory markers (IL-6, Il-8, IL-10, IFN-γ and TNF-α) were measured at time of admission., Results: Using the receiver operating characteristic curves, the area under the curve for predicting cardiovascular events was 0.71 (95%CI 0.61-0.81) for IgM-uria, 0.61 (95%CI 0.51-0.71) for IL-6, 0.63 (95%CI 0.53-0.72) for IL-8, 0.65 (95%CI 0.56-0.74) for IL-10, and 0.64 (95% CI 0.54-0.74) for TNF-α. In multivariate Cox-regression analysis adjusted for age, microalbuminuria, IgM-uria, IL-10, TNF-α, troponin T, hsCRP and ACS at baseline; IgM-uria was the only biomarker that remained an independent predictor of outcome (HR = 4.2, 95%CI 2.2-7.8, p < 0.001)., Conclusion: In patients with chest pain with or without acute coronary syndrome, IgM-uria could better predict the occurrence of cardiovascular events than plasma pro-inflammatory cytokines.

Objective: The first changes in the diabetic kidney are glycogen deposits in the epithelial cells of the thick ascending limb of Henle, which leads to decreased production of Tamm-Horsfall protein (THP). The production of THP is also influenced by nitric oxide (NO). The aims of this study were to investigate whether low excretion of THP, a sign of distal tubular dysfunction, in patients with type 1 diabetes was associated with polymorphisms in the THP gene and the endothelial NO synthase (eNOS) gene., Material and Methods: Urine was collected from 301 patients with type 1 diabetes, 164 with normoalbuminuria, 91 with microalbuminuria and 46 with macroalbuminuria. Urinary THP concentration below median (3.12 mg/l) was defined as tubular dysfunction. Representative polymorphisms were analysed in the THP and eNOS genes., Results: Patients with tubular dysfunction had longer diabetes duration and higher blood pressure than patients without tubular dysfunction. Tubular dysfunction was common in patients with macroalbuminuria (70% of patients) and it was associated with the AA+AT genotypes of rs12444268 in the THP gene [odds ratio (OR) 1.8, 95% confidence interval (CI) 1.1-2.8], and the GG genotype of rs1799983 in the eNOS gene (OR 1.6, 95% CI 1.03-2.6). When adjusting for other associated factors, diabetes duration, glycosylated haemoglobin (HbA(1c)), mean arterial pressure and albuminuria, the THP rs12444268 and macroalbuminuria were independently associated with tubular dysfunction., Conclusion: Distal tubular dysfunction was associated with the THP gene and macroalbuminuria in patients with type 1 diabetes.

Objective: This study investigated whether metabolic derangement at diagnosis of diabetes mellitus affects the function of the basement membrane and the excretion of several components and whether insulin treatment can normalize this. It was designed to evaluate urinary excretion rates of transforming growth factor-beta(1) (TGF-beta(1)), the carboxy-terminal domain of collagen IV (NC1) and albumin in children during the first 20 days of treatment after diagnosis of type 1 diabetes., Material and Methods: Thirty-four newly diagnosed diabetic children between 4 and 16 years of age and 26 healthy children of matching age were studied with timed overnight urine collections. Urine was collected during the first 20 days of treatment., Results: Urinary excretion of albumin and TGF-beta(1) in diabetic children were significantly increased at entry but normalized during 20 days of treatment with insulin compared with control children. In contrast, the non-significant high NC1 excretion at diagnosis did not change but became significantly increased after 20 days of insulin treatment. Overall, the kidney size was within normal limits and unaffected by treatment. The largest kidneys had less NC1 excretion (R= - 0.67, p<0.05, n=13) and a lower glomerular filtration rate (R= - 0.77, p<0.01, n=10) than the smallest kidneys. After 20 days of treatment TGF-beta(1) excretion had decreased in children with kidney size > 8.5 cm., Conclusion: Correction of the metabolic derangement with insulin decreased excretion of albumin and TGF-beta(1), but had no effect on kidney size and urine NC1 excretion, presumably because the observation period was too short.

Objective: The first changes in the diabetic kidney are glycogen deposits in the epithelial cells of the thick ascending limb of Henle. These cells produce Tamm-Horsfall protein (THP). Is low excretion of THP associated with the development of renal insufficiency or cardiovascular disease?, Material and Methods: Urine samples were collected at baseline in patients with type 1 (n = 131) and type 2 (n = 108) diabetes who were followed for a mean of 14 years (range 1-20 years) and 4.5 years (range 1-15 years), respectively., Results: Twenty percent of type 1 and 54% of type 2 diabetic patients died and 24% and 29%, respectively developed uraemia. A decreased urinary concentration of THP (u-THP) was associated with an eight-fold increased risk of renal failure and cardiovascular death in type 1 but not in type 2 diabetic patients, irrespective of the degree of albuminuria and glycosylated haemoglobin and blood pressure levels. There were no differences in the degrees of albuminuria, serum creatinine or u-THP between the two types of diabetic patients at baseline. Low u-THP occurred in 8% and 9% of normoalbuminuric type 1 and type 2 diabetic patients, respectively., Conclusion: A decreased u-THP was associated with an eight-fold increased risk of cardiovascular death and uraemia in type 1 but not in type 2 diabetic patients.

Objective: Do exaggerated increases in blood pressure and albuminuria during exercise occur earlier than microalbuminuria and which type of test is most predictive of diabetic nephropathy?, Material and Methods: A total of 33 insulin-dependent normoalbuminuric men (mean duration of diabetes 14 years; mean age 28 years) and 34 age-matched apparently healthy control subjects were studied. Urinary albumin excretion, heart rate and blood pressure were measured during fixed workload (150 W) and fixed heart rate (155 beats/min) tests. Mean follow-up time was 13.1 +/- 3.2 years. A urinary albumin level in early-morning urine persistently >30 mg/l was considered a sign of diabetic nephropathy., Results: Sixteen patients reached the endpoints of the study. Eleven had developed microalbuminuria and five macroalbuminuria (persistent levels of urinary albumin >300 mg/l). Of the latter patients, two needed dialysis. Systolic blood pressure and albumin excretion during the fixed heart rate test were higher in diabetic patients who developed signs of nephropathy than in control subjects and diabetic subjects with persistent healthy kidneys. Such differences were not found in the fixed workload test. There were no differences in glycated haemoglobin, blood pressure levels or albumin excretion at baseline between the two diabetic groups., Conclusions: To predict the development of diabetic nephropathy it seems important to choose a fixed heart rate test. High levels of systolic blood pressure in such a test were associated with the development of micro- and macroalbuminuria.

Serum cystatin C is believed to reflect the glomerular filtration rate (GFR) more closely than serum creatinine in many contexts and a reference interval for serum cystatin C in term pregnancy has been defined to enable its use also in pregnant women. However, serum cystatin C levels were not found to be decreased in term pregnancy, though GFR of low molecular mass substances is known to increase by at least 40% by the third trimester. The aim of this study was therefore to determine whether serum cystatin C is a reliable GFR marker also in pregnant women. GFR was determined by measurement of plasma clearance of iohexol in 48 previously healthy women in their third trimester and in 12 healthy nonpregnant women, and was compared with their serum levels of cystatin C and creatinine. Both serum cystatin C and creatinine levels were significantly related to GFR for both pregnant and non-pregnant women. However, the correlation between cystatin C and GFR was set at different levels for pregnant and nonpregnant women. Our results indicate a physiological difference between the filtration processes in kidneys of pregnant and non-pregnant women, whether it is size-dependent, configuration-dependent or charge-dependent. Nevertheless, serum cystatin C seems to reflect GFR reliably in both non-pregnant and pregnant, healthy and hypertensive women.

Objective: In diabetic nephropathy there is a decrease in glycosaminoglycans (GAG) in basement membranes and in Tamm-Horsfall protein (THP) in the distal tubules of the kidneys. Since GAG is present in both glomerular and tubular basement membranes, and the synthesis of both GAG and THP involves glycosylation, this study was carried out in order to investigate whether urinary excretion of these substances is interrelated., Material and Methods: 24-h urinary collections were analysed. A total of 94 diabetic patients were grouped in accordance with the urinary albumin excretion rate as normo- (<20 microg/min) (n = 35), micro- (20-200 microg/min) (n = 30) and macroalbuminuria (>200 microg/min) (n = 29)., Results: In comparison with 26 control subjects, the excretion rate of GAG was decreased in patients with micro- and macroalbuminuria and excretion of Tamm-Horsfall protein in patients with macroalbuminuria. The excretion rates of GAG and THP were associated (r = 0.64, p < 0.001) and correlated with creatinine clearance (r= 0.46 and r= 0.53, p < 0.001; respectively) but not with levels of HbA1c., Conclusions: In conclusion, albuminuria was associated with decreased urinary excretion of sulphated GAGs, which was associated with the excretion rate of Tamm-Horsfall protein, indicating that excretion of GAG was associated with distal tubular dysfunction in diabetic patients.

In summary, diabetic nephropathy is characterized by a multifactorial disease process. The present survey points to several factors that are treatable by available drugs. We must now consider prophylactic treatment of patients with poor metabolic control not only to lower blood glucose levels, but also to protect against the harmful effects of glucose. ACE inhibitors and several other available drugs have such effects.

Objective: The study was performed in order to evaluate to what extent hypertension or diabetes mellitus may affect the urinary excretion rate of Tamm-Horsfall protein., Materials and Method: The urinary excretion rates of albumin and Tamm-Horsfall protein, a measure of glomerular and distal tubular function, respectively were measured in patients with essential hypertension (n = 17) and in type 1 diabetes with (n = 20) or without nephropathy (n = 8) and in apparently healthy subjects (n = 10)., Results: Mean 24-h ambulatory blood pressure measurements showed higher blood pressure levels in the hypertensive (167/ 106 mmHg, p < 0.001) than in the diabetic patients with (136/84 mmHg) and without nephropathy (121/74 mmHg) and in healthy subjects (122/76 mmHg). Day and night ratios of systolic and diastolic blood pressure levels were not different among the four groups. Urinary albumin excretion rate was increased in patients with hypertension (30.8 x/ 3.4 microg/min; geometric mean x/tolerance factor; p < 0.001) and diabetes with nephropathy (462 x/ 3.5 microg/min; p < 0.001) compared with diabetic patients without nephropathy and healthy subjects (4.6 x/ 1.9 and 3.7 x/ 1.5 microg/min, respectively). The Tamm-Horsfall protein excretion rate was decreased in patients with diabetic nephropathy (11.6 x/ 3.5 microg/min) compared to patients with hypertension (36.3 x/2.1 1g/min; p < 0.01), diabetes without nephropathy (39.2 x/ 2.0 microg/min; p < 0.05) and healthy subjects (63.0 x/ 1.4 microg/min; p < 0.001), whereas no differences were found among the latter three groups., Conclusion: These data indicate that high blood pressure may be associated with albuminuria, while a decrease in excretion rate of Tamm-Horsfall protein may be associated with diabetic nephropathy. These associations need to be studied in a larger population.

Tamm-Horsfall protein (THP) is a large glycoprotein with unknown physiological function synthesized in the thick ascending limb of the loop of Henle. Urinary THP has recently been suggested as being suitable for monitoring the functional state of transplanted kidneys. In the present study, the urinary excretion of THP after uninephrectomy and transplantation among relatives was determined in order to study the influence of the acute reduction in renal mass on the excretion of this peptide. Glomerular filtration rate (GFR), estimated by the plasma clearance of 51Cr-EDTA, and the excretion rate of THP were measured 2 days before nephrectomy and 5, 12, 26 and 54 days after nephrectomy/transplantation in 22 healthy living kidney donors and in 16 of their recipients. In the donors, THP excretion rate of the kidney to remain in the donor was 22.3 micrograms/min before and 33.7 micrograms/min at 5 days after uninephrectomy (p < 0.01) and remained increased by around 40% throughout the study period. GFR of the remaining kidney rose from 47 ml/min before to 61 ml/min at 5 days after uninephrectomy (p < 0.001). The THP excretion rate/GFR ratio remained unchanged in the donors. In the kidney to be transplanted, THP excretion rate was unchanged before and after transplantation. There was no significant increase in GFR in the recipients, which was significantly lower than GFR of the donors all the time. In matched pairs of kidney donors and recipients, the THP excretion rate/GFR ratio tended to be lower in the recipients but the difference was not significant. The correlation between excretion rate of THP and GFR was significant (r = 0.66; p < 0.01). To conclude, uninephrectomy in healthy man was associated with a marked increase of around 40% in the excretion of THP from the kidney that remained in the donor. In the kidney that was transplanted, the THP excretion rate was unchanged. The THP excretion rate was correlated with GFR. The mechanism underlying this association is unknown as THP does not undergo glomerular filtration.

Whether an association exists between cystopathy and progression of diabetic nephropathy has never been clarified. The aim of the present study was to measure the degree of cystopathy in relation to the rate of progression of diabetic nephropathy. To that end, 17 insulin-dependent diabetic patients with diabetic nephropathy but without voiding symptoms were investigated urodynamically. The median age of the patients was 45 years (range 27-67 years), diabetes duration 23 years (range 14-44 years) and the serum creatinine level was 162 mumol/L (median, range 65-449 mumol/L) at the time of the study. The progression rate of diabetic nephropathy was analysed retrospectively by measuring changes in yearly mean values of Log10 serum creatinine for a period of 13 years (3-15 years) before the investigation. The progression rate was 0.028 mumol/L/year (median). Patients with a progression rate above and below the median rate were considered to be rapid (n = 8) and slow (n = 9) progressors, respectively. More women than men had a rapid progression rate of nephropathy. Rapid progressors were found to have smaller volume or residual urine (90 vs 165 ml; p < 0.05), larger volume voided (440 vs 270 ml; p < 0.05), lower opening pressure (18 vs 48 cm H2O; p < 0.05) and lower pressure at maximum flow (37 vs 64 cm H2O; p < 0.05) compared to slow progressors. However, these variables were not related to the progression rate of nephropathy (MANOVA). Furthermore, these results should be interpreted with caution because of the natural gender differences in pressure conditions. In conclusion, rapid progression of diabetic nephropathy does not seem to be associated with dysfunction of the urinary bladder measured with cystometry and pressure flow.

Diabetic cardiovascular autonomic neuropathy increases the risk of deterioration in renal function and is associated with increased mortality in patients with renal failure. Type 1 diabetic patients with long diabetes duration, matched for age (38 +/- 9 years) and diabetes duration (28 +/- 8 years) were studied regarding the association between cardiovascular autonomic nerve function and different degrees of diabetic nephropathy. Eighteen patients were normo- (< 30 mg/l), six micro- (30-300 mg/l), and 13 macroalbuminuric (> 300 mg/l) based on urinary albumin concentrations in three separate morning samples. They were compared with 33 control subjects with similar age. Autonomic nerve function was evaluated by measuring the response of heart rate to deep breathing and active standing. Beat-to-beat finger artery blood pressure (Finapres) was tested during active standing. During deep breathing both change in heart rate (17 +/- 11, 9 +/- 7 and 4 +/- 3 beats/min) and ratio between expiratory and inspiratory R-R intervals (1.32 +/- 0.24, 1.14 +/- 0.15 and 1.05 +/- 0.04) decreased from normo- over micro- to macroalbuminuria (p < 0.05 vs normoalbuminuric and control subjects [17 +/- 5 beats/min and 1.28 +/- 0.10, respectively]). Similar results were obtained during active standing with respect to change in systolic arterial blood pressure (3 +/- 8, 2 +/- 13 and -6 +/- 11 mmHg; p < 0.05 vs control subjects [8 +/- 11 mmHg]). However, the response of diastolic arterial blood pressure or mean heart rate to standing up did not differ between any of the groups. The ratio of maximum to minimum R-R interval during the dynamic response of heart rate to active standing decreased with the degree of nephropathy (1.27 +/- 0.17, 1.11 +/- 0.11 and 1.05 +/- 0.06) with significantly higher values in patients with normo- compared with patients with macroalbuminuria (p < 0.05). All patients groups had significantly lower values than control subjects (1.46 +/- 0.22, p < 0.05). The overshoot of the blood pressure after an initial fall during active standing decreased with the degree of diabetic nephropathy. In conclusion, type 1 diabetic patients with long duration of diabetes have signs of cardiovascular autonomic neuropathy, the severity of which is related to the degree of nephropathy.

Microalbuminuria is thought to be an important prognostic factor in diabetes mellitus. To study the influence of changes in blood pressure on the development of microalbuminuria during exercise, two exercise tests were carried out. A total of 32 insulin dependent diabetic men whose age at onset was less than 30 years, mean duration of diabetes 14 years (range 7 to 21) and mean age 29 years (range 21 to 40), and who did not have albuminuria (N-labstix negative) were studied. The diabetic patients were compared with a total of 29 age-matched male control subjects. Urinary albumin excretion was measured during two exercise tests: at a standardised workload (150 W) for 30 min, and at a standardised heart rate for 25 min. The diabetic patients had higher albumin excretion rates during both exercise tests compared with the control subjects. Blood pressure and heart rate during exercise were significantly higher in diabetic patients compared with control subjects in the standardised workload test. If the test was individualised to achieve the same standardised heart rate there was no significant difference in blood pressure between the diabetic patients and the control subjects. These results indicate that the diabetic kidneys were more sensitive than the healthy kidneys to similar degrees of haemodynamic stress induced by exercise.

A sensitive and simplified competitive binding enzyme linked immunosorbent assay (ELISA) has been developed for quantification of urinary albumin. It was found that, probably because of a high antibody dilution, a conventional ELISA with three incubation steps could be simplified to an assay with only one incubation step without losing sensitivity or precision. The technical conditions of the assay are described. Albumin was coated to the walls of polystyrene microtitre plates. Diluted urine was mixed with rabbit antiserum against albumin and then with alkaline phosphatase conjugated anti-rabbit immunoglobulins. The mixture was then incubated in the microtitre plate for 3 h. After washing the plate, substrate was added and the enzyme activity was measured. Detection limit of the assay was 15 micrograms/l or 1.5 ng. The intra-assay and inter-assay coefficients of variation were 6 and 9%, respectively. The range of 24-h excretion of urinary albumin in apparently healthy subjects was 0.6-27.2 mg.

Increased urinary albumin excretion rate (AER), microalbuminuria, has been regarded as a sign of incipient nephropathy. The influence of exercise on AER was investigated in 10 male type I diabetics and in 12 age-matched male controls. The duration of diabetes was 7-31 years (median 14 years). The exercise tests were performed both as a combined submaximal workload-waterload test and as a maximal workload test. Urinary albumin was measured with an ELISA technique. During exercise in both tests, no difference was seen in the AER between diabetics and their controls. However, the increase in systolic blood pressure was significantly more marked in the diabetics. There was no correlation between the blood pressure response during exercise and the AER, neither in the diabetics, nor in their controls. It is concluded, that, increased blood pressure response during exercise does not necessarily result in increased AER in type I diabetics.

The major collagenous component of glomerular basement membrane (GBM) is collagen IV. Serum concentrations of the carboxyterminal end (NCl) of collagen IV have been proposed to be related to GBM turnover, which has been suspected to increase in diabetes mellitus. For the quantification of serum and urinary concentrations of NCl, a specific, sensitive enzyme-linked immunosorbent assay (ELISA) with monoclonal antibodies was developed. The detection limit of the assay was 30 micrograms/l at the 50% intercept of the standard curve. The intra- and interassay coefficients of variation were 6.2% and 13.9% for serum, respectively, and 11.9% and 39.7% for urine, respectively. The levels of NCl in serum and urine in 67 insulin-dependent diabetics and in 90 sex- and age-matched controls were compared. There were no differences in the serum concentrations of NCl between the diabetics and healthy controls. As a group, the diabetics had a higher urinary excretion of NCl than the controls (20.1 vs 12.5 ng/min, 2p less than 0.05). Furthermore, the results showed that the excretion of NCl in the urine was normal when the urinary albumin excretion rate (AER) was normal (less than 6.5 micrograms/min). The excretion was increased during the early stage of incipient diabetic nephropathy (AER 6.5-30 micrograms/min) and decreased to normal values with progression to clinical diabetic nephropathy (AER above 500 micrograms/min). Thus, it is suggested that an increased urinary excretion of NCl may be an early marker for incipient diabetic nephropathy.