Increased urinary excretion of monocyte chemoattractant protein-1 during acute renal allograft rejection.

BACKGROUND: Acute rejection is characterized histologically by infiltration of the interstitium by mononuclear cells. Monocyte chemoattractant protein 1 (MCP-1) has recently been identified as a monocyte chemotactic factor. This study examined the possible role of MCP-1 in renal transplantation. METHODS: The concentration of MCP-1 in urine and serum of 19 renal transplant patients was investigated using an inhibition radioimmunoassay. The patients were divided into a non-rejection (NRj) and a rejection (Rj) group. Normal healthy volunteers were included as controls. Immunoperoxidase staining for MCP-1 and CD14, as a marker for macrophages, was performed in renal biopsies of transplant patients with rejection and six biopsies from histologically normal kidneys, as controls. The size of urinary MCP-1 was determined by gel filtration chromatography and in a number of fractions assessed for monocyte chemotactic activity using a modified Boyden chamber assay. RESULTS: Urinary excretion of MCP-1 in the Rj group ranged between 250 ng/mmol Cr and 3148 ng/mmol Cr with a median of 612 ng/mmol Cr. This is significantly higher than the results in the NRj group, ranging between 47 ng/mmol Cr and 288 ng/mmol Cr with a median of 229 ng/mmol Cr. In the normal control group, urinary MCP-1 levels ranged between 38 ng/mmol Cr and 74 ng/mmol Cr with a median of 50 ng/mmol Cr. The fractional excretion of MCP-1, calculated on the basis of MCP-1 and creatinine clearances, was found also to be significantly higher in the Rj group as compared to the NRj group. However, there was no significant difference in the serum levels of MCP-1 between the Rj, NRj, and normal control group. The intensity of MCP-1 staining in tubular epithelial cells and the degree of CD14+ cells in the interstitium was significantly higher in renal allograft biopsies than in the normal kidneys. In addition, MCP-1 isolated from urine of renal transplant patients with rejection was filtered with apparent molecular weight of 13 kDa and 11 kDa. Both sizes are chemotactically active for monocytes. CONCLUSIONS: These data suggest that urinary excretion of MCP-1 can be used as a marker for the episodes of acute rejection. The increase of urinary excretion of MCP-1 most likely is the result of local production by tubular epithelia cells. MCP-1 produced locally may, at least in part, be responsible for the influx of macrophages into the interstitium during rejection.

A century of mortality in five large families with polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) characteristically leads to end-stage renal failure in the fifth or sixth decade of life, which in the absence of therapeutic measures will lead to premature death. To determine excess mortality relative to the general population and chromosome 16-linked ADPKD patients, we studied 348 individuals who belonged to five large ADPKD families and who had at least a 50% probability of carrying the gene; the study data derive from a time span of approximately one century. Assessment of the diagnosis of ADPKD in the present generation was based on the characteristic roentgenographic appearance of polycystic kidneys and was confirmed by DNA analysis with flanking polymorphic markers around the polycystic gene. In the previous generation, we used Mendelian reasoning after pedigree analysis to identify persons with a 50% or 100% probability of carrying the polycystic gene. During the study period (1889 to 1992), 83 deaths occurred in 10,279 person-years. Mortality was increased 1.6-fold (95% confidence interval, 1.3 to 2.0) relative to the general population and was independent of the gender of the affected family member as well as the gender of the transmitting parent. The increased mortality was strongest in the 50 to 59 year age group (relative mortality, 3.2; 95% confidence interval, 2.0 to 4.8), but decreased after the 1970s, probably as a result of improvements in supportive care and, eventually, renal replacement therapy. In conclusion, the total life-span in ADPKD patients is improving, but remains low in comparison to the general population, and the gender of the transmitting parent or of the affected individual does not influence relative mortality.

Borderline hypertensive autosomal dominant polycystic kidney disease patients have enhanced production of renal dopamine. Normalization of renal haemodynamics by DOPA infusion.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD) the pathophysiology of hypertension, which is frequently observed before loss of renal function, is not well understood. We investigated intrarenal dopamine, the renin-angiotensin-aldosterone system (RAAS), and plasma endothelin in relation to sodium homeostasis as potential hypertensive factors in this disease. METHODS: Eight borderline hypertensive ADPKD patients with (near) normal renal function and seven matched healthy control subjects were investigated at three levels of daily dietary sodium intake: 150, 50 and 450 mmol. In the 450-mmol sodium intake period we studied the effects of renally formed dopamine by infusing its precursor DOPA (DOPAi.v., 7 micrograms kg-1 min-1). In the 50-mmol sodium intake period we studied the influence of the RAAS by administering enalaprilate (42 micrograms kg-1), followed by angiotensin II (12 ng kg-1 min-1) intravenously. GFR and ERPF were measured by continuous infusion of inulin and PAH. RESULTS: At all levels of sodium intake sodium balances were equal, but daily urinary excretions of dopamine and DOPA were higher (P < 0.01) in the ADPKD patients than in the controls. Renal vascular resistance, filtration fraction and blood pressure were higher in the ADPKD patients (all P < 0.05) while plasma renin activity was similar. DOPAi.v. normalized renal haemodynamics and increased plasma endothelin in ADPKD patients (all P < 0.05), while stimulation of natriuresis was equal in both groups. Enalaprilate increased plasma endothelin in the ADPKD patients and only partially normalized renal haemodynamics. CONCLUSIONS: In borderline hypertensive ADPKD patients: (1) urinary dopamine excretion is increased at all levels of sodium intake, suggesting that this may be needed to maintain sodium balance; (2) stimulation of renal dopamine production is able to normalize renal haemodynamics, making dopamine receptor agonism a potential therapeutic option; (3) the activity of the RAAS is not clearly enhanced; (4) renal vasodilatation increases plasma endothelin levels.

Inulin measurement in serum and urine with an autoanalyser, corrected for glucose interference.

A method is described for the semi-automated measurement of inulin concentrations in serum and urine in the presence of glucose. The concentration of glucose is measured simultaneously and is used to correct for almost all "inulin-like" interferences. The inulin standard curve is linear over a wide range (5-2500 mg/l). Between-run precision is < 6% and recovery from spiked sera is 98%. This method offers the possibility of measuring glomerular filtration rate in patients with varying glucose concentrations (e.g. diabetics).

Glomerular filtration rate measurement by "single-shot" injection of inulin.

In 14 ADPKD patients the total body clearance and the urinary clearance of inulin using the constant infusion method were compared with the "single-shot" technique. Triplicate measurements of both clearances by each infusion method were obtained in 12 out of 14 patients. A high correlation was found between the total body clearance and the urinary clearance for both the constant infusion method (r = 0.96) and the single injection technique (r = 0.96). The coefficient of variation for the total body clearance of inulin was significantly lower for the constant infusion method and the single injection technique (7.8% and 7.1%) than for the urinary clearance of inulin (11.3% vs. 9.7%, P < 0.05). A constant overestimation of the urinary clearance by the total body clearance was observed with both methods (constant infusion method 8.3 ml.min-1 x 1.73 m-2 and single injection technique 13.4 ml.min-1 x 1.73 m-2). No concentration-dependent clearance was present. Determination of plasma inulin, especially at low levels, showed substantial interference by glucose. We conclude that, taking into account a constant overestimate of urinary clearance by the total body clearance of inulin, the single injection total body clearance possesses the best reproducibility and shows a good agreement with the conventional urinary clearance, which can be calculated by: GFR = TBCLss-13.1 ml.min-1 x 1.73 m-2 (in the range of 28 to 124 ml.min-1 x 1.73 m-2).

Long-term cardiovascular morbidity and mortality in autosomal dominant polycystic kidney disease patients after renal transplantation.

Patients with autosomal dominant polycystic kidney disease (ADPKD) have an increased incidence of hypertension and cardiovascular abnormalities. In this long-term follow-up study (5.88 years on average), we evaluated cardiovascular disease and patient and graft survival in 101 ADPKD patients and 692 nondiabetic control patients receiving cadaveric renal transplants between March 1967 and April 1991 at the Leiden University Hospital. Graft and patient survival was not different between patient groups, using the same immunosuppressive therapy. However, death with functioning graft, mainly due to cardiovascular disease, was significantly more frequent in the ADPKD patients than in controls using AZA (P < 0.01). Multivariate analysis of pretransplant data showed that ADPKD patients on AZA therapy demonstrated an elevated age-adjusted relative risk of 2.07 (95% confidence interval [95% CI]: 1.12-3.80) for cardiovascular events and 2.88 (95% CI: 1.41-5.90) for cardiovascular mortality alone. After adjustment for age, gender, and other cardiovascular risk factors, a relative risk of 2.39 (95% CI: 1.06-5.40) was found. This was 2.87 (95% CI: 1.04-7.93) when cardiovascular mortality was the dependent variable. With posttransplant data, the age-adjusted relative risk for cardiovascular morbidity and mortality in ADPKD patients using AZA was 2.16 (95% CI: 1.12-4.15) and 2.97 (95% CI: 1.40-6.27), with only cardiovascular mortality as the dependent variable. After adjustment for age, gender, and other cardiovascular risk factors, this was 1.59 (95% CI: 0.64-3.91) and 2.28 (95% CI: 0.79-6.53), respectively. With CsA treatment, an elevated risk for cardiovascular morbidity and mortality in ADPKD patients was present, but the corresponding 95% CI were wide and include unity, due to the shorter period of follow-up (CsA: 3.81 +/- 2.50 years vs. AZA: 7.28 +/- 6.74 years). Survival of ADPKD patients using AZA was less in those patients without pretransplant nephrectomy as compared with control patients, but the morbidity and mortality of pretransplant nephrectomies should be taken into account. We conclude that ADPKD patients show a similar graft and patient survival after renal transplantation as control patients, but they are especially at risk for cardiovascular disease after renal transplantation.

Plasma immunoreactive endothelin-1 in pregnant women with and without pre-eclampsia.

In normotensive nonpregnant women (n = 23), the plasma concentrations of immunoreactive endothelin-1 (ir-ET-1) were not different from nonpregnant women with essential hypertension (n = 15): 3.6 (2.0-5.4) ng/L (mean, range) versus 3.8 (2.4-5.8) ng/L. In normotensive pregnant women (n = 25), the plasma level of ir-ET-1 was 2.1 (1.3-3.4) ng/L (p less than 0.01) lower than in normotensive nonpregnant women. Pre-eclamptic patients (n = 25) had elevated ir-ET-1 plasma levels of 5.0 (2.1-12.4) ng/L (p less than 0.001 for normotensive pregnant women, p less than 0.01 for nonpregnant women). The low level of ir-ET-1 in normotensive pregnant women may be explained by the increase in the distribution volume of ir-ET-1 during the course of pregnancy. Damage of vascular endothelium is a consistent morphological abnormality in pre-eclampsia. Elevated ir-ET-1 in plasma might be a biochemical marker of this abnormality and may contribute to the pathogenesis of pre-eclampsia.

[Postpericardiotomy syndrome as a cause of recurrent pleural effusion]. / Het postpericardiotomiesyndroom als oorzaak van recidiverend pleuravocht.

The postpericardiotomy syndrome occurs frequently after cardiac surgery, and shows a strong tendency to recur. It is characterized by febrile illness with an elevated erythrocyte sedimentation rate, leucocytosis, and symptoms of pulmonary and pleuro-pericardial inflammation. Pleural effusion is a common manifestation of this syndrome, and is usually left-sided. We describe a patient who shows a periodic left-sided pleural effusion with an interval of 5 to 6 weeks 18 months after cardiac surgery. This is the first description of a 'cyclic' pleural effusion due to the postpericardiotomy syndrome. On the basis of this case report and the literature, we discuss the pathogenesis, therapy and clinical outcome of this syndrome.