Antihypertensive effect of beta blockade in renal transplant recipients with or without host kidneys

Host kidneys may contribute considerably to hypertension after renal transplantation. Their role in sustaining hypertension is more prominent if glomerulonephritis (GN) than if interstitial nephritis (IN) is the original renal disease. We compared the antihypertensive effect of beta-blockade in IN (n = 10) and GN (n = 19) hypertensive renal transplant recipients with host kidneys in situ with those who had undergone bilateral nephrectomy (BN, n = 10). Pretreatment blood pressures were comparable in BN, IN, and GN patients, being 165 +/- 6/108 +/- 3, 172 +/- 5/104 +/- 3, and 161 +/- 3/104 +/- 1, mmHg, respectively. Blood pressure did not change on beta-blockade in BN patients, whereas it decreased significantly more (P less than 0.001) in GN than in IN patients, changes of mean arterial pressure being -107 +/- 1.0, -14.9 +/- 1.3, and -6.8 +/- 1.6%, respectively. This failure to respond to beta-blockade in patients without host kidneys may be related to low activity of the renin-angiotensin system or to functional denervation of the grafted kidney. Further investigations of this phenomenon may clarify the mechanism of antihypertensive action of beta-blockade as well as the nature of hypertension after renal transplantation.     

The effects of co-culture with human fibroblasts on human embryo development in vitro and implantation

In a human in-vitro fertilization (IVF) programme, the effect of co- culture of embryos with human fibroblasts was evaluated with respect to pregnancy rate and embryo development. Patients were included in the study after giving informed written consent. The IVF treatments were randomly assigned by stratification of both age (<36 versus > or =36 years) and previous IVF attempts (yes versus no). After fertilization was established, the zygotes were transferred to a 4-well dish with or without fibroblasts and cultured for 2 days. On the third day after ovum pick-up (OPU), cell number and quality [5 (good) to 1 (poor)] of the embryos were scored and a maximum of three embryos was transferred. Supernumerary embryos of good quality were cryopreserved. The design of this study was a group sequential trial with the objective of detecting differences between pregnancy rates following IVF with conventional incubation or incubation in co-culture with fibroblasts. This design included one evaluation at half-way data collection. In the study, 148 patients had an OPU, of whom 77 were allocated to the co-culture group. There was no statistically significant difference in pregnancy rate, cell number and embryo quality between the two groups. The ongoing pregnancy rate per embryo transfer was 27% in co-culture and 30% in the conventional culture group. The implantation rates per transferred embryo were 17 and 18% respectively. Using a multivariate logistic regression model for the probability of ongoing pregnancies, the odds ratio of co-culture, adjusted for age and previous IVF attempts, was not statistically significant. In conclusion, co-culture with human fibroblasts does not contribute to an improvement of embryo quality nor to a higher pregnancy rate after IVF in an unselected group of patients.      

Metallic wires with an adherent lubricious and blood-compatible polymeric coating and their use in the manufacture of novel slippery-when-wet guidewires: possible applications related to controlled local drug delivery

A new procedure was developed for the controlled application of adherent hydrophilic and biocompatible coatings onto the surface of "endless" metallic wires. Use of copolymers of 1-vinyl-2-pyrrolidinone and alkylmethacrylates provided coatings with excellent adherence and lubricity, and markedly low thrombogenicity. Coated wires could be spiralized without damaging the coating; the resulting coils are potentially useful as lubricious guidewires for use in, for example, interventional cardiology or urology. This study demonstrates that the lubricity of the coating is dependent on the composition (hydrophilicity) of the coating biomaterial, as well as on the thickness of the coating. Furthermore, the results imply that the adherence of the hydrophilic coating is essentially due to entanglement of the binder polymer chains and the hydrophilic copolymer chains. Moreover, the idea to use the hydrophilic coating on the wire as a temporary depot for controlled local drug delivery was explored. The coating was loaded with the dye rhodamine, and release of the dye upon immersion of the coated wire in water was studied. This work revealed that release of the drug is dependent on the composition of the coating. The potential utility of such wires with a drug-charged coating for controlled local drug delivery is discussed briefly.     

Urinary excretion of glutathione S transferases alpha and pi in patients with proteinuria: reflection of the site of tubular injury

In patients with renal diseases, proteinuria is a major determinant of progressive renal failure, probably by causing tubular cell injury. Little is known on extent and site of tubular cell injury in patients with proteinuria. Glutathione S transferases (GST) are cytosolic enzymes. The alpha isoform is present only in proximal tubular cells, whereas the pi isoform is confined to distal tubular cells. We have studied the urinary excretion of both isoenzymes in 56 (38 male and 18 female) patients with glomerular diseases and proteinuria. The mean age was 45 +/- (SD) 16 years, the median creatinine clearance was 80 (range 27-159) ml/min, and the median albuminuria was 4.2 (range 0.7-16.9) g/10 mmol creatinine. The excretions of both GST alpha (median 35.9 ng/10 mmol creatinine) and GST pi (median 24.8 ng/10 mmol creatinine) were elevated as compared with control values (upper limits 10 and 12 ng/10 mmol creatinine, respectively). The urinary excretion of GST pi, but not that of GST alpha, was inversely correlated with the creatinine clearance. The highest levels of GST alpha were found in patients with a well-preserved renal function, whereas highest levels of GST pi were found in patients with renal failure. In a small number of patients we performed immunofluorescent studies of renal tissue. An increased urinary excretion of GST alpha correlated with brush border damage and decreased staining of proximal tubules for that isoenzyme. Our data suggest that in patients with proteinuria initial injury is apparent at the proximal tubules. Measurements of GST alpha and GST pi appear useful to study longitudinal timing and site of proteinuria-induced tubular cell injury.     

Intensive treatment of blood pressure in patients with kidney disease and proteinuria

Blood pressure and proteinuria are important determinants of progressive renal failure in patients with renal diseases. In a 53-year-old man with hypertension and nephrotic-range proteinuria, lowering the blood pressure to a value of 125/75 mmHg resulted in a disappearance of the proteinuria. Recent literature data indicate that the treatment of blood pressure in patients with proteinuria, with emphasis on the benefits of reaching a blood pressure target of 125/75 mmHg and the use of angiotensin-converting enzyme inhibitors, may lead to a serious improvement in their prognosis.     

Captopril and atenolol are equally effective in retarding progression of diabetic nephropathy

Summary The progression of diabetic nephropathy can be positively influenced by maintaining a low blood pressure level. This has been shown in studies with conventional antihypertensive treatment as well as with ACE inhibitors. Whether the latter group of drugs is more effective remains to be proven and was the aim of our study. In a prospective randomized study we compared the effects of ACE inhibition and -blockade on retarding progression of renal function in IDDM patients with an early stage of overt diabetic nephropathy. Twenty-nine patients were studied for 2 years, 15 were randomized for treatment with captopril and 14 for atenolol. Every 6 weeks blood pressure and urinary albumin and total protein excretion were measured. GFR was measured every 6 months as ⁵¹Cr-EDTA clearance. Baseline values for blood pressure, renal function and albuminuria were identical in the two groups. The effect of both drugs on blood pressure was not significantly different. In the captopril-treated patients MAP before and after 2 years was 110±3 (SEM) and 100±2 mm Hg, respectively and in the atenolol-treated patients 105±2 vs 101±2 mm Hg. Both drugs reduced albuminuria and total proteinuria to the same extent. With captopril albuminuria decreased from 1549 (989–2399) to 851 (537–1380) mg/24 h and proteinuria from 2.5 (1.6–3.8) to 1.2 (0.8–1.8) g/24 h. With atenolol albuminuria decreased from 933 (603–1445) to 676 (437–1047) mg/ 24 h and proteinuria from 1.5 (1.0–2.4) to 0.9 (0.6–1.5) g/24 h. The rate of decline of GFR was similar with both treatments, on captopril –4.9±2.1 and on atenolol –3.7±1.6 ml · min^–1· year^–1. No major side effects with either drug were observed. We conclude that, in this 2-year study, captopril and atenolol are equally effective in retarding progression of diabetic nephropathy.Abbreviations IDDM insulin-dependent diabetes mellitus - ACE angiotensin converting enzyme - ECC endogenous creatinine clearance - MAP mean arterial pressure - GFR glomerular filtration rate     

Effect of shared care on blood pressure in patients with chronic kidney disease: a cluster randomised controlled trial

Background

Chronic kidney disease (CKD) is highly prevalent in patients with diabetes or hypertension in primary care. A shared care model could improve quality of care in these patients

Aim

To assess the effect of a shared care model in managing patients with CKD who also have diabetes or hypertension.

Design and setting

A cluster randomised controlled trial in nine general practices in The Netherlands.

Method

Five practices were allocated to the shared care model and four practices to usual care for 1 year. Primary outcome was the achievement of blood pressure targets (130/80 mmHg) and lowering of blood pressure in patients with diabetes mellitus or hypertension and an estimated glomerular filtration rate (eGFR)<60ml/min/1.73m².

Results

Data of 90 intervention and 74 control patients could be analysed. Blood pressure in the intervention group decreased with 8.1 (95% CI = 4.8 to 11.3)/1.1 (95% CI = −1.0 to 3.2) compared to −0.2 (95% CI = −3.8 to 3.3)/−0.5 (95% CI = −2.9 to 1.8) in the control group. Use of lipid-lowering drugs, angiotensin-system inhibitors and vitamin D was higher in the intervention group than in the control group (73% versus 51%, 81% versus 64%, and 15% versus 1%, respectively, [P = 0.004, P = 0.01, and P = 0.002]).

Conclusion

A shared care model between GP, nurse practitioner and nephrologist is beneficial in reducing systolic blood pressure in patients with CKD in primary care.     

Cancer Risk after Cyclophosphamide Treatment in Idiopathic Membranous Nephropathy

Background and objectives

Cyclophosphamide treatment improves renal survival in patients with idiopathic membranous nephropathy. However, use of cyclophosphamide is associated with cancer. The incidence of malignancies in patients with idiopathic membranous nephropathy was evaluated, and the cancer risk associated with cyclophosphamide use was estimated.

Design, setting, participants, & measurements

Patients who attended the clinic were included prospectively from 1995 on. A crude incidence ratio for the occurrence of malignancy was calculated. Incidence ratios were subsequently standardized to potential confounders. Latency between cyclophosphamide therapy and the occurrence of cancer was estimated by stratifying for time since the start of treatment. Finally, Poisson regression was used to obtain a multiple adjusted incidence ratio and investigate the dose–response relationship between cyclophosphamide and cancer.

Results

Data were available for 272 patients; the mean age was 51 years, and 70% of the patients were men. Median follow-up was 6.0 years (interquartile range=3.6–9.5), and 127 patients were treated with cyclophosphamide. Cancer incidence was 21.2 per 1000 person-years in treated patients compared with 4.6 per 1000 person-years in patients who did not receive cyclophosphamide, resulting in crude and adjusted incidence ratios of 4.6 (95% confidence interval, 1.5 to 18.8) and 3.2 (95% confidence interval, 1.0 to 9.5), respectively.

Conclusion

Cyclophosphamide therapy in idiopathic membranous nephropathy gives a threefold increase in cancer risk. For the average patient, this finding translates into an increase in annual risk from approximately 0.3% to 1.0%. The increased risk of malignancy must be balanced against the improved renal survival.     

Association of Anti-PLA2R Antibodies with Outcomes after Immunosuppressive Therapy in Idiopathic Membranous Nephropathy

Background

The optimal timing and duration of immunosuppressive therapy for idiopathic membranous nephropathy (iMN) have been debated. This study aimed to evaluate whether measuring the antibody against the phospholipase A₂ receptor (PLA₂R-ab) at start and end of therapy predicts long-term outcome and therefore may inform this debate.

Design, setting, participants, & measurements

This observational study included all consecutive high-risk patients with progressive iMN observed from 1997 to 2005 and treated with oral cyclophosphamide (CP) or mycophenolate mofetil (MMF) in combination with corticosteroids for 12 months. Patients were prospectively followed, and outcome was ascertained up to 5 years after completion of immunosuppressive therapy. Serum samples were collected before and after completion of therapy. PLA₂R antibodies were determined retrospectively in stored samples using ELISA.

Results

In total, 48 patients (37 men) were included. The median age was 55 years (range, 34–75), and the median serum creatinine level was 1.60 mg/dl (range, 0.98–3.37 mg/dl). Twenty-two patients received MMF and 26 received CP. At baseline, PLA₂R-abs were present in 34 patients (71%). Baseline characteristics and outcome did not significantly differ between patients negative or positive for PLA₂R-ab. In PLA₂R-ab–positive patients, treatment resulted in a rapid decrease of antibodies: median anti–PLA₂R-ab, 428 U/ml (range, 41–16,260 U/ml) at baseline and 24 U/ml (range, 0–505 U/ml) after 2 months. The PLA₂R-ab levels at baseline did not predict initial response, but antibody status at end of therapy predicted long-term outcome: After 5 years, 14 of 24 (58%) antibody-negative patients were in persistent remission compared with 0 of 9 (0%) antibody-positive patients (P=0.003).

Conclusions

These data suggest that in PLA₂R-ab–positive patients, measuring PLA₂R-abs at the end of therapy predicts the subsequent course.