de Paul Jong

Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension

BACKGROUND Hypertension is the most prevalent comorbidity in individuals with chronic kidney disease. However, whether the association of the kidney disease measures, estimated glomerular filtration rate (eGFR) and albuminuria, with mortality or end-stage renal disease (ESRD) differs by hypertensive status is unknown. METHODS We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and ESRD associated with eGFR and albuminuria in individuals with and without hypertension. FINDINGS We analysed data for 45 cohorts (25 general population, seven high-risk, and 13 chronic kidney disease) with 1,127,656 participants, 364,344 of whom had hypertension. Low eGFR and high albuminuria were associated with mortality irrespective of hypertensive status in the general population and high-risk cohorts. All-cause mortality risk was 1·1-1·2 times higher in individuals with hypertension than in those without hypertension at preserved eGFR. A steeper relative risk gradient in individuals without hypertension than in those with hypertension at eGFR range 45-75 mL/min per 1·73 m(2) led to much the same mortality risk at lower eGFR. With a reference eGFR of 95 mL/min per 1·73 m(2) in each group to explicitly assess interaction, adjusted HR for all-cause mortality at eGFR 45 mL/min per 1·73 m(2) was 1·77 (95% CI 1·57-1·99) in individuals without hypertension versus 1·24 (1·11-1·39) in those with hypertension (p for overall interaction=0·0003). Similarly, for albumin-creatinine ratio of 300 mg/g (vs 5 mg/g), HR was 2·30 (1·98-2·68) in individuals without hypertension versus 2·08 (1·84-2·35) in those with hypertension (p for overall interaction=0·019). We recorded much the same results for cardiovascular mortality. The associations of eGFR and albuminuria with ESRD, however, did not differ by hypertensive status. Results for chronic kidney disease cohorts were similar to those for general and high-risk population cohorts. INTERPRETATION Chronic kidney disease should be regarded as at least an equally relevant risk factor for mortality and ESRD in individuals without hypertension as it is in those with hypertension. FUNDING US National Kidney Foundation.

Long-term renal outcome after lung transplantation is predicted by the 1-month postoperative renal function loss

BACKGROUND Progressive renal function loss is common after lung transplantation. To facilitate the design of renoprotective strategies, identification of early predictors for long-term renal function loss would be useful. METHODS We prospectively analyzed renal function [glomerular filtration rate (GFR); 125I-iothalamate clearance] in a closely monitored cohort (minimum 24-month follow-up) of 57 patients who received lung transplants between November 1990 and September 1996 in our center. The analyzed end points were the slope of the GFR from 6 months posttransplant onward and the GFR at 24 months after transplantation. RESULTS Before transplantation, the GFR was 100 ml/min (median, range 59-163). It decreased to 67 ml/min (29-123) at 6 months, 53 ml/min (17-116) at 24 months, and 51 ml/min (20-87) at 36 months after transplantation. The magnitude of the loss of GFR 1 month post-transplantation was the only factor significantly correlated with absolute GFR at 24 months after transplantation. Pulmonary diagnosis was significantly associated with long-term rate of renal function loss. Median loss of GFR was greatest in patients with cystic fibrosis (-10 ml/min/year, range -14 to -6 ml/min/year), preserved in pulmonary hypertension (-1 ml/min/year, range -6 to +7 ml/min/year), and in between in emphysema (-6 ml/min/year, range -27 to +12 ml/min/year). No other factors could be identified. CONCLUSIONS In lung transplant recipients, the 1-month postoperative loss of GFR is an early marker for long-term renal prognosis. Pulmonary diagnosis appears to be a relevant predictor as well. These factors may guide further research and the development of preventive strategies.

Therapeutic potential of vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: optimal timing and dosing of the drug

BACKGROUND The renoprotective effect of vasopressin V2 receptor antagonist (V2RA) is currently being tested in a clinical trial in early autosomal dominant polycystic kidney disease (ADPKD). If efficacious, this warrants life-long treatment with V2RA, however, with associated side effects as polydipsia and polyuria. We questioned whether we could reduce the side effects without influencing the renoprotective effect by starting the treatment later in the disease or by lowering drug dosage. METHODS To investigate this, we administered V2RA OPC-31260 at a high (0.1%) and low (0.05%) dose to a tamoxifen-inducible kidney epithelium-specific Pkd1-deletion mouse model starting treatment at Day 21 (early) or 42 (advanced). After 3 and 6 weeks of treatment, we monitored physiologic and potential renoprotective effects. RESULTS Initiation of V2RA treatment at advanced stage of the disease lacked renoprotective effects and had less pronounced physiologic effects than early initiation. After 3 weeks on a high dose, cyst ratio and kidney weight were reduced versus untreated controls (18 versus 25%, P = 0.05, and 0.33 versus 0.45 g, P = 0.03, respectively). After 6 weeks of treatment, however, this did not reach significance anymore, even at a high dose (cyst ratio 24 versus 27%, P = 0.12, and kidney weight 0.55 versus 0.66 g, P = 0.38). CONCLUSIONS Our results suggest that intervention with V2RA should be instituted early in ADPKD and that it might be necessary to further increase the dosage of this drug later in the disease to decrease cyst growth.

Differential effects of enalapril and atenolol on proteinuria and renal haemodynamics in non-diabetic renal disease.

OBJECTIVE--To compare the antihypertensive, renal haemodynamic and antiproteinuric effect of enalapril and atenolol in patients with proteinuria of non-diabetic origin. DESIGN--Prospective, double blind, randomised 16 week study after a pretreatment period of at least three weeks. SETTING--Outpatient nephrology and hypertension unit. PATIENTS--27 patients with proteinuria (greater than 300 mg protein/day) of non-diabetic origin, moderately impaired renal function (creatinine clearance 30-90 ml/min), and a pretreatment diastolic blood pressure of greater than 80 mm Hg. INTERVENTIONS--Treatment with enalapril (10 mg/day, adjusted between 5 and 40 mg, if necessary) or atenolol (50 mg/day, adjusted between 25 and 100 mg if necessary) titrated against a target fall in diastolic blood pressure to less than 95 mm Hg or of greater than 10 mm Hg, or both. MAIN OUTCOME MEASURES--Blood pressure, renal haemodynamics, and urinary protein excretion. RESULTS--No differences were detected between the two groups before treatment. The falls in systolic and diastolic blood pressures during treatment were not significantly different between both groups. Proteinuria fell slightly with atenolol but significantly more with enalapril (mean change -0.38 (95% confidence interval -0.78 to 0.03) v -1.2 (-1.70 to -0.69) g/day respectively, p less than 0.02) as did filtration fraction (mean change -1.8 (-2.9 to -0.7) v -3.8 (-4.9 to -2.8)% respectively. Serum potassium concentration increased with enalapril (mean change 0.63 (SD 0.51) v 0.19 (0.47) mmol/l, p less than 0.05). CONCLUSIONS--Enalapril lowers proteinuria more than atenolol in patients with non-diabetic renal disease despite a similar blood pressure lowering effect of both drugs, and its antiproteinuric effect seems to be associated with the characteristic renal haemodynamic effect of angiotensin converting enzyme inhibitors.

ADDITIVE ANTIPROTEINURIC EFFECT OF THE NSAID INDOMETHACIN AND THE ACE INHIBITOR LISINOPRIL

Both angiotensin-converting enzyme (ACE) inhibitors like lisinopril and nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin have been shown to lower urinary protein excretion in renal disease. If this effect is caused by different mechanisms of action, the combination of these agents could have an additive antiproteinuric effect. We studied the effects of lisinopril and indomethacin separately and in combination in 10 patients with the nephrotic syndrome. Proteinuria was lowered from 10.5 +/- 1.8 g/24 h in the control period to 4.5 +/- 1.1 g/24 h on indomethacin, 4.3 +/- 1.0 g/24 h on lisinopril and to 2.4 +/- 0.8 g/24 h on the combination. Glomerular filtration rate (GFR) fell on either monotherapy, but particularly on the combination of drugs. The renal hemodynamic changes suggested a preglomerular vasoconstriction by indomethacin and a postglomerular vasodilation by lisinopril. Severe hyperkalemia occurred in 3 patients on the combination therapy. We conclude that the combination of indomethacin and lisinopril has an additive antiproteinuric effect. This, as well as the more pronounced fall in GFR on the combination, may suggest that both drugs lower proteinuria by decreasing intraglomerular capillary pressure but via different mechanisms. Combining these drugs may be useful in the symptomatic treatment of nephrotic syndrome, but renal function and serum potassium should be monitored carefully.

ACE Inhibition Preserves Heparan Sulfate Proteoglycans in the Glomerular Basement Membrane of Rats with Established Adriamycin Nephropathy

The gradual onset of the antiproteinuric effects of ACE inhibition suggests that structural effects on the glomerular basement membrane (GBM) may be involved in their renoprotective action. To test this hypothesis, we studied the effects of lisinopril (5 mg/kg/24 h) on proteinuria, focal glomerulosclerosis (FGS) and glomerular heparan sulfate (HS) proteoglycan (HSPG) GBM staining in rats with established Adriamycin nephrosis. Treatment was started 6 weeks after disease induction. As expected, lisinopril reduced blood pressure, proteinuria and the FGS score. In control rats, Adriamycin nephrosis was associated with significantly impaired GBM staining for both HSPG core protein (assessed from BL-31 staining) and HS staining (assessed from JM-403 staining) 12 weeks after disease induction. In rats treated with lisinopril (5 mg/kg/24 h) GBM stianing was significantly better preserved for HS as well as for HSPG core protein. These data suggest that structural effects on the GBM, improving glomerular permselectivity, may be involved in the renoprotective effects of ACE inhibition in proteinuria-induced renal damage.

Clinical factors influencing participation in society after successful kidney transplantation

Background. Little information is available on the degree of actual social functioning after successful kidney transplantation. Moreover, information on factors that influence participation in social activities is scarce. The aim of this study was to examine the influence of clinical factors on social outcome. Methods. A retrospective study was performed on a cohort of primary kidney transplantation patients, transplanted between 1996 and 2001. Cross-sectional data on participation in obligatory activities (i.e. employment, education, household tasks), leisure activities (i.e. volunteer work, assisting others, sports, clubs/associations, recreation, socializing, going out) and change in participation were collected by in-home interviews (n=239). Multivariate regression analysis was performed. Results. Thirty-six percent of the patients scored low on obligatory participation and only 52.4% was employed. Patients were actively involved in a wide range of leisure activities. Twenty-six percent participated in sports. Multivariate analysis (age-, sex-, and education-adjusted) of participation in obligatory activities showed negative associations with advanced age (P<0.01), comorbidity (previous cardiovascular events; P<0.01) and cadaveric transplantation (P<0.01). There was a positive association with time since transplantation (P<0.01). Multivariate analysis of diversity of participation in leisure activities and perceived change in participation after transplantation showed no statistically significant associations with clinical factors. Conclusions. Besides age, clinical factors such as type of donation (cadaveric versus living), comorbidity (previous cardiovascular events), and time since transplantation were associated with participation in obligatory activities such as employment, education and household tasks. Diversity of leisure activities and change in participation was not affected by clinical factors.

Proteinuria and progression of renal disease: Therapeutic implications

The relationship between proteinuria and progression of renal disease has long been an issue of debate. The present review deals with some of the recent publications on this topic. New concepts are emphasized: the possible causal role of proteinuria in the pathophysiology of progressive renal function loss, and the decrease in urinary protein loss at the beginning of renoprotective therapy as a predictor of renal function outcome during this treatment.

Screening techniques for detecting chronic kidney disease

Purpose of reviewAs patients with impaired kidney function are at increased risk not only for progressive renal function loss, but also for cardiovascular disease, it is of importance to have accurate techniques to screen patients for the presence of an impaired kidney function. Recent findingsGlomerular filtration rate can in mass screenings best be evaluated using a formula based upon a serum creatinine measurement and anthropometric parameters. The Cockcroft–Gault and Modification of Diet in Renal Disease (MDRD) formulas are mostly used. Both are easy to use, but have their limitations. Interpreting the results of such glomerular filtration rate estimates requires a good knowledge of these limitations. Urinary albumin excretion can best be measured from 24 h urine collections. As these collections are difficult to perform, however, an early morning spot urine sample for the measurement of urinary albumin concentration can be applied as preselection for screening purposes. SummaryMass screening for early kidney function impairment, expressed by an impaired glomerular filtration rate or elevated urinary albumin excretion, may help to detect patients at increased cardiac and renal risk. This can best be done using formulas to estimate glomerular filtration rate and by measuring urinary albumin loss.

The role of the cytochrome P450 3A5 enzyme for blood pressure regulation in the general Caucasian population.

Cytochrome P450 3A (CYP3A) enzymes are important for drug metabolism in gut and liver. The CYP3A5 isoenzyme is also expressed in the kidney and has been implicated in renal sodium reabsorption and blood pressure regulation. Its expression and activity is strongly linked to a polymorphism (i.e. 6986G>A). Thus, appreciable expression is found in carriers of the CYP3A5*1 (6986A) but not in homozygous carriers of the CYP3A5*3 (6986G) allele. We tested whether the presence of CYP3A5*1 affects blood pressure in Caucasian individuals who were enrolled in the Prevention of REnal and Vascular ENd stage Disease (PREVEND) study. In addition, we evaluated whether the genetic effect of CYP3A5*1 on blood pressure is modulated by sodium intake. CYP3A5*1 was found in 13.3% (901 individuals) of the cohort (6777 individuals). Diastolic blood pressure was not affected by CYP3A5*1. Overall, systolic and pulse pressure were significantly lower in carriers of CYP3A5*1, both after univariate analysis adjusted for age (P=0.012 and P=0.008) and in logistic regression analysis (P=0.015 and P=0.012). The effect on systolic blood pressure was significantly modulated by sodium intake (P=0.038). In separate analysis according to gender, CYP3A5*1 accounted for a significant age adjusted decrease in systolic blood pressure (−1.6 mmHg, P=0.04) and pulse pressure (−1.2 mmHg, P=0.04) in females but not in men. The present study demonstrates that the CYP3A5*1 allele affects systolic blood pressure and pulse pressure in the general population. Its role in hypertensive disease and potential gender differences should be investigated in further studies.