Obstetric and long-term kidney outcomes in renal transplant recipients: a 40-yr single-center study.

Female renal transplant recipients of childbearing age may ask what the outcomes are for pregnancy and whether pregnancy will affect graft function. We analyzed obstetric and transplant outcomes among renal transplant recipients in our center who have been pregnant between 1973 and 2013. A case-cohort study was performed identifying 83 pairs of pregnant and non-pregnant controls matched for sex, age, transplant vintage, and creatinine. There were 138 pregnancies reported from 89 renal transplant recipients. There were live births in 74% of pregnancies with high prevalence of prematurity (61%), low birth weight (52%), and pre-eclampsia (14%). Lower eGFR (OR 0.98; p = 0.05) and higher uPCR (OR 1.86; p = 0.02) at conception were independent predictors for poor composite obstetric outcome. Lower eGFR (OR 0.98; p = 0.04), higher uPCR (OR 1.50; p = 0.04), and live organ donation (OR 0.35; p = 0.02) were predictors of ≥20% loss of eGFR between immediately pre-pregnancy and one yr after delivery. There was no difference in eGFR at one, five, and 10 yr in pregnant women compared with non-pregnant controls and a pregnancy was not associated with poorer 10-yr transplant or 20-yr patient survival. Despite high rates of obstetric complications, most women had successful pregnancies with good long-term transplant function.

The effect of omega-3 fatty acids on the atherogenic lipoprotein phenotype in patients with nephrotic range proteinuria.

AIMS: Patients with nephrotic range proteinuria are known to have an increased risk of cardiovascular disease partly due to possessing the atherogenic lipoprotein phenotype. The aim of this study was to examine the effect of high dose omega-3 fatty acids on atherogenic triglyceride rich lipoproteins in patients with nephrotic range proteinuria, comparing their effect on lipoprotein profiles in age and sex matched controls. METHODS: 17 patients with nephrotic range proteinuria and 17 age and sex matched controls were studied. Fasting lipids and lipoproteins were measured before and after 8 weeks treatment with 4 g daily of omega-3 fatty acids (Omacor®). RESULTS: In patients with proteinuria treatment reduced plasma triglyceride by a mean of 0.45 mmol/l (95%CI 0.16 - 0.74, p = 0.005) and plasma very low density lipoprotein cholesterol by a mean of 0.38 (95%CI 0.01 - 0.75, p = 0.04). LDL III concentration fell from 178.8 mg/dl (61.6 - 231.0) to 96.1 mg/dl (49.3 - 204.5), p = 0.05. In patients treatment altered the LDL profile so that LDLIII which was the major subfraction present at baseline was reduced from 49.9% to 29.8% (p = 0.01). Remnant lipoproteins (RLP) also fell with a mean reduction of 3.5 mg/dl in RLP-Cholesterol (95%CI 0.1 - 6.9, p = 0.05) and 12.4 mg/dl in RLP-triglyceride (95%CI 2.6 - 22.2, p = 0.03). There was however a 0.6 mmol/l rise in LDL-C (p = 0.06) in the patients. Treatment did not alter HDL-C. CONCLUSION: In patients with nephrotic range proteinuria, omega-3 fatty acids reduced triglyceride rich lipoproteins, LDL III and remnant lipoproteins. A tendency to an increase in LDL-C was observed but this was offset by an alteration in the distribution of the LDL profile towards lighter, larger LDL particles. We propose that treatment with omega-3 fatty acids in conjunction with a statin may be the ideal therapy in these patients.

Comparison of urinary albumin and urinary total protein as predictors of patient outcomes in CKD.

BACKGROUND: Proteinuria is common and is associated with adverse patient outcomes. The optimal test of proteinuria to identify those at risk is uncertain. This study assessed albuminuria and total proteinuria as predictors of 3 patient outcomes: all-cause mortality, start of renal replacement therapy (RRT), and doubling of serum creatinine level. STUDY DESIGN: Retrospective longitudinal cohort study. SETTING & PARTICIPANTS: Nephrology clinic of a city hospital in Scotland; 5,586 patients with chronic kidney disease (CKD) and proteinuria measured in random urine samples (n = 3,378) or timed urine collections (n = 1,808). PREDICTORS: Baseline measurements of albumin-creatinine ratio (ACR), total protein-creatinine ratio (PCR), 24-hour albuminuria, and total proteinuria. OUTCOMES: All-cause mortality, start of RRT, and doubling of serum creatinine level were assessed using receiver operating characteristic curves and Cox proportional hazards models. MEASUREMENTS: Blood pressure, serum creatinine level, ACR, PCR, date of death, date of starting RRT. RESULTS: Patients were followed up for a median of 3.5 (25th-75th percentile, 2.1-6.0) years. For all outcomes, adjusted HRs were similar for PCR and ACR (derived from random urine samples and timed collections): death, 1.41 (95% CI, 1.31-1.53) vs 1.38 (95% CI, 1.28-1.50); RRT, 1.96 (95% CI, 1.76-2.18) vs 2.33 (95% CI, 2.06-3.01); and doubling of serum creatinine level, 2.03 (95% CI, 1.87-2.19) vs 1.92 (95% CI, 1.78-2.08). Receiver operating characteristic curves showed almost identical performance for ACR and PCR for the 3 outcome measures. Adjusted HRs for ACR and PCR were similar when derived from random urine samples or timed collections and compared with 24-hour total protein and albumin excretion for each outcome measure. LIMITATIONS: This is a retrospective study. CONCLUSIONS: Total proteinuria and albuminuria perform equally as predictors of renal outcomes and mortality in patients with CKD. ACR and PCR were as effective as 24-hour urine samples at predicting outcomes and are more convenient for patients, clinicians, and laboratories. Both ACR and PCR stratify risk in patients with CKD.

Assessing proteinuria in chronic kidney disease: protein-creatinine ratio versus albumin-creatinine ratio.

BACKGROUND: Quantification of proteinuria is important in the assessment of chronic kidney disease (CKD). The aim of this study was to investigate the optimal test to identify significant proteinuria. METHODS: We retrospectively assessed the relationship between total protein:creatinine ratio (TPCR), albumin:creatinine ratio (ACR) and 24-h urine total protein in 6842 patients with CKD focusing on performance at thresholds of 0.5 and 1 g/day of proteinuria. RESULTS: The relationship between ACR and TPCR is non-linear. TPCR is highly correlated with 24-h urine protein (Spearman's rho = 0.91), though ACR also performs well (rho = 0.84). Using receiver-operator characteristic curve analysis, TPCR outperforms ACR at predicting 0.5 g/day [area under the curve (AUC) 0.967 vs 0.951, P < 0.001] and 1 g/day of proteinuria (AUC 0.968 vs 0.947, P = 0.004). A TPCR threshold of 100 mg/mmol had a higher sensitivity (94% vs 79%) but lower specificity (88% vs 95%) than an ACR of 70 mg/mmol to predict 1 g/day of total proteinuria. To achieve comparable sensitivity, the ACR threshold falls to 17.5 mg/mmol, with lower specificity than TPCR (69.8%). Sensitivity of TPCR rose with increasing age, and in females: to achieve 95% sensitivity in a man <49 years, requires a TPCR of 65 mg/mmol, compared to 179 mg/mmol in a woman >79 years. Non-albumin proteinuria was a lower proportion of total proteinuria in patients receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockade than in those who were not (P < 0.001). CONCLUSIONS: TPCR is a more sensitive screening test than ACR to predict clinically relevant proteinuria. The diagnostic performance of both tests varies substantially with age and gender, and should be taken into consideration when interpreting results. Total proteinuria cannot be adequately predicted from ACR, and our results suggest that caution is appropriate before utilizing ACR in patients with non-diabetic CKD.

Omega-3 fatty acids improve postprandial lipaemia in patients with nephrotic range proteinuria.

BACKGROUND: Patients with nephrotic range proteinuria have a marked increase in the risk of cardiovascular disease. Qualitative and quantitative changes in lipids and lipoproteins contribute to this increased risk with an abundance of atherogenic triglyceride (TG) rich apolipoprotein B containing lipoproteins. TG rich lipoproteins predominate postprandially and are associated with increased risk of coronary heart disease (CHD). Omega-3 fatty acids derived from fish oils have been shown to have beneficial effects on lipids and lipoproteins in patients without proteinuria. METHODS: 17 patients with nephrotic range proteinuria and 17 age and sex matched controls were studied. Postprandial lipaemia was assessed in patients and controls, before and after 8 weeks treatment with 4 g daily of omega-3 fatty acids (Omacor). A standard fat load (90 g) was administered and blood sampling was performed in the fasting state and at 2, 4, 6 and 8h after the fat load. Chylomicrons and VLDL(1) density fraction was isolated from plasma by density ultracentrifugation. Postprandial chylomicron and VLDL(1) triglyceride concentrations were measured and quantified using the incremental area under the curve (AUC) method. RESULTS: Baseline postprandial chylomicron TG AUC was greater in patients compared with controls: median 18.5 mmol/lh (interquartile range 8.9-32.6) vs 9.3 mmol/lh (4.8-14.4) p=0.05. Following treatment patient chylomicron AUC fell [mean reduction 6.8 mmol/lh (95% CI 0.1-13.6) p=0.05]. No significant reduction in chylomicron AUC was observed in the controls [mean reduction 3.9 mmol/lh (95% CI -3.6 to 11.5)]. As a result, following 8 weeks treatment with omega-3 fatty acids, patient and control chylomicron AUC were no longer significantly different [patients 13.5 mmol/lh (7.4-22.9), controls 7.2 mmol/lh (4.6-14.5) both median and IQR, p=nsd]. VLDL(1) TG AUC did not differ at baseline between patients and controls. Furthermore, there was no significant effect on VLDL(1) AUC following treatment in either group. CONCLUSIONS: We have shown that there is an excess of postprandial chylomicron density fraction in patients with nephrotic range proteinuria, which is reduced by treatment with omega-3 fatty acids. We suggest that this would be an ideal therapy in combination with statins for this high risk group of patients.

Endothelial function in patients with proteinuric primary glomerulonephritis.

BACKGROUND: Cardiovascular disease is the commonest cause of mortality among patients with end-stage renal disease. Endothelial function and inflammation have previously been shown to be abnormal among such individuals, and are known to be important factors in the progression of atherosclerosis. The aim of this study was to assess endothelial function early in the natural history of renal disease. METHODS: Patients with primary glomerulonephritis, and healthy controls were recruited. In addition to routine laboratory assessment of renal function and proteinuria, assays were undertaken to measure CRP, vWF, VCAM and ICAM. Furthermore, a direct assessment of microvascular endothelial function was undertaken, using laser Doppler imaging to measure perfusion to areas of skin under the influence of transdermally delivered vasodilator agents. RESULTS: Data were collected from 39 patients and 22 controls. No patient was taking anti-platelet agents, statins or angiotensin-converting enzyme inhibitors at the time of endothelial function assessment. All 3 biomarkers of endothelial function were significantly elevated in the patient group compared to controls: ICAM 455 versus 359 ng/ml (p = 0.009), VCAM 1,101 versus 771 ng/ml (p = 0.007) and vWF 184 versus 125 IU/ml (p < 0.001). These differences remained significant after adjusting for blood pressure and body mass index. Endothelium-dependent and endothelium-independent vascular responses were blunted in the patient group, compared to controls (AUC: 2,204 vs. 3,721 PU for dependent and 2,190 vs. 3,555 PU for independent responses). CONCLUSIONS: Microvascular endothelial and vascular smooth muscle function is abnormal in patients with primary glomerulonephritis and moderate proteinuria but well-maintained renal function. We believe these findings to be of particular importance as they compare 2 well-matched groups in the absence of the confounding influence of drugs known to affect endothelial function.

Factors predicting outcome in a cohort of patients with atherosclerotic renal artery disease diagnosed by magnetic resonance angiography.

BACKGROUND: Atherosclerotic renal artery disease increasingly is recognized as a cause of chronic kidney disease and associated with high morbidity and mortality. We investigated factors predicting patient and renal survival in a cohort of patients with atherosclerotic renal artery disease diagnosed by means of magnetic resonance angiography (MRA). METHODS: We retrospectively analyzed a cohort of patients attending our unit in whom atherosclerotic renal artery disease was identified by means of MRA from 1998 to 2001. One hundred nine patients were followed up for a median of 2.3 years. Baseline clinical and laboratory data were assessed as predictors of outcome by using multivariate Cox proportional hazards analysis. RESULTS: Seventeen patients (16%) required dialysis and 37 patients (34%) died during a median follow-up of 841 days (interquartile range, 326 to 1,206). On multivariate Cox proportional hazards analysis, increased peripheral-blood eosinophil count (hazard ratio, 3.39; 95% confidence interval [CI], 1.45 to 7.88; P = 0.0097), creatinine clearance (hazard ratio, 0.97; 95% CI, 0.94 to 0.99; P = 0.0128), and peripheral arterial disease (hazard ratio, 2.09; 95% CI, 1.04 to 4.18; P = 0.0371) were associated with subsequent death. Only creatinine clearance (hazard ratio, 0.91; 95% CI, 0.87 to 0.96; P = 0.0004) was associated with the need for dialysis. There was no association between eosinophil count and other markers of inflammation. Severity of atherosclerotic renal artery disease was not associated independently with either the need for dialysis or death. CONCLUSION: An increased peripheral-blood eosinophil count predicts patient survival in those with atherosclerotic renal artery disease at the time of diagnosis. This novel risk factor may help identify a group of patients who could benefit from intensive medical therapy by using an assay readily available to most clinicians worldwide.

A prospective open-label randomised trial of quinapril and/or amlodipine in progressive non-diabetic renal failure.

BACKGROUND: Treatment of hypertension slows the progression of non-diabetic nephropathies, but the optimal regimen is unknown. Angiotensin-converting enzyme inhibitors are more effective than beta-blockers, but their merits relative to calcium channel blockers are less clear. METHODS: 73 hypertensive patients with progressive non-diabetic nephropathies were prospectively randomised to open-label quinapril (Q, n = 28), amlodipine (A, n = 28) or both drugs (Q&A, n = 17). Therapy was increased to achieve a diastolic blood pressure < 90 mm Hg. Patients were followed for 4 years or until death. The primary outcome was the combined endpoint of doubling serum creatinine, starting renal replacement therapy or death. RESULTS: There was no significant difference in the primary outcome, or in the change of glomerular filtration rate. Blood pressure was equally controlled throughout the study period. 29 (40%) patients were withdrawn from the allocated therapy (Q 39%, A 36%, Q&A 47%). Because of the large crossover between trial arms, the data were re-analysed per protocol. The effect on preventing the need for renal replacement therapy then approached significance between the groups (p = 0.089) and the combined quinapril-containing groups were less likely than the amlodipine group to achieve the primary endpoint (p = 0.038), or the individual endpoints of renal replacement therapy (p = 0.030) or doubling creatinine (p = 0.051). CONCLUSIONS: Quinapril is more effective than amlodipine at reducing the incidence of dialysis in patients with progressive renal failure, but only if they can tolerate the drug. The tolerability of these drugs in patients with advanced renal failure is poor.

A cognitive behavioral group approach to enhance adherence to hemodialysis fluid restrictions: a randomized controlled trial.

BACKGROUND: Adhering to fluid restrictions represents one of the most difficult aspects of the hemodialysis treatment regimen. This report describes a randomized controlled trial of a group-based cognitive behavioral intervention aimed at improving fluid-restriction adherence in patients receiving hemodialysis. It was hypothesized that the intervention would improve adherence, measured by means of interdialytic weight gain (IWG), without impacting negatively on psychosocial functioning. METHODS: Fifty-six participants receiving hemodialysis from 4 renal outpatient settings were randomly assigned to an immediate-treatment group (ITG; n = 29) or deferred-treatment group (DTG; n = 27). Participants were assessed at baseline, posttreatment, and follow-up stages. Treatment consisted of a 4-week intervention using educational, cognitive, and behavioral strategies to enhance effective self-management of fluid consumption. RESULTS: No significant difference in mean IWGs was found between the ITG and DTG during the acute-phase analysis (F(1,54) = 0.03; P > 0.05). However, in longitudinal analysis, there was a significant main effect for mean IWG (F(1.76,96.80) = 9.10; P < 0.001) and a significant difference between baseline and follow-up IWG values (t55 = 3.85; P < 0.001), reflecting improved adherence over time. No adverse effects of treatment were indicated through measures of psychosocial functioning. Some significant changes were evidenced in cognitions thought to be important in mediating behavioral change. CONCLUSION: The current study provides evidence for the feasibility and effectiveness of applying group-based cognitive behavior therapy to enhance adherence to hemodialysis fluid restrictions. Results are discussed in the context of the study's methodological limitations.

Early initiation of dialysis fails to prolong survival in patients with end-stage renal failure.

There is a trend to start dialysis earlier in patients with chronic renal failure. Studies that suggest improved survival from earlier initiation of dialysis are flawed in that they have measured survival from start of dialysis rather than from a time point before dialysis, when patients have the same renal function. This flaw is termed lead-time bias. Using the electronic patient record at the renal unit of Glasgow Royal Infirmary, all patients were identified who had received dialysis for chronic renal failure and who had sufficient data to calculate the time point at which they reached an estimated creatinine clearance (eC(Cr)) of 20 ml/min (n = 275). This date was used to time survival. The patients were divided into early and late start groups by the median eC(Cr) for all patients at initiation of dialysis, which was 8.3 ml/min. There was no significant benefit in patient survival from earlier initiation of dialysis. A Cox proportional hazards model demonstrated a significant inverse relationship between eC(Cr) at start of dialysis and survival (hazard ratio, 1.1; P = 0.02), i.e., patients who started dialysis with a lower eC(Cr) tended to survive longer. This relationship retained significance when gender, age, weight, presence of diabetes, mode of first dialysis, initial dialysis access, hemoglobin, serum albumin, blood leukocyte count, Wright/Khan index, and eC(Cr) at the start of dialysis were taken into account. This study fails to support a policy of earlier initiation of dialysis for patients with end-stage renal failure.

Comparative effects of cerivastatin and fenofibrate on the atherogenic lipoprotein phenotype in proteinuric renal disease.

Patients with nephrotic-range proteinuria have impaired clearance of triglyceride-rich lipoproteins. This results in the atherogenic lipoprotein phenotype (mild hypertriglyceridemia, low high-density lipoproteins [HDL], and excess small, dense low-density lipoproteins [LDLIII]). Excess remnant lipoproteins (RLP) are linked to hypertriglyceridemia and may contribute to the atherogenicity of nephrotic dyslipidemia. A randomized crossover study compared the effects of a statin (cerivastatin) and a fibrate (fenofibrate) on LDLIII and RLP in 12 patients with nephrotic-range proteinuria. Cerivastatin reduced cholesterol (21%, P: < 0.01), triglyceride (14%, P: < 0.05), LDL cholesterol (LDL-C; 23%, P: < 0.01), total LDL (18%, P: < 0.01), and LDLIII concentration (27% P: < 0.01). %LDLIII, RLP-C, and RLP triglyceride (RLP-TG) were unchanged. Plasma LDLIII reduction with cerivastatin treatment correlated with LDL-C reduction (r(2) = 34%, P: < 0.05). Fenofibrate lowered cholesterol (19%), triglyceride (41%), very low-density lipoprotein cholesterol (52%), LDLIII concentration (49%), RLP-C (35%), and RLP-TG (44%; all P: < 0.01). Fenofibrate also reduced %LDLIII from 60 to 33% (P: < 0.01). HDL-C (19%, P: < 0.01) increased with fenofibrate treatment; LDL-C and total LDL were unchanged. The reduction in LDLIII concentration and RLP-C with fenofibrate treatment correlated with plasma triglyceride reduction (LDLIII r(2) = 67%, P: < 0.001; RLP cholesterol r(2) = 58%, P: < 0.005). Serum creatinine increased with fenofibrate treatment (14%, P: < 0.01); however, creatinine clearance was unchanged. LDLIII concentration was 187 +/- 85 mg/dl after cerivastatin treatment and 133 +/- 95 mg/dl after fenofibrate treatment. Cerivastatin and fenofibrate reduce LDLIII concentration in nephrotic-range proteinuria. However, atherogenic concentrations of LDLIII remain prevalent after either treatment. Fenofibrate but not cerivastatin reduces remnant lipoproteins. The two treatments seem to reduce LDLIII by different mechanisms, suggesting a potential role for combination therapy to optimize lowering of LDLIII and RLP.