Assessment of Glomerular Filtration Rate in Health and Disease: A State of the Art Review.

Acute and chronic kidney diseases affect pharmacokinetics and pharmacodynamics. There has been substantial progress in the past 20 years in the use of glomerular filtration rate (GFR) estimating equations. In principle, use of a single equation for each filtration marker (creatinine, cystatin C, or the combination) for detection, evaluation, and management of kidney disease and for drug development and dosing would facilitate clinical practice. We review the principles for assessment of GFR, provide historical perspectives and updates regarding use of GFR estimating equations, including assay methods for filtration markers, performance of estimating equations, and recommendations by clinical practice guideline groups and regulatory agencies. We conclude that it is time to change from rigid adherence to the use of the Cockcroft-Gault equation for use in drug development and drug dosing to the more accurate and more widely used Modification of Diet in Renal Disease (MDRD) study and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations.

Filtration Markers, Cardiovascular Disease, Mortality, and Kidney Outcomes in Stable Kidney Transplant Recipients: The FAVORIT Trial.

Cystatin C and beta-2-microglobulin (B2M) are filtration markers associated with adverse outcomes in nontransplant populations, sometimes with stronger associations than for creatinine. We evaluated associations of estimated glomerular filtration rate from cystatin C (eGFRcys ), B2M (eGFRB2M ), and creatinine (eGFRcr ) with cardiovascular outcomes, mortality, and kidney failure in stable kidney transplant recipients using a case-cohort study nested within the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. A random subcohort was selected (N = 508; mean age 51.6 years, median transplant vintage 4 years, 38% women, 23.6% nonwhite race) with enrichment for cardiovascular events (N = 306; 54 within the subcohort), mortality (N = 208; 68 within the subcohort), and kidney failure (N = 208; 52 within the subcohort). Mean eGFRcr , eGFRcys , and eGFRB2M were 46.0, 43.8, and 48.8 mL/min/1.73m2 , respectively. After multivariable adjustment, hazard ratios for eGFRcys and eGFRB2M <30 versus 60+ were 2.02 (95% confidence interval [CI] 1.09-3.76; p = 0.03) and 2.56 (1.35-4.88; p = 0.004) for cardiovascular events; 3.92 (2.11-7.31) and 4.09 (2.21-7.54; both p < 0.001) for mortality; and 9.49 (4.28-21.00) and 15.53 (6.99-34.51; both p < 0.001) for kidney failure. Associations persisted with additional adjustment for baseline eGFRcr . We conclude that cystatin C and B2M are strongly associated with cardiovascular events, mortality, and kidney failure in stable kidney transplant recipients.

Estimated GFR for Living Kidney Donor Evaluation.

All living kidney donor candidates undergo evaluation of GFR. Guidelines recommend measured GFR (mGFR), using either an endogenous filtration marker or creatinine clearance, rather than estimated GFR (eGFR), but measurement methods are difficult, time consuming and costly. We investigated whether GFR estimated from serum creatinine (eGFRcr) with or without sequential cystatin C is sufficiently accurate to identify donor candidates with high probability that mGFR is above or below thresholds for clinical decision making. We combined the pretest probability for mGFR thresholds <60, <70, ≥80, and ≥90 mL/min per 1.73 m(2) based on demographic characteristics (from the National Health and Nutrition Examination Survey) with test performance of eGFR (categorical likelihood ratios from the Chronic Kidney Disease Epidemiology Collaboration) to compute posttest probabilities. Using data from the Scientific Registry of Transplant Recipients, 53% of recent living donors had predonation eGFRcr high enough to ensure ≥95% probability that predonation mGFR was ≥90 mL/min per 1.73 m(2) , suggesting that mGFR may not be necessary in a large proportion of donor candidates. We developed a Web-based application to compute the probability, based on eGFR, that mGFR for a donor candidate is above or below a range of thresholds useful in living donor evaluation and selection.

Kidney function and risk of cardiovascular disease and mortality in kidney transplant recipients: the FAVORIT trial.

In kidney transplant recipients, cardiovascular disease (CVD) is the leading cause of death. The relationship of kidney function with CVD outcomes in transplant recipients remains uncertain. We performed a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial to assess risk factors for CVD and mortality in kidney transplant recipients. Following adjustment for demographic, clinical and transplant characteristics, and traditional CVD risk factors, proportional hazards models were used to explore the association of estimated GFR with incident CVD and all-cause mortality. In 4016 participants, mean age was 52 years and 20% had prior CVD. Mean eGFR was 49 ± 18 mL/min/1.73 m(2) . In 3676 participants with complete data, there were 527 CVD events over a median of 3.8 years. Following adjustment, each 5 mL/min/1.73 m(2) higher eGFR at levels below 45 mL/min/1.73 m(2) was associated with a 15% lower risk of both CVD [HR = 0.85 (0.80, 0.90)] and death [HR = 0.85 (0.79, 0.90)], while there was no association between eGFR and outcomes at levels above 45 mL/min/1.73 m(2) . In conclusion, in stable kidney transplant recipients, lower eGFR is independently associated with adverse events, suggesting that reduced kidney function itself rather than preexisting comorbidity may lead to CVD.

Inflammation and cardiovascular events in individuals with and without chronic kidney disease.

Inflammation and chronic kidney disease predict cardiovascular events. Here we evaluated markers of inflammation including fibrinogen, albumin and white blood cell count in individuals with and without stages 3-4 chronic kidney disease to assess inflammation as a risk factor for adverse events, the synergy between inflammation and chronic kidney disease, and the prognostic ability of these inflammatory markers relative to that of C-reactive protein. Using Atherosclerosis Risk in Communities and Cardiovascular Health Study data, inflammation was defined by worst quartile of at least 2 of these 3 markers. In Cox regression models, inflammation was assessed as a risk factor for a composite of cardiac events, stroke and mortality as well as components of this composite. Among 20 413 patients, inflammation was identified in 3594 and chronic kidney disease in 1649. In multivariable analyses, both inflammation and chronic kidney disease predicted all outcomes, but their interaction was non-significant. In 5597 patients with C-reactive protein levels, inflammation and elevated C-reactive protein had similar hazard ratios. When focusing only on individuals with the worst quartile of white cell count and albumin, results remained consistent.

Long-term outcomes in nondiabetic chronic kidney disease.

The Modification of Diet in Renal Disease (MDRD) Study examined the effects of strict blood pressure control and dietary protein restriction on the progression of kidney disease. Here, we retrospectively evaluated outcomes of nondiabetic participants with stages 2-4 chronic kidney disease (CKD) from randomized and nonrandomized cohorts of the MDRD Study. Kidney failure and survival status through December of 2000, were obtained from the US Renal Data System and the National Death Index. Event rates were calculated for kidney failure, death, and a composite outcome of death and kidney failure. In the 1666 patients, rates for kidney failure were four times higher than that for death. Kidney failure was a more likely event than death in subgroups based on baseline glomerular filtration rate, proteinuria, kidney disease etiology, gender, and race. It was only among those older than 65 that the rate for death approximated that for kidney failure. In contrast to other populations with CKD, our study of relatively young subjects with nondiabetic disease has found that the majority of the participants advanced to kidney failure with a low competing risk of death. In such patients, the primary emphasis should be on delaying progression of kidney disease.

Fetuin-A is not associated with mortality in chronic kidney disease.

Fetuin-A is a serum protein that inhibits vascular calcification such that lower levels are associated with a higher prevalence of vascular calcification and mortality risk among end-stage renal disease populations. We analyzed data of 822 persons in the Modification of Diet in Renal Disease study, a randomized, controlled trial of persons with predominantly non-diabetic stage 3-4 chronic kidney disease (CKD). Serum fetuin-A levels were measured in baseline serum. Survival status and cause of death were determined by the National Death Index. Cox proportional hazard models evaluated the association of fetuin-A levels with all-cause and cardiovascular mortality. Glomerular filtration ranged from 13 to 55 ml per min per 1.73 m(2). During a median follow-up of 9.5 years, 25% of persons died from any cause and 12% died from a cardiovascular cause. Compared to the lowest tertile, no association was found between the highest fetuin-A tertile and all-cause or cardiovascular mortality. Similarly, no association was found between fetuin-A as a continuous variable and all-cause or cardiovascular mortality. Our study shows that serum fetuin-A levels are not related to all-cause or cardiovascular mortality among persons with predominantly non-diabetic stage 3 or 4 CKD.

Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes.

Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. There is now convincing evidence that CKD can be detected using simple laboratory tests, and that treatment can prevent or delay complications of decreased kidney function, slow the progression of kidney disease, and reduce the risk of cardiovascular disease (CVD). Translating these advances to simple and applicable public health measures must be adopted as a goal worldwide. Understanding the relationship between CKD and other chronic diseases is important to developing a public health policy to improve outcomes. The 2004 Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on 'Definition and Classification of Chronic Kidney Disease' represented an important endorsement of the Kidney Disease Outcome Quality Initiative definition and classification of CKD by the international community. The 2006 KDIGO Controversies Conference on CKD was convened to consider six major topics: (1) CKD classification, (2) CKD screening and surveillance, (3) public policy for CKD, (4) CVD and CVD risk factors as risk factors for development and progression of CKD, (5) association of CKD with chronic infections, and (6) association of CKD with cancer. This report contains the recommendations from the meeting. It has been reviewed by the conference participants and approved as position statement by the KDIGO Board of Directors. KDIGO will work in collaboration with international and national public health organizations to facilitate implementation of these recommendations.

Grading evidence and recommendations for clinical practice guidelines in nephrology. A position statement from Kidney Disease: Improving Global Outcomes (KDIGO).

Considerable variation in grading systems used to rate the strength of guideline recommendations and the quality of the supporting evidence in Nephrology highlights the need for a uniform, internationally accepted, rigorous system. In 2004, Kidney Disease: Improving Global Outcomes (KDIGO) commissioned a methods expert group to recommend an approach for grading in future nephrology guidelines. This position statement by KDIGO recommends adopting the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach for the grading of evidence and guidelines on interventions. The GRADE approach appraises systematic reviews of the benefits and harms of an intervention to determine its net health benefit. The system considers the design, quality, and quantity of studies as well as the consistency and directness of findings when grading the quality of evidence. The strength of the recommendation builds on the quality of the evidence and additional considerations including costs. Adaptations of the GRADE approach are presented to address some issues pertinent to the field of nephrology, including (1) the need to extrapolate from studies performed predominantly in patients without kidney disease, and (2) the need to use qualitative summaries of effects when it is not feasible to quantitatively summarize them. Further refinement of the system will be required for grading of evidence on questions other than those related to intervention effects, such as diagnostic accuracy and prognosis.

Ethnic differences and determinants of diabetes and central obesity among South Asians of Pakistan.

AIMS: To study the within ethnic subgroup variations in diabetes and central obesity among South Asians. METHODS: Data from 9442 individuals age > or = 15 years from the National Health Survey of Pakistan (NHSP) (1990-1994) were analysed. Diabetes was defined as non-fasting blood glucose > or = 7.8 mmol/l, or known history of diabetes. Central obesity was measured at the waist circumference. Distinct ethnic subgroups Muhajir, Punjabi, Sindhi, Pashtun, and Baluchi were defined by mother tongue. RESULTS: The age-standardized prevalence of diabetes varied among ethnic subgroups (P = 0.002), being highest among the Muhajirs (men 5.7%, women 7.9%), then Punjabis (men 4.6%, women 7.2%), Sindhis (men 5.1%, women 4.8%), Pashtuns (men 3.0%, women 3.8%), and lowest among the Baluchis (men 2.9%, women 2.6%). While diabetes was more prevalent in urban vs. rural dwellers [odds ratio (OR) 1.50, 95% confidence interval (CI) 1.24, 1.82], this difference was no longer significant after adjusting for central obesity (OR 1.15, 95% CI 0.95, 1.42). However, the ethnic differences persisted after adjusting for major sociodemographic risk factors (unadjusted OR for Pashtun vs. Punjabi 0.59, 95% CI 0.42, 0.84, adjusted OR 0.54, 95% CI 0.37, 0.78). Ethnic variation was also observed in central obesity, which varied with gender, and did not necessarily track with ethnic differences in diabetes. CONCLUSIONS: Unmeasured environmental or genetic factors account for ethnic variations in diabetes and central obesity, and deserve further study.

Factors associated with serum leptin in patients with chronic kidney disease.

BACKGROUND AND AIMS: Serum leptin levels are elevated in patients with kidney failure. Data on the associations of serum leptin and on the relationship of leptin with both kidney function and inflammation, are limited in patients with reduced glomerular filtration rate (GFR). We evaluated the independent associations of serum leptin in patients with reduced GFR. MATERIAL AND METHODS: Serum leptin and C-reactive protein (CRP) were measured in samples from 798 participants of the Modification of Diet in Renal Disease Study. Multivariable analysis was used to evaluate the independent effects of kidney function and CRP on leptin levels. RESULTS: Median (interquartile range) of serum leptin was 9.1 ng/ml (14.0). Female gender, higher percent body fat, higher insulin levels, older age, lower GFR and higher CRP were associated with higher serum leptin levels and explained 51% of the variability in the logarithm of serum leptin levels. After adjusting for the other variables, a 10 ml/min/1.73 m2 lower GFR was associated with 6% higher mean serum leptin levels. Percent body fat and gender, explained 45% of the variability in serum leptin levels. CONCLUSIONS: Level of kidney function and CRP are associated with serum leptin in patients with reduced GFR. However, there is a stronger association between serum leptin and indices of body fat and gender in patients in the earlier stages of chronic kidney disease. 50% of the variability remains unexplained in patients with reduced GFR.

Cardiovascular disease risk factors in chronic renal insufficiency.

BACKGROUND: Coronary heart disease (CHD) is an important cause of morbidity and mortality in end-stage renal disease (ESRD). Prevention of CHD in ESRD requires identification and treatment of coronary risk factors in chronic renal insufficiency (CRI). METHODS: We evaluated the prevalence of "traditional coronary risk factors" in CRI in 1,795 patients enrolled in the baseline period of Modification of Diet in Renal Disease (MDRD) Study. Using a cross-sectional design, we determined the relationship of these risk factors to the level of glomerular filtration rate (GFR) and proteinuria. We also predicted the CHD risk in the MDRD Study baseline cohort using the coronary point score. RESULTS: 64.0% had blood pressure > or = 130/85 mmHg despite antihypertensive therapy. 64.2% had LDL cholesterol > or = 130 mg/dl, while 38.3% had HDL cholesterol < 35 mg/dl. After adjustment for age, gender and the presence of diabetes, GFR was inversely associated with systolic blood pressure and positively associated with HDL cholesterol, but not associated with total or LDL cholesterol. After adjustment for age. gender and the presence of diabetes, proteinuria was positively associated with systolic and diastolic blood pressure, total serum cholesterol and LDL cholesterol, and inversely associated with HDL cholesterol. Nonetheless, the predicted CHD risk, even at a very low GFR, was similar to the risk in the general population and lower than the observed rate of de novo CHD in incident dialysis patients. CONCLUSIONS: "Traditional coronary risk factors" are highly prevalent in CRI and vary with the level of renal function. However, the coronary point score does not appear to explain the extent of increased CHD risk in ESRD. Non-traditional risk factors may also contribute to CHD in ESRD.

Effect of biocompatibility of hemodialysis membranes on mortality in acute renal failure: a meta-analysis.

BACKGROUND: The effect of biocompatibility of hemodialysis membranes on mortality in acute renal failure (ARF) has been a subject of intense debate, with some, but not all studies reporting a lower risk of death among patients with ARF dialyzed with biocompatible membranes (BCM) compared to bioincompatible membranes (BICM). OBJECTIVES: We performed a meta-analysis of group data extracted from previously published studies of controlled clinical trials to assess the impact of BCM on the mortality among patients with ARF who required intermittent hemodialysis (IHD). METHODS: BCM and BICM were defined as synthetic and cellulose-derived membranes (cuprophan and cellulose acetate), respectively. All controlled clinical trials comparing the effect of BCM to BICM on clinical outcomes in the setting of ARF were included. Original articles as well as abstracts were included. Data in Tables, Figures, and text were independently extracted by 2 of the authors. Risk ratios (RR) for mortality were combined using the random-effects model. RESULTS: Seven studies with a total of 722 patients met the inclusion criteria. One hundred seventy-two (45%) of 384 patients died in the BCM group, compared with 156 (46%) of 338 patients in the BICM group. The RRs for mortality ranged from 0.56-1.28. Overall, the pooled RR for mortality was 0.92 (95% CI = 0.76-1.13) in favor of the BCM group. However, the test for heterogeneity in RR among studies was significant (chi2 = 8.6, p < 0.05). One study accounted for this significance, and once removed from the model, the RR for mortality was 0.94 (95% CI = 0.79-1.12), and the test for heterogeneity among studies lost its significance. Subgroup analyses comparing BCM to cuprophan membranes revealed that the RR for mortality was 0.82 (95% CI = 0.62 - 1.08) in favor of the BCM group, whereas in the subgroup of studies comparing BCM to cellulose acetate, the RR for mortality was 1.11 (95% CI = 0.87-1.44) in favor of the BCM group. CONCLUSION: This metaanalysis demonstrates that the use of BCM does not significantly affect mortality among patients with ARF who require IHD. However, subgroup analyses suggest that cellulose acetate membranes may offer a survival advantage when compared with synthetic membranes, which, in turn, may be more beneficial than cuprophan membranes. Available evidence does not permit a recommendation for or against the use of BCM in ARF. Large trials and pooled analyses of individual patient-level data will be required to assess sources of variability among studies and non-fatal outcomes of ARF.

Resistance training to counteract the catabolism of a low-protein diet in patients with chronic renal insufficiency. A randomized, controlled trial.

BACKGROUND: Chronic renal insufficiency leads to muscle wasting, which may be exacerbated by low-protein diets prescribed to delay disease progression. Resistance training increases protein utilization and muscle mass. OBJECTIVE: To determine the efficacy of resistance training in improving protein utilization and muscle mass in patients with chronic renal insufficiency treated with a low-protein diet. DESIGN: Randomized, controlled trial. SETTING: Tufts University, Boston, Massachusetts. PATIENTS: 26 older patients with moderate renal insufficiency (17 men, 9 women) who had achieved stabilization on a low-protein diet. INTERVENTION: During a run-in period of 2 to 8 weeks, patients were instructed and their adherence to the low-protein diet (0.6 g/kg of body weight per day) was evaluated. They were randomly assigned to a low-protein diet plus resistance training (n = 14) or a low-protein diet alone (n = 12) for 12 weeks. MEASUREMENTS: Total body potassium, mid-thigh muscle area, type I and II muscle-fiber cross-sectional area, and protein turnover. RESULTS: Mean protein intake was 0.64 +/- 0.07 g/kg per day after stabilization. Total body potassium and type I and II muscle-fiber cross-sectional areas increased in patients who performed resistance training by a mean (+/-SD) of 4% +/- 8%, 24% +/- 31%, and 22% +/- 29%, respectively, compared with those who did not. Leucine oxidation and serum prealbumin levels also improved significantly. Patients assigned to resistance training maintained body weight compared with those who were not. Improvement in muscle strength was significantly greater with resistance training (32% +/- 14%) than without (-13% +/- 20%) (P < 0.001). CONCLUSION: By improving muscle mass, nutritional status, and function, resistance training seems to be effective against the catabolism of a low-protein diet and uremia in patients with renal failure.

Prediction equations to estimate glomerular filtration rate: an update.

The level of glomerular filtration rate can be estimated from the serum creatinine concentration and other easily measured patient variables from prediction equations developed using multivariable regression techniques. Recently, a new equation has been developed from the Modification of Diet in Renal Disease study, which is more accurate than other equations and more accurate than measurement of creatinine clearance. The authors recommend using prediction equations in clinical practice to estimate the level of glomerular filtration rate.

Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction.

OBJECTIVES: We sought to evaluate the relationship between the level of kidney function, level of hematocrit and their interaction on all-cause mortality in patients with left ventricular (LV) dysfunction. BACKGROUND: Anemia and reduced kidney function occur frequently in patients with heart failure. The level of hematocrit and its relationship with renal function have not been evaluated as risk factors for mortality in patients with LV dysfunction. METHODS: We retrospectively examined the Studies Of LV Dysfunction (SOLVD) database. Glomerular filtration rate (GFR) was predicted using a recently validated formula. Kaplan-Meier survival analyses were used to compare survival times between groups stratified by level of kidney function (predicted GFR) and hematocrit. Cox proportional-hazards regression was used to explore the relationship of survival time to level of kidney function, hematocrit and their interaction. RESULTS: Lower GFR and hematocrit were associated with a higher prevalence of traditional cardiovascular risk factors. In univariate analysis, reduced kidney function and lower hematocrit, in men and in women, were risk factors for all-cause mortality (p < 0.001 for both). After adjustment for other factors significant in univariate analysis, a 10 ml/min/1.73 m(2) lower GFR and a 1% lower hematocrit were associated with a 1.064 (95% CI: 1.033, 1.096) and 1.027 (95% CI: 1.015, 1.038) higher risk for mortality, respectively. At lower GFR and lower hematocrit, the risk was higher (p = 0.022 for the interaction) than that predicted by both factors independently. CONCLUSIONS: Decreased kidney function and anemia are risk factors for all-cause mortality in patients with LV dysfunction, especially when both are present. These relationships need to be confirmed in additional studies.

Comorbidity assessment using the Index of Coexistent Diseases in a multicenter clinical trial.

BACKGROUND: The Hemodialysis (HEMO) Study is a multicenter trial designed to determine whether hemodialysis dose and membrane flux affect survival. Comorbid conditions are also important determinants of survival, and thus, an accurate and reliable method to assess comorbidity was required. Comorbidity was being assessed at baseline and annually in the HEMO Study using the Index of Coexistent Disease (ICED). We describe the instrument, its implementation in the HEMO Study, and the results of comorbidity assessment in the first 1000 randomized patients in the trial. METHODS: The ICED aggregated the presence and severity of 19 medical conditions and 11 physical impairments within two scales: the Index of Disease Severity (IDS) and the Index of Physical Impairment (IPI). The final ICED score was determined by an algorithm combining the peak scores for the IDS and IPI. The range of the ICED was from 0 to 3, reflecting increasing severity. RESULTS: Study personnel at 15 clinical centers were trained to update and abstract data from the dialysis medical records. Availability of data, measures of construct validity, and measures of reliability were adequate; 99.8% and 60.6% of patients had comorbid conditions in at least one IDS or IPI category, respectively. The distribution of patients by ICED level was 0 (0.2%), 1 (34.9%), 2 (31.2%), and 3 (33.7%). In multivariable analysis, the following factors were significantly associated with more severe comorbidity: older age, diabetes and other causes of renal disease, a lower level of education, employment status (unemployed and retired), longer duration of dialysis, and lower serum creatinine. There was a significant variation in the severity of comorbidity among clinical centers after adjustment for other factors. The R2 of the model was 25.3%, indicating that a substantial proportion of the variation in the ICED was not explained by these factors. CONCLUSIONS: We conclude that comorbidity assessment using the ICED is feasible in multicenter clinical trials of dialysis patients. There is a large burden of comorbidity in dialysis patients, which is not well explained by the cause of renal disease, demographic, and socioeconomic factors and common clinical and laboratory measurements. These variables should not be considered substitutes for comorbid conditions in case-mix adjustment. Comorbidity assessment is useful to describe the sample population, to improve the precision of the treatment effect, and to use possibly as an outcome measurement.

Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce urine protein excretion and slow the progression of renal disease. The beneficial effect in slowing the progression of renal disease is greater in patients with higher urine protein excretion at the onset of treatment. We hypothesized that the greater beneficial effect of ACE inhibitors on the progression of renal disease in patients with higher baseline levels of proteinuria is due to their greater antiproteinuric effect in these patients. METHODS: Data were analyzed from 1860 patients enrolled in 11 randomized controlled trials comparing the effect of antihypertensive regimens, including ACE inhibitors to regimens not including ACE inhibitors on the progression of non-diabetic renal disease. Multivariable linear regression analysis was used to assess the relationship between the level of proteinuria at baseline and changes in urine protein excretion during follow-up. The Cox proportional hazards analysis was used to assess the relationship between changes in urine protein excretion during follow-up and the effect of ACE inhibitors on the time to doubling of baseline serum creatinine values or onset of end-stage renal disease. RESULTS: Mean (median) baseline urine protein excretion was 1.8 (0.94) g/day. Patients with higher baseline urine protein excretion values had a greater reduction in proteinuria during the follow-up in association with treatment with ACE inhibitors and in association with lowering systolic and diastolic blood pressures (interaction P < 0.001 for all). A higher level of urine protein excretion during follow-up (baseline minus change) was associated with a greater risk of progression [relative risk 5.56 (3.87 to 7.98) for each 1.0 g/day higher protein excretion]. After controlling for the current level of urine protein excretion, the beneficial effect of ACE inhibitors remained significant [relative risk for ACE inhibitors vs. control was 0.66 (0.52 to 0.83)], but there was no significant interaction between the beneficial effect of ACE inhibitors and the baseline level of urine protein excretion. CONCLUSIONS: The antiproteinuric effects of ACE inhibitors and lowering blood pressure are greater in patients with a higher baseline urine protein excretion. The greater beneficial effect of ACE inhibitors on renal disease progression in patients with higher baseline proteinuria can be explained by their greater antiproteinuric effects in these patients. The current level of urine protein excretion is a modifiable risk factor for the progression of non-diabetic renal disease. ACE inhibitors provide greater beneficial effect at all levels of current urine protein excretion.

The national epidemic of chronic kidney disease. What we know and what we can do.

The alarming increase in the incidence and mortality rate of end-stage renal disease (ESRD) over the past several years has prompted concerned physicians to ask why--and to ponder what can be done to ameliorate the situation. This article, the first in a seven-part series coordinated by the National Kidney Foundation, examines the factors surrounding the epidemic of chronic kidney disease and introduces readers to the organization's new clinical practice guidelines developed through its Kidney Disease Outcomes Quality Initiative. These recommendations emphasize early detection and treatment and offer a new avenue of communication between primary care physicians and nephrologists.