Comparison of 6 equations for estimating glomerular filtration rate in a Chinese benign hypertensive nephrosclerosis population.

ABSTRACT: Equations to estimate glomerular filtration rate (eGFR) are useful for monitoring tje renal status of benign hypertensive nephrosclerosis (BHN). This study aimed to compare the applicability of 6 equations (Cockcroft-Gault [CG] adjusted for body surface area, original modification of diet in renal disease [MDRD], American abbreviated MDRD, Chinese modified MDRD, Chinese abbreviated MDRD, and Chronic Kidney Disease Epidemiology [CKD-EPI]) to estimate GFR in a Chinese BHN population. A total of 179 patients diagnosed with BHN were enrolled. The GFR estimated by each equation was compared to the reference GFR (rGFR) measured using the dual plasma sampling technetium-labeled diethylenetriaminepentaacetic acid method. The Chinese modified and Chinese abbreviated MDRD equations overestimated the rGFR, while the CG, CG adjusted for body surface area, original MDRD, American abbreviated MDRD, and CKD-EPI equations underestimated the rGFR. The difference in performance between estimated GFR (eGFR) based on the American abbreviated MDRD equation and the rGFR was not statistically significant (P = .191), while differences in the others were statistically significant (P < .05). Furthermore, the advantages in deviation, absolute deviation, deviation degree, precision, and accuracy were also significantly different from those of the other equations. Our findings suggest that eGFR based on the American abbreviated MDRD equation is suitable for the Chinese BHN population.

Hypertension, glomerular hypertrophy and nephrosclerosis: the effect of race.

BACKGROUND: African Americans have more severe hypertensive nephrosclerosis than white Americans, possibly at similar levels of blood pressure. Glomerular volume is increased in African Americans relative to whites, but it is uncertain how this relates to nephrosclerosis and whether it contributes to or compensates for glomerulosclerosis. METHODS: Stereological disector/fractionator estimates of glomerular number (N(glom)) and average glomerular volume (V(glom)) were obtained on autopsy kidneys of 171 African Americans and 131 whites. Eighty-eight African Americans and 49 whites were identified as hypertensive. Nephrosclerosis was measured morphometrically as the percentage of glomerulosclerosis, proportion of cortical fibrosis and interlobular artery intimal thickness, and analyzed with V(glom) by age, race, gender, body mass index (BMI) and blood pressure. RESULTS: African Americans were more frequently hypertensive (58.5%) than whites (35.8%) and when hypertensive had higher levels of blood pressure (P = 0.02). N(glom) was significantly lower in hypertensive compared with non-hypertensive subjects among white women (P = 0.02) but not white males (P = 0.34) or African American females (P = 0.10) or males (P = 0.41). For each race and gender, glomerulosclerosis, cortical fibrosis and arterial intimal thickening were statistically correlated with age (P < 0.001) and hypertension (P < 0.001) and increased V(glom) with hypertension (P < 0.001) and BMI (P < 0.001). In multivariate analysis, African American race was associated with increased V(glom) (P = 0.01) and arterial intimal thickening (P < 0.01), while interactions between race and blood pressure indicated that the severity of nephrosclerosis including increased V(glom) was linked most directly to hypertension without significant contributions from race. The hypertension-associated enlargement of V(glom) was present with mild degrees of glomerulosclerosis and changed little as the severity of glomerulosclerosis increased. CONCLUSIONS: Glomerular hypertrophy was identified as an integral feature of hypertensive nephropathy and appeared to precede rather than compensate for glomerulosclerosis. An effect of race on V(glom) and arterial intimal thickening seemed to be related to the more frequent and more severe hypertension among African Americans.

Net endogenous acid production is associated with a faster decline in GFR in African Americans.

Increased acid excretion may promote renal injury. To evaluate this in African Americans with hypertensive nephrosclerosis, we studied the association between the net endogenous acid production and progression of kidney disease in 632 patients in the AASK trial. Protein and potassium intakes were estimated from 24 h urea nitrogen and potassium excretion, and used to estimate net endogenous acid production, averaged over 2 years, approximating routine intake. The link between net endogenous acid production and the I(125)iothalamate glomerular filtration rate (iGFR) and time to end-stage renal disease or doubling of serum creatinine was analyzed using mixed models and Cox proportional hazards regressions. The trend in higher net endogenous acid production was significantly associated with a faster decline in iGFR over a median of 3.2 years. After adjustment for age, body mass index, baseline iGFR, urine protein-to-creatinine ratio, and randomized treatment group, the trend in higher net endogenous acid production remained significantly associated with a faster decline in iGFR at a rate of 1.01 ml/min per 1.73 m(2) per year faster in the highest compared to the lowest quartile. However, in time-to-event analyses over a median of 7.7 years, the adjusted hazard ratio (1.10) for composite renal events per 25 mEq/day higher net endogenous acid production was not significant. Hence, our findings implicate endogenous acid production as a potential modifiable risk factor for progressive kidney disease.

Methylenetetrahydrofolate reductase (MTHFR) polymorphism A1298C (Glu429Ala) predicts decline in renal function over time in the African-American Study of Kidney Disease and Hypertension (AASK) Trial and Veterans Affairs Hypertension Cohort (VAHC).

BACKGROUND: Hyperhomocysteinemia is associated with increased venous thrombosis and cardiovascular disease (CVD). Mutations in the human methylenetetrahydrofolate reductase (MTHFR) gene have been associated with increased homocysteine levels and risks of CVD in various populations including those with kidney disease. Here, we evaluated the influence of MTHFR variants on progressive loss of kidney function. METHODS: We analyzed 821 subjects with hypertensive nephrosclerosis from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases African-American Study of Kidney Disease and Hypertension (AASK) Trial to determine whether decline in glomerular filtration rate (GFR) over ∼4.2 years was predicted by common genetic variation within MTHFR at non-synonymous positions C677T (Ala222Val) and A1298C (Glu429Ala) or by MTHFR haplotypes. The effect on GFR decline was then supported by a study of 1333 subjects from the San Diego Veterans Affairs Hypertension Cohort (VAHC), followed over ∼4.5 years. Linear effect models were utilized to determine both genotype [single-nucleotide polymorphism (SNP)] and genotype (SNP)-by-time interactions. RESULTS: In AASK, the polymorphism at A1298C predicted the rate of GFR decline: A1298/A1298 major allele homozygosity resulted in a less pronounced decline of GFR, with a significant SNP-by-time interaction. An independent follow-up study in the San Diego VAHC subjects supports that A1298/A1298 homozygotes have the greatest estimated GFR throughout the study. Haplotype analysis with C677T yielded concurring results. CONCLUSION: We conclude that the MTHFR-coding polymorphism at A1298C is associated with renal decline in African-Americans with hypertensive nephrosclerosis and is supported by a veteran cohort with a primary care diagnosis of hypertension. Further investigation is needed to confirm such findings and to determine what molecular mechanism may contribute to this association.

[Clinical and genetic basis of hypertensive nephrosclerosis. NEFROSEN Study]. / Bases clínicas y genéticas de la nefroesclerosis hipertensiva. Estudio NEFROSEN.

BACKGROUND: Hypertensive nephrosclerosis is a chronic kidney disease (CKD) associated with essential hypertension. The lack of correlation between hypertension control and progression to end-stage CKD suggests an intrinsic and primitive disease. New evidence suggests that MYH9 gene alterations are associated with polymorphisms in African Americans. The aim of this study is to investigate whether a polymorphism of MYH9 in Caucasians is linked to essential hypertension and nephrosclerosis. The secondary objective is to identify the clinical risk factors of progression to end-stage CKD. This is a retrospective study that will compare patients with nephrosclerosis and essential hypertensives without renal disease, and also patients with nephrosclerosis and impaired renal function with those that are stable. METHOD: Between October 2009 and October 2010, 500 patients with stages 3-5 CKD attributed to nephrosclerosis according to usual clinical criteria, and 300 essential hypertensives (eGFR>60 mL/min/1.73 m2; microalbuminuria <300 mg/g) are to be recruited. A total of 200 healthy controls from the general population are also to be included for the genetic study. There are two study sections, being the first and final visits to the clinic (for stage 5 cases, the start of replacement therapy will be the end of follow-up). Clinical and laboratory data will be recorded, and blood samples will be collected. DISCUSSION: Our study will aim to determine if there is a relationship between the diagnosis of nephrosclerosis and the MYH9 gene in Caucasians, and to study possible risk factors for progression to end-stage CKD, on both clinical and genetic bases.

Relationship between body mass index and proteinuria in hypertensive nephrosclerosis: results from the African American Study of Kidney Disease and Hypertension (AASK) cohort.

BACKGROUND: Few studies have examined the association between obesity and markers of kidney injury in a chronic kidney disease population. We hypothesized that obesity is independently associated with proteinuria, a marker of chronic kidney disease progression. STUDY DESIGN: Observational cross-sectional analysis. SETTING & PARTICIPANTS: Post hoc analysis of baseline data for 652 participants in the African American Study of Kidney Disease (AASK). PREDICTORS: Obesity, determined using body mass index (BMI). MEASUREMENTS & OUTCOMES: Urine total protein-creatinine ratio and albumin-creatinine ratio measured in 24-hour urine collections. RESULTS: AASK participants had a mean age of 60.2 ± 10.2 years and serum creatinine level of 2.3 ± 1.5 mg/dL; 61.3% were men. Mean BMI was 31.4 ± 7.0 kg/m(2). Approximately 70% of participants had a daily urine total protein excretion rate <300 mg/d. In linear regression analyses adjusted for sex, each 2-kg/m(2) increase in BMI was associated with a 6.7% (95% CI, 3.2-10.4) and 9.4% (95% CI, 4.9-14.1) increase in urine total protein-creatinine and urine albumin-creatinine ratios, respectively. In multivariable models adjusting for age, sex, systolic blood pressure, serum glucose level, uric acid level, and creatinine level, each 2-kg/m(2) increase in BMI was associated with a 3.5% (95% CI, 0.4-6.7) and 5.6% (95% CI, 1.5-9.9) increase in proteinuria and albuminuria, respectively. The interaction between older age and BMI was statistically significant, indicating that this relationship was driven by younger AASK participants. LIMITATIONS: May not generalize to other populations; cross-sectional analysis precludes statements regarding causality. CONCLUSIONS: BMI is associated independently with urine total protein and albumin excretion in African Americans with hypertensive nephrosclerosis, particularly in younger patients.

Progression of chronic kidney disease: Adrenergic genetic influence on glomerular filtration rate decline in hypertensive nephrosclerosis.

BACKGROUND: African-Americans are likely to develop hypertension and hypertensive nephrosclerosis. This grave prognosis, coupled with familial aggregation of end-stage renal disease (ESRD) in Blacks, prompts a search for genetic risk factors for ESRD. Recent evidence implicates a crucial role for the sympathetic nervous system in progressive renal disease. METHODS: We used the African-American Study of Kidney Disease to probe whether beta2-adrenergic receptor (ADRB2) predicts glomerular filtration rate (GFR) decline rate. A total of 580 participants were included. Baseline GFR was 51.2 +/- 0.5 ml/min/1.73 m2. Subjects were randomized in a 2 x 3 block design: to intensively lowered (MAP < or = 92 mm Hg) versus 'usual' (MAP = 102-107 mm Hg) blood pressure goal groups, and also divided by three randomized antihypertensive drugs (ramipril, metoprolol, or amlodipine). We scored 4 SNPs at the ADRB2 locus. RESULTS: Haplotypes at ADRB2 predicted chronic GFR decline rate, GFR declined more slowly in individuals with haplotype-1 (-804G-->173T-->16Gly-->27GIn), and faster in those who carried haplotype-3 (-804G-->173T-->16Arg-->27Gln). ADRB2 genotype interacted with antihypertensive drug class to influence GFR slope (p = 0.001-0.037). We extended our findings to an independent case/control sample of Black hypertensive ESRD, in which we found that variant Gly16Arg that tagged the GFR slope-determining ADRB2 haplotype also conferred risk for the ESRD trait in Blacks. CONCLUSIONS: The GFR decline/progression rate in hypertensive renal disease is controlled in part by genetic variation within the adrenergic pathway.

A perspective on arterionephrosclerosis: from pathology to potential pathogenesis.

The morphological findings of so-called hypertensive nephrosclerosis, rather than implying a linear direct relationship to damage induced by hypertension, may indicate complex environmental and genetic factors, which together foster the coexistence of renal lesion and hypertension in this clinical setting. We discuss the clinical and pathological criteria for diagnosis of arterionephrosclerosis, and possible pathogenetic factors, including hypertension, ethnicity, aberrant autoregulation, prothrombotic mechanisms, low birth weight, decreased nephron number, genetic factors and dysmetabolic syndrome.

Hypertension and kidney disease: a deadly connection.

Kidney disease may be the cause or a consequence of hypertension. Hypertension affects 25% of the adult population in the United States. Similarly, chronic kidney disease (CKD) and end-stage renal disease (ESRD) have been steadily increasing in incidence because of the increasing age of the US population and rise in the incidence of risk factors, including hypertension. Substantial evidence supports the notion that elevated blood pressure is the most significant risk factor for the development of CKD. Microalbuminuria has been shown to be the early marker of hypertensive renal disease. Furthermore, therapy to reduce microalbuminuria was associated with delay in the progression of renal disease. Black Americans are at higher risk for developing hypertensive nephrosclerosis than whites. Hypertension is a major risk factor for cardiovascular events in patients with CKD and ESRD and those who have undergone renal transplantation. Studies have documented that elevated serum creatinine and CKD are risk factors for a cardiovascular event. Tight blood pressure control has been shown to reduce microalbuminuria and proteinuria and to delay progression of renal disease. Tailoring the choice of antihypertensive medication to the clinical setting to achieve a blood pressure goal is critical in reducing complications from this deadly connection.

Cardiovascular outcomes in the African American Study of Kidney Disease and Hypertension (AASK) Trial.

BACKGROUND: Patients with chronic kidney disease are at increased risk for cardiovascular (CV) events. METHODS: We randomly assigned 1,094 African Americans with hypertensive nephrosclerosis (glomerular filtration rate [GFR], 20 to 65 mL/min/1.73 m(2) [0.33 to 1.08 mL/s]) to initial antihypertensive treatment with either: (1) a beta-blocker, metoprolol; (2) an angiotensin-converting enzyme inhibitor, ramipril; or (3) a dihydropyridine calcium channel blocker, amlodipine, and either a usual-blood pressure (BP) or low-BP treatment goal. Using a design powered to detect renal outcome differences, we compared the effect of treatment on the CV event rate (cardiac death, myocardial infarction, stroke, and heart failure) during a mean follow-up period of 4.1 years and determined baseline factors that predict CV outcomes. RESULTS: Thirty-one patients died of CV disease (0.7%/patient-year), and 149 patients experienced at least 1 CV outcome (3.3%/patient-year). Overall, 202 CV events (4.5%/patient-year) occurred. The CV outcome rate was not related significantly to randomized interventions. In multivariable analyses, 7 baseline risk factors remained independently associated with increased risk for the CV composite outcome after controlling for age, sex, baseline GFR, and baseline proteinuria group: pulse pressure, duration of hypertension, abnormal electrocardiogram result, non-high-density lipoprotein cholesterol level, serum urea nitrogen level, urine protein-creatinine ratio, urine sodium-potassium ratio, and annual income less than 15,000 dollars. CONCLUSION: Neither randomized class of antihypertensive therapy nor BP level had a significant effect on the occurrence of CV events, possibly because of limited power. However, this analysis identifies unique and potentially modifiable CV risk factors in this high-risk cohort.

Lessons from the African-American Study of Kidney Disease and Hypertension: an update.

Hypertension is the second leading attributable cause of end-stage renal disease in the United States today. The African-American Study of Kidney Disease and Hypertension was a randomized, double-blind, controlled trial designed to determine whether strict blood pressure (BP) control, angiotensin-converting enzyme inhibitor (ACEI)-based, or calcium channel blocker (CCB)-based regimens were superior to less strict BP control and beta-blocker (BB)-based regimens, respectively. The study enrolled 1093 African Americans with hypertensive nephrosclerosis and followed them for 4 years with repeated direct measurement of glomerular filtration rate (GFR) and monitoring of end points, including rapid decline in GFR, end-stage kidney disease, and death. From this landmark study, we learned that strict BP control is achievable in this study population, but it did not slow progression of kidney disease, and we learned that an ACEI-based therapy was superior to either a BB- or CCB-based regimen. In addition, we learned that proteinuria is the most important predictor of progression of kidney disease; ACEI and CCB have differential effects on proteinuria; and a CCB-based regimen combined with strict BP control may be the next best choice to an ACEI-based regimen in this population.

Quality of life in the African American Study of Kidney Disease and Hypertension: effects of blood pressure management.

BACKGROUND: The African American Study of Kidney Disease and Hypertension was a multicenter trial comparing the effects of 2 levels of blood pressure control (usual or low goal) and initial therapy with metoprolol, ramipril, or amlodipine. We examined effects of treatment-group assignment on health-related quality of life (HRQOL) measures and reported symptoms during 4 years of follow-up. METHODS: HRQOL was assessed at baseline and annually by using the Medical Outcomes Study 36-Item Short Form (SF-36) and a symptom checklist. Using a 2-slope model, treatment effects were evaluated for change from baseline to year 1 and for average change during the first 4 years of follow-up. RESULTS: A total of 1,094 participants were randomly assigned. Average age was 55 years, 61% were men, and the mean of the first glomerular filtration rate in the study was 46 mL/min/1.73 m2 (0.76 mL/s). No significant differences in HRQOL were seen between the low- and usual-blood-pressure groups. Reported side effects also were similar between blood-pressure groups. Mean Physical Health Component (PHC) and Mental Health Component (MHC) scores had a significantly smaller decrease in the ramipril than metoprolol group in both the initial period from baseline to year 1 (PHC, 2.08 +/- 0.56; MHC, 1.89 +/- 0.62) and during the first 4 years of follow-up (PHC, 1.60 +/- 0.44; MHC, 1.48 +/- 0.48). The MHC also had a slightly smaller decrease during the first 4 years in the ramipril group than amlodipine group (1.20 +/- 0.61). CONCLUSION: Aggressive blood pressure control is well tolerated in African Americans with hypertensive kidney disease, measured by using the SF-36 and reported symptoms. The clinical significance of smaller decreases in PHC and MHC scores in the ramipril compared with metoprolol group is not clear.

Systemic and glomerular hypertension and progression of chronic renal disease: the dilemma of nephrosclerosis.

The link between the kidney and hypertension has been considered a villain-victim relationship. High blood pressure levels are a well-recognized feature in chronic renal disease, but the ability of mild-to-moderate hypertension to produce renal insufficiency has been questioned. Nephrosclerosis, benign nephrosclerosis, and hypertensive kidney disease are terms that clinicians use when renal damage is thought to be secondary to essential hypertension. Many cases of end-stage renal disease are ascribed to so-called benign nephrosclerosis. This entity could actually be a primary renal disease affecting the preglomerular microvasculature, perhaps genetically mediated and ethnically influenced, and showing a heterogeneous clinical expression. African Americans suffer from nephrosclerosis more frequently than Caucasians. Nephrosclerosis affecting Caucasians seems to show a less aggressive pattern and could represent early age-related renal sclerosis. The risk of end-stage renal disease is increased when atherosclerotic lesions in large renal arteries coexist. Age, systolic blood pressure, proteinuria, and concomitant cardiovascular disease are well-known promoters of renal failure. A multifactorial strategy, including antihypertensive and antiproteinuric drugs, and lipid-lowering and anti-platelet agents, could improve cardiovascular and renal outcomes in patients with nephrosclerosis.

The MTHFR 677TT and 677CT/1298AC genotypes in Cypriot patients may be predisposing to hypertensive nephrosclerosis and chronic renal failure.

AIM: The homozygous 677TT mutation of the MTHFR gene has been linked to deep vein thrombosis and to arterial atherosclerotic events of the coronary, carotid and peripheral arteries. Its putative association with renal arteriosclerosis and chronic renal failure (CRF) in the presence of hypertensive nephrosclerosis is yet to be investigated. METHODS: Two hundred and twenty-one Greek-Cypriot patients with CRF from one single renal unit in Cyprus were divided into 6 diagnostic categories: 49 due to chronic glomerulonephritis (22.2%), 43 due to diabetes mellitus (19.4%), 26 due to autosomal dominant polycystic kidney disease (11.8%), 30 due to essential hypertension leading to nephrosclerosis (13.6%), including 4 patients with primary malignant hypertension, 32 with other rarer causes of CRF (14.5%) and 41 of uncertain etiology (18.5%). These 221 CRF patients had their MTHFR C677T and A1298C genotypes analyzed by the polymerase chain reaction and agarose gel electrophoresis after restriction enzyme digestion. The frequency of the homozygous states 677TT and 1298CC and the double heterozygous 677CT/1298AC were compared to those of 210 unrelated normal local controls. RESULTS: A statistically significant increase in the frequency of the 677TT genotype compared to controls was only found in the hypertensive nephrosclerosis CRF sub-group of patients. The prevalence rate of the 677TT genotype was 46.7% (controls 17.6%, P=0.0007). Combined together the homozygous 677TT and the double heterozygous 677CT/1298AC genotypes were found in 86.7% of the hypertensive nephrosclerotic CRF patients, compared to 46.6% in normal controls (P=0.0001). CONCLUSIONS: The findings support the hypothesis that Caucasian patients with essential hypertension, homozygous for 677TT or doubly heterozygous for 677CT/1298AC genotypes, are predisposed to develop hypertensive nephrosclerosis and CRF.

Proteinuria and hypertensive nephrosclerosis in African Americans.

Proteinuria is a known risk factor for both renal disease progression and cardiovascular morbidity and mortality in hypertensive populations. African Americans are among the highest risk groups for development of renal disease in the setting of hypertension and suffer a disproportionate burden of end-stage renal disease attributed to hypertension. Population-based studies indicate that African Americans have higher rates of albuminuria compared to non-African Americans in part due to higher rates of hypertension and diabetes in African Americans as compared to non-Hispanic whites for example. The African American Study of Kidney Disease and Hypertension (AASK) Trial was a prospective long-term clinical trial that examined the effect of aggressive blood pressure lowering versus usual blood pressure lowering in three different classes of antihypertensives on renal outcomes in approximately 1200 African Americans with hypertensive nephrosclerosis. Two thirds of trial participants had < 300 mg protein, and one third had > or = 300 mg of protein in a 24-hour urine specimen at baseline. Those with > 300 mg protein excretion compared to those with < 300 mg protein excretion at baseline had more rapid decline in renal function and ESRD events. Moreover, lower levels of proteinuria than previously thought may be important for identifying those at higher risk for kidney disease progression. The AASK cohort study, a follow-up to the trial, is now underway. The longer term follow-up will provide new insights into proteinuria and other risk factors for progression of kidney disease in hypertensive nephrosclerosis.

Hypertensive risk factors in kidney disease in African Americans.

African Americans with hypertension more commonly develop renal insufficiency compared to Caucasians. The African American Study of Kidney Disease (AASK) included a renal biopsy pilot study that demonstrated that the clinical diagnosis of so-called hypertensive nephrosclerosis in these African American patients indeed was accurate. This biopsy study demonstrated extensive global glomerulosclerosis, far exceeding that expected for patients' age. We further compared our clinically indicated renal biopsies to determine if any phenotypic differences were present in hypertensive nephrosclerosis in African Americans versus Caucasians. These studies point to an excess of the solidified type of global glomerulosclerosis (GS) (also called "decompensated benign nephrosclerosis") in African Americans compared to more obsolescent type GS in Caucasians. We speculate that these phenotypic differences might reflect differing mechanisms of tissue injury in hypertensive African Americans versus Caucasians, and discuss possible contributors to this injury.

A stereological study of glomerular number and volume: preliminary findings in a multiracial study of kidneys at autopsy.

BACKGROUND: This report describes preliminary results of a study of glomerular number and volume and their associations, in kidneys of people coming to autopsy. METHODS: Both kidneys were weighed at autopsy and the right kidney was perfusion-fixed and sub-sampled for stereological estimation of total glomerular number, and of mean renal corpuscle volume, using the physical disector/fractionator combination. RESULTS: The 78 kidneys studied so far were from Australian Aborigines, Australian non-Aborigines, US blacks and US whites, ages newborn to 84 years. Glomerular number ranged almost ninefold (from 210,332 to 1,825,380), with mean (SD) of 784,909 (314,686); it decreased throughout adult life (r=-0.32, P=0.009). Mean renal corpuscle volume varied 5.6-fold in adults and was inversely correlated with glomerular number (r=-0.38, P=0.001). Total renal corpuscle volume varied in adults by a factor of 15.8. Kidney weight correlated with body surface area (BSA) at all ages (r=0.76, P < 0.001); it varied 3.4-fold among adults, while kidney weight/m2 varied 3.7-fold. The percentage of sclerosed glomeruli varied from 0 to 23%, and it correlated strongly with age (r=0.58, P < 0.001). Females had smaller kidneys than males, and, marginally, fewer glomeruli. There were no significant variations by ethnic group. CONCLUSIONS: These extraordinary ranges of glomerular number and size among ostensibly "normal" people, and their inverse relationship, probably have important implications for susceptibility to renal insufficiency. People with low glomerular (nephron) numbers are likely to be particularly predisposed, with the process marked by compensatory hypertrophy of residual nephrons, which, in turn, accelerates their obsolescence. Much, however, remains to be done, including evaluation of history, clinical features, accompanying pathology, detailed renal morphology, and further pursuit of potentially defining characteristics in high risk groups.

ACE inhibition is effective and renoprotective in hypertensive nephrosclerosis: the African American Study of Kidney Disease and Hypertension (AASK) trial.

An interim analysis of the AASK trial at three years demonstrates a renoprotective effect [slower decline in glomerular filtration rate (GFR), delayed onset of significant decrease in GFR, end-stage renal disease (ESRD) or death, and a decrease in urinary protein excretion] of the angiotensin converting enzyme (ACE) inhibitor, ramipril, as compared to the dihydropyridine calcium channel blocker (DHP-CCB), amlodipine, in patients with mild-to-moderate renal insufficiency. The beneficial effect occurred in the presence of similar levels of blood pressure control and was apparent in patients with proteinuric (beyond the threshold of "dipstick positive" proteinuria, 300 mg/day) and non-proteinuric hypertensive nephrosclerosis. At the time of the interim analysis, the effectiveness of the beta-blocker metoprolol was not significantly different from that of the ACE inhibitor. The data suggest that DHP-CCBs should be used with caution in the presence of mild-to-moderate renal insufficiency.

Hypertensive nephrosclerosis in African Americans versus Caucasians.

BACKGROUND: Extensive global glomerulosclerosis (GS) has been reported in African Americans with hypertension and renal insufficiency, far exceeding that in Caucasians. To assess and compare severity and phenotype of injury in biopsied African Americans and Caucasians who morphologically had hypertensive nephrosclerosis, we performed a retrospective biopsy study. METHODS: All renal biopsies with a histological diagnosis of hypertensive nephrosclerosis from the last 11 years were identified from our clinical files. Lesions of global and segmental sclerosis, interstitial fibrosis and vascular sclerosis were semiquantitatively analyzed as percent involved, or on a 0 to 3 scale, respectively. The phenotypes of global glomerulosclerosis also were categorized as either the solidified (that is, the entire tuft is solidified) or the obsolescent type (that is, Bowman's space is occupied by collagenous material and the tuft is retracted). RESULTS: Sixty-two patients (19 African Americans, 43 Caucasians) were included in the study. At biopsy, African Americans were younger than Caucasians with higher serum creatinine, but no difference in proteinuria or mean arterial pressure (MAP). African Americans had a marked increase in the solidified form of GS (25 +/- 6 in African Americans vs. 8 +/- 2% in Caucasians, P < 0.01). This extensive solidification of glomeruli was associated with segmental sclerosis in African Americans (38 +/- 10%), contrasting low prevalence of solidified GS in Caucasians with segmental sclerosis (10 +/- 3%, P < 0.05) and in African Americans without segmental sclerosis (10 +/- 4%, P < 0.05). African Americans with segmental sclerosis were younger and clinically expressed a more severe renal disease than Caucasians with this lesion. Interstitial fibrosis was greater in African Americans than in Caucasians (54 +/- 6 vs. 33 +/- 3%, P < 0.01) and correlated with proteinuria and serum creatinine levels, especially in African Americans, and also with GS. Vascular sclerosis was worse in African Americans than in Caucasians (0.96 +/- 0.04 vs. 0.77 +/- 0.08 score, P < 0.05) and did not correlate with GS. By modeling, neither MAP nor age was useful in predicting any morphological lesions and proteinuria accounted only minimally for the variability of GS. CONCLUSIONS: Blood pressure levels and proteinuria did not account for morphological lesions, suggesting other factors (such as genetic factors, microvascular disease) may play a role. The phenotype of GS differs in biopsied African Americans versus Caucasians with hypertensive nephrosclerosis, with a marked increase in the solidified form of GS in African Americans. The association of extensive solidified GS with segmental sclerosis lesions in African Americans, but not in Caucasians, suggests different mechanisms may contribute to the development and progression of sclerosis in these two patient groups.

Comparison of cross-sectional renal function measurements in African Americans with hypertensive nephrosclerosis and of primary formulas to estimate glomerular filtration rate.

Renal function measurements were obtained in 1,703 African Americans with presumed hypertensive nephrosclerosis who were screened for entry into the African-American Study of Hypertension and Kidney Disease (AASK). We examined the effect of race on relationships involving renal variables by comparing African Americans enrolled into the AASK with non-African Americans enrolled into the Modification of Diet in Renal Disease (MDRD) study. We examined the effect of gender on renal variables by comparing African American men and women. We compared various methods for estimating glomerular filtration rate (GFR) with iodine 125-labeled ((125)I)-iothalamate GFR. AASK data were also used to derive a new formula for estimating GFR in African Americans. After adjusting for age, sex, and baseline GFR, African American patients on the AASK study were heavier and had larger body surface areas and body mass indices than either MDRD African Americans or non-African Americans. African Americans had greater serum creatinine levels and urinary creatinine excretions for any given level of GFR. Mean GFR was greater in African American men than African American women (59.7 versus 51.7 mL/min/1.73 m(2)), although serum creatinine levels were also greater in men (1.91 versus 1.73 mg/dL). Seventy-eight percent of women with serum creatinine levels between 1.2 and 1.5 mg/dL had GFRs less than 65 mL/min/1.73 m(2). For African Americans in the AASK, GFR was overestimated by the 24-hour creatinine clearance and underestimated by the Cockcroft-Gault formula. A prediction formula developed in the MDRD study more accurately predicted GFR in AASK patients than these measurements. AASK data were also used to derive a new five-term formula for estimating GFR that was slightly more accurate in the African Americans in the AASK than the MDRD formula (median percentage of error, 12.4% for the MDRD formula versus 12.1% for the AASK formula). Important differences exist in renal variables between African Americans and non-African Americans and between African American men and African American women. Formulas using demographic data and readily measured serum values estimate (125)I-iothalamate GFR.