Diabetic renal disease in African Americans

Diabetic nephropathy (DN) is the No. 1 cause of end-stage renal disease in the United States and is highly prevalent in African Americans. Almost all DN in African Americans is caused by type 2 diabetes. Glycemic control and control of blood pressure are essential to prolong renal survival and to protect against cardiovascular events. Among African Americans, diabetic nephropathy seems to affect women more than men, which may be related to increased rates of obesity and diabetes in African American women. In addition to gender, the development of albuminuria, family history, and possibly birth weight are factors that predict progression of renal disease in African Americans with DN. The impact of glycemic control, appropriate antihypertensives, and the optimal level of blood pressure control in African Americans with advanced DN require further study. This article will review the clinical characteristics, risk factors, predictors of disease progression, and treatment of diabetic nephropathy in African Americans.     

The effect of potassium and extracellular volume on renal bicarbonate reabsorption

Bicarbonate reabsorption was measured in dogs infused with either KCl or KHCO₃. As has been previously reported, potassium loading depressed bicarbonate reabsorption. Similar studies in dogs with partial obstruction of the thoracic inferior vena cava failed to demonstrate an effect of potassium loading on bicarbonate reabsorption. Extracellular volume was expanded with isotonic saline in three groups of dogs: one with potassium depletion, a second with hyperkalemia, and a third normal group. Bicarbonate reabsorption varied inversely with fractional chloride excretion in all three groups. At any one level of fractional chloride excretion, however, bicarbonate reabsorption was higher in the potassium depleted animals than in the normal dogs, and higher in the normal dogs than in those subjected to potassium loading. This study demonstrates a significant regulatory role of potassium over renal bicarbonate reabsorption. This role can only clearly be defined, however, when the precise state of effective extracellular volume is delineated.     

The epidemiology of end-stage renal disease among African Americans

Although disparities in outcomes among African Americans compared with whites with respect to cardiovascular disease, cancer, diabetes, infant mortality, and other health standards have been well-described, these disparities are most dramatic with respect to kidney diseases. End-stage renal disease (ESRD) occurs almost 4 times more commonly in African Americans than in their white counterparts. These disparate rates of kidney disease may be caused by the complex interplay of genetic, environmental, cultural, and socioeconomic factors. African Americans are particularly vulnerable to the deleterious renal effects of hypertension and may require more aggressive blood pressure control than whites to accrue benefit with respect to preservation of renal function. Diabetes, the leading cause of ESRD in the United States, is another important factor in the excess renal morbidity and mortality of African Americans because of its prevalence in this population. Other renal diseases, especially those associated with HIV/AIDS, are also much more likely to affect African Americans than other American population subgroups. A more thorough understanding of the epidemiology of renal diseases in African Americans and the cultural, social, and biological differences that underlie racial disparities in prevalence of renal disease will be essential to the design of effective public health strategies for prevention and treatment of this burdensome problem.     

Medullary thick ascending limb buffer vasoconstriction of renal outer-medullary vasa recta in salt-resistant but not salt-sensitive rats

We have demonstrated previously that paracrine signaling occurs between medullary thick ascending limb (mTAL) and the contractile pericytes of outer-medullary vasa recta (VR), termed "tubular-vascular cross-talk." The aim of the current study was to determine whether tubular-vascular cross-talk has a functional effect on vasoconstrictor responses to angiotensin II and to determine whether this is altered in the Dahl salt-sensitive (SS) rat. Studies were performed on salt-resistant consomic SS.13 Brown Norway (BN) and SS rats using a novel outer medullary tissue strip preparation in which freshly isolated VRs within VR bundles were perfused either alone or in combination with nearby mTAL. In VRs from SS.13 (bn) rats, angiotensin II (1 μmol/L) increased VR bundle intracellular Ca(2+) concentration 19 ± 9 nmol/L (n=8) and reduced focal diameter in perfused VRs by -20 ± 7% (n=5). In the presence of nearby mTAL, however, VR bundle intracellular Ca(2+) concentration (-9 ± 8 nmol/L; n=8) and VR diameter (-1 ± 4%, n=7) in SS.13(bn) rats were unchanged by angiotensin II. In contrast, in Dahl SS rats, angiotensin II resulted in rapid and sustained increase in VR bundle intracellular Ca(2+) concentration (89 ± 48 nmol/L, n=7; 50 ± 24%, n=8) and a reduction in VR diameter of (-17 ± 7%, n=7; -11 ± 4%, n=5) in both isolated VRs and VRs with nearby mTAL, respectively. In VRs with mTAL from SS13(bn) rats, inhibiton of purinergic receptors resulted in an increase in VR bundle intracellular Ca(2+) concentration, indicating that purinergic signaling buffers vasoconstriction. Importantly, our in vitro data were able to predict medullary blood flow responses to angiotensin II in SS and SS.13(bn) rats in vivo. We conclude that paracrine signaling from mTAL buffers angiotensin II vasoconstriction in Dahl salt-resistant SS.13(bn) rats but not SS rats.     

Antihypertensive effects of cicletanine and renal protection in Dahl salt-sensitive rats.

We designed experiments to reveal the antihypertensive properties of cicletanine, a novel antihypertensive drug, in Dahl salt-sensitive (Dahl-S) rats. Cicletanine (39 mg/kg body weight per day for 6 weeks) ameliorated the development of hypertension in Dahl-S rats fed a high-salt (4% NaCl) diet. This blood pressure reduction was associated with a decrease in heart weight and vascular wall thickness. Moreover, urinary prostacyclin (PGl2) excretion was increased with cicletanine treatment, being inversely related to systolic blood pressure. Proteinuria and urinary excretion of n-acetyl-beta-D-glucosaminidase were decreased and glomerular filtration rate was increased with this treatment. Morphological investigation revealed an improvement in glomerulosclerosis, renal tubular damage and intrarenal arterial injury in the salt-induced hypertensive rats. In contrast, trichloromethiazide, which decreased blood pressure to the same extent as cicletanine, lowered urinary PGl2 excretion and generally did not ameliorate the deteriorated renal functions and morphological abnormalities. Thus, these data indicate that cicletanine ameliorates the development of hypertension in Dahl-S rats and protects the cardiovascular and renal systems against the injuries seen in the hypertension. The enhanced vasodepressor PGl2 synthesis probably participates, to some extent, in these beneficial properties of long-term cicletanine treatment.     

血压盐敏感者内皮功能损伤及补钾的保护作用研究

目的通过观察血、尿-氧化氮（NO）水平的变化,探讨盐敏感者血管内皮功能损伤及补钾的保护作用。方法选39例年龄16～60岁、血压正常或血压轻度偏高者参与为期3周的慢性盐负荷及补钾试验,包括基线3天,低盐饮食、高盐饮食和高盐加补钾饮食各7天的研究。各个阶段测量体重、血压,并收集血、尿标本。结果盐敏感者血浆NO浓度和尿中NO水平在基线、低盐和高盐阶段均低于盐不敏感者;限盐后血、尿NO浓度增加,而高盐饮食后NO浓度显著减少;盐敏感者在高盐摄入的基础上大剂量口服补钾后血浆NO浓度、尿NO水平显著升高。结论盐敏感者尽管尚处在血压正常或血压轻度偏高阶段已存在一定程度的内皮功能损伤,且这种损伤与盐负荷相关联;大剂量补钾可能通过增加NO水平而改善盐敏感者的血管内皮功能。     

Systemic and renal hemodynamic effects of celiprolol in essential hypertensives

To evaluate the humoral and hemodynamic (both systemic and renal) effects of celiprolol and to assess whether these effects are at least partially due to the activation of dopamine (DA) receptors, 9 out-patients with mild to moderate uncomplicated essential hypertension, without any therapy for at least 3 weeks, received celiprolol (400 mg once daily) and placebo, each for 1 month, according to a double-blind randomized trial pattern. At the end of each treatment period, blood pressure, heart rate, renal plasma flow, glomerular filtration rate, plasma renin activity, plasma aldosterone and plasma norepinephrine were measured after administration of saline solution and intravenous metoclopramide. Compared with placebo, celiprolol significantly reduced mean blood pressure, heart rate and plasma norepinephrine. Plasma renin activity showed a tendency toward a reduction during celiprolol treatment, which was not associated with changes in plasma aldosterone. Despite the decrease in mean blood pressure, renal plasma flow did not change, so that renovascular resistances were significantly reduced. Glomerular filtration rate was unchanged and the filtration fraction showed a trend toward a reduction during celiprolol treatment. Percent decrements of renovascular resistances and of mean blood pressure induced by celiprolol tended to correlate with changes in plasma norepinephrine. Metoclopramide did not influence the hemodynamic (systemic and renal) effects of celiprolol nor plasma renin activity and plasma norepinephrine, and it increased aldosterone levels to a similar extent before and after administration of celiprolol.(ABSTRACT TRUNCATED AT 250 WORDS)     

African Americans and renal transplantation: disproportionate need, limited access, and impaired outcomes

BACKGROUND: Renal transplantation is the therapy of choice for patients with end-stage renal disease (ESRD). However, African Americans' (AA) access to this modality is not commensurate with that of other races. This imbalance, coupled with AA disproportionately representing those with ESRD, has kept AA disadvantaged compared with other races, especially whites. METHODS: We reviewed published reports that examined the connection between race and the incidence of chronic renal failure, access to optimal therapy, and outcomes of renal transplantation. RESULTS: The incidence of ESRD in AA is 4 times greater than in whites, but AA remain less likely than whites to be referred for or undergo renal transplantation. Also, AA are at greater risk than whites to experience premature graft failure. CONCLUSIONS: ESRD management has improved dramatically with the advent of successful renal transplantation. However, AA remain significantly disadvantaged in both access and outcomes compared with whites. Further evaluation of underlying causes and development of specific remedies is warranted.     

Focal segmental glomerulosclerosis in African Americans: effects of steroids and angiotensin converting enzyme inhibitors

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a common primary glomerulopathy in African Americans. In this report, we present data on 40 African American patients with FSGS from our medical center. METHODS: Patients were identified from a review of all charts seen in our conservative management renal clinic in 1996, a review of renal biopsy rolls (1994-1998), and a review of patients entering the end-stage renal disease (ESRD) program with a primary diagnosis of FSGS (1993- 1997). Charts were reviewed for demographic, biopsy, and treatment data. Patients who were observed for at least 4 months (range, 4-125 months) were included. ESRD was used as the primary endpoint (n = 12). Data were analyzed using univariate and multivariate Cox hazards and Kaplan-Meier survival analysis. Twenty-four patients were treated with angiotensin-converting enzyme (ACE) inhibitors. Similarly, 24 patients were treated with corticosteroids for a mean of 8.75 +/- 2.6 months and a total dose of 9.3 +/- 2.2 g. RESULTS: On univariate analysis, factors found to be significant determinants for reaching ESRD were the initial creatinine (P = 0.0001), interstitial fibrosis (P = 0.032), the percentage of globally sclerosed glomeruli (P = 0.0018), and the mean arterial blood pressure over the course of follow-up (P = 0.05). Neither the ACE inhibitors nor the corticosteroids had a significant impact on reaching ESRD. The patients reaching ESRD (n = 12) were analyzed separately. The mean time from biopsy to ESRD was 24.7 +/- 9.8 months. ACE inhibitors prolonged renal survival (P = 0.023), but steroids did not. Initial creatinine was the only factor found to be a significant determinant for ESRD. CONCLUSIONS: We conclude that FSGS is common in African Americans. Early diagnosis and blood pressure control are important, but the beneficial effects of steroids and ACE inhibitors in this population are still unclear.     

The humoral renal antihypertensive system: nervous and hemodynamic effects in normotensive and unclipped renal hypertensive rats

A series of studies of the humoral renal antihypertensive system in normotensive and 2K 1C-renal antihypertensive rats is outlined. The rapid structural upward resetting of the cardiovascular system in renal hypertensive rats was associated with a structural downward resetting in the vasculature of the hypotensive clipped kidney. Unclipping of this kidney caused a pronounced release of renomedullary depressor agents, explaining the rapid normalization of pressure seen after unclipping. This normalization of pressure masks a state of pronounced functional hypotension in a structurally still hypertensive cardiovascular system, characterized by marked splanchnic vasodilatation and a lack of neurogenic counter-regulation. Only when this state has lasted long enough to normalize the structural upward resettings, characteristic of hypertension does the cardiovascular system return to normal. Further, cross-circulation techniques have shown that the humoral antihypertensive agents suppress tonic sympathetic activity, thereby inhibiting normal reflex counter-regulation of their vasodilator effects. Presumably this occurs via both vagal cardiac afferents and central actions. Further, behavior and awareness become depressed during intense and prolonged renomedullary release. Finally, experiments for which a normotensive kidney is cross-circulated from a normotensive rat suggest that the humoral renomedullary antihypertensive system has its threshold of release set so low as to contribute to normal blood pressure regulation, presumably in reciprocal balance with the renocortical renin-angiotensin system. Stepwise pressure elevations increasingly enhance release of the depressor agents from the cross-perfused kidney.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of ramipril on ambulatory blood pressure in African Americans and Caucasians

BACKGROUND: On average, angiotensin-converting enzyme inhibitors produce less office blood-pressure lowering in African Americans compared with Caucasians. Past studies did not compare daytime and nighttime ambulatory blood-pressure responses to angiotensin-converting enzyme inhibitors in African Americans and Caucasians. METHODS: We measured the office and ambulatory blood-pressure response to 8 weeks of a fixed dose of 10 mg daily of the angiotensin-converting enzyme inhibitor ramipril in a cohort of 72 African Americans and 89 Caucasians. RESULTS: Ramipril lowered age-adjusted daytime ambulatory systolic blood pressure 6 mm Hg and diastolic blood pressure 3 mm Hg less in African Americans compared with Caucasians (both P=.02). This difference persisted after adjusting for baseline blood pressure, body mass index, urine sodium and potassium, plasma aldosterone, and other covariates. Despite the difference in mean response, there was a 72% overlap in daytime blood-pressure response to ramipril between African Americans and Caucasians. Among Caucasians, ramipril lowered systolic blood pressure 2 mm Hg less during nighttime compared with daytime, whereas among African Americans, blood pressure lowering was equivalent during day and night. Nighttime blood-pressure response to ramipril did not differ significantly between African Americans and Caucasians. CONCLUSIONS: Ramipril was more effective in lowering daytime blood pressure in Caucasians compared with African Americans, but appreciable differences in response did not persist at night. Despite the small difference in mean response between groups, the majority of African Americans and Caucasians had a similar blood-pressure response to a fixed dose of ramipril.