Effects of Sustained-Release Beraprost in Patients With Primary Glomerular Disease or Nephrosclerosis: CASSIOPEIR Study Results.

TRK-100STP, a sustained-release preparation of the orally active prostacyclin analogue beraprost sodium, targets renal hypoxia. This study aimed to show the superiority of TRK-100STP over placebos in patients with chronic kidney disease (with either primary glomerular disease or nephrosclerosis) to determine the recommended dose. CASSIOPEIR (Chronic Renal Failure Asian Study with Oral PGI2 Derivative for Evaluating Improvement of Renal Function) was a randomized, double-blind, placebo-controlled study conducted at 160 sites in seven Asia-Pacific countries and regions. Eligible patients (n = 892) were randomized to TRK-100STP 120, 240 µg, or placebo for a treatment period of up to 4 years. The primary efficacy endpoint was time to first occurrence of a renal composite: doubling of serum creatinine or occurrence of end-stage renal disease. No significant differences were observed in composite endpoints between TRK-100STP and placebo (P = 0.5674). Hazard ratios (95% CI) in the TRK-100STP 120 and 240 µg vs. placebo groups were 0.98 (0.78, 1.22) and 0.91 (0.72, 1.14), respectively. The overall incidence of adverse events and adverse drug reactions was comparable between treatment arms.

Amplified Association Between Blood Pressure and Albuminuria in Overweight Patients With Biopsy-Proven Hypertensive Nephrosclerosis.

BACKGROUND: An overweight person is at high risk for hypertensive renal damage. The effect of weight on the association between systolic blood pressure (SBP) and albuminuria remains unknown in patients with histologically diagnosed hypertensive nephrosclerosis. METHODS: A total of 97 patients with biopsy-confirmed hypertensive nephrosclerosis were recruited from 13 centers throughout Japan. We examined the relationship between SBP and proteinuria among those who were overweight, which is defined as a body mass index ≥25 kg/m2, and those who were not. We examined the interaction of weight and SBP with albuminuria at baseline and with the changes in estimated glomerular filtration rate (eGFR) during the observational period. RESULTS: Our results included mean age (54 years old), blood pressure (138/80), eGFR (53 ml/min/1.73 m2), and urine albumin levels (0.2 g/day). SBP was significantly correlated with log-transformed urine albumin levels (r = 0.4, P = 0.01) in patients who were overweight (n = 38) compared with patients who were not overweight (n = 59). Multiple regression analysis revealed that the interaction between being overweight and SBP with respect to albuminuria was significantly correlated with the log-transformed urine albumin level (ß = 0.39, P = 0.047) and was independent of age, sex, and potential confounding factors. The interaction between weight and SBP ≥140 mm Hg was significantly associated with a greater decrease in eGFR in the following 3 years. CONCLUSIONS: Being overweight may enhance susceptibility to hypertensive glomerular damage and may eventually lead to renal progression in patients with hypertensive nephrosclerosis.

Volume Ratio of Glomerular Tufts to Bowman Capsules and Renal Outcomes in Nephrosclerosis.

BACKGROUND: The concomitant appearance of glomerular collapse and enlargement is characteristic of the histological findings in nephrosclerosis. However, no previous study quantitatively examined the clinicopathological significance of this feature in patients with biopsy-proven nephrosclerosis. METHODS: Renal biopsy specimens and follow-up data from nephrosclerosis patients with estimated glomerular filtration rates >30 ml/min/1.73 m2 at diagnosis were retrospectively reviewed. Mean volumes for glomerular tufts (GV) and Bowman capsules (BV) were separately calculated, based on the measurement of all areas of glomerular tufts and Bowman capsules in a cross-section of biopsy specimens. The G/B ratio was defined as the ratio of GV to BV. The doubling of serum creatinine levels (DSC) and the initiation of renal replacement therapies (end-stage renal disease (ESRD)) were examined as renal outcome indices. RESULTS: A total of 67 patients with biopsy-proven nephrosclerosis were included. Clinicopathological findings at biopsy, other than GV, were comparable among all patients, irrespective of G/B ratio. Overall, 25 patients (37%) developed DSC and 9 (13%) developed ESRD during the median observation periods of 7.8 and 8.5 years, respectively. Renal survival curve analyses indicated a significantly worse prognosis for patients with a low G/B ratio, as compared with those with a high G/B ratio. Cox hazard analyses for DSC identified low G/B ratio as a significant predictor, but not low GV or BV. CONCLUSIONS: These results suggest that the quantitative evaluation of G/B ratio may detect subtle abnormalities in the glomerulus, indicating the subsequent renal outcomes of nephrosclerosis patients.

Effect of Proteinuria and Glomerular Filtration Rate on Renal Outcome in Patients with Biopsy-Proven Benign Nephrosclerosis.

BACKGROUND: Reduced estimated glomerular filtration rate (eGFR) and proteinuria are risk factors for end-stage renal disease (ESRD), of which benign nephrosclerosis is a common cause. However, few biopsy-based studies have assessed these associations. METHODS: We performed retrospective cohort study of 182 Japanese patients who underwent renal biopsy from June 1985 through March 2014 and who were diagnosed with benign nephrosclerosis. Competing risk regression analyses were used to investigate the effect of eGFR and proteinuria levels at the time of renal biopsy on the risk for renal events (ESRD or a 50% decline in eGFR from baseline). RESULTS: During a median 5.8-year follow-up, 63 (34.6%) patients experienced renal events. The incidence of renal events increased with lower baseline eGFR and greater baseline proteinuria levels. After adjustment for baseline covariates, lower eGFR levels (subhazard ratios [SHRs], 1.30; 95% confidence interval [CI], 1.01-1.67, per 10 mL/min/1.73 m2) and higher proteinuria levels (SHR, 1.52; 95% CI, 1.23-1.87, per 1.0 g/day) at the time of renal biopsy were associated independently with higher risk for renal events. Lower levels of serum albumin (SHR, 2.07; 95% CI, 1.20-3.55 per 1.0 g/dL) were also associated with renal events. Patients with both eGFR <30 mL/min/1.73 m2 and proteinuria ≥0.5 g/day had a 26.7-fold higher risk (95% CI, 3.97-179.4) of renal events than patients with both eGFR ≥60 mL/min/1.73 m2 and proteinuria <0.5 g/day. CONCLUSIONS: Reduced eGFR and increased proteinuria as well as lower serum albumin at the time of renal biopsy are independent risk factors for renal events among patients with biopsy-proven benign nephrosclerosis.

Nephrosclerosis: a term in quest of a disease.

For a century, nephrosclerosis was ascribed to nonmalignant hypertension and aging. However, it was intuitively perceived that hypertension may follow rather than explain this nephrovasculopathy. Hypertensive nephrosclerosis was long considered a major cause of end-stage renal failure (ESRD). This is especially true in blacks of African descent but not in other ethnic populations. The term 'nephrosclerosis' is still an easy way out to classify a patient with renal insufficiency. This leads to neglect the possibility of an overlooked nephropathy complicated by hypertension and to believe that drastic blood pressure control may retard the progression to ESRD. Several clinical and experimental lines of evidence lead to the understanding that nephrosclerosis, especially in blacks, is a genetic renovasculopathy that precedes the rise in blood pressure. The identification of coding region variants in APOL1 encoding apolipoprotein L-1 in black but also white and Asians opens new lines of research on the genetics of nephroangiosclerosis and of FSGS. Metabolic derangements, such as obesity, oxidative stress, dyslipidemia and atherosclerosis may be considered confounding factors with regard to nephrosclerosis. Histomorphometric studies led to sorting out the lesions due to aging from those stemming from hypertension. They shed new light not only on glomerular lesions that comprise ischemic obsolescence but also on glomerulomegaly and focal-segmental sclerosis, the latter due to a loss of renal autoregulation. It appears that the control of hypertension is not credited with the expected benefit for slowing the decline of renal function. 'Nephrosclerosis' can be considered an umbrella term of poor significance that should be replaced by its pathologic description, that is, arterionephrosclerosis and incite to elucidate the various genetic and metabolic factors that lead to a lesion in quest of a specific disease.

Patients with biopsy-proven nephrosclerosis and moderately impaired renal function have a higher risk for cardiovascular disease: 15 years' experience in a single, kidney disease center.

BACKGROUND: Nephrosclerosis progresses slowly to end-stage renal disease (ESRD) in only a small percentage of patients. However, because hypertension and nephrosclerosis are normally found simultaneously, nephrosclerosis is a risk factor for cardiovascular disease (CVD). In turn, the onset of CVD may progress to further renal impairment. AIM: To evaluate clinical outcomes and the association between nephrosclerosis and CVD in the long term. DESIGN: Prospective study METHODS: We prospectively assessed 35 patients (male/female: 19/16) with nephrosclerosis aged >30 years at disease onset, attending the Kidney Disease Center, Saitama Medical University, in a single teaching hospital center between 1995 and 2014. Nephrosclerosis was diagnosed in accordance with the criteria outlined in the World Health Organization (WHO) monograph of renal diseases. All patients were followed by means of registries for 10 years to record subsequent events, if any. OUTCOMES: The primary study outcome was correlating the occurrence of CVD, defined as a composite of cardiovascular deaths, nonfatal and fatal myocardial infarction, and stroke, with the development of ESRD or death. RESULTS: The mean age of patients at the time of biopsy was 54.8 ± 12.7 years (range 33-72 years). Of these patients, seven were affected by nonfatal CVD and two died due to CVD. Only one patient developed ESRD during the follow-up period. Using Kaplan-Meier analysis, risk factors for the primary study outcome were estimated to include an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2), systolic blood pressure > 130 mmHg and proteinuria > 1 g/g creatinine. Univariate analysis was used for the assessment of the relative risk for the primary study endpoint of several covariates: age, systolic blood pressure, eGFR and proteinuria at time of renal biopsy. eGFR was found to be the strongest factor determining an event-free period [relative risk (RR) =1.931, p = 0.014]. CONCLUSIONS: Patients with nephrosclerosis are at high risk of CVD when they have moderately advanced renal impairment.

Glomerular Density in Biopsy-Proven Hypertensive Nephrosclerosis.

BACKGROUND: Previous autopsy studies suggested that a reduced nephron number is associated with increased risk of hypertension and chronic kidney disease. However, the significance of the nephron number estimated from a renal biopsy in patients with hypertensive nephrosclerosis (HNS) has not yet been elucidated. METHODS: In this cross-sectional study, we examined the clinicopathological findings of biopsy-proven HNS patients with preserved renal function (estimated glomerular filtration rate ≥ 60 ml/min/1.73 m(2)). The glomerular density (GD; the number of glomeruli per total renal cortical area) in biopsy specimens was evaluated as a surrogate of the nephron number. Renal biopsies from kidney transplant donors were used as healthy controls. RESULTS: A total of 58 HNS patients were enrolled. The GD value in the HNS patients was low compared with those in the kidney transplant donors (2.0 vs. 3.2 /mm(2)). These differences remained significant when globally sclerotic glomeruli were included in the calculation of the GD. Of note, the GD in HNS patients with overt proteinuria (≥1 g/day) was significantly lower than that of HNS patients with mild proteinuria (<1g/day; 1.8 vs. 2.2/mm(2), P = 0.014). In contrast, other histopathological parameters, including the severity of global glomerulosclerosis, interstitial fibrosis/tubular atrophy and arterial and arteriole lesions were comparable between the 2 HNS subgroups. In addition, the GD was identified as a factor that was associated with the amount of urinary protein excretion at biopsy, independent of other clinicopathological factors. CONCLUSIONS: These results suggest that a low GD is a renal histological characteristic of HNS patients, especially those with overt proteinuria.

Distinct protein signature of hypertension-induced damage in the renal proteome of the two-kidney, one-clip rat model.

BACKGROUND: Hypertensive nephrosclerosis is one of the most frequent causes of chronic kidney failure. Proteome analysis potentially improves the pathophysiological understanding and diagnostic precision of this disorder. In the present exploratory study, we investigated experimental nephrosclerosis in the two-kidney, one-clip (2K1C) hypertensive rat model. METHODS: The renal cortex proteome from juxtamedullary cortex and outer cortex of 2K1C male Wistar-Hannover rats (n = 4) was compared with the sham-operated controls (n = 6), using mass spectrometry-based quantitative proteomics. We combined a high abundant plasma protein depletion strategy with an extended liquid chromatographic gradient to improve peptide and protein identification. Immunohistology was used for independent confirmation of abundance. RESULTS: We identified 1724 proteins, of which 1434 were quantified with at least two unique peptides. Comparative proteomics revealed 608 proteins, including the platelet-derived growth factor receptor-ß signalling pathway, with different abundances between the non-clipped kidney of hypertensive 2K1C rats and the corresponding kidney of the normotensive controls (P < 0.05, absolute fold change ≥1.5). Among the most significantly altered proteins in the whole cortex were periostin, transgelin, and creatine kinase B-type. Relative abundance of periostin alone allowed clear classification of 2K1C and controls. Enrichment of periostin in 2K1C rats was verified by immunohistology, showing positivity especially around the fibrotic vessels. CONCLUSION: The proteome is altered in hypertension-induced kidney damage. We propose periostin, especially in combination with transgelin and creatine kinase B-type, as possible proteomic classifier to distinguish hypertensive nephrosclerosis from the normal tissue. This classifier needs to be further validated with respect to early diagnosis of fibrosis, prognosis, and its potential as a novel molecular target for pharmacological interventions.

Automated assessment of renal cortical surface roughness from computerized tomography images and its association with age.

RATIONALE AND OBJECTIVES: Nephrosclerosis occurs with aging and is characterized by increased kidney subcapsular surface irregularities at autopsy. Assessments of cortical roughness in vivo could provide an important measure of nephrosclerosis. The purpose of this study was to develop and validate an image-processing algorithm for quantifying renal cortical surface roughness in vivo and determine its association with age. MATERIALS AND METHODS: Renal cortical surface roughness was measured on contrast-enhanced abdominal computed tomography (CT) images of potential living kidney donors. A roughness index was calculated based on geometric curvature of each kidney from three-dimensional images and compared to visual observation scores. Cortical roughness was compared between the oldest and youngest donors, and its interaction with cortical volume and age assessed. RESULTS: The developed quantitative roughness index identified significant differences in kidneys with visual surface roughness scores of 0 (minimal), 1 (mild), and 2 (moderate; P < .001) in a random sample of 200 potential kidney donors. Cortical roughness was significantly higher in the 94 oldest (64-75 years) versus 91 youngest (18-25 years) potential kidney donors (P < .001). Lower cortical volume was associated with older age but not with roughness (r = -0.03, P = .75). The association of oldest age group with roughness (odds ratio [OR] = 1.8 per standard deviation [SD] of roughness index) remained significant after adjustment for total cortex volume (OR = 2.0 per SD of roughness index). CONCLUSIONS: A new algorithm to measure renal cortical surface roughness from CT scans detected rougher surface in older compared to younger kidneys, independent of cortical volume loss. This novel index may allow quantitative evaluation of nephrosclerosis in vivo using contrast-enhanced CT.

Critical blood pressure threshold dependence of hypertensive injury and repair in a malignant nephrosclerosis model.

Most patients with essential hypertension do not exhibit substantial renal damage. Renal autoregulation by preventing glomerular transmission of systemic pressures has been postulated to mediate this resistance. Conversely, malignant nephrosclerosis (MN) has been postulated to develop when severe hypertension exceeds a critical ceiling. If the concept is valid, even modest blood pressure (BP) reductions to below this threshold regardless of antihypertensive class (1) should prevent MN and (2) lead to the healing of the already developed MN lesions. Both predicates were tested using BP radiotelemetry in the stroke-prone spontaneously hypertensive rats receiving 1% NaCl as drinking fluid for 4 weeks. Severe hypertension (final 2 weeks average systolic BP, >200 mm Hg) and MN (histological damage score 36±5; n=27) developed in the untreated stroke-prone spontaneously hypertensive rats but were prevented by all antihypertensive classes (enalapril [n=15], amlodipine [n=13], or a hydralazine/hydrochlorothiazide combination [n=15]) if the final 2-week systolic BP remained <190 mm Hg. More impressively, modest systolic BP reductions to 160 to 180 mm Hg (hydralazine/hydrochlorothiazide regimen) initiated at ≈4 weeks in additional untreated rats after MN had already developed (injury score 35±4 in the right kidney removed before therapy) led to a striking resolution of the vascular and glomerular MN injury over 2 to 3 weeks (post-therapy left kidney injury score 9±2, P<0.0001; n=27). Proteinuria also declined rapidly from 122±9.5 mg/24 hours before therapy to 20.5±3.6 mg 1 week later. These data clearly demonstrate the barotrauma-mediated pathogenesis of MN and the striking capacity for spontaneous and rapid repair of hypertensive kidney damage if new injury is prevented.

Estudio traslacional de la vía Notch en nefropatía hipertensiva / Translational study of the Notch pathway in hypertensive nephropathy

Introducción: La ruta de señalización de Notch está activada en una gran variedad de patologías renales humanas. Recientemente hemos demostrado que la activación de esta ruta no estaría implicada en la fibrosis renal experimental inducida por angiotensina II o hipertensión. Objetivos: Evaluar si la vía Notch está activada en la fibrosis renal asociada a nefroesclerosis hipertensiva. Para validar la hipótesis se estudiaron varias patologías glomerulares caracterizadas por fibrosis túbulo-intersticial. Métodos: Se utilizaron biopsias renales de pacientes con nefroesclerosis hipertensiva, en comparación con nefropatía diabética y nefropatía membranosa en diferentes etapas de progresión. La expresión génica y proteica se evaluó por hibridación in situ e inmunohistoquímica, respectivamente. Resultados: En nefroesclerosis hipertensiva se observó baja expresión renal de proteínas de la vía Notch, no existiendo asociación entre la fibrosis túbulo-intersticial y los niveles de estas proteínas. Por el contrario, en las patologías glomerulares estudiadas se observó una elevada expresión de los transcritos Jagged-1, HES-1 y TGF-β, y de las proteínas Jagged-1 y Notch-1, localizados principalmente en células túbulo-epiteliales. Los niveles de expresión de los componentes de la vía Notch se relacionaron con el grado de fibrosis túbulo-intersticial, lo que confirma la activación de esta vía en nefropatías progresivas. Conclusiones: Nuestros datos muestran que la vía Notch no está activada en el riñón de pacientes con nefropatía hipertensiva, ampliando los resultados de los modelos experimentales de daño renal asociado a hipertensión a la patología humana. Nuestros estudios aportan nueva información sobre la compleja regulación del sistema Notch en el riñón (AU)

Introduction: The Notch signalling pathway is activated in a wide variety of human renal diseases. We have recently demonstrated that the activation of this pathway is not involved in experimental renal fibrosis induced by angiotensin II or hypertension. Objectives: To assess whether the Notch pathway is activated in renal fibrosis related to hypertensive nephrosclerosis. To test the hypothesis, various glomerular diseases characterised by tubulointerstitial fibrosis were analysed. Method: Renal biopsies were performed on patients with hypertensive nephrosclerosis, in comparison with diabetic nephropathy and membranous nephropathy at various stages. Gene and protein expression were evaluated by in-situ hybridisation and immunohistochemistry respectively. Results: In hypertensive nephrosclerosis low renal expression of notch-related proteins was observed. There was no link between tubulointerstitial fibrosis and the levels of these proteins. By contrast, in the glomerular diseases studied we observed high expression of the transcripts Jagged-1, HES-1 and TGF-β and the proteins Jagged-1 y Notch-1, localised primarily in tubuloepithelial cells. The levels of expression of the components of the Notch pathway correlate to the degree of tubulointerstitial fibrosis, which confirms the activation of this pathway in progressive nephropathies. Conclusions: Our data demonstrate that the Notch pathway is not activated in the kidneys of patients with hypertensive nephropathy, which extends the results of experimental models of kidney damage related to hypertension to the realm of human pathology. Our studies provide new information on the complex regulation of the Notch pathway in the kidney (AU)

[Nephrotic proteinuria in hypertensive nephrosclerosis: clinical and evolution characteristics]. / Proteinuria de tipo nefrótico en la nefroangioesclerosis hipertensiva: características clínicas y evolutivas.

BACKGROUND AND OBJECTIVE: Nephrotic range proteinuria can occur in patients with biopsy proven hypertensive nephrosclerosis (HN). We analysed the differential clinical and evolution characteristics of these patients compared with other glomerular diseases. MATERIAL AND METHOD: This is a case-control descriptive analysis obtained from the renal pathology registry of our hospital. Clinical features, treatment and evolution of these patients (cases) were compared with nephrotic patients with other glomerular diseases (controls). RESULTS: Five point one percent of biopsies with HN diagnosis. Case/control characteristics were: proteinuria 4.7 [3-11.4] versus 5.5 [3-28.1] g/24h/1.73m(2) (P=NS). Normal albumin compared with controls (39.5 [6.4] versus 29.4 [10] g/dL; P=.001), significant oedemas only in 10 versus 63% of controls. HN were older (58.8 [12.6] versus 45.5 [19.6] years), had longer hypertension duration before renal biopsy and more previous cardiovascular events (39 versus 16%). Mean blood pressure was higher (166/90 versus 133/75mmHg; P=.01) and had worse renal outcome. CONCLUSIONS: HN must be included in the differential diagnosis of nephrotic range proteinuria in hypertensive patients. The absence of oedema and normal serum albumin are distinctive clinical characteristics that can help in decision-making before performing a renal biopsy.

Subclinical nephrosclerosis is linked to left ventricular hypertrophy independent of classical atherogenic factors.

Recently, cardio-renal interactions have been considered to be important and it has been demonstrated that mild renal dysfunction is associated with left ventricular hypertrophy (LVH). However, the correlation between LVH and subclinical renal damage is unclear. We investigated this association by assessing pretransplant biopsies from living kidney donors with normal renal function. We retrospectively categorized 238 living kidney donors into tertiles according to the percentage of global glomerulosclerosis (%GGS) observed in pretransplant biopsies (low, 0-3.45% (n=80); moderate, 3.46-11.76% (n=78); high, ⩾11.77% (n=80)) to analyze trends in their left ventricular mass index (LVMI) measured by echocardiography and baseline factors. LVH was defined as LVMI >110 g m(-2) in female and >125 g m(-2) in male subjects. We used a logistic regression model to evaluate any correlations between %GGS and LVH. LVMI increased significantly with increasing tertiles of %GGS, as did the prevalence of left ventricular remodeling and LVH. According to multivariate logistic regression analysis, subjects with high %GGS tertiles had a sevenfold greater risk of LVH than did those with low tertiles, even after adjusting for age, sex, systolic blood pressure, history of diabetes mellitus, total serum cholesterol and glomerular filtration rate (GFR) measured by a radioisotopic technique. There is an association between GGS and LVH in subjects with normal renal function. This association is significant after adjustment for age, sex, blood pressure, GFR and other atherogenic factors.

Renal transplant elasticity ultrasound imaging: correlation between normalized strain and renal cortical fibrosis.

After transplantation, over a widely variable time course, the cortex of the transplanted kidney becomes stiffer as interstitial fibrosis develops and renal function declines. Elasticity ultrasound imaging (EUI) has been used to assess biomechanical properties of tissue that change in hardness as a result of pathologic damage. We prospectively assessed the hardness of the renal cortex in renal transplant allograft patients using a normalized ultrasound strain procedure measuring quasi-static deformation, which was correlated with the grade of renal cortical fibrosis. To determine cortical strain, we used 2-D speckle-tracking software (EchoInsight, Epsilon Imaging, Ann Arbor, MI, USA) to perform offline analysis of stored ultrasound loops capturing deformation of renal cortex and its adjacent soft tissue produced by pressure applied using the scanning transducer. Normalized strain is defined as the mean developed strain in the renal cortex divided by the overall mean strain measured in the soft tissues from the abdominal wall to pelvic muscles. Using the Banff scoring criteria for renal cortical fibrosis as the gold standard, we classified 20 renal transplant allograft biopsy tissue samples into two groups: group 1 (n = 10) with mild (<25%) renal cortical fibrosis and group 2 (n = 10) with moderate (26%-50%) renal cortical fibrosis. An unpaired two-tailed t-test was used to determine the statistical difference in strains between patients with mild and those with moderate renal cortical fibrosis. Receiver operating characteristic curve analysis was performed to assess the accuracy of developed strain and normalized strain in predicting moderate renal cortical fibrosis. The reference strain did not significantly differ between the two groups (p = 0.10). However, the developed renal cortical strain in group 1 with mild fibrosis was higher than that in group 2 with moderate fibrosis (p = 0.025). The normalized strain in group 1 was also higher than that in group 2 (p = 0.0014). The areas under receiver operating characteristic curves for developed strain and normalized strain were 0.78 and 0.95, respectively. The optimal cutoff for distinguishing moderate renal cortical fibrosis was -0.08 for developed strain (sensitivity = 0.50, specificity = 1.0) and 2.5 for normalized strain (sensitivity = 0.80, specificity = 1.0). In summary, renal cortex strain is strongly correlated with grade of renal cortical fibrosis. Normalized strain is superior to developed strain in distinguishing moderate from mild renal cortical fibrosis. We conclude that free-hand real-time strain EUI may be useful in assessing the progression of cortical fibrosis in renal transplant allografts. Further prospective study using this method is warranted.

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.

The implications of anatomical and functional changes of the aging kidney: with an emphasis on the glomeruli.

Aging is both a natural and inevitable biological process. With advancing age, the kidneys undergo anatomical and physiological changes that are not only the consequences of normal organ senescence but also of specific diseases (such as atherosclerosis or diabetes) that occur with greater frequency in older individuals. Disentangling these two processes, one pathologic and the other physiologic, is difficult. In this review we concentrate on the glomerular structural and functional alterations that accompany natural aging. We also analyze how these changes affect the identification of individuals of advancing age as having chronic kidney disease (CKD) and how these changes can influence prognosis for adverse outcomes, including all-cause mortality, end-stage renal disease, cardiovascular events and mortality, and acute kidney injury. This review describes important shortcomings and deficiencies with our current approach and understanding of CKD in the older and elderly adult.

Senile nephrosclerosis--does it explain the decline in glomerular filtration rate with aging?

Nephrosclerosis can be defined by the presence of glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis on renal biopsy. Chronic kidney disease is identified clinically by a reduction in glomerular filtration rate (GFR) and has been characterized histologically by nephrosclerosis. Many relatively healthy older adults have been diagnosed with chronic kidney disease because of a decline in GFR with normal aging. Recent data show that in healthy adults (living kidney donors), nephrosclerosis on renal biopsy does not associate with GFR independent of age. This may be explained by the decline in GFR and nephrosclerosis being universal with aging (i.e. senescence), by structural changes in the kidney other than nephrosclerosis impacting GFR, or by extrarenal factors affecting GFR decline with age. However, the argument that the age-related decline in GFR can be fully explained by the development of nephrosclerosis in a subset of older adults is not supported by existing data.

Podocyte injury damages other podocytes.

Loss of podocytes promotes glomerulosclerosis, but whether this results from a continued primary insult or a secondary mechanism triggered by the initial loss of podocytes is unknown. We generated chimeric mice in which only a subpopulation of podocytes expressed hCD25, which is the receptor for the immunotoxin LMB2. In addition, genetic labeling of hCD25-negative cells with human placental alkaline phosphatase allowed the study of these two distinct podocyte populations. Administration of LMB2 did not cause podocyte injury in hCD25-negative control mice. In contrast, LMB2 severely damaged or sloughed off the subpopulation of hCD25-positive podocytes within the chimeric glomeruli. Moreover, hCD25-negative podocytes, which were immune to the initial toxin injury, developed injury as early as 4 d after LMB2 injection, evidenced by foot process effacement, upregulation of desmin, and downregulation of nephrin, podocin, and podocalyxin. Furthermore, the magnitude of secondary injury correlated with the magnitude of primary injury, supporting the concept of an amplified cascade of podocyte injury. In conclusion, podocyte damage can propagate injury by triggering secondary damage of "remnant" intact podocytes, even when the primary insult is short-lived. This transmission of podocyte injury may form a vicious cycle leading to accelerated podocyte deterioration and glomerulosclerosis.