Time-averaged proteinuria during follow-up and renal prognosis in patients with biopsy-proven benign nephrosclerosis.

BACKGROUND: Heavy proteinuria at diagnostic renal biopsy has been reported as an independent risk factor for deteriorating renal function in benign nephrosclerosis (BNS). However, studies investigating the relationship between the amount of proteinuria during follow-up and long-term renal prognosis in BNS are limited. This study aimed to assess the relationship between time-averaged proteinuria (TAP) and renal prognosis in BNS. METHODS: The study participants included 98 patients with biopsy-proven BNS (average age 52 ± 13 years, estimated glomerular filtration rate (eGFR) 53 ± 25 ml/min/1.73 m2, urine protein excretion at baseline 1.34 ± 1.30 g/gCr) from the Jikei University Hospital. Multivariate analysis was used to investigate the effects of TAP and other clinicopathological findings on the risk for renal outcome in biopsy-proven BNS (a 30% decline in eGFR from baseline or end-stage renal disease). Proteinuria was measured every 6 months and the mean value was used as an indicator of TAP. RESULTS: The average observation period was 56 ± 43 months. In the unadjusted model, higher levels of TAP and urinary protein at baseline, glomerulosclerosis, and tubulointerstitial damage were associated with renal prognosis. The adjusted model demonstrated a significant association between TAP and renal outcomes (hazard ratio 5.45, 95% confidence interval 3.02-10.7), which was independent of higher baseline proteinuria, glomerulosclerosis, and tubulointerstitial damage. CONCLUSIONS: TAP is an independent risk factor for renal prognosis in patients with BNS, indicating the significance of urinary protein excretion during follow-up for the progression of BNS. Clinicians should understand the importance of follow-up evaluation for proteinuria in patients with BNS.

Intrarenal and Urinary Th9 and Th22 Cytokine Gene Expression in Lupus Nephritis.

OBJECTIVE: We studied the urinary sediment mRNA level of Th9- and Th22-related cytokines in patients with systemic lupus erythematosus (SLE). METHODS: We quantified urinary mRNA levels of interleukin (IL) 9, IL-10, IL-22, and their corresponding transcription factors in 73 patients with active lupus nephritis, 13 patients with hypertensive nephrosclerosis (HTN), and 25 healthy subjects. RESULTS: There was no detectable IL-9 mRNA in all samples. Patients with proliferative lupus nephritis had significantly lower urinary IL-22 mRNA levels than those with nonproliferative nephritis (2.2 ± 5.4 vs 8.6 ± 20.0 copies, p = 0.019), and urinary IL-22 mRNA level inversely correlated with the histological activity index (r = -0.427, p < 0.0001). In contrast, patients with lupus nephritis had significantly higher urinary IL-10 mRNA levels than patients with HTN (7.8 ± 18.5 vs 1.9 ± 4.0 copies, p = 0.012), and urinary IL-10 mRNA levels correlated with its intrarenal mRNA levels (r = 0.337, p = 0.004) and SLE disease activity index (r = 0.277, p = 0.018). Urinary IL-10 mRNA level was significantly lower among patients who achieved complete remission than those with partial remission or no response (4.1 ± 6.5 vs 14.1 ± 28.0 copies, p = 0.036). CONCLUSION: Urinary IL-22 mRNA level is decreased in patients with SLE with proliferative nephritis, while urinary IL-10 mRNA levels correlates with its intrarenal mRNA level and disease activity. Urinary IL-10 mRNA levels may also predict treatment response. These results suggest that urinary mRNA levels of IL-10 and IL-22 might be used as biomarkers for assessing disease activity and risk stratification in lupus nephritis.

Urinary mRNA levels of ELR-negative CXC chemokine ligand and extracellular matrix in diabetic nephropathy.

BACKGROUND: Inflammation and fibrosis play important roles in the progression of diabetic nephropathy. We determine the urinary mRNA levels of ELR-CXC chemokine ligand and extracellular matrix in diabetic nephropathy. METHODS: We studied 26 patients with biopsy-proven diabetic nephropathy, 15 with hypertensive nephrosclerosis and 10 healthy controls. Urinary mRNA levels of CXCL9, CXCL10, CXCL11, collagen I A1 chain, collagen IV A3 chain and fibronectin were measured. Patients were followed for 36.9 ± 7.4 months to determine the rate of glomerular filtration rate (GFR) decline. RESULTS: Urinary mRNA levels of CXCL10 and CXCL11 are decreased, and those of collagen I A1 chain and fibronectin are increased in diabetic nephropathy. Baseline estimated GFR correlates with urinary mRNA level of CXCL9 (r = 0.583, p = 0.002) and CXCL11 (r = 0.703, p < 0.0001), respectively. The rate of GFR decline significantly correlates with urinary CXCL9 (r = -0.618, p = 0.0008) and CXCL11 mRNA levels (r = -0.726, p < 0.0001). Multivariate linear regression analysis confirms that urinary CXCL9 mRNA level is independently associated with the rate of GFR decline, while the correlation with urinary CXCL11 mRNA level has borderline significance. CONCLUSION: Urinary CXCL9 and CXCL11 mRNA levels correlate with baseline renal function. The rate of renal function decline correlates with urinary CXCL9 mRNA level. Our results suggest that urinary CXCL9 mRNA levels may be used for risk stratification of diabetic nephropathy.

[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.

MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis.

Micro (mi)RNAs are frequently dysregulated in the development of renal fibrosis. Exosomes are small membrane vesicles that could be isolated from urine secreted from all nephron segments. Here we sought to observe for the first time whether miRNA in urine exosome could serve as a potential biomarker of renal fibrosis. Urine samples were collected from 32 chronic kidney disease (CKD) patients who underwent kidney biopsy and 7 controls. Exosome was isolated and confirmed by immunogold staining of exosome marker. Members of miR-29, miR-200, and RNU6B as endogenous control were detected by RT quantitative PCR. Electronic microscopy verified a typical shape of exosome with average size of 65.1 nm and labeled it with anti-CD9 and anti-aquaporin 2 antibody. Members of miR-29 and miR-200 are readily measured with reduced levels compared with controls (P < 0.05) and can robustly distinguish CKD from controls [area under the curve (AUC) varied from 0.902 to 1 by receiver operating characteristics analysis]. miR-29c correlated with both estimated glomerular filtration rate (r = 0.362; P < 0.05) and degree of tubulointerstitial fibrosis (r = -0.359; P < 0.05) for CKD patients. Moreover, miRNA in exosome was decreased in mild fibrosis group compared with moderated to severe group. miR-29a and miR-29c could predict degree of tubulointerstitial fibrosis with AUC of 0.883 and 0.738 (P < 0.05). The sensitivity and specificity for distinguishing mild from moderate to severe fibrosis were 93.8 and 81.3% with the use of miR-29a and 68.8 and 81.3% for miR-29c. Overall, miR-29c in urinary exosome correlates with both renal function and degree of histological fibrosis, suggesting it as a novel, noninvasive marker for renal fibrosis.

Beta2-microglobulin and alpha1-microglobulin as markers of Balkan endemic nephropathy, a worldwide disease.

BACKGROUND: Urine beta2-microglobulin (beta2-MG) was mainly used as a tubular marker of Balkan endemic nephropathy (BEN) but recently alpha1-microglobulin (alpha1-MG) was proposed for the diagnosis of BEN. In this study, the potential of urine beta2-MG, alpha1-MG, albumin, and total protein in the differentiation of BEN from healthy persons and patients with glomerulonephritis (GN) and nephrosclerosis (NS) was examined. METHODS: This study involved 47 patients with BEN, 36 with GN, 11 with NS, 30 healthy subjects from BEN families, and 46 healthy subjects from non-BEN families. RESULTS: In BEN patients area under the curve (AUC) for urine beta2-MG (0.828) and alpha1-MG (0.782) was higher than for urine albumin (0.740), but in GN patients AUC for urine protein (0.854) and albumin (0.872) was significantly higher than for the two low molecular weight proteins. AUC for all four urinary markers in NS patients was significantly lower than in BEN patients, ranging between 500 and 595. Median urine beta2-MG excretion in BEN patients was 17.5 times higher than in GN patients and 18.3 times higher than in controls; median alpha1-MG excretion was higher only 3.0 and 2.25 times, respectively. In the differentiation of BEN from healthy controls, beta2-MG had higher sensitivity and specificity at the cutoff levels (p < 0.001) than alpha1-MG (p < 0.05). In the differentiation of BEN from GN, beta2-MG was the best marker. CONCLUSION: All four urinary markers can be used for the differential diagnosis of BEN, beta2-MG being the best. Like in aristolochic acid nephropathy, beta2-MG seems to be an early marker of tubular damage in BEN.

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.

Rapid progression to end-stage renal disease in young hypertensive African Americans with proteinuria.

Hypertensive nephrosclerosis (HN) remains the most common cause of end-stage renal disease (ESRD) in blacks. This study examined whether renal histology corresponds with clinical hypertension in proteinuric blacks. Nondiabetic hypertensive blacks who satisfied inclusion criteria were enrolled in this study. Four male patients, each with a family history of hypertension and mean age 41 years, consented to kidney biopsy. Their mean arterial pressure was 116.5 mm Hg, mean urine protein excretion was 7.7 +/- 3.5 g/day. All patients progressed to ESRD within a mean duration of 14 months; the mean rate of decline in glomerular filtration rate was 53 mL/min/y, with an ESRD incidence of 80%/y. The histologic findings were consistent with previously described features of HN. Prominent glomerulosclerosis involved 30% to 75% of the glomeruli and extensive arteriolosclerosis/arteriosclerosis, tubular atrophy, and interstitial fibrosis. There was no evidence of immune complex disease by either immunofluorescence, electron microscopy, or serologic studies. The mean arterial pressure showed a strong but nonsignificant correlation with progression to ESRD (r = 0.8) and arteriosclerosis/arteriolosclerosis (r = 0.8). Glomerular sclerosis correlated with the reciprocal of serum creatinine (r = 0.6), interstitial fibrosis (r = 0.8), and arteriosclerosis/arteriolosclerosis (r = 0.3). Urine protein excretion correlated weakly with progression to ESRD (r = 0.4). These results indicate a poor correlation between clinical findings and histologic features on renal biopsy in young hypertensive African Americans. Hypertension remains a major cause of ESRD among African Americans, and progression to ESRD may be rapid in patients with marked proteinuria. Early and aggressive intervention is warranted.

[Significance of daily hydroxyprolinuria in the early diagnosis of nephrosclerosis in patients with chronic pyelonephritis]. / Znachenie sutochnoi oksiprolinurii dlia rannei diagnostiki nefroskleroza u bol'nykh khronicheskim pielonefritom.

Studies of daily excretion of hydroxyproline with the urine in patients with chronic pyelonephritis (CP) showed manifest hyper-hydroxyprolinuria at the early stages of the disease, which augmented with the development of renal insufficiency. Measurement of hydroxyproline in the urine of CP patients is proposed as a test reflecting the renal connective tissue metabolism at the early stages of the disease. It can be used for assessing the activity of the sclerotic process in the kidneys of CP patients, for predicting the disease course and outcome, and, probably, for developing methods of adequate pathogenetic therapy based on biochemical monitoring. The method is noninvasive, sufficiently informative, and available for clinical diagnostic laboratories.

[Circadian hydroxyprolinuria in the early diagnosis of nephrosclerosis in patients with chronic pyelonephritis]. / Sutochnaia oksiprolinuriia v rannei diagnostike nefrosklerosa pri khronicheskom pielonefrite.

The time course of daily urinary excretion of hydroxyproline (HOP) was followed up in patients with chronic pyelonephritis. Manifest hyperhydroxyprolinuria was observed in these patients at the earliest stages of nephrosclerosis, and it augmented with development of renal insufficiency. Measurements of HOP in the urine of patients with chronic pyelonephritis is proposed as an indicator reflecting the metabolic status of renal connective tissue at the early stages of nephrosclerosis. It can be used to assess the activity of the sclerotic process in the kidneys of patients with chronic pyelonephritis, predict the disease course and outcome, and, probably, to develop methods of adequate pathogenetic therapy with biochemical monitoring. The method is not invasive, sufficiently informative, and available for clinical diagnostic laboratories.

The effects of sevoflurane and isoflurane anesthesia on renal tubular function in patients with moderately impaired renal function.

Increasing evidence indicates that sevoflurane anesthesia does not impair renal function in healthy patients despite higher concentrations of plasma inorganic fluoride. However, whether sevoflurane further affects renal tubular function in patients with impaired renal function is not known. We compared the effect of sevoflurane anesthesia with that of isoflurane anesthesia on renal tubular function in patients with moderately impaired renal function. Fourteen patients with creatinine clearance between 10 and 55 mL/min were anesthetized with either sevoflurane or isoflurane using a semiclosed circuit system. Plasma inorganic fluoride concentrations and urine N-acetyl-beta-D-glucosaminidase (NAG), gamma-glutamyltranspeptidase (gamma-GTP), and beta 2-microglobulin (beta 2MG) excretions were measured up to post-anesthetic day 14. Although both the peak plasma inorganic fluoride concentrations and the areas under the curve of plasma inorganic fluoride concentration versus time were significantly greater in the sevoflurane group than in the isoflurane group, urine NAG, gamma-GTP, and beta 2MG excretions per day did not differ between the two groups. These results indicate that sevoflurane and isoflurane may have similar effects on the renal tubules in patients with moderately impaired renal function.

Difference of serum levels of type IV collagen 7S between early or overt nephropathy and nondiabetic renal disease in diabetic patients with micro- or macroalbuminuria.

We determined serum levels of type IV collagen 7S (IV 7S) in 73 (23 with normoalbuminuria, 21 with microalbuminuria, 17 with macroalbuminuria, and 12 primarily affected by nondiabetic renal disease (NDRD)) and 24 (10 with only macroangiopathy and 14 with retinopathy and macroangiopathy) diabetic patients to see whether IV 7S can be a useful index for differentiating early or overt diabetic nephropathy from NDRD in micro- or macroalbuminuric diabetics. IV 7S was significantly elevated in diabetic patients with micro-or macroalbuminuria compared to those with normoalbuminuria and healthy controls (p < 0.001). On the contrary, all 12 diabetic patients with micro- or macroalbuminuria due to NDRD showed normal or low IV 7S level. IV 7S was significantly higher in diabetic patients with both retinopathy and macroangiopathy than in those with only macroangiopathy (p < 0.001). We conclude that IV 7S levels may be a useful index to differentiate diabetic early or overt nephropathy from NDRD, especially nephrosclerosis, in micro- or macroalbuminuric diabetics.

Inappropriately high plasma renin activity accompanies chronic loss of renal function.

Stimulation of both the systemic and local renin-angiotensin systems participates in the pathogenesis of tissue injury observed in experimental renal disease. However, substantial information demonstrating excessive activation of the renin-angiotensin system in patients with chronic renal disease is not available in spite of the well-established role of this system in the progression of renal damage. This investigation examined the plasma renin activity (PRA) and the ratio of this parameter to the simultaneously measured glomerular filtration rate (PRA/GFR) in normal volunteers (mean values 3.2 ng/ml/h and 3.0 ng/ml/h/100 ml GFR, respectively) and in patients with chronic renal disease (1.6 ng/ml/h and 28.5 ng/ml/h/100 ml GFR, respectively). A mean tenfold increase in the PRA/GFR ratio was observed in patients with chronic renal disease as compared to normal volunteers. The observed augmentation in PRA was not caused by physiologic mechanisms aimed at conserving urinary sodium since a positive correlation was found between PRA/GFR and the fractional excretion of sodium (y = 2.75 + 2.23x; r = 0.781, p < 0.01), as opposed to that of normal controls (y = 5.3 - 1.46x; r = -0.640, p < 0.01). Consequently, our results support the existence of inappropriate activation of the renin-angiotensin system in humans with chronic renal disease. Such stimulation might play a critical role in the pathophysiology of advanced renal injury.

Urinary excretion rate of guanidinoacetic acid as a new marker in hypertensive renal damage.

This study was undertaken to evaluate the relation between the urinary excretion of guanidinoacetic acid (GAA) and other substances in hypertensive patients (6 with borderline hypertension and 29 with hypertension) and 12 normal controls. In 10 of the hypertensive patients, GAA was measured before and after 4 weeks of treatment with calcium entry blocker. In hypertensive patients the rate of GAA urinary excretion was 43.5 +/- 17-4 micrograms/min, which was much lower than in the controls (77.2 +/- 35.9 micrograms/min) (p less than 0.01). There was no significant difference among these groups in creatinine clearance (CCr), serum creatinine (Cr), beta 2-microglobulin (BMG) or in the urinary excretion of BMG, N-acetyl-D-glucosaminidase (NAG) or radiosensitive microalbumin (mAlb). The urinary excretion rate of GAA was positively correlated with CCr (r = 0.62; p less than 0.01), and negatively correlated with mean blood pressure (r = -0.49; p less than 0.01). Finally, the GAA excretion was significantly correlated with urinary NAG (r = 0.24; p less than 0.05) and serum BMG (r = -0.31; p less than 0.05), but not with urinary mAlb (r = 0.12; p less than 0.05). Ten hypertensive patients followed for 4 weeks attained their ultimate mean blood pressure reduction after treatment (from 119.3 +/- 8.0 to 101.7 +/- 13.5 mm Hg; p less than 0.001), but the GAA/Cr ratio in the urinary excretion was significantly elevated (from 0.054 +/- 0.016 to 0.070 +/- 0.02; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Proteinuria in benign nephrosclerosis.

Benign nephrosclerosis seldom is associated with significant proteinuria or reduced renal function. This study demonstrated that, despite the finding of benign nephrosclerosis on a renal biopsy specimen, concomitant proteinuria is predictive of a poor prognosis. Twelve patients, ranging in age from 24 to 59 years, with hypertension, proteinuria (greater than 1 g/d), and findings of benign nephrosclerosis on renal biopsy specimens were studied retrospectively. In three of these patients, the hypertension and proteinuria were diagnosed during pregnancy. Follow-up was possible in 11 patients. Nine patients became nephrotic in the course of their disease. Two patients had endstage renal disease and required maintenance dialysis treatment. Seven patients had decreased renal function as shown by the increase in serum creatinine levels. Thus, the combination of hypertension, proteinuria (greater than 1 g/d), and benign nephrosclerosis may be indicative of a progressive condition with a high percentage of patients having renal failure.

N-acetyl-beta-glucosaminidase and beta 2-microglobulin. Their urinary excretion in patients with renal parenchymal disease.

The urinary excretion of N-acetyl-beta-glucosaminidase (NAG) and beta 2-microglobulin (beta 2M) was studied in 43 patients with various forms of renal parenchymal disease. Patients with membranous nephropathy, membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis, obstructive pyelonephritis, nephrosclerosis, and minimal change nephropathy generally had urinary NAG and beta 2M levels more than 3 SDs above those seen in normal subjects. Patients with progressive renal disease averaged higher NAG and beta 2M urinary levels than those with the same renal lesion and stable function. Since elevated urinary levels of NAG and beta 2M suggest renal tubular injury or dysfunction, our observations suggest tubulointerstitial involvement in a wide variety of renal diseases.

Urinalysis and clinical renal disease.

Urinalysis is a simple, efficient, and accurate guide in the diagnosis of renal disease. By determining a patient's history and obtaining a physical examination, the physician is very often able to diagnose a patient's renal lesion. Heavy proteinuria and a microscopic sediment containing red cells and red cell casts strongly suggest acute glomerulonephritis. The causes of this nephropathy are legion. On the other hand, mild proteinuria and a lack of microscopic findings suggest nephrosclerosis, interstitial nephritis, or acute tubular necrosis in the proper clinical setting. When glomerular disease produces nephrotic syndrome, the various types of glomerular disease can be diagnosed accurately without biopsy in a high percentage of cases.