Tubular biomarkers to assess progression of diabetic nephropathy

Despite aggressive management, many patients with diabetic nephropathy still develop end-stage renal disease. Accompanying tubulointerstitial damage is important in the progression of diabetic nephropathy. Markers of tubular damage, such as NGAL, KIM-1, and LFABP, have been proposed for monitoring the effectiveness of therapy. However, Nielsen et al. report a lack of an independent correlation between these biomarkers and glomerular filtration rate. Therefore, these markers seem to offer no improvement in the management of diabetic nephropathy.     

Kidney injury molecule-1 correlates with kidney function in renal allograft recipients

IntroductionKIM-1 (kidney injury molecule-1) is responsible for the clearance of debris from damaged renal tubules. KIM-1 can be expressed and excreted in urine within 12 hours after the initial ischemic insult and before regeneration of the epithelium, persisting over time thereafter. Urinary KIM-1 has been reported to be a noninvasive, rapid, sensitive, and reproducible biomarker of experimental nephrotoxic and ischemic acute kidney injury. Renal KIM-1 expression is significantly increased in human kidney tissue among patients with a wide range of kidney diseases, including various types of glomerulonephritis, chronic allograft nephropathy, acute rejection, hypertension, and Wegener's granulomatosis. Both renal and urinary KIM-1 correlate with kidney damage and negatively with renal function, but not with proteinuria. The aim of this study was to assess whether urinary KIM-1 correlated with kidney function in kidney allograft recipients.MethodsSerum NGAL, creatinine and estimated glomerular filtration rate (eGFR) were evaluated in 170 kidney allograft recipients on therapy with a calcineurin inhibitor plus mycophenolate mofetil or azathioprine and prednisone as well as in healthy volunteers. KIM-1 was estimated in urine using a commercially available kit.ResultsKidney transplant recipients showed significantly higher KIM-1 values than the control group. Normotensive kidney allograft recipients displayed significantly lower NGAL results than hypertensive subjects. Urinary KIM-1 was significantly higher among diabetic than nondiabetic subjects, whereas creatinine did not differ significantly between them. Upon univariate analysis urinary KIM-1 strongly correlated with serum creatinine (r = .64) and eGFR (r = ?.71), and only weakly with other parameters. Upon multiple regression analysis, the best predictor of urinary KIM-1 was eGFR (beta ?0.61), which explained 61% of KIM-1 concentrations.ConclusionEven a successful kidney transplantation is associated with kidney injury as reflected by elevated urinary KIM-1 and lower eGFR. Therefore, KIM-1 needs to be investigated as a potential early marker for impaired renal function/kidney injury, especially in patients with other risk factors for damage such as hypertension or diabetes.     

Potential biomarkers for the early detection of acute kidney injury after percutaneous nephrolithotripsy

This study aims to investigate the role of urinary biomarkers in the determination of the potential risks of renal parenchymal tubular damage in adult patients who underwent percutaneous nephrolithotomy (PNL) with the indication of renal stone. A randomized and prospective controlled study was performed between June and December 2013. We enrolled 29 consecutive patients with renal calculi?>?2?cm and who underwent PNL, as well as 47 healthy control subjects. Urine samples, including 2 h before surgery, 2 and 24 h after surgery were collected from the patient group. Freshly voided urine samples were collected from the control group. Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-glucosaminidase (NAG), and liver-type fatty acid binding protein (LFABP) levels were measured from these urine samples. The mean KIM-1/Cr value that measured 24 h after the operation was statistically significant, higher than its preoperative (preop) level (p?= 0.045). A significant difference was detected between the mean preop and postoperative (postop) 24 h NAG/Cr values (p?< 0.001). Also, postop 24 h NGAL/Cr levels were statistically significant, higher than its preop levels (p?= 0.013). According to the comparison of preop and postop levels, an increase in LFABP/Cr values secondary to surgical intervention was observed without any statistically significant difference. Besides the LFABP/Cr levels do not change after percutaneous kidney surgery, KIM-1/Cr, NAG/Cr, and NGAL/Cr levels increase postop period, especially at 24 h. Further studies with a larger series and repeated measurements should be performed to clarify if they can be used to demonstrate renal damage after percutaneous surgery or not.     

Urinary and Serum Biomarkers after Cardiac Catheterization in Diabetic Patients with Stable Angina and without Severe Chronic Kidney Disease

Background/Aims. Different serum and urinary biomarkers have been recently proposed to serve as markers of acute kidney injury. We tested the hypothesis whether NGAL and other biomarkers could represent an early biomarker of contrast nephropathy (CIN) in diabetic patients with normal serum creatinine undergoing cardiac catheterization in comparison with non-diabetic patients. Methods. Serum, urinary NGAL, cystatin C, urinary kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and liver-type fatty acid binding protein (L-FABP) were evaluated before and 2, 4, 8, 24, and 48 hours after cardiac catheterization using commercially available kits. Results. In both groups we found a significant rise in serum NGAL after 2, 4, and 8 hours, and in urinary NGAL and IL-18 after 4, 8, and 24 hours after cardiac catheterization. Serum cystatin C increased significantly 8 hours, reaching peak 24 hours after cardiac catheterization in both groups, and then decreased after 48 hours. L-FABP and KIM-1 increase significantly after 24 and 48 hours after cardiac catheterization. Conclusions. CIN was similarly prevalent in both diabetic and non-diabetic patients undergoing cardiac catheterization. NGAL seems to be a potential early marker for nephrotoxicity and predictor of contrast nephropathy. It is particularly important in the upcoming setting of short-time hospitalizations for cardiac catheterization.     

Persistent renal hypertrophy and faster decline of glomerular filtration rate precede the development of microalbuminuria in type 1 diabetes

Soon after the onset of type 1 diabetes, renal hypertrophy and hyperfiltration become manifest, particularly among patients who will subsequently develop diabetic nephropathy. Whether these early renal dysfunctions are involved in the pathogenesis of diabetic nephropathy is currently unclear. We evaluated, during the same day, kidney volume and glomerular filtration rate (GFR) in 146 patients with type 1 diabetes and normal renal function. All the individuals were then monitored for a mean of 9.5 +/- 4.4 years for the development of microalbuminuria. Kidney volume and GFR were reevaluated in a subset of 68 patients 4 years after baseline. During follow-up, microalbuminuria developed in 27 of 146 diabetic patients. At baseline, kidney volume (312.8 +/- 52.6 vs. 281.4 +/- 46.1 vs. 236.8 +/- 41.6 ml/1.73 m(2), P < 0.05) but not GFR was increased in patients predisposed to microalbuminuria. Risk of progression was higher in patients with increased kidney volume (P = 0.0058). Patients predisposed to microalbuminuria showed a stable increase in kidney volume (P = 0.003), along with a faster decline of GFR (P = 0.01). Persistent renal hypertrophy and faster decline of GFR precede the development of microalbuminuria in type 1 diabetes. These findings support the hypothesis that renal hypertrophy precedes hyperfiltration during the development of diabetic nephropathy.     

Progression of diabetic nephropathy

BACKGROUND: Diabetic nephropathy is a major cause of renal failure. The decline in glomerular filtration rate (GFR) is highly variable, ranging from 2 to 20, with a median of 12 mL/min/year. The risk factors of losing filtration power (progression promoters) have not been clearly identified. Furthermore, information on optimal arterial blood pressure, glycemic control, and cholesterol levels are lacking. METHODS: We measured GFR with (51)Cr-EDTA plasma clearance technique, blood pressure, albuminuria, glycosylated hemoglobin A1c, and serum cholesterol every year for seven years (range 3 to 14 years) in 301 consecutive type 1 diabetic patients with diabetic nephropathy recruited consecutively during 1983 through 1997. Diabetic nephropathy was diagnosed clinically if the following criteria were fulfilled: persistent albuminuria> 200 microg/min, presence of diabetic retinopathy, and no evidence of other kidney or renal tract disease. In total, 271 patients received antihypertensive treatment at the end of the observation period. RESULTS: Mean arterial blood pressure was 102 +/- 0.4 (SE) mm Hg. The average decline in GFR was 4.0 +/- 0.2 mL/min/year and even lower (1.9 +/- 0.5 mL/min/year) in the 30 persistently normotensive patients, none of whom had ever received antihypertensive treatment (P < 0.01). A multiple linear regression analysis revealed a significant positive correlation between the decline in GFR and mean arterial blood pressure, albuminuria, glycosylated hemoglobin A(1c), and serum cholesterol during follow-up (R(adj)(2) = 0.29, P < or = 0.001). No threshold level for blood pressure, glycosylated hemoglobin A(1c), or serum cholesterol was demonstrated. A two-hit model with mean arterial blood pressure and glycosylated hemoglobin A(1c) below and above the median values (102 mm Hg and 9.2%, respectively) revealed a rate of decline in GFR of only 1.5 mL/min/year in the lowest stratum compared with 6.1 mL/min/year in the highest stratum (P < 0.001). CONCLUSIONS: The prognosis of diabetic nephropathy has improved during the past decades, predominantly because of effective antihypertensive treatment. Genuine normotensive patients have a slow progression of nephropathy. Several modifiable variables have been identified as progression promoters.     

Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbuminuria.

BACKGROUND: Intervention studies in microalbuminuric type 2 diabetic patients have demonstrated that it is possible to avoid progression to overt diabetic nephropathy and even to achieve regression to normoalbuminuria. However, the long-term impact of stabilization/regression in albuminuria on decline in glomerular filtration rate (GFR) has not been established. METHODS: 151 patients with type 2 diabetes and microalbuminuria at baseline in whom GFR was measured at least three times during 7.8 years of follow-up were divided into three groups according to the level of albuminuria during follow-up. Overt nephropathy was diagnosed as a urinary albumin excretion rate (AER) >300 mg/24 h and remission to normoalbuminuria was defined as an AER <30 mg/24 h at the last examination. RESULTS: During follow-up, 46 patients achieved remission to normoalbuminuria, 58 remained microalbuminuric and 47 patients progressed to overt nephropathy. The mean (+/- SE) yearly decline in GFR was lowest (2.3+/-0.4 ml/min/year) in patients who obtained remission, in comparison with patients remaining microalbuminuric, in whom the decline was 3.7+/-0.4 ml/min/year, and patients progressing to overt nephropathy, who had a decline in GFR of 5.4+/-0.5 ml/min/year (ANOVA, P<0.001). Start of antihypertensive treatment during follow-up was strongly associated with remission to normoalbuminuria [odds ratio: 2.32; 95% confidence interval (CI): 1.09-4.93] whereas a decrease in HbA(1c) by 1% increased the probability for remission (odds ratio: 1.48; 95% CI: 1.11-1.97). CONCLUSIONS: Remission to normoalbuminuria was associated with a decreased GFR decline during 7.8 years of follow-up in type 2 diabetic patients with microalbuminuria. Antihypertensive therapy and improved glycaemic control were independent predictors for remission.     

Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function

To better understand the diagnostic and predictive performance of urinary biomarkers of kidney injury, we evaluated γ-glutamyltranspeptidase (GGT), alkaline phosphatase (AP), neutrophil-gelatinase-associated lipocalin (NGAL), cystatin C (CysC), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) in a prospective observational study of 529 patients in 2 general intensive care units (ICUs). Comparisons were made using the area under the receiver operator characteristic curve (AUC) for diagnosis or prediction of acute kidney injury (AKI), dialysis, or death, and reassessed after patient stratification by baseline renal function (estimated glomerular filtration rate, eGFR) and time after renal insult. On ICU entry, no biomarker had an AUC above 0.7 in the diagnosis or prediction of AKI. Several biomarkers (NGAL, CysC, and IL-18) predicted dialysis (AUC over 0.7), and all except KIM-1 predicted death at 7 days (AUC between 0.61 and 0.69). Performance was improved by stratification for eGFR or time or both. With eGFR <60?ml/min, CysC and KIM-1 had AUCs of 0.69 and 0.73, respectively, within 6?h of injury, and between 12 and 36?h, CysC (0.88), NGAL (0.85), and IL-18 (0.94) had utility. With eGFR >60?ml/min, GGT (0.73), CysC (0.68), and NGAL (0.68) had the highest AUCs within 6?h of injury, and between 6 and 12?h, all AUCs except AP were between 0.68 and 0.78. Beyond 12?h, NGAL (0.71) and KIM-1 (0.66) performed best. Thus, the duration of injury and baseline renal function should be considered in evaluating biomarker performance to diagnose AKI.     

The Renal Effects of Blood Glucose-Lowering Plant-Derived Extracts in Diabetes Mellitus—an Overview

Diabetes mellitus, a disorder characterized by chronic hyperglycemia and excessive urine excretion, is associated with complications such as atherosclerosis, cardiac dysfunction, and nephropathy. Renal disease, which develops through a number of metabolic pathways in diabetes, is characterized by functional as well as structural abnormalities of the kidney. The most common cause of end-stage renal disease (ESRD) is diabetic nephropathy, which accounts for significant morbidity and mortality. Current conventional diabetes therapy using blood glucose-lowering medications has limitations in averting the development of renal diseases. The onset of diabetic nephropathy is associated with a progressive rate of decline in renal function, urinary albumin excretion, and glomerular filtration rate (GFR). Diabetes mellitus treatment should therefore aim to intervene on promoters of the decline in renal function in diabetes to avert adverse outcomes. Preventing the pathogenesis of nephropathy with therapeutic interventions based on specific alterations in kidney function represents a plausible approach. Cumulative evidence suggests that some herbal extracts with hypoglycaemic properties may have beneficial effects on some processes associated with a decline in renal function, as well as reduce the severity of nephropathy in diabetic experimental animals. On the other hand, some herbal extracts may be hazardous in diabetes, as reports indicate impairment of renal function. This review outlines current evidence supporting plant extracts with the potential of averting progressive renal diabetic complications as well as the nephrotoxicity of some herbal extracts.     

Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions

Increased urinary albumin excretion rate is widely accepted as the first clinical sign of diabetic nephropathy. However, it is possible that some diabetic patients could first manifest reduced glomerular filtration rate (GFR) or hypertension. Relatively advanced diabetic renal lesions can be present in some diabetic patients with long-standing normoalbuminuria, and this might indicate increased risk of progression to microalbuminuria and then to overt diabetic nephropathy. The aim of this study was to identify a group of normoalbuminuric type 1 diabetic patients with low GFR and compare them with normoalbuminuric patients with normal GFR. Altogether, 105 normoalbuminuric type 1 diabetic patients with at least 10 years of diabetes duration that had a renal biopsy performed for research purposes were studied. Patients were divided according to GFR into groups with normal (>/=90 ml x min(-1) x 1.73 m(-2)) or reduced (<90 ml x min(-1) x 1.73 m(-2)) GFR. Clinical and renal structural parameters were compared between these two groups. Glomerular structural parameters were estimated by electron microscopic morphometry. The 23 patients with reduced GFR had more advanced diabetic glomerular lesions. The finding of reduced GFR was much more common among female patients, particularly if retinopathy and/or hypertension were also present. This report confirms that reduced GFR occurs among long-standing normoalbuminuric type 1 diabetic patients and is associated with more advanced diabetic glomerular lesions and, probably, with increased risk of progression. For these reasons, we suggest that regular measurements of GFR be performed in long-standing normoalbuminuric type 1 diabetic female diabetic patients, especially in those with retinopathy or hypertension.     

尿生物标志物在儿童急性肾损伤早期诊断中的作用研究

目的：评价尿NGAL,KIM-1和β2-MG在儿童不同基础疾病导致的AKI早期诊断中的价值。方法：我们做的是前瞻性临床研究,检测在我院儿科门急诊不同疾病患儿尿中性粒细胞明胶酶相关的脂质运载蛋白（NGAL）,肾脏损伤因子-1（KIM-1）和-β2微球蛋白（β2-MG）的水平,以AKIpRIFLE为分期标准将入选患儿分组,比较尿NGAL,KIM-1和β2-MG在儿童急性肾损伤诊断中的敏感性,特异性,阳性似然比,阴性似然比,分析比较这3个指标在急性肾损伤早期诊断中的作用。结果：入选262例患儿中,23例患儿可诊断为AKI,15例患儿为AKI-R期,8例患儿为AKI-I期,入选患儿中没有AKI-F期,23例患儿中只有5例临床有AKI的诊断。尿NGAL,KIM-1和β2-MG的水平在血肌酐没有明显升高之前已经升高,随着肾损伤的加重升高的更明显,不同组间差异有统计学意义。尿NGAL和β2-MG在预测儿童AKI的早期诊断方面好于尿KIM-1（AUC〉0.8）。结论：尿NGAL,KIM-1和β2-MG均可以在Scr没有升高之前预测儿童AKI的发生,是儿童AKI的早期生物标志物。尿NGAL在早期预测不同基础疾病可能发生AKI方面好于其他两项指标。     

Progression of nephropathy in type 2 diabetic patients

BACKGROUND: Nephropathy in type 2 diabetes is the single most common cause of end-stage renal disease (ESRD), but the decline in kidney function varies considerably between individuals, and determinants of renal function loss, early in the course of renal disease, have not been clearly identified. METHODS: In a prospective observational study, we followed 227 (60 female) Caucasian type 2 diabetic patients with nephropathy for 6.5 (range 3 to 17) years from a baseline glomerular filtration rate (GFR) of 83 (SD30) mL/min/1.73m(2) with 7 (range 3 to 22) measurements of GFR ((51)Cr-EDTA) per patient. We evaluated determinants of (1) rate of decline in GFR, (2) risk of doubling in serum creatinine or ESRD, and (3) mortality using potential risk factors at baseline and during follow-up. RESULTS: The mean (SD) rate of decline in GFR was 5.2 (4.1) mL/min/year. In multivariate regression analysis, higher baseline albuminuria, systolic blood pressure (SBP), hemoglobin A1c, GFR, age, and degree of diabetic retinopathy were significantly associated with increased rate of decline in GFR (R(2) (adj) 0.24). During follow-up, elevated mean albuminuria, SBP, hemoglobin A1c, and lower hemoglobin, heavy smoking, and presence of diabetic retinopathy were significantly associated with increased decline in GFR (R(2) (adj) 0.26). During follow-up, 63 patients had a doubling in serum creatinine or developed ESRD, and 79 patients died, primarily due to cardiovascular disease. In Cox regression analysis, higher baseline albuminuria, hemoglobin A1c, and SBP, together with lower GFR and hemoglobin, were significantly associated with shorter time to doubling of serum creatinine or ESRD. Higher baseline albuminuria, hemoglobin A1c, SBP, and age were significantly associated with increased mortality. CONCLUSION: Our long-term prospective study of type 2 diabetic patients with nephropathy has revealed several modifiable risk factors of enhanced progression in kidney disease and increased mortality.     

Mean glomerular volume and rate of development of diabetic nephropathy

We studied kidney glomerular structure and function in two groups of type I (insulin-dependent) diabetic subjects with 14-16 yr (group 1, n = 16) and 24-26 yr (group 2, n = 13) duration of diabetes and compared them to a group of 18 nondiabetic subjects with similar age ranges. Within each diabetic group, subjects were selected for normal kidney function (urinary albumin excretion less than 40 mg/24 h, normal blood pressure, creatinine clearance greater than 90 ml.min-1.1.73 m-2) or for nephropathy (urinary albumin excretion greater than 200 mg/24 h). Morphometric analysis of glomeruli revealed a significantly larger mean glomerular volume in subjects with nephropathy (group 2). Mesangial volumes were significantly greater in the nephropathic than the normoalbuminuric diabetic subjects in each group, but filtration surface per glomerulus was constant among all subjects. The percentage of sclerosed glomeruli was also significantly increased in the nephropathic subjects compared with the subjects with normal kidney function, in whom sclerosed glomeruli did not exceed 8%. In addition, there was a significant correlation between percentage of globally sclerosed glomeruli and glomerular volume in group 2 (rs = .79, P less than .01) but not group 1 (rs = -.20, NS) subjects. Thus, glomerular size or individual capacity for glomerular expansion may determine the rate of progression of the loss of kidney function in subjects destined to develop diabetic nephropathy.     

PC-1 amino acid variant (K121Q) has no impact on progression of diabetic nephropathy in type 1 diabetic patients.

BACKGROUND: Recently, an amino acid variant (K121Q) in the glycoprotein PC-1 (Q allele) has been associated with faster progression of diabetic nephropathy, as estimated by calculated creatinine clearance. We tested the impact of the PC-1 (K121Q) variant on loss of glomerular filtration rate (GFR) measured by the [(51)Cr]EDTA plasma clearance technique. METHODS: We performed an observational follow-up study of 295 (182 males) type 1 patients with diabetic nephropathy [mean age 37 (SE 0.7) years, mean duration of diabetes 23 (SE 0.5) years]. All patients were followed for at least 3 years, median 8 years (range 3-17), with at least three measurements of GFR using [(51)Cr]EDTA (median 11 measurements (range 3-32)). Two hundred and seventeen patients had the KK genotype and 78 carried the Q allele (71 KQ and 7 QQ). RESULTS: Patients carrying the Q allele had a mean rate of decline in GFR during follow-up of 3.6 ml/min per year (SE 0.4) compared with 4.0 ml/min per year (SE 0.3) in patients with the KK genotype. Other risk factors for progression of diabetic nephropathy were similar in Q carriers and KK carriers. When dividing patients in tertiles based on rate of decline in GFR, we found no difference in distribution of K121Q genotypes. No difference in the number of patients who died or reached end-stage renal disease during follow-up according to K121Q genotype were found. A multiple linear regression analysis revealed that albuminuria, mean arterial blood pressure, haemoglobin A(1C) and serum cholesterol during follow-up predicted a steeper decline in GFR [R(2) (adjusted)=0.27], whereas the PC-1 genotype did not contribute. CONCLUSIONS: Our study did not reveal an association between the PC-1 amino acid variant K121Q and progression of diabetic nephropathy.     

Protective effect of L-glutamine against diabetes-induced nephropathy in experimental animal: Role of KIM-1, NGAL,TGF-β1, and collagen-1

Diabetic nephropathy is a serious microvascular complication and one of the main causes of end-stage renal disease. L-Glutamine (LG) is naturally occurring amino acids with antidiabetic and antioxidant potential. The aim of present investigation was to evaluate the potential of LG against streptozotocin (STZ)-induced diabetic nephropathy (DN) in laboratory rats. DN was induced in male Wistar rats (200–220?g) by intraperitoneal administration of STZ (55?mg/kg). Animals were treated orally with either distilled water (10?mg/kg) or LG (250, 500, and 1000?mg/kg) or Sitagliptin (5?mg/kg). Various biochemical, molecular, and histological (hematoxylin–eosin and Masson’s trichrome stain) parameters were assessed. Administration of LG (500 and 1000?mg/kg) significantly inhibited (p?<?.05) STZ-induced alterations in serum and urine biochemistry (urine creatinine, uric acid, albumin, and BUN). It also significantly increased creatinine clearance rate. STZ induced increase in renal oxidonitrosative stress was significantly decreased (p?<?.05) by LG (500 and 1000?mg/kg) treatment. Upregulated renal KIM-1, NGAL, TGF-β1, and collagen-1 mRNA expression after STZ administration was significantly inhibited (p?<?.05) by LG (500 and 1000?mg/kg) treatment. Correlation analysis also revealed that antidiabetic potential of LG attenuates STZ-induced elevated renal KIM-1, NGAL, TGF-β1, and collagen-1 mRNA expression. Histopathological alteration induced by STZ in renal tissue was ameliorated by LG treatment. In conclusion, results of present investigation suggest that treatment with LG ameliorated STZ-induced DN via the inhibition of oxidonitrosative stress as well as downregulation of KIM-1, NGAL, TGF-β1, and collagen-1 mRNA expressions.     

Prevention and treatment of diabetic nephropathy with blood pressure lowering drugs

Summary: Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (>300 mg/24 h), a relentless decline in glomerular filtration rate (GFR), and raised arterial blood pressure. the prevalence of abnormal elevated albumin excretion rate (>30 mg/24 h) is approximately 40% in insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) patients. Diabetes has become the leading cause of end-stage renal failure in the United States of America and Japan and it remains the second leading cause in Europe. Patients suffering from diabetic nephropathy have an enormous increase in morbidity and mortality from cardiovascular disease in addition to renal death. Elevated blood pressure is an early and frequent phenomenon and furthermore accelerates the course of diabetic nephropathy. Studies in humans suggest that angiotensin-converting enzyme (ACE) inhibitors postpone and may even prevent progression to clinical overt diabetic nephropathy in normotensive IDDM and NIDDM patients with persistent microalbuminuria. Conventional antihypertensive therapy and ACE inhibition usually combined with a diuretic reduces albuminuria and postpones renal insufficiency in hypertensive IDDM patients with overt nephropathy. A more beneficial effect on the rate of decline in glomerular filtration rate has been demonstrated by ACE inhibitors compared to conventional antihypertensive treatment in IDDM patients with diabetic nephropathy and reduced kidney function (serum creatinine >133 mmol/L). These findings suggest that ACE inhibition causes renal protection (i.e. a beneficial effect on kidney function [structure] above and beyond what would be expected from blood pressure lowering effect alone). Finally, it should be stressed that ACE inhibition and conventional antihypertensive treatment postpone end-stage renal failure and improve survival in diabetic nephropathy.     

Early diagnosis of contrast-induced renal damage and the protective effect of hydration therapy

Objective To investigate the diagnostic value of urine neutrophil gelatinase apolipoprotein (NGAL) and kidney injury molecule 1 (KIM-1) as markers of CIN, and the effectiveness of hydration therapy in the prevention of CIN. Methods One hundred and twenty patients were randomly divided into control group and treatment group. The patients of treatment group received hydration therapy through intravenous fluid infusion. Urine samples were taken for detecting the value of albumin (mAlb), NGAL, and KIM-1 before surgery (T0), after surgery 12 h (T1), 24 h (T2), 48 h (T3), 72 h (T4) by ELISA assay. The levels of urinary mAlb, Scr, BUN and cystatin C were detected at the same time. Results ⑴ The urine NGAL/Cr and KIM-1/Cr significantly increased and were more than twice the baseline value at the time of 12 h after PCI in 87 of 120 cases of the participants. There are eight cases occurred CIN (6.67%) and one case occurred in hydration treatment group (1.7%), seven cases were in control group (11.7%). The difference was statistically significant. ⑵ There were no significant difference in BUN, Scr, mAlb/Cr, Cys-C and GFR between two groups (P＞0.05). ⑶ NGAL/Cr, KIM-1/Cr were elevated at T1 in both groups (P＜0.01). In hydration treatment group, levels of NGAL/Cr and KIM-1/Cr decreased substantially to the level of T0 at T4(P＜0.01), while in the control group they didn't. ⑷ Area under the ROC curve (AUC) of NGAL/Cr and KIM-1/Cr 12 h after PCI were 0.931 [95% CI (0.889, 0.973)] and 0.811 [95% CI(0.736, 0.886)] respectively (all P＜0.05). Conclusions NGAL and KIM-1 are sensitive and specific indicators for predicting early renal injury induced by contrast medium and can be used for early diagnosis of CIN. Hydration therapy can prevent the contrast agent-induced renal damage.     

Urinary calprotectin,NGAL, and KIM-1 in the differentiation of primarily inflammatory vs. non-inflammatory stable chronic kidney diseases

Introduction It has been demonstrated that urinary neutrophil gelatinase-associated lipocalin (NGAL) and calprotectin are helpful biomarkers in the differentiation of intrinsic and prerenal acute kidney injury.Objective The present cross-sectional study investigates, whether urinary biomarkers are able to differentiate primarily inflammatory from non-inflammatory entities in chronic kidney disease (CKD).Methods Urinary calprotectin, NGAL, and kidney injury molecule-1 (KIM-1) concentrations were assessed in a study population of 143 patients with stable CKD and 29 healthy controls. Stable renal function was defined as an eGFR fluctuation ≤5 ml/min/1.73 m² in the past 12 months. Pyuria, metastatic carcinoma, and renal transplantation were regarded as exclusion criteria. Diabetic nephropathy, hypertensive nephropathy, and polycystic kidney disease were categorized as ‘primarily non-inflammatory renal diseases’ (NIRD), whereas glomerulonephritis and vasculitis were regarded as ‘primarily inflammatory renal diseases’ (IRD).Results Urinary calprotectin and NGAL concentrations significantly differed between CKD and healthy controls (p < 0.05 each), whereas KIM-1 concentrations did not (p = 0.84). The three biomarkers did neither show significant differences in-between the individual entities, nor the two categories of IRD vs. NIRD (calprotectin 155.7 vs. 96.99 ng/ml; NGAL 14 896 vs. 11 977 pg/ml; KIM-1 1388 vs. 1009 pg/ml; p > 0.05 each). Albumin exceeds the diagnostic power of the investigated biomarkers by far.Conclusions The urinary biomarkers calprotectin, NGAL, and KIM-1 have no diagnostic value in the differentiation of primarily inflammatory vs. non-inflammatory etiologies of CKD.     

Should there be an expanded role for kidney biopsy in the management of patients with type I diabetes?

Diabetic nephropathy is the single most important cause of end-stage renal disease (ESRD) in the United States. Further, the increased risk of mortality from type I diabetes is almost entirely confined to patients developing clinical diabetic nephropathy. Nonetheless, kidney biopsy has had little role in the clinical assessment of diabetic patients or in the design of clinical research in diabetic nephropathy. The development of dipstick-positive proteinuria in patients with type I diabetes of more than 10 years' duration is regularly associated with advanced structural changes of diabetic nephropathology; in these patients, clinical parameters, especially the rate of decline of glomerular filtration rate (GFR), are accurate monitors of disease progression. Microalbuminuria indicates a very high risk of overt proteinuria and thus ESRD. This increased risk is associated with levels of urinary albumin excretion (UAE; greater than 30 micrograms/min [45 mg/24 h]), which are frequently accompanied by hypertension and reduced or decreasing GFR. At this stage, lesions of diabetic nephropathy are usually already well established. Thus, microalbuminuria is more a marker of early nephropathy than a predictor of later renal injury. Before these clinical stages of nephropathy, there are no accurate predictors of renal risk. Renal biopsy may serve this role by indicating those patients who are developing significant lesions during the "silent" phase of the disease. In large measure, this value of the biopsy derives from evidence that the lesions tend to develop linearly over time and can be measured by techniques that are relatively easily established in standard surgical pathology environments. Renal biopsies can serve to assure the majority of diabetic patients that they are developing serious lesions slowly, if at all.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of Losartan on Prevention and Progression of Early Diabetic Nephropathy in American Indians With Type 2 Diabetes

Angiotensin receptor blockers are renoprotective in hypertensive azotemic patients with type 2 diabetes, but their efficacy in early diabetic kidney disease is uncertain. We performed a 6-year randomized clinical trial in 169 American Indians with type 2 diabetes and normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g; n = 91) or microalbuminuria (ACR 30–299 mg/g; n = 78) at baseline. The primary outcome was decline in glomerular filtration rate (GFR) to ≤60 mL/min or to half the baseline value in subjects who entered with GFR <120 mL/min. Another outcome was differences in glomerular structure at end of treatment. Subjects received 100 mg losartan or placebo daily. GFR was measured annually; 111 subjects underwent kidney biopsies. Only nine subjects reached the GFR outcome, and the unadjusted hazard ratio (losartan vs. placebo) was 0.50 (95% CI, 0.12–1.99). Differences in mesangial fractional volume were not estimated in the combined albuminuria groups because of an interaction with treatment assignment. In separate analyses, mesangial fractional volume was lower in subjects treated with losartan in the microalbuminuria group (18.8 vs. 25.6%; P = 0.02), but not in the normoalbuminuria group (19.6 vs. 17.8%; P = 0.86). Treatment with losartan may preserve some features of kidney structure in American Indians with type 2 diabetes and microalbuminuria.Angiotensin receptor blockers (ARBs) reduce the rate of diabetic kidney disease progression in hypertensive azotemic patients with type 2 diabetes (1,2). Their efficacy in slowing progression of early kidney disease, however, is less certain, and surrogate end points, such as albuminuria progression, complicate interpretation of most studies (3). In the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study (4), frequency of progression to macroalbuminuria was reduced by the study drug, but decline in glomerular filtration rate (GFR), as estimated by creatinine clearance, was not. Similarly, in the Steno-2 study (5), intensive multifactorial intervention in patients with type 2 diabetes and microalbuminuria significantly reduced progression to proteinuria but did not alter the rate of GFR decline.Efficacy of ARBs in the primary prevention of diabetic kidney disease is less certain. The Renin Angiotensin System Study (RASS) (6), a clinical trial of losartan or enalapril versus placebo in patients with type 1 diabetes and normoalbuminuria, found no benefit of treatment over 5 years in either change in GFR or change in mesangial fractional volume of serial kidney biopsies. Moreover, the 5-year cumulative incidence of microalbuminuria was higher in those receiving losartan than in either of the other groups, suggesting the potential for harm.We performed a randomized, placebo-controlled, clinical trial to test whether the ARB losartan offered renoprotection to persons with type 2 diabetes who had either normal urinary albumin excretion or microalbuminuria at baseline. Clinical outcomes included changes in GFR from baseline and differences in glomerular structure on kidney biopsies performed at the end of the study period. We also examined the effect of losartan on urinary albumin excretion.