The effect of cause, timing, kidney function recovery, and recurrent events on the prognosis of acute kidney injury in kidney transplant recipients.

AIM: To assess the incidence of acute kidney injury (AKI) and its common etiologies in kidney transplant recipients and the effect of AKI's characteristics on graft survival. METHODS: In a retrospective longitudinal cohort study, all serum creatinine (SCr) values of patients that had kidney transplantation between 01/2002-12/2010 were retrieved. AKI was defined as a 50% increase in SCr. Etiologies, recurrence, timing, and kidney function dynamics during the event were evaluated. The primary endpoint was defined as graft loss. Time-varying Cox model was used for the analysis. RESULTS: Of 659 patients, 208 (31.6%) patients had 321 documented AKI events. Of these, 138 (66.4%) patients had one event, and 70 (33.6%) patients had recurrent events. The leading etiologies of the first AKI event were as follows: infection (33.4%), hypovolemia (14.3%), and unknown etiology (16.8%). Both first and recurrent AKI events were associated with an increased risk of graft loss (HR: 2.76, 95% CI: 1.95-3.89) and (HR: 4.54, 95% CI: 2.59-7.93), respectively. This deleterious association was lower within three months after transplantation, compared to later events. Patients in whom kidney function returned to baseline were less prone to graft loss. CONCLUSIONS: Late-onset, incomplete recovery, and recurrent AKI events are associated with increased graft loss.

A New Cutoff for Abnormal Proteinuria in Diabetes Mellitus Patients: Relationship to Albuminuria.

BACKGROUND: Proteinuria and albuminuria are markers of kidney injury and function, serving as a screening test as well as a means of assessing the degree of kidney injury and risk for cardiovascular disease and death in both the diabetic and the non-diabetic general population. OBJECTIVES: To evaluate the association between proteinuria below 300 mg/24 hours and albuminuria, as well as a possible association with kidney function in patients with diabetes mellitus (DM). METHODS: The medical files of patients with type 1 and type 2 DM with proteinuria below 300 mg/24 hours at three different visits to the Diabetic Nephropathy Clinic were screened. This involved 245 patient files and 723 visits. The data collected included demographics; protein, albumin and creatinine levels in urine collections; blood biochemistry; and clinical and treatment data. RESULTS: The association between proteinuria and albuminuria is non-linear. However, proteinuria in the range of 162-300 mg/24 hours was found to be linearly and significantly correlated to albuminuria (P < 0.001, r = 0.58). Proteinuria cutoff, based on albuminuria cutoff of 30 mg/24 hours, was found to be 160.5 mg/24 hr. Body mass index (BMI) was the sole independent predictor of proteinuria above 160.5 mg/24 hr. Changes in albuminuria, but not proteinuria, were associated with changes in creatinine clearance. CONCLUSIONS: A new cutoff value of 160.5 mg/hr was set empirically, for the first time, for abnormal proteinuria in diabetic patients. It appears that proteinuria below 300 mg/24 hr is not sufficient as a sole prognostic factor for kidney failure.

Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study.

BACKGROUND: Clinical trials of nephropathy in people with type 2 diabetes mellitus have not examined the effects of systolic blood pressure (SBP) or pulse pressure (PP) on the time to end-stage renal disease (ESRD) or death. OBJECTIVES: To evaluate the impact of baseline and treated SBP, diastolic blood pressure (DBP), and PP on composite and individual outcomes including doubling of serum creatinine, ESRD, or death in participants of the Reduction of Endpoints in NIDDM (non-insulin-dependent diabetes mellitus) With the Angiotensin II Antagonist Losartan (RENAAL) Study; to assess the specific effect of the angiotensin receptor blocker losartan potassium on composite and renal outcomes; and to explore the implications of dihydropyridine calcium channel blockers as concurrent therapy on composite and renal outcomes. DESIGN: A Cox proportional hazards regression model was used to assess the hazard risk profile of baseline SBP (categories: <130, 130-139, 140-159, 160-179, and > or =180 mm Hg), DBP (categories: <70, 70-79, 80-89, 90-99, and > or =100 mm Hg), and PP (categories: <60, 60-69, 70-79, 80-89, and > or =90 mm Hg) on renal outcomes. PARTICIPANTS: The study comprised 1513 participants with established nephropathy and hypertension associated with type 2 diabetes. INTERVENTIONS: The RENAAL study was a randomized, placebo-controlled study of losartan vs placebo, with other agents added to achieve the goal of a trough BP (ie, BP immediately prior to the next dosing) below 140/90 mm Hg, and had a mean follow-up of 3.4 years. MAIN OUTCOME MEASURES: The primary analysis was time to composite end point of doubling of serum creatinine, ESRD, or death. RESULTS: A baseline SBP range of 140 to 159 mm Hg increased risk for ESRD or death by 38% (P =.05) compared with those below 130 mm Hg. In a multivariate model, every 10-mm Hg rise in baseline SBP increased the risk for ESRD or death by 6.7% (P =.007); the same rise in DBP decreased the risk by 10.9% (P =.01) when adjusting for urinary albumin-creatinine ratio, serum creatinine, serum albumin, hemoglobin, and hemoglobin A1c. Those randomized to the losartan group with a baseline PP above 90 mm Hg had a 53.5% risk reduction for ESRD alone (P =.003) and a 35.5% risk reduction for ESRD or death (P =.02) compared with the placebo group. CONCLUSIONS: Baseline SBP is a stronger predictor than DBP of renal outcomes in those with nephropathy resulting from type 2 diabetes. Those with the highest baseline PP have the highest risk for nephropathy progression but also garner the greatest risk reduction with SBP lowered to less than 140 mm Hg.

Involvement of human heparanase in the pathogenesis of diabetic nephropathy.

BACKGROUND: Decreased heparan sulfate proteoglycan content of the glomerular basement membrane has been described in proteinuric patients with diabetic nephropathy. Heparanase is an endo-beta-D-glucuronidase that cleaves negatively charged heparan sulfate side chains in the basement membrane and extracellular matrix. OBJECTIVES: To investigate whether urine from type I diabetic patients differs in heparanase activity from control subjects and whether resident glomerular cells could be the source of urinary heparanase. METHODS: Using soluble 35S-HSPG and sulfate-labeled extracellular matrix we assessed heparanase activity in human glomerular epithelial cells, rat mesangial cells, and urine from 73 type I diabetic patients. Heparanase activity resulted in the conversion of a high molecular weight sulfate-labeled HSPG into heparan sulfate degradation fragments as determined by gel filtration analysis. RESULTS: High heparanase activity was found in lysates of both epithelial and mesangial cells. Immunohistochemical staining localized the heparanase protein to both glomeruli capillaries and tubular epithelium. Heparanase activity was detected in the urine of 16% and 25% of the normoalbuminuric and microalbuminuric diabetic patients, respectively. Urine from 40 healthy individuals did not possess detectable heparanase. Urinary heparanase activity was associated with worse glycemic control. CONCLUSION: We suggest that heparanase enzyme participates in the tunover of glomerular HSPG. Hyperglycemia enhances heparanase activity and/or secretion in some diabetic patients, resulting in the loss of albumin permselective properties of the GBM.