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1.  Nephrotic Syndrome in Diabetic Kidney Disease: An Evaluation and Update of the Definition 
Nephrotic syndrome is defined as urine total protein >3.5 g/d or total protein-creatinine ratio of >3.5 g/g, low serum albumin, high serum cholesterol, and peripheral edema. These threshold levels have not been rigorously evaluated in diabetic kidney disease or using urine albumin, the preferred measure of proteinuria in diabetes.
Study Design
Diagnostic test study
Setting and Participants
Adults with type 2 diabetes, hypertension and urine total protein >0.9 g/d enrolled in the Irbesartan in Diabetic Nephropathy Trial.
Index Test
Baseline measures of proteinuria (total protein, albumin, and protein-creatinine and albumin-creatinine ratios). Linear regression to relate measures.
Reference Test
Other signs and symptoms of nephrotic syndrome at baseline (serum albumin <3.5g/dl, serum total cholesterol >260mg/dl or use of a statin, edema or use of a loop diuretic); progression of chronic kidney disease during follow up (doubling of baseline serum creatinine or requirement for dialysis or kidney transplantation). Logistic regression to relate index and reference tests.
Among 1608 participants, total urine protein of 3.5 g/d was equivalent to urine albumin of 2.2 (95% confidence interval 1.4–3.5) g/d. Of 1467 participants, 641 (44%) had urine total protein ≥3.5 g/d at baseline, 132 (9%) had other signs and symptoms of nephrotic syndrome at baseline and 385 (26%) had progression of kidney disease over a mean follow-up interval of 2.6 years. Areas under the receiver operating curves for measures of proteinuria were 0.80 to 0.83 for other signs and symptoms of nephrotic syndrome and 0.72 to 0.74 for kidney disease progression. The threshold levels for nephrotic-range proteinuria and albuminuria were close to the points of maximal accuracy for both outcomes.
Study population limits generalizability; inability to adjust for several variables known to affect serum albumin; lack of spot urine samples
The historical definition for nephrotic-range proteinuria appears reasonable in diabetic kidney disease. The equivalent thresholds for nephrotic-range albuminuria and albumin-creatinine ratio are 2.2 g/d and 2.2 g/g, respectively.
PMCID: PMC4036614  PMID: 19556043
nephrotic syndrome; urine protein; urine albumin; proteinuria; albuminuria; protein-creatinine ratio; albumin-creatinine ratio; diabetic kidney disease; edema; hypercholesterolemia; hypoalbuminemia; chronic kidney disease progression; CKD
2.  25-hydroxyvitamin D Levels and chronic kidney disease in the AusDiab (Australian Diabetes, Obesity and Lifestyle) study 
BMC Nephrology  2012;13:55.
Low 25-hydroxy vitamin D (25(OH)D) levels have been associated with an increased risk of albuminuria, however an association with glomerular filtration rate (GFR) is not clear. We explored the relationship between 25(OH)D levels and prevalent chronic kidney disease (CKD), albuminuria and impaired GFR, in a national, population-based cohort of Australian adults (AusDiab Study).
10,732 adults ≥25 years of age participating in the baseline survey of the AusDiab study (1999–2000) were included. The GFR was estimated using an enzymatic creatinine assay and the CKD-EPI equation, with CKD defined as eGFR <60 ml/min/1.73 m2. Albuminuria was defined as a spot urine albumin to creatinine ratio (ACR) of ≥2.5 mg/mmol for men and ≥3.5 for women. Serum 25(OH)D levels of <50 nmol/L were considered vitamin D deficient. The associations between 25(OH)D level, albuminuria and impaired eGFR were estimated using multivariate regression models.
30.7% of the study population had a 25(OH)D level <50 nmol/L (95% CI 25.6-35.8). 25(OH)D deficiency was significantly associated with an impaired eGFR in the univariate model (OR 1.52, 95% CI 1.07-2.17), but not in the multivariate model (OR 0.95, 95% CI 0.67-1.35). 25(OH)D deficiency was significantly associated with albuminuria in the univariate (OR 2.05, 95% CI 1.58-2.67) and multivariate models (OR 1.54, 95% CI 1.14-2.07).
Vitamin D deficiency is common in this population, and 25(OH)D levels of <50 nmol/L were independently associated with albuminuria, but not with impaired eGFR. These associations warrant further exploration in prospective and interventional studies.
PMCID: PMC3441805  PMID: 22759247
Albuminuria; Chronic kidney disease; Glomerular filtration rate; and Vitamin D
3.  Nonalbuminuric Renal Impairment in Type 2 Diabetic Patients and in the General Population (National Evaluation of the Frequency of Renal Impairment cO-existing with NIDDM [NEFRON] 11) 
Diabetes Care  2009;32(8):1497-1502.
Most diabetic patients with impaired renal function have a urinary albumin excretion rate in the normal range. In these patients, the etiology of renal impairment is unclear, and it is also unclear whether this nonalbumunuric renal impairment is unique to diabetes.
In this study, we examined the frequency and predictors of nonalbumunuric renal impairment (estimated glomerular filtration rate [eGFR] <60 ml/min per 1.73 m2) in a nationally representative cohort of 3,893 patients with type 2 diabetes and compared our findings with rates observed in the general population from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) survey (n = 11,247).
Of the 23.1% of individuals with type 2 diabetes who had eGFR <60 ml/min per 1.73 m2 (95% CI 21.8–24.5%), more than half (55%) had a urinary albumin excretion rate that was persistently in the normal range. This rate of renal impairment was predictably higher than that observed in the general population (adjusted odds ratio 1.3, 95% CI 1.1–1.5, P < 0.01) but was solely due to chronic kidney disease associated with albuminuria. In contrast, renal impairment in the absence of albuminuria was less common in those with diabetes than in the general population, independent of sex, ethnicity, and duration of diabetes (0.6, 0.5–0.7, P < 0.001).
Nonalbuminuric renal impairment is not more common in those with diabetes. However, its impact may be more significant. New studies are required to address the pathogenesis, prevention, and treatment of nonalbuminuric renal disease.
PMCID: PMC2713618  PMID: 19470839
4.  Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE) 
Journal of Clinical Investigation  2001;108(12):1853-1863.
Tubulointerstitial disease, a prominent phenomenon in diabetic nephropathy, correlates with decline in renal function. The underlying pathogenic link between chronic hyperglycemia and the development of tubulointerstitial injury has not been fully elucidated, but myofibroblast formation represents a key step in the development of tubulointerstitial fibrosis. RAGE, the receptor for advanced glycation end products (AGEs), induces the expression of TGF-β and other cytokines that are proposed to mediate the transdifferentiation of epithelial cells to form myofibroblasts. Here we report specific binding of 125I-AGE-BSA to cell membranes prepared from a rat proximal tubule cell line and show that the binding site was RAGE. AGE exposure induced dose-dependent epithelial-myofibroblast transdifferentiation determined by morphological changes, de novo alpha smooth-muscle actin expression, and loss of epithelial E-cadherin staining. These effects could be blocked with neutralizing Ab’s to RAGE or to TGF-β. Transdifferentiation was also apparent in the proximal tubules of diabetic rats and in a renal biopsy from a patient with type 1 diabetes. The AGE cross-link breaker, phenyl-4,5-dimethylthiazolium bromide (ALT 711) reduced transdifferentiation in diabetic rats in association with reduced tubular AGE and TGF-β expression. This study provides a novel mechanism to explain the development of tubulointerstitial disease in diabetic nephropathy and provides a new treatment target.
PMCID: PMC209461  PMID: 11748269
5.  The Pathogenic Role of Macrophage Migration Inhibitory Factor in Immunologically Induced Kidney Disease in the Rat 
The Journal of Experimental Medicine  1997;185(8):1455-1466.
Macrophage migration inhibitory factor (MIF) plays a pivotal role in the inflammatory response in endotoxemia and in the delayed-type hypersensitivity response, but its potential as a regulator of immunologically induced disease is unknown. We have addressed this issue by administering a neutralizing anti-MIF antibody in a rat model of immunologically induced crescentic anti-glomerular basement membrane (GBM) glomerulonephritis. Six individual experiments using paired inbred littermates were performed. Rats were primed with rabbit immunoglobulin on day −5 and then injection with rabbit anti–rat GBM serum on day 0. Pairs of animals were treated with anti-MIF or a control monoclonal antibody from the time of anti-GBM serum administration until being killed 14 d later. Control antibody-treated animals developed severe proteinuria and renal function impairment with severe histological damage due to marked leukocytic infiltration and activation within the kidney. In contrast, anti-MIF treatment substantially reduced proteinuria, prevented the loss of renal function, significantly reduced histological damage including glomerular crescent formation, and substantially inhibited renal leukocytic infiltration and activation (all P <0.001 compared with control treatment). Inhibition of renal disease by anti-MIF treatment was attributed to preventing the marked upregulation of interleukin-1β, leukocyte adhesion molecules including intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and inducible nitric oxide synthase expression seen in the control antibody-treated animals. This inhibition of progressive renal injury was mirrored by the complete suppression of the skin delayed-type hypersensitivity response to the challenge antigen (rabbit IgG). Interestingly, anti-MIF treatment did not effect the secondary antibody response or immune deposition within the kidney, indicating that MIF participates in cellular-based immunity in this primed macrophage-dependent anti-GBM glomerulonephritis. In conclusion, this study has demonstrated a key regulatory role for MIF in the pathogenesis of immunologically induced kidney disease. These results argue that blocking MIF activity may be of benefit in the treatment of human rapidly progressive glomerulonephritis, and suggest that MIF may be important in immune-mediated disease generally.
PMCID: PMC2196273  PMID: 9126926
The addition of bone marrow cells or peripheral lymphocytes to the isolated pig spleen markedly enhanced the primary antibody response after 3-day perfusion and antigenic challenge in vitro. The splenic preparation without added cells or with the addition of marrow cells to an irradiated spleen gave a limited response. Contributory evidence is provided that at least two distinct cell types are needed for antibody production. For optimal antibody response by an isolated perfused spleen, marrow cells or peripheral lymphocytes should be added to the system.
PMCID: PMC2138782  PMID: 5464381

Results 1-6 (6)