W. Kline Bolton

Randomized trial of an inhibitor of formation of advanced glycation end products in Diabetic nephropathy

Background/Aims: Pimagedine inhibits the formation of advanced glycation end products and slows the progression of diabetic complications in experimental models. This study was undertaken to determine if pimagedine ameliorates nephropathy in type 1 (insulin-dependent) diabetes mellitus. Methods: This was a randomized, double-masked, placebo-controlled study performed in 690 patients with type 1 diabetes mellitus, nephropathy, and retinopathy. The patients received twice daily dosing with placebo, pimagedine 150 mg, or pimagedine 300 mg for 2–4 years. The primary end point was the time to doubling of serum creatinine; the secondary end points included evaluations of proteinuria, kidney function, and retinopathy. Results: Serum creatinine doubled in 26% (61/236) of the placebo-treated patients and in 20% (91/454) of those who received pimagedine (p = 0.099). The estimated glomerular filtration rate decreased more slowly in the pimagedine-treated patients with a 36-month decrease from baseline of 6.26 ml/min/1.73 m2 as compared with 9.80 ml/min/1.73 m2 in the placebo-treated patients (p = 0.05), and pimagedine reduced the 24-hour total urinary proteinuria. (The mean reduction from baseline at month 36 was 732 mg/24 h at the low dose and 329 mg/24 h at the high dose as compared with 35 mg/24 h in the placebo group; p ≤ 0.001.) Fewer pimagedine-treated patients with baseline and end point evaluations (31/324; 10%) as compared with those receiving placebo (16%; 28/179) experienced a three-step or greater progression of the retinopathy (Early Treatment of Diabetic Retinopathy Study) score (p = 0.030). Three patients receiving high-dose pimagedine but none receiving low-dose treatment developed glomerulonephritis. Conclusions: While this study did not demonstrate a statistically significant beneficial effect of pimagedine on the progression of overt nephropathy resulting from type 1 diabetes, it is noteworthy in providing the first clinical proof of the concept that inhibiting advanced glycation end product formation can result in a clinically important attenuation of the serious complications of type 1 diabetes mellitus.

The prevalence of anemia in patients with chronic kidney disease

SUMMARY Objective: Anemia is a complication of chronic kidney disease and may contribute to adverse clinical outcomes. Early identification and treatment of anemia may improve cardiovascular morbidity and mortality. No large-scale population data are available specifically for patients with chronic kidney disease regarding prevalence of anemia, subpopulations at risk, and relationships between anemia and kidney function. This study was undertaken to address these questions in patients with chronic kidney disease, and investigate the relationship between anemia and glomerular filtration rate. Research design and methods: Large-scale, cross-sectional, US multicenter survey; 5222 patients (mean age, 68.2 years; 46.6% male); 237 physician practices. Eligible patients: ≥ 18 years of age; serum creatinine: 1.5 mg/dL–6.0 mg/dL (females), 2.0 mg/dL–6.0 mg/dL (males). Main outcome measures: Primary study end point: prevalence and severity of anemia (hemoglobin ≤ 12 g/dL). Data further stratified by hemoglobin (≤ 12 g/dL, ≤ 10 g/dL). Results: Primary etiologies of chronic kidney disease (5222 evaluable patients): diabetes (49.5%); hypertension (33.0%). Glomerular filtration rate: < 60 mL/min/1.73 m2 for 97.7% of evaluable patients. Mean ± SD serum creatinine level: 2.2 mg/dL ± 0.9 mg/dL; 2.5 mg/dL ± 1.0 mg/dL for males, 2.0 mg/dL ± 0.8 mg/dL for females. Mean ± SD hemoglobin: 12.2 g/dL ± 1.6 g/dL (47.7% had hemoglobin ≤ 12 g/dL; 8.9% had hemoglobin ≤ 10 g/dL). Prevalence of anemia was strongly associated with declining glomerular filtration rate. Percentage of patients with hemoglobin ≤ 12 g/dL increased from 26.7% to 75.5% when glomerular filtration rate decreased from ≥ 60 mL/min/1.73 m2 to < 15 mL/min/1.73 m2. Prevalence of hemoglobin ≤ 10 g/dL increased substantially from 5.2% to 27.2% when glomerular filtration rate diminished from ≥ 60 mL/min/1.73 m2 to < 15 mL/min/1.73 m2. After controlling for other patient characteristics associated with increased prevalence of anemia, the prevalence odds ratio for hemoglobin ≤ 10 g/dL was 0.54 (0.49–0.60) and for hemoglobin ≤ 12 g/dL was 0.68 (0.65–0.72), with each 10-mL/min/1.73 m2 increase in glomerular filtration rate. Predictors of anemia: diabetes, female sex, and race/ethnicity. Conclusions: Anemia was present in 47.7% of 5222 predialysis patients with chronic kidney disease. Prevalence of anemia increased as kidney function decreased. Certain subgroups are at increased risk for anemia.

Pimagedine: a novel therapy for diabetic nephropathy

Hyperglycaemia is directly involved in causing long-term diabetic complications. The non-enzymatic glycation of proteins, yielding irreversible advanced glycation end products and advanced glycation end products-derived protein crosslinking, participates in the development of diabetic complications, such as diabetic nephropathy. Diabetic nephropathy is becoming a major medical problem with increasing numbers of these patients progressing to end stage renal disease, thus requiring renal replacement therapy. While several interventions may slow the development and progression of diabetic nephropathy, there is no effective treatment to prevent or reverse the disease. Pimagedine (aminoguanidine HCl) has been shown to be an effective agent in reducing the severity of the structural and functional alterations associated with experimental diabetic nephropathy. Preliminary studies suggest a beneficial effect of pimagedine in treating patients with diabetic nephropathy. In summary, these observations support a role for advanced glycation end products inhibitors, like pimagedine, in the management of diabetic nephropathy, either alone or in combination with other therapies.

Monocyte/macrophage chemokine receptor CCR2 mediates diabetic renal injury

Monocyte/macrophage recruitment correlates strongly with the progression of renal impairment in diabetic nephropathy (DN). C-C chemokine receptor (CCR)2 regulates monocyte/macrophage migration into injured tissues. However, the direct role of CCR2-mediated monocyte/macrophage recruitment in diabetic kidney disease remains unclear. We report that pharmacological blockade or genetic deficiency of CCR2 confers kidney protection in Ins2(Akita) and streptozotocin (STZ)-induced diabetic kidney disease. Blocking CCR2 using the selective CCR2 antagonist RS504393 for 12 wk in Ins2(Akita) mice significantly attenuated albuminuria, the increase in blood urea nitrogen and plasma creatinine, histological changes, and glomerular macrophage recruitment compared with vehicle. Furthermore, mice lacking CCR2 (CCR2(-/-)) mimicked CCR2 blockade by reducing albuminuria and displaying less fibronectin mRNA expression and inflammatory cytokine production compared with CCR2(+/+) mice, despite comparable blood glucose levels. Bone marrow-derived monocytes from CCR2(+/+) or CCR2(-/-) mice adoptively transferred into CCR2(-/-) mice reversed the renal tissue-protective effect in diabetic CCR2(-/-) mice as evaluated by increased urinary albumin excretion and kidney macrophage recruitment, indicating that CCR2 is not required for monocyte migration from the circulation into diabetic kidneys. These findings provide evidence that CCR2 is necessary for monocyte/macrophage-induced diabetic renal injury and suggest that blocking CCR2 could be a novel therapeutic approach in the treatment of DN.

Congo red-negative amyloidosis-like glomerulopathy

Three cases of amyloidosis-like glomerulopathy are presented in which renal amyloidosis was initially diagnosed on the basis of ultrastructural findings, despite negative Congo red staining. The histologic and immunofluorescence findings and, on careful examination, ultrastructural features of this amyloidosis-like glomerulopathy all serve to distinguish it from true amyloidosis. The clinical behavior suggests that it is a primary glomerulopathy since, with time, no other systems become involved.

Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes

Sphingosine 1-phosphate (S1P), a pleiotropic lipid mediator, binds to five related G-protein-coupled receptors to exert its effects. As S1P1 receptor (S1P1R) activation blocks kidney inflammation in acute renal injury, we tested whether activation of S1P1Rs ameliorates renal injury in early-stage diabetic nephropathy (DN) in rats. Urinary albumin excretion increased in vehicle-treated diabetic rats (single injection of streptozotocin), compared with controls, and was associated with tubule injury and increased urinary tumor necrosis factor-α (TNF-α) at 9 weeks. These effects were significantly reduced by FTY720, a non-selective, or SEW2871, a selective S1P1R agonist. Interestingly, only FTY720 was associated with reduced total lymphocyte levels. Albuminuria was reduced by SEW2871 in both Rag-1 (T- and B-cell deficient) and wild-type diabetic mice after 6 weeks, suggesting that the effect was independent of lymphocytes. Another receptor, S1P3R, did not contribute to the FTY720-mediated protection, as albuminuria was also reduced in diabetic S1P3R knockout mice. Further, both agonists restored WT-1 staining along with podocin and nephrin mRNA expression, suggesting podocyte protection. This was corroborated in vitro, as SEW2871 reduced TNF-α and vascular endothelial growth factor mRNA expression in immortalized podocytes grown in media containing high glucose. Whether targeting kidney S1P1Rs will be a useful therapeutic measure in DN will need direct testing.

Rapidly progressive silicon nephropathy

Rapidly progressive renal failure developed in four patients with silica exposure. Three presented with manifestations of a connective tissue disorders. All had abnormal proteinuria, hypoalbuminemia and active urinary sediments. Histologically, a distinct constellation of findings was present, consisting of glomerular hypercellularity and sclerosis, crescents, interstitial cellular infiltrates and tubular necrosis with red cell casts as seen on light microscopy. On electron microscopy there was foot process obliteration, characteristic cytoplasmic dense lysosomes, microtubules and dense deposits. Despite vigorous treatment, two patients died of the systemic illness and one is on hemodialysis. The fourth is improved after pulse methylprednisolone therapy. We propose that silica induced this multisystem disease through activation of the immune system and a direct tissue toxic effect.

Membranoproliferative glomerulonephritis with primary Sjögren's syndrome

Glomerular involvement in primary Sjögrens syndrome is rare and only five cases of membranoproliferative glomerulonephritis have been reported. We present a case of a 31-year-old white woman with primary Sjögrens syndrome who developed nephrotic syndrome. Evaluation showed no evidence of an associated connective tissue disease. Kidney biopsy was consistent with type I membranoproliferative glomerulonephritis. The patients nephrotic syndrome resolved spontaneously, a course that has not been reported previously in this setting.

A Nephritogenic Peptide Induces Intermolecular Epitope Spreading on Collagen IV in Experimental Autoimmune Glomerulonephritis

This group previously identified a peptide p13 of alpha3(IV)NC1 domain of type IV collagen that induces experimental autoimmune glomerulonephritis (EAG) in rats with generation of antibodies to sites on alpha3(IV)NC1 external to the peptide as a result of intramolecular epitope spreading. It was hypothesized that intermolecular epitope spreading to other collagen IV chains also was induced. Rats were immunized with nephritogenic peptide that was derived from the amino terminal part of rat alpha3(IV)NC1 domain, and serum and kidney eluate were examined for antibodies to both native and recombinant NC1 domains of collagen IV. Peptide induced EAG with proteinuria and decreased renal function and glomerular basement membrane IgG deposits. Sera from these rats were examined by ELISA, which revealed reactivity not only to immunizing peptide but also to human and rat alpha3(IV)NC1 and to human alpha4(IV)NC1 domains. Kidney eluate that was depleted of alpha3(IV)NC1 antibodies still reacted to alpha4(IV)NC1, and alpha3(IV)NC1 column-bound antibody reacted with alpha3(IV)NC1. There was minimal reactivity to other collagen chains. Eluate that was adsorbed to NC1 hexamer from rat glomerular basement membrane lost all reactivity to glomerular constituents, and the eluted antibodies reacted to alpha3(IV)NC1 and alpha4(IV)NC1 domains. These studies show that a T cell epitope of alpha3(IV)NC1 induces EAG, intramolecular epitope spreading along alpha3(IV)NC1, and intermolecular epitope spreading to alpha4(IV)NC1 domain with minimal or no reactivity to other collagen chains or glomerular constituents. This is the first demonstration in EAG of intermolecular epitope spreading and identification of the spread epitopes.

Renal Physicians Association Clinical Practice Guideline: Appropriate Patient Preparation For Renal Replacement Therapy: Guideline Number 3

JASN is cooperating with the Renal Physicians Association and other renal journals in publishing this executive summary of a clinical practice guideline on appropriate patient preparation for renal replacement therapy. The full text of the guideline is available from the Renal Physicians Association