Relapse or worsening of nephrotic syndrome in idiopathic membranous nephropathy can occur even though the glomerular immune deposits have been eradicated.

BACKGROUND: Relapse or worsening of nephrotic syndrome (NS) in idiopathic membranous nephropathy (IMN) is generally assumed to be due to recurrent disease. Here we document that often that may not be the case. SUBJECTS AND METHODS: This is a prospective study of 7 consecutive IMN patients whose renal status improved, then worsened after completing a course of immunosuppressive therapy. Each underwent detailed testing and repeat kidney biopsy. RESULTS: In 4 patients (group A), the biopsy showed recurrent IMN (fresh subepithelial deposits). Immunosuppressive therapy was begun. In the other 3 patients (group B), the biopsy showed that the deposits had been eradicated. However, the glomerular basement membrane (GBM) was thickened and vacuolated. Immunosuppressive therapy was withheld. Groups A and B were comparable except that group B had very high intakes of salt and protein, based on 24-hour urine testing. Reducing their high salt intake sharply lowered proteinuria to the subnephrotic range and serum creatinine stabilized. CONCLUSION: This work is the first to demonstrate that relapse/worsening of NS can occur in IMN even though the GBM deposits have been eradicated. High salt and protein intake in combination with thickened and vacuolated GBM appears to be the mechanism.

Management of glomerular proteinuria: a commentary.

It is widely accepted that proteinuria reduction is an appropriate therapeutic goal in chronic proteinuric kidney disease. Based on large randomized controlled clinical trials (RCT), ACE inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy have emerged as the most important antiproteinuric and renal protective interventions. However, there are numerous other interventions that have been shown to be antiproteinuric and, therefore, likely to be renoprotective. Unfortunately testing each of these antiproteinuric therapies in RCT is not feasible. The nephrologist has two choices: restrict antiproteinuric therapies to those shown to be effective in RCT or expand the use of antiproteinuric therapies to include those that, although unproven, are plausibly effective and prudent to use. The goal of this work is to provide the documentation needed for the nephrologist to choose between these strategies. This work describes 25 separate interventions that are either antiproteinuric or may block injurious mechanisms of proteinuria. Each intervention is assigned a level of recommendation (Level 1 is the highest; Level 3 is the lowest) according to the strength of the evidence supporting its antiproteinuric and renoprotective efficacy. Pathophysiologic mechanisms possibly involved are also discussed. The number of interventions at each level of recommendation are: Level 1, n = 7; Level 2, n = 9; Level 3, n = 9. Our experience indicates that we can achieve in most patients the majority of Level 1 and many of the Level 2 and 3 recommendations. We suggest that, until better information becomes available, a broad-based, multiple-risk factor intervention to reduce proteinuria can be justified in those with progressive nephropathies. This work is intended primarily for clinical nephrologists; therefore, each antiproteinuria intervention is described in practical detail.

Culture-negative peritoneal dialysis peritonitis associated with pancreaticoduodenocystotomy leak of a pancreas transplant.

BACKGROUND: Peritoneal dialysis (PD) peritonitis is usually caused by infection and less commonly by a sterile inflammatory reaction. METHODS: The authors report the case of a kidney-pancreas transplant recipient who was receiving PD after kidney transplant rejection 5 years after transplantation. The patient had a viable pancreas transplant. He had abdominal pain associated with cloudy PD effluent. The PD leukocyte count was elevated with a predominance of monocytic leukocytes. RESULTS: Blood, urine, and PD effluent cultures were negative. An ultrasound scan of the transplanted kidney and a computerized tomography (CT) scan of the abdomen and pelvis did not identify the cause of the peritonitis. Foley catheter decompression of the bladder resulted in improvement of the abdominal pain and PD effluent leukocytosis. Twenty-five days later, the patient again experienced abdominal pain and cloudy PD effluent. Cultures of blood and PD effluent were again negative. CT scanning and cystoscopy of the transplanted pancreas identified a leak at the pancreaticoduodenocystotomy anastamosis. Urinary bladder decompression was followed by surgical exploration that identified an erosion of the distal transplanted duodenum, necessitating enteric diversion of the transplanted pancreas's exocrine secretions. The patient underwent conversion to hemodialysis, and the pancreas transplant continued to function well. He has subsequently received a living related kidney transplant. CONCLUSION: This is the first reported case of noninfectious PD peritonitis caused by pancreaticoduodenocystotomy leak in a patient with a functional pancreas transplant.

Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment.

Calciphylaxis is a small vessel vasculopathy involving mural calcification with intimal proliferation, fibrosis, and thrombosis. This syndrome occurs predominantly in individuals with renal failure and results in ischemia and necrosis of skin, subcutaneous fat, visceral organs, and skeletal muscle. The syndrome causes significant morbidity in the form of infection, organ failure, and pain. Mortality rates are high. In individuals with renal failure, risk factors for the development of calciphylaxis include female sex, Caucasian race, obesity, and diabetes mellitus. Many cases occur within the first year of dialysis treatment. Several recent reports demonstrate that prolonged hyperphosphatemia and/or elevated calcium x phosphorus products are associated with the syndrome. Protein malnutrition increases the likelihood of calciphylaxis, as does warfarin use and hypercoagulable states, such as protein C and/or protein S deficiency. Recent advances in diagnostic tools and therapeutic strategies have helped in the management of patients with calciphylaxis.

15-Deoxy-Delta12,14-prostaglandin J2 regulates mesangial cell proliferation and death.

BACKGROUND: Proliferation of intrinsic glomerular cells is a common response to renal injury. Acutely, proliferation may be beneficial, but sustained glomerular hypercellularity after injury is associated with progressive renal failure. To identify endogenous factors that may be responsible for regulating glomerular cell number, the effects of J-series cyclopentenone prostaglandins (PGs) on human glomerular mesangial cell proliferation and death were examined. METHODS: Human mesangial cells were grown in the presence or absence of PGJ2 or its metabolite 15-Deoxy-Delta12,14-PGJ2 (15dPGJ2). The number of viable cells was measured by the reduction of the tetrazolium MTS to a colored formazan product. Apoptosis was assessed by caspase-3 activation and DNA fragmentation. RESULTS: PGJ2 at concentrations up to 10 micromol/L caused mesangial proliferation. 15dPGJ2 also caused mesangial proliferation at low concentrations (< or =2.5 micromol/L), but induced mesangial cell death at higher concentrations (>5 micromol/L). Cell death occurred in part through apoptosis, measured as an increase in caspase-3 activity and DNA fragmentation in 15dPGJ2-treated cells. Cell death was associated with a decline in baseline phosphorylation of the survival factor Akt and increased Akt degradation, whereas 15dPGJ2-induced mesangial proliferation was blocked by inhibition of the PI 3-kinase/Akt pathway. 15dPGJ2 is a potent PPARgamma agonist. Like 15dPGJ2, treatment of mesangial cells with thiazolidinedione-type PPARgamma ligands (10 to 20 micromol/L) caused significant cell death, but at lower concentrations also caused a small degree of proliferation. CONCLUSIONS: J-series prostaglandins thus may be involved in the initiation of glomerular hypercellularity through Akt-dependent proliferation, and restoration of normal glomerular architecture through PPARgamma-mediated apoptosis. Manipulation of these prostaglandins may be relevant to the treatment of progressive glomerular disease.

PPAR-alpha ligands inhibit H2O2-mediated activation of transforming growth factor-beta1 in human mesangial cells.

Transforming growth factor-beta1 (TGF-beta1) mediates the development of glomerulosclerosis by stimulating mesangial cell production of extracellular matrix (ECM) proteins. TGF-beta1 and several ECM genes are regulated by promoter O-tetradecanoylphorbol 13-acetate-responsive elements (TREs) that are transactivated by the activator protein-1 (AP-1) transcription factor complex. AP-1-TRE interactions are regulated by redox changes. Recently, peroxisome proliferator-activated receptors (PPARs) were shown to negatively regulate several transcription factor families. In these studies, we postulated that PPAR-alpha could antagonize TGF-beta1 expression by cultured human mesangial cells (HMC). A TGF-beta1 luciferase expression plasmid was transduced into HMC via recombinant deficient adenoviral vectors. The TGF-beta1 promoter activity increased twofold (209%) following 18-h treatments with H(2)O(2) (1,000 micro M). Using RT-PCR, we demonstrated that HMC possess PPAR-alpha RNA, and PPAR-alpha protein was identified by immunohistochemistry. Pretreatment of cells with the PPAR-alpha ligands WY14643 (100-500 micro M) or clofibrate (100-500 micro M) dose-dependently inhibited oxidant-mediated induction of TGF-beta1. This inhibition occurred without affecting the H(2)O(2)-mediated activation of the mitogen-activated protein kinase (MAPK) pathways extracellular regulated kinase, p38 MAPK, or Jun N-terminal kinase, which are responsible for the regulation of AP-1 phosphorylation. These studies are the first to identify PPAR-alpha expression by HMC. The results of these studies suggest that TGF-beta1 expression mediated by oxidant stress may be suppressible by PPAR-alpha activation.