K.N. Lai

Treatment of membranous lupus nephritis with nephrotic syndrome by sequential immunosuppression

The optimal therapy for pure membranous lupus nephritis (MLN) with nephrotic syndrome remains controversial. While the risk of progressive renal deterioration may be small, persistent heavy proteinuria leads to the complications of oedema, hypoalbuminaemia, hyperlipidaemia, hypercoagulability, and venous thrombosis. We examined prospectively the efficacy and tolerability of a sequential immunosuppressive regimen in a cohort of 20 patients with nephrotic syndrome due to pure MLN (WHO Class Va and Vb). Initial therapy comprised prednisolone (0.8 mg/kg/d p.o.) and cyclophosphamide (2–2.5 mg/kg/d p.o.). Prednisolone dosage was gradually tapered to 10 mg/d at 6 months, when cyclophosphamide was replaced by azathioprine (2 mg/kg/d p.o.) as maintenance therapy. Within 12 months of therapy 11(55%) patients had complete remission (CR), 7(35%) patients achieved partial remission (PR) (proteinuria reduced from 6.2 4.0 to 2.0 1.7 g =24 h, P < 0.01), and 2 patients failed to respond. Improvements in proteinuria and serum albumin level were observed after 3–6 months of treatment. Non-responders had lower baseline serum albumin compared to complete responders. Renal function remained stable during follow-up for 73.5 48.9 months. 8 patients had disease relapse at 47 15 months. Early complications (12 months) included herpes zoster (40%), minor respiratory or urinary tract infections (25%), mild leukopenia (15%), and transient amenorrhea (14.3%). 4 of the 20 patients developed pulmonary tuberculosis during follow-up, at 35 24 months after the diagnosis of MLN. 8 patients had hyperlipidaemia. Haemorrhagic cystitis, permanent amenorrhea, vascular complications, and mortality were not observed. We conclude that this sequential immunosuppressive regimen is effective in 90% of patients with MLN and heavy proteinuria. Prudent consideration of the benefits and potential side-effects is required to determine the optimal management for individual patients.

Angiotensin inhibition or blockade for the treatment of patients with quiescent lupus nephritis and persistent proteinuria.

Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) reduces proteinuria and the rate of renal function deterioration in diabetic nephropathy and other glomerular diseases, but its role in quiescent lupus nephritis has not been established. We conducted a retrospective study to investigate the effects of ACEI/ARB on proteinuria and renal function in patients with persistent proteinuria (>1 g/day) despite resolution of acute lupus nephritis following immunosuppressive treatment. Fourteen out of 92 patients were included. The duration of treatment with ACEI/ARB was 52.1 ± 35.7 months. The levels of proteinuria, serum albumin, serum creatinine, systolic and diastolic blood pressure were 1.10 to 6.90 g/day, 35.8 ± 3.6 g/L, 102.54 ± 34.48 μmol/L, 137.6 ± 10.9 and 81.9 ± 9.2 mmHg at baseline. Proteinuria and serum albumin showed significant sustained improvements after 6 and 24 months of treatment. Comparison of slopes for serial proteinuria, albumin and reciprocal of serum creatinine before and after treatment showed significant improvements in six (43%), eight (57%) and two patients, respectively. At last follow-up proteinuria remained significantly lower (0.36 g/day, P = 0.043) and albumin higher (41.3 ± 2.2 g/L, P = 0.023). Eleven (78.6%) patients had proteinuria improved by >50%, and five had insignificant proteinuria at last follow-up. Systolic blood pressure was significantly reduced from 6 months onwards, but this did not correlate with proteinuria reduction. Diastolic blood pressure, serum creatinine, creatinine clearance, anti-dsDNA, C3 and haemoglobin were not altered. We conclude that ACEI/ARB effectively reduces proteinuria and improves serum albumin in patients with persistent proteinuria despite quiescent lupus nephritis.

Differential expression of receptors for advanced glycation end-products in peritoneal mesothelial cells exposed to glucose degradation products

Autoclaving peritoneal dialysate fluid (PDF) degrades glucose into glucose degradation products (GDPs) that impair peritoneal mesothelial cell functions. While glycation processes leading to formation of advanced glycation end‐products (AGE) were viewed commonly as being mediated by glucose present in the PDF, recent evidence indicates that certain GDPs are even more powerful inducers of AGE formation than glucose per se. In the present study, we examined the expression and modulation of AGE receptors on human peritoneal mesothelial cells (HPMC) cultured with GDPs, conventional PDF or PDF with low GDP content. HPMC cultured with GDPs differentially modulated AGE receptors (including RAGE, AGE–R1, AGE–R2 and AGE–R3) expression in a dose‐dependent manner. At subtoxic concentrations, GDPs increased RAGE mRNA expression in HPMC. 2‐furaldehyde (FurA), methylglyoxal (M‐Glx) and 3,4‐dideoxy‐glucosone‐3‐Ene (3,4‐DGE) increased the expression of AGE–R1 and RAGE, the receptors that are associated with toxic effects. These three GDPs up‐regulated the AGE synthesis by cultured HPMC. In parallel, these GDPs also increased the expression of vascular endothelial growth factor (VEGF) in HPMC. PDF with lower GDP content exerted less cytotoxic effect than traditional heat‐sterilized PDF. Both PDF preparations up‐regulated the protein expression of RAGE and VEGF. However, the up‐regulation of VEGF in HPMC following 24‐h culture with conventional PDF was higher than values from HPMC cultured with PDF containing low GDP. We have demonstrated, for the first time, that in addition to RAGE, other AGE receptors including AGE–R1, AGE–R2 and AGE–R3 are expressed on HPMC. Different GDPs exert differential regulation on the expression of these receptors on HPMC. The interactions between GDPs and AGE receptors may bear biological relevance to the intraperitoneal homeostasis and membrane integrity.

Effect of low molecular weight heparin on bone metabolism and hyperlipidemia in patients on maintenance hemodialysis.

The effect of low molecular weight heparin (LMWH) on serum lipid profile in hemodialysis remains controversial and its effect on bone metabolism has not been studied. A crossover study was conducted in 40 patients on stable hemodialysis using unfractionated heparin (UFH) for more than 24 months. These patients were then treated with a LMWH (nadroparin-Ca) for 8 months during hemodialysis and subsequently switched back to UFH for 12 months. Serum lipid profile, biochemical markers for bone metabolism, and bone densitometry (BMD) were monitored at four-month intervals while all medications remained unchanged. Cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), lipoprotein(a) (Lp(a)), apolipoprotein B (Apo B) were raised in 35%, 29%, 12%, 24% and 24% of patients respectively. High-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 (Apo A-1) were reduced in 47% and 9% of patients. Bone-specific alkaline phosphatase (BALP) and intact osteocalcin (OSC), both reflecting osteoblastic activity, were raised in 65% and 94% of patients. Tartrate-resistant acid phosphatase (TRACP) reflecting osteoclastic activity and parathyroid hormone (PTH) were elevated in 35% and 88% of patients. Following LMWH treatment, TC, Tg, Lp(a) and Apo B were reduced by 7%, 30%, 21% and 10% respectively (p<0.05 or <0.01) while Apo A-1 were raised by 7% (p<0.01). Simultaneously, TRACP was reduced by 13% (p<0.05). These biochemical changes were detected soon after 4 months of LMWH administration. Although BMD values in our patients were lower than those of age-matched normal subjects, significant changes were not observed with LMWH treatment. After switching back to UFH for hemodialysis, these biochemical indices reverted to previous values during UFH treatment with a significant higher level in TC and Apo B while serum Apo A-1 remained elevated. Our study suggests LMWH may partially alleviate hyperlipidemia and, perhaps, osteoporosis associated with UFH administration in patients on maintenance hemodialysis.

Star fruit intoxication in uraemic patients: case series and review of the literature

Abstract

Original ArticleInteraction between proximal tubular epithelial cells and infiltrating monocytes/T cells in the proteinuric state

We hypothesize an interaction between T cells/monocytes and the tubules in the development of tubulointerstitial injury in chronic proteinuric nephropathy. We established in vitro co-culture systems of proximal tubular epithelial cells (PTEC) and T cells/monocytes to study the contribution of soluble factors and cell-to-cell contact in the development of tubulointerstitial injury. The release of monocyte chemoattractant protein-1 (MCP1 or CCL2), Regulated upon Activation, normal T cell Expressed and Secreted (RANTES or CCL5), soluble intracellular adhesion molecules-1 (sICAM-1), or interleukin-6 (IL-6) was increased in PTEC following apical exposure to human serum albumin (HSA). The release of CCL2, CCL5, or sICAM-1 from PTEC was enhanced by contact of monocytes/T cells on the basolateral surface. Tumor necrosis factor-alpha (TNF-alpha) and IL-1beta are important soluble factors as suggested by the blocking effect of antibodies (Abs) against TNF-alpha or IL-1beta but not against other cytokines. The percentage of CD4+ T cells expressing both chemokine receptors, CCR2 and CCR5, was increased after culturing with supernatant from the apical or basolateral surface of PTEC following apical exposure to HSA. However, only CCR2 was upregulated in CD8+ T cells, whereas CCR5 expression was increased in monocytes. The chemotaxis of CD4+ or CD8+ T cells to supernatant from PTEC upon apical exposure to HSA was reduced with neutralizing Abs against CCL5 and/or CCL2, whereas the chemotaxis of monocytes was only reduced by anti-CCL5 but not by anti-CCL2. In summary, chemokines released by HSA-activated PTEC are amplified by monocytes/T cells. Mediators released by HSA-activated PTEC can differentially modulate the expression of chemokine receptors in monocytes/T cells and hence, alter their chemotaxis towards activated PTEC. These interactions are pivotal in the development of tubulointerstitial injury.

Rhodococcus lung abscess complicating kidney transplantation: successful management by combination antibiotic therapy

Abstract: In this report, a renal transplant recipient with Rhodococcus lung abscess is described. A high clinical suspicion and appropriate combination antibiotic therapy obviated the need for surgical intervention and was associated with a good clinical outcome. The optimal regimen of combination antibiotic therapy is discussed.

Modulation of intra-pulmonary TGF-b expression by mycophenolate mofetil in lupus prone MRL/lpr mice

We investigated the expression profile of inflammatory cytokines in the lung of lupus-prone MRL/lpr mice and evaluated the therapeutic potential of mycophenolate mofetil (MMF) in reducing pulmonary cytokines in active lupus. Eight-week old female MRL/lpr mice (n = 20) were treated with MMF in vehicle by oral gavage. Disease control MRL/lpr mice (n = 30) or normal control MRL mice (n = 20) received vehicle alone. The mice were sacrificed after eight or 12 weeks of treatment. Gene expression and protein synthesis of IL-1β, MCP-1 and TGF-β1 in lung tissues were determined. We found an increase in the gene expression of IL-1β, MCP-1 and TGF-β1 in lung tissues of untreated MRL/lpr mice compared with MRL mice at either 16 weeks or 20 weeks of age. MMF treatment significantly prolonged the survival of MRL/lpr mice, down-regulated the gene expression of IL-1β, MCP-1 and TGF-β1 in lung tissues at the end of eight or 12 weeks of treatment. Protein synthesis of TGF-b1 was decreased following eight weeks of MMF treatment. We conclude that MMF treatment can reduce the TGF-b1 gene expression and protein synthesis in lung tissues of lupus-prone mice. Our findings provide experimental data suggesting a beneficial potential of MMF therapy in pulmonary involvement of lupus.

Early detection of hepatocellular carcinoma in hepatitis-B-positive renal transplant recipients.

Hepatocellular carcinoma (HCC) is a leading cause of malignancy after renal transplantation in Asia, where hepatitis B virus infection is endemic. Early detection and resection are the key to successful treatment because the mortality rate for HCC is high. The value of α‐fetoprotein monitoring in the early detection of HCC in renal transplant recipients has not been reported before. We describe 2 patients who had successful resection of HCC following early diagnosis by α‐fetoprotein monitoring. The epidemiology of post‐transplant HCC in various parts of the world and its pathogenesis are discussed. J. Surg. Oncol. 1999;72:99–101.

Burkholderia urinary tract infection after renal transplantation

Abstract: Urinary tract infection is a common complication after renal transplantation. The etiologies are diverse and the bacterial agents may sometimes be acquired during the hospital stay. We report a patient who developed Burkholderia cepacia urinary tract infection after renal transplantation. The bacteria showed in vivo resistance to all of the available antibiotics. A graft nephrectomy was eventually required to clear the infection. The consequence of some fastidious infection may be catastrophic and early recognition and treatment is necessary to optimize the treatment.