Kwok W. Chan

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.

Carcinoma of the Esophagus. an Autopsy Study of 231 Cases

&NA; Summary Autopsy findings for 231 cases of carcinoma of the esophagus are presented. Cases with tumour resection constituted 57% of the series. Residual malignancy was present in 81% of all cases. Local residual or recurrent tumour was found in 53%, lymph node metastases in 65% and visceral metastases in 54% of cases. Intrathoracic lymph node metastases were present in 41% of patients after tumour resection and were probably significant in the failure of radical surgery. Adequate clearance of intrathoracic lymph nodes during radical surgery may reduce the incidence of tumour recurrence in this group of patients. Survival was poor in patients with or without resection of the primary tumour. Less than 12% were alive 1 yr after presentation. The average duration of dysphagia at presentation was 2.5 mth. The poor survival of our patients suggests that, by the time they presented clinically, the disease was already advanced. Early disease detection is important for a chance of cure in patients with esophageal cancer.

Effect of mycophenolate mofetil on severity of nephritis and nitric oxide production in lupus-prone MRL/lpr mice

Mycophenolate mofetil (MMF), an immunosuppressive drug commonly used in organ transplantation, is increasingly being used to treat autoimmune diseases including systemic lupus erythematosus (SLE). Excessive production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesisof lupus nephritis. We evaluated the effect of MMF on the severity of nephritis and the production of NO in lupus-prone MRL/lpr mice. Eight-week-old female MRL/lpr mice (n = 20) were treated with MMF (100 mg/kg/day) by oral gavage for 12 weeks. Control mice (n = 20) received vehicle on the same schedule. The mice were killed after 12 weeks of treatment. Treatment with MMF significantly decreased the amount of proteinuria, prolonged survival and reduced the histological severity of glomerulonephritis.Urinary nitrite/nitrate excretion in the MMF-treated mice was significantly reduced during the first 8 weeks of treatment. However, by the end of the 12 weeks treatment period, there was no significant difference between vehicle and MMF-treated mice in terms of urinary nitrite/nitrate excretion, intra-renal production of NO, expression of iNOS protein and induction of iNOS mRNA. We conclude that MMF is effective in attenuatingthe severity of nephritis in MRL/lpr mice. The beneficial effects of MMF on lupus nephritis during the early phase of the disease might be partly attributed to the inhibition of NO production. The inhibitory effect of MMF on NO production diminishes as the disease progresses. MMF probably has additional, as yet undefined mode of actions to fully account for its beneficial effects on lupus nephritis.

Rapamycin attenuates the severity of established nephritis in lupus-prone NZB/W F1 mice

BACKGROUNDnRapamycin is a potent immunosuppressive drug with proven efficacy in rejection prophylaxis in solid organ transplantation. By virtue of its immunosuppressive properties, rapamycin might also be useful in the treatment of autoimmune diseases. The aim of this study was to determine the effect of rapamycin on the severity of established nephritis in lupus-prone New Zealand Black/White F(1) (NZB/W F(1)) mice.nnnMETHODSnSix-month-old female NZB/W F(1) mice with active nephritis (albuminuria >100 mg/dL) were treated with rapamycin (3 mg/kg body weight) or saline once daily by oral gavage for 4 months. The effect of rapamycin on the severity of nephritis was evaluated by clinical manifestations, biochemical parameters, renal histology, immunohistochemistry and semi-quantitative gene expression studies.nnnRESULTSnTreatment with rapamycin significantly decreased albuminuria, improved survival, diminished splenomegaly, preserved renal function and reduced serum anti-dsDNA antibody levels. Kidney sections from saline-treated mice revealed marked mesangial proliferation, tubular dilation with intra-tubular protein cast deposition and leukocytic infiltration of the interstitium. The rapamycin-treated mice, in contrast, had relatively mild histological changes in their kidneys. Rapamycin treatment also significantly reduced the amount of immune complex deposition in the glomeruli, suppressed the interstitial infiltration by T-cells, B-cells and macrophages as well as down-regulated the intra-renal expression of RANTES.nnnCONCLUSIONSnWe conclude that rapamycin is effective in attenuating the severity of established nephritis in NZB/W F(1) mice. The beneficial effects of rapamycin are mediated, at least in part, through inhibition of lymphoproliferation, reduced RANTES expression and decreased inflammatory cell infiltration in the kidneys. Rapamycin could be of therapeutic value in the treatment of human lupus nephritis.

Rapamycin prevents the development of nephritis in lupus-prone NZB/W F1 mice

Rapamycin is a potent immunosuppressive drug currently used mainly for rejection prophylaxis in renal transplantation. The aim of this study was to determine the effect of rapamycin treatment on the development of nephritis in lupus-prone New Zealand Black/White F1 (NZB/W F1) mice. Twelve-week-old female NZB/W F1 mice were treated with rapamycin (3 mg/kg body weight) or saline once daily by oral gavage for 20 weeks. The severity of nephritis was assessed by clinical and biochemical parameters, renal histology, immunohistochemistry and gene expression studies. Rapamycin treatment markedly reduced proteinuria, improved renal function, decreased serum anti–double stranded DNA antibody levels and diminished splenomegaly. Kidney sections from saline-treated mice showed marked mesangial proliferation, tubular dilation with protein cast deposition and interstitial inflammatory cell infiltration. Rapamycin-treated mice had near normal renal histology, with marked reduction in glomerular immune deposition and the infiltration by T cells, B cells and macrophages. Rapamycin treatment was associated with down-regulation of intra-renal expression of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein. We conclude that rapamycin is highly effective in preventing the development of nephritis in NZB/W F1 mice. The beneficial effects of rapamycin are mediated through inhibition of lymphoproliferation and reduced MCP-1 expression.

Focal segmental glomerulosclerosis and mesangial sclerosis associated with myeloproliferative disorders

The myeloproliferative disorders (MPDs) are clonal disorders of the hematopoietic stem cell and classified as polycythemia vera (PV), essential thrombocythemia (ET), or agnogenic myeloid metaplasia (AMM), depending on the main hematopoietic lineage involved. Primary renal parenchymal lesions are not commonly reported in these cases. We conducted a retrospective analysis of 138 consecutive patients with MPD to determine the frequency of renal parenchymal complications. Five patients (3.6%) (two PV, two ET, one AMM) were found to have focal segmental glomerulosclerosis (FSGS) and diffuse mesangial sclerosis, presenting as proteinuria in all the cases and progressing to chronic renal failure in two cases. A possible common risk factor was a high platelet count, because abnormal platelet activation in MPD has been shown to contribute to the development of glomerulosclerosis. The pathophysiologic basis of our observations and the implications in management of MPD patients remain to be studied.

Effect of rapamycin on renal ischemia-reperfusion injury in mice.

The aim of this study was to determine the effect of rapamycin on renal ischemia‐reperfusion injury (IRI) in mice. Renal IRI was induced in male BALB/c mice by clamping both renal pedicles for 45u2003min. The mice were treated with either vehicle or rapamycin (2u2003mg/kg/day) by oral gavage, starting 1u2003day before the IRI and continued daily till killing. The mice were killed on days 1, 3 and 7 after the operation. The severity of the renal IRI was assessed by serum creatinine levels and renal histology. Proliferation of renal tubular cells was quantified by immunohistochemical staining for proliferating cell nuclear antigen (PCNA). One day after the IRI, the serum creatinine levels of rapamycin‐treated mice were significantly higher than those of the vehicle‐treated mice. Kidney sections from rapamycin‐treated mice showed more marked tubular damage and significantly lower number of PCNA‐positive cells. The number of PCNA‐positive cells in the rapamycin‐treated mice remained significantly lower on day 3 after the IRI. By day 7 after the IRI, the serum creatinine levels, renal histology and positive PCNA staining in the kidney sections became similar between the two treatment groups. We conclude that in this murine model of renal IRI, rapamycin treatment aggravates renal IRI during the first 3u2003days after the insult. This effect might be mediated, at least partly, through inhibition of renal tubular cell proliferation.

Pattern of Glomerulonephritis in Hong Kong

&NA; A retrospective analysis of all renal biopsies (961) performed in two regional hospitals in Hong Kong during 1977–1985 revealed that IgA nephropathy was the most frequently encountered glomerulopathy. Lipoid nephrosis (minimal change nephrotic syndrome) remained the commonest cause of nephrotic syndrome in children. The frequencies of mesangiocapillary glomerulonephritis, focal glomerulosclerosis, and idiopathic membranous nephropathy were lower than in other populations. Membranous nephropathy was frequently associated with hepatitis B virus antigenemia, especially in children. Other chronic infections did not have a significant pathogenetic role in glomerular diseases. Lupus nephritis was the commonest secondary glomerular disease in our study, and over seventy percent of the renal biopsies showed advanced pathologies with either diffuse proliferative glomerulonephritis or membranous nephropathy.

Microsatellite Analysis in Post-Transplantation Lymphoproliferative Disorder to Determine Donor/Recipient Origin

Post-transplantation lymphoproliferative disorders (PTLD) are a group of heterogeneous diseases that occur after organ transplantation. Determination of the origin of the tumor cells not only provides clues to its possible pathogenetic mechanism, but also gives prognostic guidance in the clinical management of patients. We reviewed the clinicopathological features of four cases of PTLD that developed after solid organ transplantation. Using microsatellite analysis performed on paraffin-embedded tissue and using multiple, highly polymorphic markers, we have successfully determined the recipient/donor origin of the tumor cells in all of them. The time of onset of the PTLD ranged from 5 to 11 mo. All cases were diffuse large cell lymphomas of B-cell lineage, and the two cases that have been tested for EBV by in situ hybridization were positive. Three of the 4 PTLD were of donor origin and these three patients died of diseases unrelated to PTLD. The single patient with PTLD of recipient origin died of disseminated PTLD. The mean survival length of the three patients with donor origin was 26.3 mo, whereas that of the patient with recipient origin was 12 mo. Our results indicate a relatively high incidence of PTLD of donor origin among our patients with solid organ transplantation, as compared to other reported series. Moreover, the finding of the relatively indolent nature of PTLD of donor origin supports that determination of the donor/recipient origin of PTLD is of prognostic significance.

Age-related glomerular sclerosis: baseline values in Hong Kong.

A study was undertaken to estimate the incidence of glomerular sclerosis in the normal population in Hong Kong. The percentage glomerular sclerosis in 100 cadavers without clinical evidence of kidney disease or hypertension was determined by histologic examination of the kidneys. The mean percentage values in the normal population at all age groups were calculated based on this sample. The subcapsular cortical area generally had a higher proportion of sclerotic glomeruli than the deeper cortex. Statistical analysis showed that 95% of the normal population up to 40 years of age would be expected to have less than 6% sclerotic glomeruli. After the age of 55, the upper limit containing 95% of the normal population would exceed 10% sclerosis. A broad scatter of observed percentage glomerular sclerosis was present in the elderly after the age of 70 years. The data obtained provide the baseline values of glomerular scarring that would allow age-related involutional changes to be distinguished from those due to disease.