Patrizia Passerini

Benefits and risks of protracted treatment with human recombinant erythropoietin in patients having haemodialysis

Fourteen patients with uraemic anaemia and having regular haemodialysis were given human recombinant erythropoietin in increasing doses, beginning with 24 U/kg thrice weekly. One patient was dropped from the study because of recurrent thrombosis of vascular access sites. In the other 13 patients, followed up for a mean of 9.1 months (range 8-11), haemoglobin concentrations increased from 62 (SD 8) to 105 (9) g/l. No antierythropoietin antibodies were detected during the study. The correction of anaemia was associated with a tendency to hyperkalaemia and a mild increase of unconjugated bilirubinaemia. In eight previously hypertensive patients antihypertensive treatment had to be reinforced, but in normotensive patients blood pressure did not change. Thrombosis of arteriovenous fistulas occurred in two patients and a cerebral ischaemic lesion in one. Protracted treatment with human recombinant erythropoietin evidently can maintain normal haemoglobin concentrations in uraemic patients over time. Full correction of anaemia, however, may trigger some vascular problems, particularly in hypertensive patients and those with a tendency to thromboembolism.

Gastrointestinal complications in renal transplant recipients

Gastrointestinal complications are frequent in renal transplant recipients and can include oral lesions, esophagitis, peptic ulcer, diarrhea, colon disorders and malignancy. Oral lesions may be caused by drugs such as cyclosporine and sirolimus, by virus or fungal infections. Leukoplakia may develop in patients with Epstein–Barr virus (EBV) infection. The commonest esophageal disorder is represented by fungal esophagitis usually caused by candida. A number of patients may suffer from nausea, vomiting and gastric discomfort. These disorders are more frequent in patients treated with mycophenolate mofetil (MMF). Peptic ulcer is more rare than in the past. Patients with a history of peptic ulcer are particularly prone to this complication. Other gastroduodenal disorders are caused by cytomegalovirus (CMV) and herpes simplex infection. Diarrhea is a frequent disorder which may be caused by pathogen microorganisms or by immunosuppressive agents. The differential diagnosis may be difficult. Colon disorders mainly consist of hemorrhage, usually sustained by CMV infection, or perforation which may be caused by diverticulitis or intestinal ischemia. Colon cancer, anal carcinoma, and EBV‐associated lymphoproliferative disorders are particularly frequent in transplant recipients. A particular gastric lymphoma called mucosa‐associated lymphoid tissue (MALT) lymphoma may develop in renal transplant patients. It usually responds to the eradication of Helicobacter pylori.

Methylprednisolone plus Chlorambucil as Compared with Methylprednisolone Alone for the Treatment of Idiopathic Membranous Nephropathy

BACKGROUND AND METHODS Treatment with methylprednisolone and chlorambucil may protect renal function and increase the chance of remission of the nephrotic syndrome in patients with idiopathic membranous nephropathy. To determine whether similar results might be obtained with methylprednisolone alone, we compared the effects of methylprednisolone and chlorambucil with those of methylprednisolone alone in 92 patients with the nephrotic syndrome caused by idiopathic membranous nephropathy. The patients were randomly assigned to receive either alternating one-month courses of methylprednisolone and then chlorambucil for a total of six months (group 1) or methylprednisolone alone for six months at the same cumulative dosage (group 2). RESULTS Four of the 45 patients in group 1 (9 percent) and 1 of the 47 in group 2 (2 percent) stopped treatment because of side effects. At one, two, and three years, the percentage of patients who did not have the nephrotic syndrome was significantly higher in group 1 than in group 2. It was 58, 54, and 66 percent, respectively, in group 1, as compared with 26, 32, and 40 percent in group 2 (P = 0.002, 0.029, and 0.011). By year 4, the difference was no longer statistically significant: 62 percent of the patients in group 1 and 42 percent of those in group 2 did not have the nephrotic syndrome (P = 0.102). The patients in group 1 were in remission longer than those in group 2 (P = 0.008). CONCLUSIONS In patients with the nephrotic syndrome caused by idiopathic membranous nephropathy, treatment with methylprednisolone and chlorambucil for six months induces an earlier remission of the nephrotic syndrome than methylprednisolone alone, but the difference may diminish with time.

Can prolonged treatment improve the prognosis in adults with focal segmental glomerulosclerosis

Eighty nephrotic adults with focal segmental glomerulosclerosis (FSGS) and plasma creatinine lower than 3 mg/dL were given corticosteroids (53 patients) or immunosuppressive agents (27 patients) for a median of 16 and 75 weeks, respectively. Forty-two patients responded with complete remission (29 patients, 36%) or partial remission (13 patients, 16%). Twenty-six patients who did not respond were treated again. Two patients obtained complete remission and 13 partial remission. The probability of remission was associated with treatment with corticosteroids (P = 0.0001; RR, 3. 93; 95% CI, 2.00 to 7.72), absence of arterial hypertension (P = 0. 0023; RR, 2.59; 95% CI, 1.41 to 4.79), and a percentage of hyaline glomeruli lower than 5% (P = 0.0152; RR, 2.04; 95% CI, 1.15 to 3.64). The probability of being alive at 110 months without doubling of plasma creatinine was 69%. The risk of renal insufficiency was correlated with mesangial proliferation (P = 0.0025; RR, 5.50; 95% CI, 1.82 to 16.60) and with interstitial fibrosis (P = 0.0231; RR, 4. 44; 95% CI, 1.23 to 16.08) at initial biopsy. Considering partial or complete remission as a time-dependent variable, only the lack of remission (P = 0.0027; RR, 7.23; 95% CI, 1.98 to 26.33) and mesangial proliferation (P = 0.0069; RR, 4.59; 95% CI, 1.52 to 13. 88) were correlated with renal failure. Major side effects were observed in 11 patients (5 infections, 1 peptic ulcer, 2 diabetes, 3 neoplasias). This study shows that 70% of nephrotic adults with FSGS may obtain complete or partial remission and maintain stable renal function for about 10 years when given a prolonged therapy with corticosteroids or immunosuppressive drugs.

Natural history of hepatitis B and C in renal allograft recipients.

Background. In renal allograft recipients, most cases of liver dysfunction are caused by hepatitis B virus and hepatitis C virus (HCV). The natural history of hepatitis C and B was studied in 286 renal allograft recipients who received a kidney allograft between 1972 and 1989 when tests for anti-HCV became available. Methods. In all patients, hepatitis B (HB) surface (s) antigen (Ag) was tested before and anti-HCV (by enzyme-linked immunosorbent assay II) after transplantation. Results. At enrollment in 1989 (5.5±4 years after transplantation), 209 patients were anti-HCV positive (C+), 42 patients were HBsAg-positive (B+), and 35 patients were both B+ and C+ (C+B+). One hundred four patients were receiving azathioprine (AZA) and 182 were on cyclosporine A (CsA). Since transplantation, the median follow-up was 18 years in AZA-treated and 13 years in CsA-treated patients. Liver biopsy showed chronic hepatitis in 73 patients, cirrhosis in 20 patients, and fibrosing cholestatic hepatitis in 2 patients. In 34 patients, liver biopsy was repeated, and progression of fibrosis was observed in 24 patients. The 12-year patient survival rate was similar in B+, C+, and B+C+ patients (67%, 78%, and 71%, respectively; P=not significant). Liver-related death was the first cause of death in B+ and B+C+ infected patients (58% and 72%, respectively), whereas cardiovascular disease was the leading cause of death in C+ patients (40%). Multivariate analysis showed that older age (>40 years) (relative risk [RR], 2.8), B+ status (RR, 2.36), and C+ status (RR, 1.65) were independently associated with a worse patient survival. Conclusions. In the long term, B+ patients had a higher risk of death related to liver disease than C+ patients, and co-infection did not worsen patient survival.

Long-term outcome of renal transplantation in patients with idiopathic membranous glomerulonephritis (MN)

BACKGROUND Little information is available about the long-term outcome of renal transplanted patients with idiopathic membranous nephropathy (MN). METHODS The outcomes of 35 first renal transplants performed between 1975 and 2008 in patients with MN were compared with those of 70 controls transplanted in the same period and matched for sex, age and source of donors. RESULTS The mean post-transplant follow-up was 117 ± 86 months for MN patients and 123 ± 83 months for controls. At 15 years, patient survival was 96% in patients with MN and 88% in the controls (P = ns), while graft survival rates were respectively 40% and 69% (P = 0.06). MN recurred in 12 patients (34%), namely in 4/8 (50%) patients who received the kidney from related living donors and in 8/27 (29.6%) who received the kidney from a deceased donor. Recurrence led to graft failure in six patients, all deceased donor kidney recipients, within 54 ± 33 months. The other six grafts are functioning 134 ± 73 months after transplantation. Patients with recurrence were more frequently females (42% vs 4.3%, P = 0.02). The recurrence occurred earlier (4.8 ± 3.0 vs 45.6 ± 46.9 months, P = 0.05), and there was a trend to develop a higher proteinuria (7.1 ± 5.5 vs 3.67 ± 2.6 g/24 h, P = 0.1) in grafts eventually lost because of recurrence. CONCLUSIONS The long-term patient survival was similar in renal transplant recipients with MN and in controls. The graft survival was lower in MN patients than in controls, although the difference was at borderline significance. Recurrence occurred in one-third of the patients and caused graft loss in half of them.

Serological and genetic factors in early recurrence of IgA nephropathy after renal transplantation

Abstract:  Background:  The relative role of IgA anomalies and genetic factors in IgA nephropathy (IgAN) recurrence after transplantation has never been investigated in a single cohort.

Corticosteroids, Cyclophosphamide, and Chlorambucil Therapy of Membranous Nephropathy

Corticosteroids and cytotoxic agents have been studied widely in membranous nephropathy (MN). However, controlled studies with corticosteroids have not shown a clear benefit of these agents on the outcome of the disease. Some controlled trials reported that cytotoxic agents can reduce proteinuria significantly, but it was difficult to assess the efficacy of these drugs in protecting renal function because of the short follow-up period of the studies. Three randomized controlled trials showed that a 6-month treatment regimen based on corticosteroids and a cytotoxic agent, giving each for 1 month at a time in an alternating schedule, could favor remission of the nephrotic syndrome and protect renal function. Taken together, the results of these trials at the end of the follow-up period, 74% of the 174 treated patients were without nephrotic syndrome, 4 patients were on chronic dialysis, and 2 patients died. Good results with cytotoxic drugs, often associated with corticosteroids, also have been reported in progressive membranous nephropathy. However, in patients with renal insufficiency side effects were frequent and severe. Moreover, in most cases renal function improved but did not return to normal.

Is cyclosporine in renal-transplant recipients more effective when given twice a day than in a single daily dose?

Background. It is still unknown whether it is better to administer cyclosporine (CsA) once or twice a day to renal-transplant patients. Methods. Fifty-four patients were randomized to receive CsA once a day (OD group, 28 patients) or twice a day (BD group, 26 patients). Clinical parameters and pharmacokinetic studies were regularly monitored over the first year. Results. Two patients lost their grafts because of renal vascular thrombosis. A patient in the BD group died. The other 51 patients were alive with graft functioning after a minimum follow-up of 1 year. Five patients per group had reversible acute rejection. There was a not significant trend toward a lower mean serum creatinine in OD than in BD (1.38±0.38 and 1.7±0.80 mg/dL at 1 year posttransplant, respectively). In 47 patients, 319 pharmacokinetic studies were performed. We measured the area under the concentration-time curve during the first 4 hours (AUC0–4) and CsA blood levels at 0, 2, and 4 hours after dosing. C0 was significantly lower in OD than in BD (P=0.0011), whereas C2 (P<0.0001) and C4 (P<0.0001) were significantly higher in OD than in BD. In OD, the AUC was higher than in BD (P<0.0001). OD allows us to reach high levels of C2 and AUC for several hours after dosing, whereas BD showed persistently high levels throughout the whole day. Conclusion. No difference in survival and rejection rates were observed between OD and BD groups.

Management of idiopathic membranous nephropathy

Importance of the field: Idiopathic membranous nephropathy (IMN) can have a variable natural course. Treatments able to induce remission can improve the long-term prognosis. However, the optimal therapy for IMN remains controversial. Area covered in this review: We reviewed the historical and current literature from 1979 to 2010 regarding the natural course of IMN and the possible treatments giving special emphasis to randomized controlled trials and to more recent approaches. What the reader will gain: The reader will gain a comprehensive review of the available treatments of IMN. A personal therapeutic algorithm for nephrotic patients with IMN is also provided. Take home message: At least five different treatments showed efficacy in many (but not all) patients with IMN.