Effects of zoledronic acid and dexamethasone on early phases of socket healing after tooth extraction in rats: A preliminary macroscopic and microscopic quantitative study.

BACKGROUND: The exact pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) is still unknown. The aim of this paper was to investigate the effects of zoledronic acid and dexamethasone on the early phases of socket healing in rats subjected to tooth extractions. MATERIAL AND METHODS: Thirty male Sprague-Dawley rats were divided into 2 groups: pharmacologically treated group (T, n=20) and non-pharmacologically treated group (C, n=10). T group rats received 0.1 mg/Kg of zoledronic acid (ZOL) and 1 mg/Kg of dexamethasone (DEX) three times a week for 10 consecutive weeks. C group rats were infused with vehicle. After 9 weeks from the first infusion, first maxillary molars were extracted in each of the rats. Quantitative macroscopic and microscopic analysis was performed to evaluate socket healing 8 days after extraction. RESULTS: Pharmacologically treated rats showed significant inhibition of bone remodeling. Connective tissue/alveolar bone ratio, osteoclast number and woven bone deposition were significantly reduced in group T compared to group C. Conversely, the proportion of necrotic bone was higher in group T compared to group C (0.8% and 0.3%, respectively. P=0.031). ZOL plus DEX do not cause gross effects on socket healing at a macroscopic level. CONCLUSIONS: Our findings confirmed that exposure to ZOL plus DEX impairs alveolar wound repair. Inhibition of osteoclastic resorption of socket walls after tooth extraction and the inability to dispose of the necrotic bone may be considered the initial steps of MRONJ onset.

[Controversial issues in the Giornale Italiano di Nefrologia: how to treat patients with focal segmental glomerular sclerosis]. / Le contoversie del Giornale Italiano di Nefrologia: come trattare i pazienti con glomerulosclerosi focale segmentaria?

Primary focal segmental glomerular sclerosis (FSGS) commonly presents with nephrotic syndrome. Spontaneous remission is rare and persistent nephrotic syndrome is a marker of poor prognosis. For this reason, obtaining remission using drugs with minimal side effects is desirable. The treatment of FSGS, however, represents a challenge. Not only is there a lack of prospective controlled trials, but FSGS is a syndrome of unknown pathophysiology, generally treated with drugs having a mechanism of action that is poorly understood in this setting, the use of which has often drawn criticism because it is based on empirical assumptions rather than pathogenetic evidence. At present, corticosteroids are the standard first-line approach in patients with idiopathic FSGS. Cytotoxic agents and cyclosporin A constitute a good therapeutic option for steroid-dependent patients or frequent relapsers. Mycophenolate mofetil, rituximab and plasmapheresis should be used as rescue treatment because further studies are required to determine their safety and efficacy. Clearly, real progress in FSGS treatment can only be obtained by research focused on the pathophysiology of this disease, so that a therapeutic approach can be defined that is based on reason rather than chance.

[Treatment of membranous nephropathy with chronic renal insufficiency]. / Il trattamento della nefropatia membranosa con insufficianza renale cronica.

Several studies have suggested that, in patients with membranous nephropathy, immunosuppressive therapy is effective even when started in the presence of already established renal insufficiency. Most of the favorable results reported have been obtained with the use of cytotoxic agents given together with glucocorticoids, which produce a 70-80% reduction of proteinuria and can preserve renal function. However, patients with renal insufficiency are more exposed to the risk of side effects caused by these drugs. Since the published results have shown that the actual target of immunosuppressive agents is the nephrotic syndrome and the favorable response of renal function is always subordinate to its remission, the selection of patients who are likely to benefit from treatment should take this aspect into account. In addition, patient selection should avoid excessive costs associated with negligible benefits when biopsy-proven advanced chronic renal damage or serum creatinine above 3-4 mg/dL are present. Finally, drug dosage should be adjusted in cases of chronic renal insufficiency.

Hepatitis C virus infection and rituximab therapy after renal transplantation.

BACKGROUND: Rituximab, a chimeric monoclonal antibody, has been successfully given in various diseases including HCV-associated mixed cryoglobulinemia. However, only preliminary data exists on its efficacy and safety after renal transplantation. METHODS: We report on a renal transplant recipient with chronic hepatitis C who received rituximab therapy for gastric cancer. Four rituximab infusions of 375 mg/m(2) were given. RESULTS: Rituximab therapy was complicated by cholestatic hepatitis C with very high HCV RNA levels; liver insufficiency occurred. The patient developed bacterial pneumoniae and respiratory insufficiency was the cause of death. Although other mechanisms cannot be excluded, we found that rituximab therapy was implicated in the pathogenesis of cholestatic hepatitis C in our patient. CONCLUSIONS: We suggest that rituximab therapy may be associated with significant side effects. More experience has to be accumulated before any conclusions on efficacy and safety of rituximab therapy after RT can be drawn.

[Therapeutic strategies for membranous nephropathy: guideline from the Italian Society of Nephrology]. / Terapia della nefropatia membranosa idiopatica: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of interventions for idiopathic membranous nephropathy (MN) is presented. METHODS: SR of RCT and RCT on interventions for MN were identified referring to a Cochrane Library and Renal Health Library search (2005 update). RESULTS: Three SR and 18 RCT were available to address this issue. Methodological quality of available RCT was suboptimal according to current methodological standards. In patients with MN, nephrotic syndrome and normal renal function, methylprednisolone and chlorambucil or cyclophosphamide for 6 months alternately increase the probability of nephritic syndrome remission (evidence from SR) and long-term renal protection (evidence from RCT). Other drugs (ACTH and cyclosporine) are associated with nephrotic syndrome remission, but there is no evidence of significant effects on renal function (evidence from RCT). In patients with impaired renal function, association of corticosteroids and cytotoxic agents is proven to cause a short-term delay of renal damage progression, even though benefits are counterbalanced by complications (evidence from RCT). CONCLUSION: In patients with MN, nephrotic syndrome and normal renal function, current available evidence supports the hypothesis that primary intervention should be the association of corticosteroids and cytotoxic agents. Secondary therapeutic choices include ACTH and cyclosporine. Further studies are necessary to test new immunosuppressive agents such as mycophenolate mofetil.

[Corticosteroid treatment for a first episode of steroid-sensitive nephrotic syndrome (SSNS) in children: guideline from the Italian Society of Nephrology]. / Terapia corticosteroidea del primo episodio di sindrome nefrosica steroido-sensitiva nel bambino: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of the use of corticosteroid treatment for a first episode of steroid-sensitive nephrotic syndrome (SSNS) in children is presented. METHODS: SR of RCT and RCT on SSNS therapeutic interventions were identified referring to a Cochrane Library and Renal Health Library search (2005 update). Results. One SR including 15 RCT was available on this topic. Methodological quality of available RCT was suboptimal according to current methodological standards. RESULTS: In children with a first episode of SSNS, corticosteroids administered for 3 months or more compared with 2 months' administration are associated with a significant reduction in the risk of relapse at 6, 12 and 24 months, and in frequent relapsing rates, even though complications did not seem significantly increased (psychological, ocular, gastrointestinal disorders, hypertension, growth delay, Cushingoid syndrome, infection and osteoporosis) (evidence from SR). 6-month compared to 3-month treatment regimens are associated with a significant reduction in the risk of relapse at 12-24 months (evidence from SR). Increasing steroids cumulative doses are associated with increasing improvements in the risk of relapse (evidence from RCT). The risk of relapse at 12-24 months correlates inversely with duration of treatment (evidence from SR). CONCLUSION: In SSNS children, current available evidence supports the hypothesis that primary intervention should be a high dose of corticosteroids administered for 3 months or more. Further studies are necessary to test this hypothesis in adult patients.

[Immunosuppressive and non-immunosuppressive agents for patients with IgA nephropathy: guideline from the Italian Society of Nephrology]. / Terapia immunosoppressiva e non immunosoppressiva della glomerulonefrite a depositi mesangiali di IgA: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of the use of immunosuppressive and non-immunosuppressive treatments in IgA nephropathy (IgAN) is presented. METHODS: SR of RCT and RCT on treatment in patients with IgAN were identified referring to a Cochrane Library and Renal Health Library search (2005 update). Quality of SR and RCT was assessed according to current methodological standards. RESULTS: Two SR of RCT (13 and 3 RCT, respectively), and 18 further RCT were available to address this issue. Methodological quality of available trials was suboptimal. In patients with IgAN and normal or mildly impaired renal function, steroids significantly delay the progression to end stage kidney disease (evidence from SR) and improve proteinuria. Associating steroids and cytotoxic agents (cyclophosphamide followed by oral azathioprine) proves effective in patients with rapidly progressive renal disease (evidence from RCT). Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers significantly improve proteinuria (evidence from RCT), but there are no conclusive data on efficacy on hard patient level endpoints. There are no conclusive data available on the use of a therapy combining these agents. CONCLUSION: In IgAN patients current evidence supports the hypothesis that immunosuppressive agents delay the progression to end stage renal disease. Further studies are necessary to test this hypothesis in selected patient populations.

[Treating lupus nephritis: guideline from the Italian Society of Nephrology]. / Terapia delle nefriti proliferative lupiche; confronto degli schemi di associazione di farmaci citotossici più steroide rispetto al solo steroide: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of lupus nephritis (LN) treatment is presented. METHODS: SR of RCT and RCT on different therapeutic options for LN were identified referring to a Cochrane Library and Renal Health Library search (2005 update). RESULTS: One SR of 25 RCT and 6 further RCT were available to address this issue. Methodological quality of available RCT was suboptimal according to current methodological standards. In LN patients, combining cyclophosphamide (CyA) and steroids as induction therapy results in a reduced risk of serum creatinine doubling compared to steroids alone, although there is no evidence of significant survival advantage and risk of ovarian failure was demonstrated (evidence from SR). The association of azathioprine (Aza) and steroids significantly reduces the risk of all-cause mortality compared to steroids alone (evidence from SR). No significant survival advantages from the association of plasma exchange and CyA or Aza are proven (evidence from SR). No significant differences on renal and survival endpoints are demonstrated with different dosing of CyA (evidence from RCT). CONCLUSION: In LN patients available evidence supports the hypothesis that immunosuppressive agents reduce the risk of all-cause mortality and the risk of progressive renal disease. Further studies are necessary to test new immunosuppressive agents such as mycophenolate mofetil in severe LN patients.

Natural history of hepatitis C virus infection in adult renal graft recipients.

AIM: To study the natural history of hepatitis C virus infection in renal transplantation, 464 HbsAg negative patients were prospectively studied from 1989. METHODS: AntiHCV was tested by ELISA II and HCVRNA by Amplicor HCV RNA tests. RESULTS: Two hundred nine patients were antiHCV positive (C+). HCVRNA was confirmed in 89% of C+ patients. Compared with the 255 anti-HCV negative (C-), C+ had undergone longer periods of dialysis (P = .0001), were more transfused (P = .01), and included more retransplants (P = .002). Immunosuppression was azathioprine (AZA) plus steroids in 133 and cyclosporine (CsA) in 331 patients. Liver biopsy showed chronic active hepatitis in 50, cirrhosis in 8, and fibrosing cholestatic hepatitis in 2 patients. Histologic progression of liver disease was confirmed in 18 of 26 patients. The causes of death in 84 patients (51 C+ vs 33 C-) were cardiovascular disease in 49%, sepsis in 13%, liver failure in 14%, neoplasia in 21%, and hepatocarcinoma in 2%. The 14-year patient survival was 75% in C+ and 86% in C- (P = .002). By multivariate analysis, age (>40) (P = .001) and C+ (P = .019) correlated with a worse patient survival. If patients were stratified according to age (<40 vs > or =40), younger C+ patients had a lower survival probability (P = .03). The 14-year graft survival was 44% in C+ vs 60% in C- patients (P = .001) but pure graft survival was similar (68% in C+ vs 72% in C-) (P = .13). CONCLUSION: The presence of C+ significantly reduced both patient and graft survival in the long-term with liver failure being the second most frequent cause of death.

[Treatment of idiopathic membranous nephropathy]. / Terapia della nefropatia membranosa idiopatica.

Corticosteroids and cytotoxic agents have been largely used in idiopathic membranous nephropathy (MN). A meta-analysis of controlled studies with corticosteroids did not demonstrate any benefit in using these agents on disease outcome. On the contrary, some controlled trials reported that cytotoxic agents can significantly reduce proteinuria. Three multicenter randomized controlled studies demonstrated that a regimen based on a 6-month treatment alternating every other month methylprednisolone with chlorambucil or cyclophosphamide, not only favors nephrotic syndrome remission, but can also protect long-term renal function. Cyclosporine has also been shown to be effective in inducing a partial or the complete remission of nephrotic syndrome. The main problem with cyclosporine is that in many responders proteinuria relapses when the drug is stopped. However, if the drug is given for a prolonged period and is tapered off gradually the risk of relapse can be reduced. A recent study showed that treatment with a long acting ACTH preparation for 1 yr was associated with significant long-term improvements in serum lipoprotein patterns, urinary protein excretion and glomerular function. Unfortunately, the study was not randomized, the number of patients was small and the follow-up was short. Advances in understanding the pathogenetic mechanisms of glomerulonephritis produced specifically new approaches to selected cell types or molecular pathways involved in MN pathogenesis. These therapies should guarantee therapeutic efficacy while limiting the adverse effects of non-selective immunosuppression. However, we need randomized clinical trials to ascertain how well they perform in practice rather than just on a theoretical basis.

From cyclosporine to the future.

Most of the experience acquired in our unit with cyclosporine (CsA) comes from randomized trials. A first trial demonstrated that CsA-treated patients had a better 10-year graft survival than azathioprine-treated patients. A second trial showed equivalence between double therapy with CsA plus steroids and triple therapy with CsA, steroids, and azatioprine. A third trial showed similar 2-year graft survival with CsA monotherapy and triple therapy. A larger multicenter study that compared three different CsA-based regimens showed similar long-term graft survival with monotherapy, double therapy, and triple therapy. However, patients given monotherapy had less frequent steroid-related side-effects. Finally a more recent multicenter international trial showed that the rate of acute rejection can be reduced without increasing side effects by adding the monoclonal antibody basiliximab to the triple therapy. By reviewing our cumulative experience with CsA we found a mean graft half-life of 18.7 years for cadaver renal transplant recipients and 31.9 for the living transplant recipients. No significant attrition of graft function was found for patients with grafts functioning at 15 years. Two important issues with the present immunosuppression concern the long-term nephrotoxicity of calcineurin inhibitors and the cardiovascular disease, which is at least in part related to the use of steroids. To face these problems, we are currently involved in two multicenter trials, one comparing sirolimus plus mycophenolate mofetil to sirolimus plus low-dose CsA, while the other trial compares certican plus CsA to certican plus CsA plus corticosteroids.

Treatment of membranous nephropathy.

Several therapeutic approaches have been tried in patients with membranous nephropathy. Corticosteroids have been largely used, but a meta-analysis of the available controlled trials did not show any benefit of corticosteroids either in favouring remission of the nephrotic syndrome or in preventing renal dysfunction. Controversial results have been obtained with cytotoxic agents. Unfortunately, most of the available trials were small in size and had short-term follow-ups. Three controlled trials evaluated the role of a 6-month treatment with methylprednisolone and chlorambucil. The first trial showed that the 10-year renal survival rate was 92% in treated patients compared with 60% in untreated controls. A second trial compared the effects of methylprednisolone/chlorambucil with those of methylprednisolone alone. The combined treatment achieved remission of nephrotic syndrome in 64% of cases vs 38% in patients given steroids alone. A third trial showed equivalent results in patients randomized to be given methylprednisolone/chlorambucil or methylprednisolone/cyclophosphamide. A number of non-controlled studies and a randomized trial also showed the efficacy of cyclosporine in reducing proteinuria. In many but not all cases, proteinuria reappeared when cyclosporine was stopped. In conclusion, although the treatment of membranous nephropathy remains difficult, some therapeutical approaches have proved to favour remission and protect renal function

Alternative treatments for focal and segmental glomerular sclerosis.

Corticosteroids represent the first therapeutic approach for patients with focal and segmantal glomerulosclerosis. What to do in patients who do not respond to corticostetoids is still uncertain. Cytotoxic agents have been tried. The results are usually poor when these drugs are given for short periods but almost half of patients may enter remission ir treatment is prolonged. Some decrease in proteinuria may be obtained with mycophenolav, mofetil but the available reports are still scanty and the follow ups are short. Cyclosporine has been largely used both in controlled and non controlled trials with favorable results. However, being the drug nephrotoxic caution should be recommended with its use. Plasma-exchange and lipopheresis may attempted in resistant cases.

Treatment of focal segmental glomerulosclerosis.

The prognosis of untreated patients with focal segmental glomerulosclerosis is poor, as the disease progress to end-stage renal disease in approximately 50--70% of nephrotic patients. Although focal segmental glomerulosclerosis was initially considered to be a steroid-resistant disease, several studies have shown a better responsiveness to more prolonged courses of steroids. For patients with steroid-resistant or -dependent focal segmental glomerulosclerosis, cyclosporine A and cytotoxic agents have shown efficacy in clinical trials. Plasmapheresis or LDL-apheresis may represent a rescue treatment in patients who do not respond to other therapies. The role of other agents used in focal segmental glomerulosclerosis, including azathioprine, mycophenolate mofetil, tacrolimus, pefloxacin or vitamin E is still poorly defined.

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.

The place of cyclosporin in the management of primary nephrotic syndrome.

The 3 main causes of primary nephrotic syndrome are minimal change nephropathy, focal segmental glomerulosclerosis and membranous nephropathy. Corticosteroids result in remission of proteinuria in most patients with minimal change nephropathy. Many patients, however, develop corticosteroid dependency. A course of cytotoxic drugs can also achieve remission but these agents cannot be administered for prolonged periods or in repeated cycles because their toxicity is cumulative. Review of the available literature indicates that cyclosporin may maintain remission of nephrotic syndrome in about 80% of patients with corticosteroid-sensitive disease, indicating an important role for this drug in patients with frequent relapses or corticosteroid dependency. Although cyclosporin is less effective in patients with focal segmental glomerulosclerosis, which is often corticosteroid-resistant, a number of studies indicate that it may be successful both in the few steroid-sensitive patients with frequent relapses and in some corticosteroid-resistant patients. In patients with membranous nephropathy, a 6-month course of corticosteroids and cytotoxic agents may favour remission of nephrotic syndrome and protect renal function. Several studies have shown that cyclosporin can improve proteinuria, and there is a tentative suggestion that it might also protect against renal function deterioration. The risk of nephrotoxicity can be minimised if cyclosporin is used at the correct doses and if renal function is carefully monitored during treatment. In summary, cyclosporin can be considered a useful tool for treating patients with nephrotic syndrome associated with primary glomerulonephritis.

A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy.

To assess whether chlorambucil or cyclophosphamide may have a better therapeutic index in patients with idiopathic membranous nephropathy, we compared two regimens based on a 6-mo treatment, alternating every other month methylprednisolone with chlorambucil or methylprednisolone with cyclophosphamide. Patients with biopsy-proven membranous nephropathy and with a nephrotic syndrome were randomized to be given methylprednisolone (1 g intravenously for 3 consecutive days followed by oral methylprednisolone, 0.4 mg/kg per d for 27 d) alternated every other month either with chlorambucil (0.2 mg/kg per d for 30 d) or cyclophosphamide (2.5 mg/kg per d for 30 d). The whole treatment lasted 6 mo; 3 mo with corticosteroids and 3 mo with one cytotoxic drug. Among 87 patients followed for at least 1 yr, 36 of 44 (82%; 95% confidence interval [CI], 67.3 to 91.8%) assigned to methylprednisolone and chlorambucil entered complete or partial remission of the nephrotic syndrome, versus 40 of 43 (93%; 95% CI, 80.9 to 98.5%) assigned to methylprednisolone and cyclophosphamide (P = 0.116). Of patients who attained remission of the nephrotic syndrome, 11 of 36 in the chlorambucil group (30.5%) and 10 of 40 in the cyclophosphamide group (25%) had a relapse of the nephrotic syndrome between 6 and 30 mo. The reciprocal of plasma creatinine improved in the cohort groups followed for 1 yr for both treatment groups (P < 0.01) and remained unchanged when compared with basal values in the cohort groups followed for 2 and 3 yr. Six patients in the chlorambucil group and two in the cyclophosphamide group did not complete the treatment because of side effects. Four patients in the chlorambucil group but none in the cyclophosphamide group suffered from herpes zoster. One patient per group developed cancer. It is concluded that in nephrotic patients with idiopathic membranous nephropathy both treatments may be effective in favoring remission and in preserving renal function for at least 3 yr.