Should we really STOP treating patients with IgA nephropathy with steroids?

IgA nephropathy (IgAN) is the most common primary glomerulonephritis all over the world. Once considered as a benign disease, today the scientific community is aware that a significant percentage of patients eventually progress to end-stage kidney disease (ESKD). The rate of progression is often very slow. Since 1980s, several therapeutic attempts have been made with steroids. Despite different molecules, doses, and lengths of treatment, the majority of uncontrolled and controlled studies found benefits in terms of proteinuria reduction and reduction of the risk of ESKD. This was obtained with reasonable safety and tolerability, especially when steroids are given at relatively low dose and for a period not exceeding 6 months. Recently, two randomized controlled trials have questioned the efficacy and safety of steroid therapy in IgAN. However, these trials have many drawbacks that are to be considered when interpreting the findings.

Synthetic pharmacotherapy for lupus nephritis.

INTRODUCTION: Lupus nephritis is a frequent complication and a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Area covered: The main characteristics and mechanisms of action of the synthetic drugs more frequently used in lupus nephritis are described. Possible strategies aimed to reduce the potential adverse events without affecting efficacy are reported. Expert opinion: Many synthetic immunosuppressive drugs used in lupus nephritis have a low therapeutic index. Good knowledge of their pharmacologic characteristics, mechanisms of action, and drug-to-drug interactions, coupled with a strategy aimed to increase immunosuppression in the active phases of SLE while reducing the dosage in quiescent periods can reduce the iatrogenic morbidity while maintaining efficacy. Biologic agent may allow to reduce the use or the dosage of synthetic immunosuppressive drugs.

Hydroxychloroquine in systemic lupus erythematosus (SLE).

INTRODUCTION: Hydroxychloroquine (HCQ) is an alkalinizing lysosomatropic drug that accumulates in lysosomes where it inhibits some important functions by increasing the pH. HCQ has proved to be effective in a number of autoimmune diseases including systemic lupus erythematosus (SLE). Areas covered: In this review the mechanisms of action, the efficacy, and the safety of HCQ in the management of patients with SLE have been reviewed. HCQ may reduce the risk of flares, allow the reduction of the dosage of steroids, reduce organ damage, and prevent the thrombotic effects of anti-phospholipid antibodies. The drug is generally safe and may be prescribed to pregnant women. However, some cautions are needed to prevent retinopathy, a rare but serious complication of the prolonged use of HCQ. Expert opinion: HCQ may offer several advantages not only in patients with mild SLE but can also exert important beneficial effects in lupus patients with organ involvement and in pregnant women. The drug has a low cost and few side effects. These characteristics should encourage a larger use of HCQ, also in lupus patients with organ involvement.

A randomized trial of everolimus and low-dose cyclosporine in renal transplantation: with or without steroids?

This multicenter, randomized, prospective, controlled trial (EVIDENCE study) aimed to determine short-term effects of early steroid withdrawal in renal transplant patients initially treated with everolimus, low-dose cyclosporine (CsA), and steroids. Patients were randomized to standard triple therapy with CsA, everolimus twice daily and steroids (group A), steroid-free immunosuppression (group B), or triple therapy once daily (group C). However, since patient enrollment was slower than expected, group C randomization was prematurely discontinued. The primary end point was treatment failure rate (composite end point of death, graft loss, biopsy-proven acute rejection, and loss to follow-up) between randomization and month 12. Patients evaluable for the primary end point included 139 randomized patients. According to intention-to-treat analysis, 2.8% of patients in group A and 14.7% in group B experienced treatment failure (95% upper confidence limit 19.7%). As this was higher than the predefined noninferiority limit of 10%, noninferiority could not be proved. No conclusive statements can be made on noninferiority of the steroid withdrawal regimen vs the standard regimen in these patients. Additional studies with longer follow-up are required to determine the efficacy of steroid-free immunosuppression in renal transplant recipients receiving everolimus.

Progressive improvement of patient and renal survival and reduction of morbidity over time in patients with lupus nephritis (LN) followed for 20 years.

Whether the long-term patient and renal survival of those diagnosed with lupus nephritis (LN) has improved over the decades is still debated. Eighty-nine patients diagnosed between 1968 and 1990 entered this study and their outcome was evaluated after 20 years. At presentation 54% of patients had class IV LN, 39.3% had renal insufficiency and 59.5% had nephrotic syndrome. Patients were divided into two groups: Group 1 consisted of 30 patients diagnosed between 1968 and 1980; Group 2 consisted of 59 patients diagnosed between 1981 and 1990. In Group 1 patient survival at 20 years was 84% versus 95% in Group 2 (p=0.05). Survivals without end-stage renal failure were respectively 75% and 84% at 20 years (p=0.05). Survivals without severe infection at 20 years were 44% in Group 1 and 66.5% in Group 2 (p=0.02). Survivals without cardiovascular events at 20 years were: 53% in Group 1 and 90% in Group 2 (p=0.005). At presentation, patients in Group 1 had higher serum creatinine (1.96 vs 1.15 mg/dl, p=0.01), higher activity index (8 vs 5.5, p=0.01), lower hematocrit (31% v s6%, p=0.008) and lower serum C4 levels (p=0.04) than Group 2 patients. Patients in Group 1 also received less frequent methylprednisolone pulses (43% vs 81%, p=0.0006). In Italian patients with LN, long-term life expectancy and renal survival progressively improved over the decades, while morbidity progressively declined. An earlier referral and refinement of therapy achieved this goal.

Present and future of immunosuppressive therapy in kidney transplantation.

Patient and graft survivals following kidney transplantation, the treatment of choice for patients with end-stage renal disease, have dramatically increased in recent years. This is mainly due to improvements in immunosuppression and medical care posttransplantation. Original immunosuppressive protocols were based on glucocorticoids and azathioprine but many patients developed acute rejection requiring high-dose prednisone. These immunosuppressive protocols nonselectively inhibit elements of host resistance, such as monocytes, granulocytes, and macrophages, and because of this high mortality rates due to opportunistic infections were often observed. The introduction of newer agents, such as tacrolimus, sirolimus, anti-interleukin-2 receptor monoclonal antibodies, and mycophenolate salts with a more selective mechanism for T- and B-cell alloimmune responses, led to a reduction in the incidence of infection. Clinical trials based on the combination of these drugs with steroids and cyclosporine show a reduced incidence of acute rejection episodes (<10%) and allow a steroid-sparing policy in kidney transplantation. Today, the main problem is related to the adverse events associated with vigorous and prolonged immunosuppression, mainly cardiovascular disease, infections, and malignancies. Further studies are required to find the optimal dosage and combination of new and old drugs in renal transplantation. It is likely that calcineurin inhibitors (CNIs) will continue to be prescribed in the near future, but their association with synergistic drugs will allow using them at minimal doses.

Calcineurin inhibitors in renal transplantation still needed but in reduced doses: a review.

Despite their contribution in the success of organ transplantation, calcineurin inhibitors (CNIs) may be responsible for frequent and severe side effects that can affect graft survival and life expectancy. In this article, we have reviewed registry studies and randomized controlled trials (RCTs) that seek to avoid, withdraw, or minimize CNIs in renal transplant recipients. Attempts to completely avoid CNIs by administering mycophenolate mofetil (MMF) and/or sirolimus (SRL) have resulted in increased risks of rejection and side effects, with small advantage to improve renal graft function. Early withdrawal of CNIs after transplantation using administration of MMF can improve graft function but may be associated with a greater risk of acute or chronic rejection and graft failure. RCTs in which CNIs were replaced a few months after transplantation by SRL reported improved graft function among SRL-treated patients, but such a treatment was complicated by iatrogenic toxicity. Late replacement of CNIs with SRL did not produce a particular advantage and again was complicated by more frequent side effects. On the basis of these trials, it seems that CNI elimination can trigger rejection or side effects. Recent RCTs showed that minimization of CNI doses in association with everolimus does not increase the risk of rejection, allows one to obtain good graft function, and is well tolerated. Such an approach seems therefore preferable to complete elimination of CNIs with substitution of the current immunosuppressive drugs.

Gitelman syndrome: pathophysiological and clinical aspects.

Giltelman syndrome (GS) is a recessive salt-losing tubulopathy of children or young adults caused by a mutation of genes encoding the human sodium chloride cotransporters and magnesium channels in the thiazide-sensitive segments of the distal convoluted tubule. The plasma biochemical picture is characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis and hypereninemic hyperaldosteronism. However, patients with GS present some clinical and biochemical alterations resembling that observed in thiazide diuretics abuse. On the pathophysiological point of view, GS represents a useful and interesting human model to better understand the clinical consequences of plasma hydro-electrolytes and acid-base derangements, associated with multiple hormonal alterations. The impact of this complex disorder involves cardiovascular, muscle-skeletal and some other physiological functions, adversely affecting the patient's quality of life. This review tries to summarize and better explain the linkage between the electrolytes, neurohormonal derangements and clinical picture. Moreover, the differential diagnosis between other similar electrolyte-induced clinical disorders and GS is also discussed.

Once-a-day administration of everolimus, cyclosporine, and steroid after renal transplantation: a review of the rationale.

The Evidence study (EVerolImus once-a-Day rEgimen with Neoral versus Corticosteroid Elimination) sought to compare once-a-day administration with steroid withdrawal versus twice-daily administration among de novo kidney transplant recipients treated with everolimus, cyclosporine, and steroids. This article describes the study design and rationale of once-daily administration and steroid withdrawal among recipients of de novo kidney transplants treated with everolimus and cyclosporine.

Cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome : workshop recommendations.

Management of idiopathic glomerular disease associated with nephrotic syndrome (INS) remains controversial and one of the most complex areas relates to utilization of the drug cyclosporin. This is despite its demonstrated effectiveness in several histologic types of the INS in randomized controlled trials. Cyclosporin is effective in inducing remission of proteinuria in approximately 80% of steroid-sensitive cases of minimal change disease (MCD). Cyclosporin is also effective in both the induction of remission and long-term preservation of renal function in steroid-dependent/-resistant MCD and steroid-resistant focal segmental glomerulosclerosis (FSGS). The overall response rate in FSGS is lower than in MCD, and long-term therapy (>12 months) may be required to both achieve remission and sustain it. Cyclosporin therapy is also of benefit in reducing proteinuria in 70-80% of patients with steroid-resistant membranous nephropathy (MGN). In MGN, the maximum benefit is often delayed compared to MCD (>12 weeks). Cyclosporin is generally well tolerated and safe. The major concern remains the nephrotoxicity, but with careful monitoring of the patient's renal function; minimizing the maintenance dose and utilizing repeat renal biopsy in those receiving long-term therapy, this risk can be minimized. The algorithms have been developed derived from the best evidence in the literature in each of the histologic types to help provide a guide to the integration of cyclosporin into the management of INS for the practicing nephrologist.

The long-term prognosis of renal transplant in patients with systemic vasculitis.

Little information is available about the long-term outcome of renal transplantation in patients with systemic vasculitis (SV). We compared the outcomes of 19 renal transplant recipients with SV with those of 38 controls matched for time of transplantation, age, gender and source of donor. The mean post-transplant follow-up was 58 +/- 57 months for vasculitic patients and 61 +/- 49 months for controls. The actuarial 10-year patient survival was 87% in vasculitic patients and 90% in controls, death-censored graft survival were 84% and 100%, respectively. The risks of acute and chronic rejection, and arterial hypertension were not significantly different between the two groups. Infection was significantly more frequent in vasculitic patients (74% vs. 34%; p = 0.01). Seven patients (36.8%) had a recurrence of vasculitis in mean 45 months after renal transplant (0.076/patients/year). After recurrence, one patient had an irreversible humoral rejection, another died from hemophagocytosis and another restarted dialysis 1 year later. Long-term patient and renal allograft survival in vasculitic patients was good. Although graft function recovered in most relapsers after reinforcement of immunosuppression, one patient died and two lost graft function.

De novo thrombotic microangiopathy. An underrated complication of renal transplantation.

After kidney transplantation thrombotic microangiopathy (TMA) may recur in patients with previous hemolytic uremic syndrome or may develop de novo. De novo TMA has been reported to occur in less than 1% of renal transplant recipients by large registries, but single center series reported an incidence of the disease as high as 14-20%. A number of factors may predispose to posttransplant TMA, including ischemia-reperfusion injury, acute rejection, viral infection. Immunosuppressive treatment can also contribute to the development of de novo TMA. Calcineurin inhibitors may cause or aggravate endothelial lesions through their pronecrotic, vasoactive and profibrotic activity. Anti-mTOR agents may delay the repair of the endothelial damage through their interference with endothelial growth factor. Usually, TMA develops in the early posttransplant period but may also occur later. Clinically, TMA is characterized by progressive renal failure and hypertension. Microangiopathic hemolytic anemia and thrombocytopenia may occur in about 60% of cases. Histologically, TMA may be localized to glomeruli or may involve arteries or both. The prognosis depends on the timely diagnosis and on histological picture. Treatment is based on the removal of inciting factors. Early plasmapheresis could improve clinical signs and symptoms and rescue renal function in a number of patients. Anecdotal successes have also been reported with intravenous immunoglobulins and rituximab.

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.

Immediate graft function positively affects long-term outcome of renal allografts from older but not from younger donors.

There is disagreement about the impact of delayed graft function (DGF) on renal allograft outcome. This may depend on several variables including the age of the donor. We evaluated whether DGF could have different effects in recipients of kidneys from donors aged more than 60 years versus well-matched recipients of younger kidney donors. Patients were retrospectively subdivided into 3 groups. Immediate graft function (IGF), DGF without dialysis (DGF-ND), DGF requiring dialysis (DGF-D). DGF-ND and DGF-D occurred more frequently among 198 older than 198 younger donors (P = .016 and P = .044, respectively). The 5-year patient (96% vs 93%) and pure graft (96% vs 89%) survivals were significantly better in younger recipients, while the incidence of acute rejection was similar. After a mean follow-up of 66 +/- 44 months in older donor recipients, the graft survival was significantly better among IGF than patients in the DGF-ND (P = .046) or DGF-D (P = .003) groups. Instead, in younger recipients there was no difference in graft survival between IGD and DGF-ND. Only patients with DGF-D showed a significantly worse outcome. Upon multivariate analysis of older donors, their recipients, showed the pattern of graft function recovery to be the only variable associated with allograft outcome. Instead in younger donor recipients, acute rejection and time on dialysis were the main variables associated with a poor outcome. In older donor recipients, DGF was an independent variable associated with a poor graft outcome. In younger donor recipients, duration of dialysis and rejection were the most important predictors of poor graft outcomes.

Risk factors associated to kidney stones in primary hyperparathyroidism.

Nephrolithiasis is the most important clinical manifestation of primary hyperparathyroidism (PHPT), although nowadays this disorder is often asymptomatic. Clinical or biochemical differences between PHPT patients with and without nephrolithiasis have not been clearly identified in most of the previous studies. The aim of the study was to investigate clinical and biochemical parameters in kidney stone former (SF) and non-stone former (NSF) patients with PHPT in order to identify potential risk factors. Serum and plasma samples from 55 consecutive patients (43 females, 12 males) with PHPT were collected after overnight fasting; 24-h urine collection and a fresh sample of urine for sediment analysis were obtained from all patients. Clinical data were recorded in all. Out of 55 patients, 22 had kidney stones, which were symptomatic in 73%. SFs showed circulating PTH, total and ionized calcium, 1,25 dihydroxyvitamin D3, urinary calcium excretion and 24-h urine oxalate levels significantly higher than NSFs. Hypercalciuria was often concomitant with massive quantities of calcium oxalate crystals in urine sediment. Hypercalciuria and relatively high oxaluria were associated with stone formation with an odds ratio (OR) of 4.0 and 7.0, respectively, which rose to 33.5 when they coexisted. Hypomagnesuria and hypocitraturia were common in at least one third of all PHPT patients, but they were not associated to an increased OR. As expected, they were positively correlated with urine calcium excretion, suggesting that calcium, magnesium and citrate are commonly regulated at renal level. In conclusion, hypercalciuria, higher oxalate excretion and severe PHPT are associated with kidney stones in PHPT.

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.

A randomized trial of steroid avoidance in renal transplant patients treated with everolimus and cyclosporine.

In this randomized trial renal transplant recipients were treated with basiliximab, everolimus 3 mg/day, low-dose CsA. At transplantation, patients were randomized to stop steroids at the seventh day (group A) or to continue oral steroids in low doses (group B). Of the 113 patients enrolled, 65 were randomized to group A and 68 to group B. All patients were followed for 2 years. During the study 28 (43%) group A patients required reintroduced corticosteroids. One patient died, in group B. The Graft survival rate was 97% in group A and 90% in group B. There were more biopsy-proven rejections in group A (32% vs 16%; P = .044). The mean creatinine clearance was 54 +/- 21 mL/min in group A vs 56 +/- 22 mL/min in group B. Mean levels of serum cholesterol tended to be lower in group A, but the difference was of borderline significance (191 +/- 91 vs 251 +/- 188 mg/dL; P = .07). Vascular thrombosis (0 vs 5) and pneumonia requiring hospitalization (2 vs 7) tended to be more frequent in group B. Only three cases of CMV infection (1 vs 2) occurred. An immunosuppressive therapy with everolimus and low-dose CsA allows one to obtain excellent renal graft survival and stable graft function at 2 years. Early interruption of steroids in patients treated with this regimen may increase the risk of acute rejection, but neither affects graft survival nor graft function, while possibly reducing the risk of hyperlipemia and vascular thrombosis. About 60% of patients given everolimus and low-dose CsA can definitively stop steroids after 1 week.

Pregnancy after lupus nephritis.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects primarily women, commonly in their reproductive years but does not influence fertility. For these reasons, the clinician has often to face the many problems of pregnancy in patients with SLE including the influence of SLE on fetal outcome and that of pregnancy on SLE. As there is increasing evidence of an important role of sex hormones in immunity, the influence of pregnancy on SLE is probably due to the changes in sex hormone levels during pregnancy that are more important than in any other period of life. Early reports emphasized a high fetal and maternal risk in particular in patients with lupus nephritis. However in the same period the prognosis of lupus nephritis was poor, so it was difficult to know whether pregnancy actually influenced the prognosis of the disease. More recent prospective studies indicate that pregnancy is safe for the majority of mothers if it is planned when SLE is quiescent. Instead, although fetal risk has been progressively reduced in the last 40 years, it continues to be higher than that occurring in pregnancies of healthy women. In particular the presence of antiphospholipid antibodies considerably worsen the fetal outcome.

Renal transplantation in lupus nephritis.

Most patients with systemic lupus erythematosus (SLE) are suitable candidates for renal transplantation. However, a number of them may present some disease-related problems. As cardiovascular disease is a leading cause of morbidity and mortality in SLE patients, a careful pretransplant cardiovascular screening is recommended. A search for antiphospholipid antibodies is also useful as the presence of these antibodies can cause an early graft thrombosis. The risk of recurrence of SLE nephritis after transplantation may range between 2 and 30%. In most cases recurrence is characterized by mild histologic lesions. Only rarely does it lead to graft failure. Postransplant immunosuppression does not differ from that used routinely. Whenever possible, a steroid-free immunosuppression should be scheduled to prevent iatrogenic toxicity in patients who have already received long-term steroid treatment. The results of kidney transplantation largely depend on the clinical conditions at transplantation. In patients with poor clinical status or receiving an aggressive immunosuppression it is advisable to postpone the transplant. When some selection criteria are respected, the results of renal trasplantation in SLE patients are at least as good as in other transplant recipients.

Steroid-sparing strategies.

Corticosteroids have represented the mainstay for immunosuppression since the beginning of organ transplantation. However, these agents may be responsible of a number of invalidating and even life-threatening side effects. After the introduction of cyclosporine, some randomized trials have been attempted to avoid or withdraw corticosteroids. Meta-analyses of these studies showed that acute rejection was more frequent in patients who eliminated steroids than in patients who continued steroids. However, although graft survival was not affected by steroid avoidance, an increased risk of graft failure was reported in patients with late withdrawal of steroids. Only one multicenter trial provided a long-term follow-up of patients treated with the old formulation of cyclosporine. That study showed that, in spite of a higher incidence of rejection, in patients with an early avoidance of steroids, the 9-year graft survival rate was similar to that observed in patients given cyclosporine and steroids but with reduced risks of cardiovascular, ocular, and bone complications. A more recent study with everolimus and low-dose cyclosporine showed that the 3-year patient and graft survival rates were similar in patients who stopped steroids within 1 week after transplantation and in patients who continued low doses of prednisone. The available data indicate that an early elimination of corticosteroids is feasible today in many renal transplant recipients. A steroid-sparing strategy may reduce the side effects and improve the compliance of transplant recipients.