Angiotensin antagonists and steroids in the treatment of focal segmental glomerulosclerosis

The use of angiotensin converting enzyme inhibitors (ACEIs) along with good blood pressure control have been shown to significantly decrease the level of proteinuria and slow the progression of renal insufficiency in patients with nondiabetic glomerular disease including focal segmental glomerulosclerosis (FSGS). Thus, this should be part of the therapeutic approach for all proteinuric patients with FSGS and should be considered the mainstay of therapy for patients with FSGS secondary to conditions associated with hyperfiltration and/or reduced nephron mass and those patients with nonnephrotic primary FSGS. However, nephrotic patients with primary FSGS may continue to have marked proteinuria and progression of renal disease despite these measures and thus require a more aggressive approach with the use of steroids and immunosuppressive agents. Although primary FSGS was once thought to be a steroid-nonresponsive lesion, recent experience has provided a note of optimism in the use of steroids and immunosuppressive agents in treating this otherwise progressive glomerulopathy. As a result, a course of steroid therapy in primary FSGS is now warranted in nephrotic patients with reasonably well preserved renal function in whom it is not otherwise contraindicated.     

The treatment of primary focal segmental glomerulosclerosis

Nephrotic patients with primary focal segmental glomerulosclerosis (FSGS) have a poor prognosis with 50% progressing to end stage renal disease (ESRD) over 3 to 8 years. The achievement of a remission in proteinuria has been associated with a significantly improved renal survival as compared to those patients not attaining a remission. Unfortunately, spontaneous remissions are rare in FSGS, and the response to therapy has historically been poor. Recent experience with more aggressive immunosuppressive therapy has lead to an increase in the remission rate for FSGS patients and given rise to optimism in the treatment of this glomerulopathy.     

Case report: successful treatment of recurrent focal segmental glomerulosclerosis with a novel rituximab regimen

Focal segmental glomerulosclerosis (FSGS) is the cause of renal failure in more than 10% of pediatric patients undergoing renal transplantation. Recurrent FSGS is a major cause of pediatric allograft failure, with the risk increasing for patients undergoing retransplantation. Standard therapy for recurrent posttransplantation FSGS includes the use of intensive plasmapheresis (PP) in conjunction with cyclophosphamide or high-dose cyclosporine. However, many patients exhibit refractory disease, with rapid progression to allograft loss despite these interventions. Prior studies have reported conflicting data on the efficacy of adding rituximab therapy to the standard treatment regimen for recurrent posttransplantation FSGS. Here we present a successful therapeutic protocol with rapid elimination of PP after initiation of rituximab therapy for an adolescent patient with recurrent FSGS in the immediate postoperative period. The patient has maintained excellent allograft function through 12 months posttransplantation.     

Therapeutic approach to focal and segmental glomerulosclerosis recurrence in kidney transplant recipients

Primary focal segmental glomerulosclerosis (FSGS) leads to end-stage renal disease in a high proportion of cases. The recurrence of FSGS after kidney transplantation is frequent (20%–40%) and associated with poor graft survival. The pathophysiology of primary FSGS remains uncertain, but secretion of a circulating factor is suspected to play a key role in excessive glomerular permeability. The treatment of recurrence is still controversial, and most reports related to use of plasma exchange have been uncontrolled trials with relatively small groups of patients and conflicting results. Plasma exchange and protein immunoadsorption can markedly reduce urinary protein excretion and induce complete remission in some cases but usually fail to achieve sustained remission. Steroids and high-dose cyclosporine can reduce proteinuria based on their immunosuppressive properties and through stabilization of the podocyte actin cytoskeleton. Recent advances in our understanding of primary FSGS and podocyte function open the way to more targeted therapies. This review summarizes the therapeutic approach to FSGS recurrence.     

Treatment of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) has been increasing in incidence over the past 2 decades and may currently be the most common form of primary nephrotic syndrome in the United States. Nephrotic patients with FSGS who do not achieve a remission in proteinuria usually advance to end-stage renal disease within 5 to 10 years. Although initially felt to be a steroid-resistant disease, especially in adults, studies show significant responsiveness to more prolonged courses of steroids. For patients with steroid-resistant or steroid-dependent FSGS, cyclosporine A and cytotoxic agents have shown efficacy in clinical trials. Other agents used include pulse methylprednisolone, azathioprine, tacrolimus, mycophenolate mofetil, and combination therapy. For recurrent FSGS after renal transplantation, plasmapheresis is often used but appears not to be as efficacious in adults as in the pediatric population.     

Focal and segmental glomerulosclerosis: definition and relevance of a partial remission

Focal and segmental glomerulosclerosis (FSGS) is one of the most common primary glomerular diseases to terminate in ESRD. A complete remission (CR) confers an excellent long-term prognosis, but the quantitative benefits of partial remissions (PR) have not been defined. This study evaluated the rate of renal function decline (slope of creatinine clearance) and renal survival in nephrotic FSGS patients with CR, PR, or no remission. It also examined relapse rate from remission and its impact on outcome. Multivariate analysis included clinical and laboratory data at presentation and over follow-up, BP control, the agents used, and immunosuppressive therapy. The study cohort was 281 nephrotic FSGS patients who had a minimum of 12 mo of observation and were identified from the Toronto Glomerulonephritis Registry. Over a median follow-up of 65 mo, 55 experienced a CR, 117 had a PR, and 109 had no remission. A PR was independently predictive of slope and survival from renal failure by multivariate analysis (adjusted time-dependent hazard ratio, 0.48; 95% confidence interval, 0.24 to 0.96; P = 0.04). Immunosuppression with high-dose prednisone was associated with a higher rate of PR and CR. Relapse from PR was frequent (56%) and associated with a more rapid rate of renal function decline and worse renal survival compared with relapse-free partial remitters. Only female gender and the nadir of proteinuria during remission were associated with a sustained remission. A PR in proteinuria and its maintenance are important therapeutic targets in FSGS, with implications for both slowing progression rate and improving renal survival.     

Treatment of FSGS with plasma exchange and immunadsorption

In primary focal and segmental glomerulosclerosis (FSGS) renal prognosis is poor if no remission of proteinuria can be achieved with treatment. Currently, most children with FSGS are treated with cyclosporine and steroids after establishing steroid resistance, and approximately 60% of patients benefit from this therapy. For the remaining 40%, no generally approved therapeutic recommendations exist for children. We treated nine children with cyclosporine-resistant primary FSGS with plasma exchange (PE), two with relapsing FSGS after renal transplantation and seven with FSGS in their native kidneys. Three patients did not respond to PE, but five came into complete remission and one patient achieved partial remission. Three patients relapsed between 6 weeks and 2 years following cessation of PE, and were subsequently treated with plasma immunadsorption (PIA), which also reliably reduced proteinuria. The patients without response to PE tended to have a longer duration of the disease. We conclude that PE and PIA are a useful option for treatment of steroid- and cyclosporine-resistant FSGS, particularly if applied early in the course of the disease. Although more demanding on supportive resources, PIA seems preferable to PE, since there is no necessity for additional albumin or fresh-frozen plasma, as with PE.     

Long-term response to peginterferon in hepatitis C virus-associated nephrotic syndrome from focal segmental glomerulosclerosis

Abstract

Hepatitis C virus (HCV) infection is a global public health problem. Chronic HCV infection is an important cause of chronic liver disease. Since the first reported association between HCV and membranoproliferative glomerulonephritis (MPGN) in 1993, HCV has been described with other types of glomerular diseases, although less frequently. Focal segmental glomerulosclerosis (FSGS) is one such glomerular disease that has been rarely reported in association with HCV. Antiviral therapy with interferon and ribavirin has been shown to be beneficial in HCV-associated MPGN. The optimal therapy of HCV-associated FSGS is not currently known. To our knowledge, long-term response to pegylated interferon monotherapy in treatment of HCV-associated FSGS has not been reported. We report an adult patient with HCV-associated FSGS who presented with nephrotic syndrome and renal failure. Treatment with pegylated interferon alfa-2a monotherapy resulted in sustained virological response with a clinical remission of nephrotic syndrome and stabilization of renal function. Patient continued to remain in clinical remission of nephrotic syndrome with stable renal function, 5 years after treatment. We also briefly review the literature on HCV-associated glomerular diseases, particularly HCV-associated FSGS.     

Idiopathic focal segmental glomerulosclerosis

Idiopathic focal segmental glomerulosclerosis (FSGS) is a primary glomerular disease that essentially represents a form of chronic, progressive renal fibrosis for which there is no discernible cause. Often presenting with or eventually manifesting the nephrotic syndrome, this disease is increasing in incidence in both children and adults. Therapy continues to be a challenge, although some patients clearly respond to corticosteroids or cyclosporine with a decrease in, or remission of, proteinuria. A favorable response is associated with a decreased likelihood of progression to kidney failure. Given our clinical experience and recent advances in understanding the genetics of FSGS, a stochastic model of disease pathogenesis can be proposed.     

263例成人原发性局灶节段肾小球硬化性肾小球肾炎临床病理分析

目的 了解我国南方地区原发性局灶节段肾小球硬化性（FSGS）肾小球肾炎的发病情况及探讨FSGS临床与病理特征的关系。方法 收集1988年7月至2005年7月经我院肾活检确诊为原发性FSGS的263例成人患者的临床及肾脏病理资料并进行分析。 结果 （1）原发性FSGS占同期成人原发性肾小球疾病 7.02%,占成人原发性肾病综合征（NS）6.33%，其构成比近年有逐渐升高的趋势。青壮年为成人FSGS的主要患病人群，临床以不同程度的蛋白尿为特征，以NS为主要临床表现的有133例，占50.6%。（2）主要病理特征： 48.4%患者肾小球硬化比率≥25%，肾小球硬化并伴有肾小管间质病变者占88.6%，其中伴严重肾小管间质病变占25.2%。（3）肾小球硬化程度及小管间质病变程度与Ccr呈负相关 (P ＜ 0.01），并与Scr水平呈正相关(P ＜ 0.05）。肾小球硬化程度与小管间质病变程度呈正相关(P ＜ 0.01），与血浆白蛋白水平呈正相关(P ＜ 0.05）。肾小管间质病变是FSGS患者出现肾功能不全的重要影响因素。结论 原发性FSGS是成人肾病综合征的主要病理类型之一，就诊时肾小球硬化及肾小管间质纤维化已损害明显，并与肾功能损害密切相关。早期诊断和及时治疗，从而延缓FSGS的进展仍是广大肾脏病工作者探索的重要课题。     

Focal segmental glomerulosclerosis in association with Cushing's disease

Focal segmental glomerulosclerosis (FSGS) may be idiopathic or secondary to a variety of causes. Clinical distinction between primary and secondary forms of FSGS has crucial therapeutic consequences. Whereas the former may respond to immunosuppressive therapy, treatment of secondary forms of FSGS must aim to resolve the underlying diseases. Although the combination of nephrotic syndrome and Cushing's syndrome has been described anecdotally, the causal relationship between these two diseases remains controversial. We report herein a 37-year-old man who presented with lower extremity pitting edema. Heavy proteinuria and mild renal insufficiency prompted to perform a kidney biopsy and the specimen showed FSGS. On the other hand, admission physical examination was notable for a Cushingoid appearance. After endocrinological investigations, the patient was diagnosed as having Cushing's disease caused by pituitary adrenocorticotropic hormone-producing microadenoma. Immunosuppressive therapy for the treatment of FSGS was not carried out and we treated his Cushing's disease with transsphenoidal resection of the pituitary microadenoma. Surprisingly, resolution of heavy proteinuria occurred when the patient's physical features characteristic of Cushing's disease were gradually resolved 3 months later. This case suggests a possible association of Cushing's disease with FSGS.     

Focal and segmental glomerular sclerosis (FSGS) in a man and a woman with Fabry's disease

We describe a man and a woman with Fabry's disease. Renal biopsies showed late and early stages respectively of focal and segmental glomerulosclerosis (FSGS) and vascular changes. Clinically the hemizygous patient had advanced renal disease with nephrotic range proteinuria and serum creatinine 122 micromol/l. The female carrier had minimal albuminuria, borderline GFR with a normal serum creatinine, acroparesthesias, moderate fatigue, tinnitus and headache accompanied by ischemic cerebral lesions. Enzyme replacement therapy (ERT) was initiated according to our Fabry protocol, partly due to the renal morphologic findings. We conclude that FSGS and vascular changes may be an early morphologic finding in Fabry's disease, even in patients with subtle albuminuria. The potential role of FSGS as a marker of progressive renal disease in some Fabry patients is discussed. As FSGS and vascular changes obviously may exist across a wide range of clinical presentations and have potential prognostic implications, we suggest that a renal biopsy should be performed prior to enzyme replacement therapy in all adult Fabry patients with proteinuria of various levels. Efforts should be made to develop a scoring system to evaluate potential histologic markers. Protocol biopsies may have therapeutic implications and may provide valuable information in the evaluation of start and dosing of ERT.     

Rituximab Failed to Improve Nephrotic Syndrome in Renal Transplant Patients With Recurrent Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) recurs in 30% of patients with FSGS receiving a first renal transplant and in over 80% of patients receiving a second transplant after a recurrence. Recurrence often leads to graft failure. The pathogenesis remains unknown and may involve a circulating permeability factor that initiates injury to the glomerular capillary. There are anecdotal reports of pediatric patients with posttransplant lymphoproliferative disorder (PTLD) and recurrent FSGS who have had remission of proteinuria after treatment with rituximab. These observations have prompted speculation that B cells may play a role in the pathogenesis of recurrent FSGS. We report four consecutive adult patients with early recurrent FSGS refractory or dependent on plasmapheresis who received rituximab (total dose 2000–4200 mg). None of the patients treated with rituximab achieved remission in proteinuria, and one patient experienced early graft loss. In these four adult renal transplant patients with recurrent FSGS, rituximab failed to diminish proteinuria.     

Apheresis in primary focal segmental glomerulosclerosis of native and transplanted kidneys: a therapeutic protocol

BACKGROUND: Patients with focal segmental glomerulosclerosis (FSGS) develop nephrotic syndrome and terminal renal failure in most cases. FSGS reappears in 15-50% of transplanted kidneys and frequently causes the graft loss. Sera from patients with FSGS of native or transplanted kidneys contain some proteinuric or permeability factors (PF) which can be removed by means of plasma exchange (PE) or protein A Immunoadsorption (IA). METHODS: We suggest a therapeutic protocol, for patients with biopsy proven FSGS of native or transplanted kidneys, resistant to steroid and immunosuppressive therapy, based on the association of PE or IA to conventional drug therapy. Daily proteinuria, renal function, serum albumin and circulating level of proteinuric factors (permeability test) will be monitored at regular time intervals during the apheresis cycle, which will be intensive at the beginning (8-10 sessions in 4 weeks) and very gradually discontinued. Results. We will consider satisfactory remission the reduction of proteinuria below 1 g/day, improvement of renal function, normalization of serum albumin level (> 3.5 g/dl). Partial remission will be considered: proteinuria below 3 g/day, stable renal function, serum albumin level between 3 and 3.5 g/dl. Permeability test, if positive at baseline examination, should be negative after apheresis. CONCLUSIONS: The primary endpoint of our protocol is: lasting remission (satisfactory or partial) after the apheresis suspension. Secondary endpoints are: maintained remission with continuing apheresis sessions, correlation between permeability activity and disease activity, identification of responders and non responders patients on the basis of positive permeability test.     

Renal pathology in idiopathic membranous nephropathy: a new perspective

Histology findings in idiopathic membranous nephropathy (MGN) have been associated with the risk of renal failure, but whether they are independent of the clinical variables at the time of biopsy, predict rate of progression, or should guide therapy is uncertain. Renal biopsies of 389 adult MGN patients were evaluated semiquantitatively for interstitial fibrosis, tubular atrophy, vascular sclerosis, focal and segmental glomerulosclerosis lesions (FSGS), complement deposition, and stage and synchrony of deposits by electron microscopy (EM). Associations were tested between these findings and the rate of renal function decline (slope), renal survival, remission in proteinuria, and response to immunosuppression. Patients with a greater degree of tubulo-interstitial disease, vascular sclerosis, and secondary FSGS were older, had a higher mean arterial pressure, and a lower creatinine clearance at presentation. Although these histologic features were associated with a reduced renal survival, they did not predict this outcome independently of the baseline clinical variables nor did they correlate with the rate of decline in function or with baseline proteinuria. Furthermore, the severity of tubulo-interstitial and vascular lesions did not preclude a remission in proteinuria in those who received immunosuppressive therapy. Neither stage nor synchronicity of EM deposits nor the amount of complement deposition predicted renal survival but the latter did correlate with progression rate. In MGN, certain histologic changes are associated with renal survival outcome. However, the indicators of chronic injury are associated with age, blood pressure, and creatinine clearance at presentation and not with rate of disease progression or initial proteinuria.     

Focal and segmental glomerulosclerosis: varying biologic mechanisms underlie a final histopathologic end point

Focal and segmental glomerulosclerosis (FSGS) is a pathologic entity that is a common and increasing cause of end-stage renal disease. Typical manifestations include proteinuria, hypertension, worsening renal insufficiency, and, frequently, renal failure. The etiology, however, remains unknown in a majority of patients. There is an estimated recurrence rate of 30% to 40% in renal transplant patients, suggesting that the pathogenesis is not solely a result of intrinsic kidney disease. Although some of its characteristics have been reported, the precise identification of a circulating factor associated with FSGS has not been made. Remarkable progress has been made in recent years regarding biologic mechanisms surrounding FSGS and proteinuria. Insight into the pathogenesis of FSGS has been gained through the study of hereditary forms of FSGS and nephrotic syndromes. Mutations in cytoskeletal proteins that affect podocyte structure have been the target until recently. Here we review the current understanding of this glomerular disease and areas for future concentration.     

Focal segmental glomerulosclerosis associated with essential thrombocythemia

Focal segmental glomerulosclerosis (FSGS) is a primary glomerular disease that is characterized by progressive proteinuria and declining renal function. Secondary FSGS is known to be associated with various diseases. However, an association of FSGS with essential thrombocythemia (ET) has been reported in few cases. We report a 76-year-old man who presented with nephrotic syndrome and hepatosplenomegaly. He had thrombocythemia after a splenectomy, which had been carried out at a nearby hospital. A renal biopsy showed that he had focal segmental glomerulosclerosis (FSGS), while assessment of the bone-marrow specimen revealed that he had ET. A possible relationship between FSGS, which occurred in association with a dramatic increase of thrombocytes after a splenectomy in a patient with ET, and increased serum levels of transforming growth factor (TGF)-β, basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF)-BB was suggested.     

Collapsing glomerulopathy

Collapsing glomerulopathy is a morphologic variant of focal segmental glomerulosclerosis (FSGS) characterized by segmental and global collapse of the glomerular capillaries, marked hypertrophy and hyperplasia of podocytes, and severe tubulointerstitial disease. The cause of this disorder is unknown, but nearly identical pathologic findings are present in idiopathic collapsing glomerulopathy and human immunodeficiency virus (HIV)-associated nephropathy, and collapsing glomerulopathy has been associated with parvovirus B19 infection and treatment with pamidronate. The pathogenesis of collapsing glomerulopathy involves visceral epithelial cell injury leading to cell cycle dysregulation and a proliferative phenotype. Clinically, collapsing glomerulopathy is characterized by black racial predominance, a high incidence of nephrotic syndrome, and rapidly progressive renal failure. Collapsing glomerulopathy also may recur after renal transplantation or present de novo, often leading to loss of the allograft. The optimal treatment for collapsing glomerulopathy is unknown. Treatments may include steroids or cyclosporine in addition to aggressive blood pressure control, angiotensin converting enzyme inhibitors and/or angiotensin II receptor blockers, and lipid lowering agents. The role of other immunosuppressive agents such as mycophenolate mofetil in the treatment of collapsing FSGS remains to be defined. Prospective clinical trials are needed to define optimal therapy of this aggressive form of FSGS.     

Pathogenesis of focal glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is the histologic expression of diverse processes affecting the renal glomeruli and occurring in primary and secondary forms. A number of pathogenic factors have been identified in primary FSGS, and multiple etiologies have been defined as contributing factors for the development of secondary FSGS. There is a complex interplay between etiologic and pathogenic factors, progression factors and intervention in the phenotypic expression of FSGS. Key components include genetic predisposition, environmental influences and the impact on phenotype of pharmacologic intervention. The phenotypic spectrum for FSGS ranges from mild proteinuria and slow progression to a devastating clinical syndrome characterized by heavy proteinuria and rapid loss of renal function over a period of months. While the pathogenesis is unknown, much is known about factors which are involved in the development and progression of both primary and secondary FSGS. The ultimate goal of understanding pathogenesis is to provide specific nontoxic therapy for those patients who have a definable form of FSGS. While this goal is not yet in sight, many types of intervention, not addressed in the current chapter, can influence the course of various diseases presenting as FSGS. Until specific therapy can be fashioned, it is necessary for the clinician caring for these patients to appreciate the complex interaction of pathogenetic factors involved in the development and pregression of FSGS, as a rationale for providing intervention to prevent development of the disease and to slow its course.