Familial collapsing focal segmental glomerulosclerosis.

The majority of patients with non-HIV-related collapsing focal segmental glomerular sclerosis (FSGS) have idiopathic disease. Only a few genetic forms associated with rare syndromes have been described in families. Here we report two families with multiple members who have collapsing FSGS with no clear associated secondary etiology. Genetic analysis revealed a defect in the TRPC6 gene in one family, but excluded all known common inherited podocyte defects in the other family. The course and response to treatment differed dramatically among members of the same family.

Recurrent focal segmental glomerulosclerosis in the renal allograft: single center experience in the era of modern immunosuppression.

FSGS is an important cause of ESRD and tends to recur in allografts (rFSGS). Older series suggest recurrence rates of 30-60%. In the modern era of transplant immunosuppression, recurrence rates are unknown. There are also few data regarding prevalence of known genetic mutations in adult FSGS patients who undergo transplantation. Recently, FSGS has been subdivided into histological variants, which may predict renal outcomes; there is little information on patterns of recurrence and outcomes in these variants. Finally, treatment for rFSGS relies upon up-titrating calcineurin inhibitors and plasmapheresis. Insufficient information exists on the use of these regimens for rFSGS in the era of modern immunosuppression. We conducted a retrospective chart review involving all renal transplant recipients at Columbia University Medical Center from December 1999 to March 2007. Those with biopsy confirmed primary FSGS were included and information regarding baseline characteristics, histologic variants, genetics, treatment, and clinical outcomes were collected. FSGS recurred in 23% of patients. Those with collapsing histology on native kidney biopsy, tended to recur with the same histology. No known genetic mutations were identified among those with recurrence. Plasmapheresis resulted in complete or partial remission in 75% of those with recurrence. Recurrent FSGS resulted in a trend toward the combined outcome of ESRD or death compared to those without recurrence (27% vs. 12%). Modern immunosuppression does not reduce the rate of rFSGS, known genetic mutations are uncommon in such adult patients, collapsing FSGS tends to recur with the same histology, and plasmapheresis may be helpful in the treatment of recurrence.

The treatment of acute interstitial nephritis: More data at last.

Acute interstitial nephritis (AIN) is an uncommon form of acute renal failure that is usually medication related. Although the clinical features and renal histopathology are well recognized, therapy beyond discontinuing the offending drug has been a challenge. The use of corticosteroids, although supported by numerous small retrospective studies and anecdotal case reports, has been controversial. The study by González et al., although it has limitations, provides solid support for the early use of corticosteroids in the treatment of drug-related AIN.

Update on the treatment of lupus nephritis.

Lupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus. Although the use of aggressive immunosuppression has improved both patient and renal survival over the past several decades, the optimal treatment of LN remains challenging. Improved outcomes have come at the expense of significant adverse effects owing to therapy. Moreover with long-term survival, the chronic adverse effects of effective therapies including risk of malignancy, atherosclerosis, infertility, and bone disease all become more important. Finally, some patients fail to achieve remission with standard cytotoxic therapy and others relapse when therapy is reduced. For these reasons, recent clinical trials have attempted to define alternate treatment protocols that appear to be efficacious in achieving and maintaining remission, but with less toxicity than standard regimens. This paper discusses established and newer treatment options for patients with proliferative and membranous LN, with an emphasis on the results of these recent clinical trials. We also review the experimental and human data regarding some of the novel targeted forms of therapy that are under investigation and in different phases of clinical trials.

The IgA nephropathy treatment dilemma.

Although IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, our understanding of the pathogenesis of this complex disease remains limited. IgA nephropathy may appear with a variety of clinical presentations, a number of different clinical and histopathologic risk factors for progressive renal disease, and a very variable course over time. Thus, it is not surprising that a single therapeutic treatment plan has not been established. Many of the studies dealing with IgAN are retrospective, lack statistical significance, or have confounding designs, which hinder their general acceptance. Nevertheless, a number of well-designed studies have been performed. This paper reviews currently available therapeutic options for IgAN. It attempts to address several important questions: Why do we treat patients with IgAN? How do we decide which patients should be treated? What are the general treatment guidelines for all IgAN patients? What is the role of specific therapy such as fish oils, tonsillectomy, and immunosuppression in the treatment of patient with IgAN? It also addresses several on-going trials and goals for future therapeutic studies for IgAN patients.

Membranous glomerulopathy and acute interstitial nephritis following treatment with celecoxib.

Both membranous glomerulopathy and acute interstitial nephritis have been reported to occur following treatment with non-steroidal anti-inflammatory drugs. We report the first cases of membranous glomerulopathy and acute interstitial nephritis following treatment with celecoxib (Celebrex), a selective COX-2 inhibitor. The rapid and complete resolution of both conditions following discontinuation of Celebrex strongly implicates this agent in disease pathogenesis. These cases enlarge the spectrum of potential renal toxicities of the COX-2-specific non-steroidal anti-inflammatory drugs.

Minimal change disease in systemic lupus erythematosus.

We report the clinical and pathologic findings in 7 patients with systemic lupus erythematosus and minimal change disease. All 7 patients presented with full nephrotic syndrome including peripheral edema, nephrotic range proteinuria (mean 9.6 g/day), and hypoalbuminemia (mean 1.8 g/dl). In all cases, renal biopsy revealed diffuse foot process effacement in the absence of significant peripheral capillary wall immune deposits, findings consistent with minimal-change disease. In addition, 5 cases displayed mesangial electron-dense deposits, with or without associated mesangial proliferation, consistent with underlying lupus nephritis class II. In all cases, steroid therapy induced a rapid remission of nephrotic syndrome. Minimal change disease is an underrecognized and readily reversible form of nephrotic syndrome in systemic lupus erythematosus. Because it may occur superimposed on mild mesangial proliferative lupus nephritis, this entity may be misinterpreted as an atypical presentation of lupus nephritis class II. Proper recognition of this entity requires careful integration of the renal biopsy immunofluorescence and electron microscopic findings.

COX-2 inhibitors and the kidney.

Cyclooxygenase-2 (COX-2) selective inhibitors are now extensively used for their anti-inflammatory and analgesic efficacy. Several large controlled trials provide evidence to support the proposition that they cause fewer major gastro-intestinal side effects and less toxicity than routine nonsteroidal anti-inflammatory drugs (NSAIDs). In view of the documented different localizations of the cyclooxygenase-1 and COX-2 enzymes in the kidney, it was initially hoped that COX-2 inhibitors would be associated with fewer renal side effects than other NSAIDs. This has not been borne out by subsequent studies. Like other NSAIDs, COX-2 inhibitors can cause salt and water retention, leading to edema and worsening hypertension. They can also cause acute declines in renal function and glomerular filtration rate. These events are, however, uncommon in large rheumatology populations and infrequently lead to discontinuation of the medications. Judicious use of COX-2 inhibitors in high-risk patients (such as those with chronic renal insufficiency, diabetes or congestive heart failure) will lead to a decreased incidence of adverse renal events.

Plasmapheresis treatment of recurrent FSGS in adult renal transplant recipients.

Plasmapheresis (PP) is often employed in the treatment of recurrent focal segmental glomerulosclerosis (FSGS) in the renal allograft, where it appears to be effective in the pediatric population. The efficacy of PP in adults and predictors of response are not well documented. We analyzed the records of 13 adult patients from three transplant centers who underwent PP for recurrent FSGS between 1993 and 1999. One patient (8%) had a complete response, one (8%) had a partial response, and 3 (23%) partially responded but remain PP-dependent. All 5 responders were started on PP within 30 days of recurrence, while 7 of the 8 non-responders initiated PP after a delay of at least 42 days (p = 0.0047). FSGS recurred within 30 days of transplantation in all 5 responders, while 4 of 8 non-responders had no evidence of recurrence until 42-150 days after transplantation (p = 0.098). Post-transplant biopsies were examined in 10 patients and revealed either cellular (6) or collapsing (4) variants of FSGS. We conclude PP is less effective in adults than in children as a treatment for recurrent FSGS in the renal allograft. Predictors of response to PP include early initiation of treatment after recurrence and possibly an early recurrence of disease.

Membranous glomerulopathy associated with graft-versus-host disease following allogeneic stem cell transplantation. Report of 2 cases and review of the literature.

We report two cases of nephrotic syndrome presenting 18 and 20 months after allogeneic stem cell transplantation (alloSCT) with chronic myelogenous leukemia. Both patients had acute and chronic graft-versus-host disease (GVHD) and renal biopsy findings of membranous glomerulopathy (MG). A review of the literature revealed 10 additional cases of immune-complex-mediated glomerular disease following alloSCT, 8 of which were diagnostic of MG. All patients showed evidence of acute or chronic GVHD. Patients typically presented with preserved renal function (mean creatinine 1.2 mg/dl) and full nephrotic syndrome including heavy proteinuria (mean 9.2 g/24 h), edema, hypoalbuminemia (mean 2.1 g/dl) and hypercholesterolemia (mean 472 mg/dl). Most patients showed stabilization of renal function and significant decreases in proteinuria when treated with steroids and/or cyclosporine. The close temporal association as well as evidence from murine models of GVHD support a pathogenetic association between GVHD and the development of MG.

Racial and socioeconomic factors in glomerular disease.

The influence of racial and socioeconomic factors on the incidence, prognosis, and response to therapy of many diseases has long been noted. Although glomerular diseases comprise 10% to over 16% of the dialysis and renal transplant populations, respectively, only recently have racial and socioeconomic factors been evaluated. Several glomerular diseases are associated with a striking African-American predominance. These include idiopathic focal sclerosis, and especially its collapsing variant, human immunodeficiency virus (HIV)-associated nephropathy, and severe lupus nephritis. In many of these entities the renal disease is also more aggressive and rapidly progressive than in other populations. Recent data points to genetic-biologic as well as social and economic factors that may be responsible for these findings. Studies dealing with the therapy of glomerular lesions must be stratified for racial and social background differences to avoid bias in outcome. Whether racial and socioeconomic data should be used in treating individual patients, and how, remains an area of controversy.

Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.

BACKGROUND: A clinical trial of cyclosporine in patients with steroid-resistant membranous nephropathy (MGN) was conducted. Although MGN remains the most common cause of adult-onset nephrotic syndrome, its management is still controversial. Cyclosporine has been shown to be effective in cases of progressive MGN, but it has not been used in controlled studies at an early stage of the disease. METHODS: We conducted a randomized trial in 51 biopsy-proven idiopathic MGN patients with nephrotic-range proteinuria comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 78 weeks, and the short- and long-term effects on renal function were assessed. RESULTS: Seventy-five percent of the treatment group versus 22% of the control group (P < 0.001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 43% (N = 9) of the cyclosporine remission group and 40% (N = 2) of the placebo group by week 52. The fraction of the total population in remission then remained almost unchanged and significant different between the groups until the end of the study (cyclosporine 39%, placebo 13%, P = 0.007). Renal function was unchanged and equal in the two groups over the test medication period. In the subsequent follow-up, renal insufficiency, defined as doubling of baseline creatinine, was seen in two patients in each group, but remained equal and stable in all of the other patients. CONCLUSION: This study suggests that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of MGN. Although a high relapse does occur, 39% of the treated patients remained in remission and were subnephrotic for at least one-year post-treatment, with no adverse effect on filtration function.

Antiphospholipid antibody syndrome and renal disease.

The antiphospholipid syndrome is a disorder of hypercoagulability in association with circulating antiphospholipid antibodies directed against epitopes on oxidized phospholipids complexed with a glycoprotein, beta 2-glycoprotein I, or against the glycoprotein itself. Disorders associated with antiphospholipid antibodies but not the antiphospholipid syndrome, such as HIV and hepatitis C infection, appear to lack antibodies to beta 2-glycoprotein I. Patients with systemic lupus erythematosus have a high incidence of antiphospholipid antibodies with a high risk of thrombosis, often associated with anticardiolipin antibodies, beta 2-glyocoprotein I antibodies, and the presence of the lupus anticoagulant. Antiphospholipid antibodies are a significant cause of morbidity and mortality in renal patients with and without systemic lupus erythematosus. Renal manifestations include thrombotic microangiopathy and large vessel thrombosis. In patients with end-stage renal disease, antiphospholipid antibodies are prevalent and may increase in frequency with time on dialysis, possibly as a result of oxidative stress incurred during dialysis. The presence of anticardiolipin antibodies have been associated with a high incidence of hemodialysis access clotting. In renal transplant recipients, the incidence of antiphospholipid antibodies is also elevated and may be associated with a higher incidence of primary graft non-function. Although patients with systemic lupus erythematosus have similar renal allograft survival rates to the general population, survival is worse for those patients who are also antiphospholipid antibody positive. Additionally, in hepatitis C positive renal transplant recipients, the presence of anticardiolipin antibodies confers an increased risk of thrombotic complications and the development of thrombotic microangiopathy. Treatment of antiphospholipid antibody syndrome remains centered around anticoagulation with warfarin. The use of immunosuppressive agents has had no dramatic effect on antiphospholipid antibody titers and little clinical effect on thrombotic events.

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.

Membranous glomerulopathy with Bowman's capsular and tubular basement membrane deposits.

Bowman's capsular and tubular basement membrane (TBM) deposits are an extremely unusual finding in non-lupus membranous glomerulopathy (MGN). We report three atypical cases of MGN with abundant Bowman's capsular and TBM deposits. In two cases, MGN was idiopathic; in the third case, MGN occurred in the renal allograft in the setting of HCV seropositivity. In addition to the usual glomerular capillary wall deposits, immunofluorescence and electron microscopy revealed extensive immune deposits within Bowman's capsule and TBMs, predominantly at the base of parietal and tubular epithelial cells. These cases suggest a potential pathomechanism of autoantibody to secreted epithelial antigens shared by visceral, parietal, and tubular epithelial cells. In all three cases, indirect immunofluorescence was unable to detect autoantibody to normal renal epithelial or matrix constituents. Furthermore, ELISA was unable to demonstrate circulating antibody to major extracellular matrix components. The implications of these findings for the pathogenesis of MGN are explored.

A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group.

UNLABELLED: A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. BACKGROUND: A clinical trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis (FSGS) was conducted. Despite the fact that it is the most common primary glomerulonephritis to progress to renal failure, treatment trials have been very limited. METHODS: We conducted a randomized controlled trial in 49 cases of steroid-resistant FSGS comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 200 weeks, and the short- and long-term effects on renal function were assessed. RESULTS: Seventy percent of the treatment group versus 4% of the placebo group (P < 0. 001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 40% of the remitters by 52 weeks and 60% by week 78, but the remainder stayed in remission to the end of the observation period. Renal function was better preserved in the cyclosporine group. There was a decrease of 50% in baseline creatinine clearance in 25% of the treated group compared with 52% of controls (P < 0.05). This was a reduction in risk of 70% (95% CI, 9 to 93) independent of other baseline demographic and laboratory variables. CONCLUSIONS: These results suggest that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of FSGS. Although a high relapse rate does occur, a long-term decrease in proteinuria and preservation of filtration function were observed in a significant proportion of treated patients.

Hepatitis C virus-associated glomerular disease in patients with human immunodeficiency virus coinfection.

Chronic infection with hepatitis C virus (HCV) has been linked to the development of glomerular disease. HCV infection is highly prevalent among intravenous drug users, a population that is also at risk for HIV coinfection. This study reports the clinical-pathologic features and outcome of HCV-associated glomerular disease (HCV-GD) in 14 patients with HIV coinfection. All were intravenous drug users and all but one were African-Americans. Renal presentations included renal insufficiency, microscopic hematuria with active urine sediment, hypertension, and nephrotic syndrome or nephrotic-range proteinuria without hypercholesterolemia. Hypocomplementemia and cryoglobulinemia were present in 46 and 33% of patients, respectively. The predominant renal biopsy findings were membranoproliferative glomerulonephritis type 1 or type 3 (Burkholder subtype) in 79% of patients and membranous glomerulopathy with atypical features in 21% (including overlap with collapsing glomerulopathy in one patient). The clinical course was characterized by rapid progression to renal failure requiring dialysis. The overall morbidity and mortality were high with median time of 5.8 mo to dialysis or death. Although most patients died in renal failure, cause of death was primarily attributable to long-term immunosuppression and advanced AIDS. Patients with AIDS had shorter survival than those without (median survival time of 6.1 mo versus 45.9 mo, log-rank test P = 0.02). Only two patients were alive with stable renal function at follow-up of 28.5 mo. In patients with HCV-GD, coinfection with HIV leads to an aggressive form of renal disease that can be easily confused with HIV-associated nephropathy. Although hypocomplementemia, cryoglobulinemia, and more prominent hypertension and microscopic hematuria may provide clues to the presence of HCV-GD, renal biopsy is essential to differentiate HCV-GD from HIV-associated nephropathy.

Heavy chain deposition disease: the disease spectrum.

A 45-year-old white woman was found to have microscopic hematuria during her annual physical examination. After a negative urologic workup, she returned 5 months later with nephrotic syndrome, renal insufficiency, and hypocomplementemia. Renal biopsy showed a nodular sclerosing glomerulopathy that could not be further characterized because of inadequate tissue for immunofluorescence. The patient returned 8 months later with chronic renal failure. A repeat renal biopsy showed deposits composed of immunoglobulin G (IgG) heavy chain and complement components C3 and C1 along glomerular, tubular, and vascular basement membranes, with negativity for kappa and lambda light chains, findings consistent with heavy chain deposition disease (HCDD). The heavy chain subclass was exclusively IgG3. Staining with monoclonal antibodies to epitopes of the constant domains of IgG heavy chain showed a CH1 deletion, indicating a truncated heavy chain. On review of the previously reported cases of HCDD, common clinical presentations include nephrotic syndrome, renal insufficiency, hematuria, and, in some cases, hypocomplementemia. In most patients, the hematologic disorder is mild, without overt myeloma. Light microscopy shows a nodular sclerosing glomerulopathy, and heavy chain deposits are detectable within basement membranes throughout the kidney by immunofluorescence and electron microscopy. There is no effective treatment for this condition, and virtually all patients progress to chronic renal failure.

Renal pathology of human immunodeficiency virus infection.

Renal complications of HIV infection are clinically and morphologically diverse. These may affect the glomerular, tubulointerstitial, and vascular compartments. Tubulointerstitial injury predominates in most autopsy-based studies, whereas glomerular disease is most frequently identified in biopsy-based studies. The most common glomerular lesion is HIV-associated focal segmental glomerulosclerosis and related mesangiopathies (collectively termed HIV-associated nephropathy). Increasingly, a variety of immune complex-mediated glomerular diseases such as membranoproliferative glomerulonephritis, IgA nephropathy and lupus-like nephritis, as well as hemolytic uremic syndrome/thrombotic thrombocytopenic purpura have been reported. The spectrum of tubulointerstitial lesions includes acute tubular necrosis, interstitial nephritis, diffuse infiltrative lymphocytosis syndrome, renal infection, and neoplasms including lymphoma and Kaposi's sarcoma. The pathological features of these conditions are reviewed with emphasis on clinical-pathological correlations and pathogenesis.