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"Kidney Terminology

From the Microscope: Five Types of FSGS
Some Variants of FSGS Have Better Outcomes

The so-called Columbia classification defines five subtypes of focal segmental glomerulosclerosis (FSGS) based on light microscopic assessment of kidney biopsies.  A research laboratory in the Netherlands now re-evaluated this classification by analyzing retrospectively 93 adult patients with biopsy-proven FSGS and determining the clinical features and outcome of the investigated FSGS variants.  The frequencies of the FSGS subtypes were:  32% NOS (FSGS not otherwise specified), 37% tip, 26% perihilar and 5% collapsing.  The fifth subtype, termed cellular FSGS, was not found in the biopsies. 

   The authors found that nephrotic syndrome was less frequent in FSGS NOS (57%) and perihilar FSGS (25%) compared to the tip variant (97%).  In addition, kidney function was significantly better in patients with the tip variant compared to FSGS NOS.  Glomerular scarring was most severe in patients with perihilar FSGS, intermediate in FSGS NOS and the least severe in patients with the tip variant.  Moreover, renal survival at 5 years was significantly better for patients with the tip variant (78% for tip vs 63% and 55% for FSGS NOS and perihilar FSGS).  Finally, the remission rate was higher in patients with the tip variant.

   Overall, this study supports the concept that it does matter where glomerular damage develops, and confirms that the tip variant of FSGS is associated with the most favorable outcome.

Deegens JK, Steenberger EJ, Borm GF, Wetzels JFM | Department of Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands | Pathological variants of focal segmental glomerulosclerosis in an adult Dutch population – epidemiology and outcome | Nephrol Dial Transplant. 2007, Aug 17; [Epub ahead of print].

Retrospective Study on Sequential Therapy
Evaluates Outcome in Children with Steroid-Resistant Nephrotic Syndrome

Around 20% of children diagnosed with nephrotic syndrome do not respond to treatment with the steroid prednisone, which is effective in reducing proteinuria in the majority of patients.  This subgroup of patients is referred to as steroid-resistant and presents a serious dilemma regarding their treatment because, although one-third can later go into remission, another one-third develops end-stage renal disease (ESRD) on a varying timescale.  Focal segmental glomerulosclerosis (FSGS) is the most frequent cause of steroid-resistant nephrotic syndrome and ESRD of glomerular origin in children. 

    A recent study carried out at the University Hospital of La Paz in Madrid, Spain, retrospectively looked at the outcome of a particular sequential therapy regime involving intravenous injection of methylprednisolone (which is a derivative of prednisone) plus orally administered prednisone plus cyclophosphamide in a total of 30 children with steroid-resistant nephrotic syndrome.  The results with respect to remission of proteinuria are encouraging: total remission was achieved in 22 patients, and partial remission in three patients.  Although, the authors also identified a downside; 20% of patients developed a condition called steroid dependence.  In these patients, the remission of proteinuria was only sustainable when the administration of medication was upheld, which is not preferred due to the side and adverse effects of long-term sequential therapy. 

    Because the study was retrospective, the presented data have to be interpreted with caution.  However, these are promising findings, and, when validated in a randomized controlled trial, the investigated sequential therapy regimen might eventually turn out to be a milestone for the treatment of steroid-resistant syndrome in children.

Pena A, Bravo J, Melgosa M, Fernandez C, Meseguer C, Espinosa L, Alonso A, Picazo ML, Navarro | Department of Pathology, Hospital Universitario La Paz, Madrid, Spain | Steroid-resistant nephrotic syndrome: long-term evolution after sequential therapy | Pediatr Nephrol. 2007, 22:1875-1880.

Treatment of Idiopathic Nephrotic Syndrome
In Managing Disease, Know the Guidelines for Cyclosporin Therapy

Management of idiopathic disease of glomerular origin associated with nephrotic syndrome remains controversial and one of the most complex areas relates to utilization of the drug cyclosporin.  Cyclosporin is an immunosuppressant drug widely used during organ transplants to reduce the activity of the patient's immune system and so the risk of organ rejection. Cyclosporin A, the main form of the drug, is a cyclic peptide of 11 amino acids produced by the fungus Tolypocladium inflatum Gams.

Besides its use as an immunosuppressant during organ transplants, cyclosporin also has demonstrated effectiveness in reducing proteinuria in several types of idiopathic nephrotic syndrome in randomized controlled trials.  For example, cyclosporin is effective in inducing remission of proteinuria in approximately 80% of steroid-sensitive cases of minimal change disease. Cyclosporin has also been shown to be effective in both the induction of remission and long-term preservation of kidney function in some cases of steroid-resistant focal segmental glomerulosclerosis (FSGS)..

   While being generally well tolerated and safe, a major concern remains the nephrotoxicity of long-term cyclosporin treatment: tragically, one of the main adverse effects of this drug is that while helping reduce proteinuria, cyclosporin is toxic for the kidney in the long run, creating a paradoxical situation for doctors.  They weigh the potential benefits of continued kidney filtration (keeping the engine running) versus possible progressive damage to the kidney (ruining the engine.)

   In 2005, an international workshop of renowned clinical practitioners was convened to address the complex issue of cyclosporin administration during idiopathic nephrotic syndrome.  The results of this multidiciplinary expert review of the clinical data currently available was recently presented in the journal Kidney International.  The main outcome of the presented findings are algorithms for the use of cyclosporin in the treatment of minimal change disease and FSGS in children and adults.  The authors conclude that cyclosporin can serve as a useful tool to manage idiopathic nephrotic syndrome when the patient’s kidney function remains carefully monitored, and repeated kidney biopsies are carried out in individuals receiving long-term cyclosporin therapy.  Having said that, the authors also emphasize that due to the complexity of the matter, their featured recommendations outlined in this article can serve merely as a guide, and are intended for use only in conjuction with the physician’s careful clinical jugdment.

   In summary, the presented results will certainly help physicians determine the appropriate therapeutic intervention in the context of cyclosporin.  Patients affected by cyclosporin therapy should therefore feel encouraged to make their doctors aware of this study.

Cattran DC, Alexopoulos E, Herring P, Hoyer PF, Johnston A, Meyrier A, Ponticelli C, Saito T, Choukroun G, Nachman P, Praga M, Yoshikawa N | Cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome: workshop recommendations | Pediatr Nephrol. 2007, 22:1875-1880.

Probable Shift Towards More Cases of FSGS?
Is FSGS Increasing in Children with Nephrotic Syndrome?

Idiopathic nephrotic syndrome in children has conventionally been associated with minimal change disease (MCD).  Data from the 1978 International Study on Kidney Diseases in Children (ISKDC) indicated that MCD is by far the most frequent lesion in children and adolescents with idiopathic nephrotic syndrome, occuring in 77% of patients.  FSGS represented the second most prevalent lesion and was observed in 8-10% of cases.

   It is a well-known phenomenon that in the past 20-30 years the incidence of FSGS in adults with idiopathic nephrotic syndrome has increased in the United States, mainly among African Americans and Hispanics.  Whereas the relative frequency of FSGS was 15% of 1,000 renal biopsies between 1976 and 1979, FSGS was present in 35% of cases among 1,000 biopsies between 1995 and 1997, which implies a roughly two-fold increase in FSGS frequency.

   A recent study by Fábio Borges and colleagues investigated whether such an increase in FSGS frequency could also be observed in children and adolescents of 0-18 years of age.  The authors conducted a review of the medical literature to collect studies that had quantified FSGS frequency as a cause of idiopathic nephrotic syndrome in pediatric patients over two different time periods in the past three decades.  The results, based on the comprehensive evaluation of six different clinical studies, suggest that a shift in the pathological pattern of nephrotic syndrome in children may indeed be occurring, resulting in an increase in FSGS frequency.  However, the authors concede that more studies will have to be carried out before this hypothesis can be accepted as definitively proven since the significance of the currently available data may be compromised by several factors such as small sample number, changes in kidney biopsy techniques over time, and a potential publication bias.

   Despite the intrinsic limitations associated with the present study, the results are interesting and in line with the previous findings in adults with idiopathic nephrotic syndrome.  While it is currently not possible to determine the cause for this phenomenon, it is conceivable that the increased FSGS frequency in children may be due to the epidemic of obesity that currenty affects children and adolescents worldwide.  After all, it has been demonstrated that individuals with increased body mass index (BMI) present a predisposition to renal injury.  In conclusion, the findings of this study, if confirmed, may be of great clinical importance since patients with nephrotic syndrome in conjunction with FSGS have a poorer prognosis than patients without FSGS, and are more likely to require kidney transplants.

Borges FF, Shiraichi L, da Silva MP, Nishimoto EI, Nogueira PC | Faculdade de Ciências Médicas de Santos, UNILUS, São Paulo, Brazil | Is focal segmental glomerulosclerosis increasing in patients with nephrotic syndrome? | Pediatr Nephrol. 2007 Jun 6; [Epub ahead of print].

Urine Biomarkers to Predict Glomerular Disease
May Become Alternative to Kidney Biopsy

Glomerular diseases such as Neprotic Syndrome and FSGS are associated with proteinuria that results from increased permeability of the glomerular filtration barrier.  For appropriate treatment, it is necessary to obtain a definitive diagnosis of the underlying cause of the disease.  The standard diagnostic procedure currently is a kidney biopsy.  However, the utility of this approach is limited.  For example, some patients with bleeding disorders or obesity are not suitable or are at higher risk for a biopsy.  This is why researchers try to find alternative, non-invasive ways to diagnose certain kidney diseases.  One novel approach is testing urine for biomarkers, that is, certain proteins or protein fragments that are present in individuals carrying the disease but are absent in healthy individuals. 

Utilizing proteomic techniques, a recent study published in the Journal of the American Society of Nephrology identified a set of promising biomarkers that could identify and differentiate four different glomerular diseases including FSGS. 

While the biomarker discovery will require confirmation from the study of larger sets of patients and the development of a useful clinical assay, this finding provides hope for a method to diagnose specific glomerular diseases without a kidney biopsy.

Varghese SA, Powell TB, Budisavljevic MN, Oates JC, Raymond JR, Almeida JS, Arthur JM | Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA | Urine Biomarkers Predict the Cause of Glomerular Disease | J Am Soc Nephrol. 2007,  18:913-922.

FDA Issues Warning on Erythropoiesis Stimulating Agents
Caution on Drugs That Treat Anemia in Chronic Kidney Failure

Anemia is a condition in which the blood contains a lower than normal number of red blood cells.  Red blood cells are responsible for carrying oxygen from the lungs to the tissues and organs throughout the body, a fundamental process required for organ function and survival.  Having too few red blood cells can result in severe health problems.  Anemia is common in people with kidney disease.  The reason: healthy kidneys produce a hormone, erythropoietin, or EPO, which stimulates the production of a sufficient amount of red blood cells to maintain the proper transport of oxygen.  In contrast, damaged kidneys are often impaired in their ability to produce enough EPO, resulting in a lowered production of red blood cells.  Dialysis also can contribute to anemia through the loss of blood.

Recently, two clinical studies and an editorial published in the New England Journal of Medicine addressed safety concerns about the use of erythropoiesis stimulating agents (ESAs), which are man-made versions of EPO, in the prevention and treatment of anemia in patients with chronic kidneys failure.

The 1,400 subject Choir study demonstrated increases in serious and potentially life threatening cardiovascular events when epoetin alfa (Procrit) was administered to reach higher target hemoglobin levels.  Chronic kidney failure patients had increased numbers of deaths and of non-fatal heart attacks, strokes, heart failure, and blood clots when ESAs were adjusted to maintain higher red blood cell levels (hemoglobin more than 12 g/dL).  The 600 subject Create study trended towards more cardiovascular events in a pattern similar to the Choir study, thus strengthening the findings of the Choir study.  The Create study examined the use of epoetin beta, a product not approved in the US.

Following these reports, the Food and Drug Administration (FDA) on March 9, 2007 issued a Public Health Advisory about the drugs epoetin alfa (marketed as Procrit, Epogen) and darbepoetin alfa (marketed as Aranesp).  The FDA also informed nephrologists via an edditional e-mail communication distributed through medical professional organizations.  Furthermore, the manufacturers of the affected drugs have revised product labeling to include the new warnings and dosing recommendations.

At this time, ESAs appear to be safe and effective when used according to the revised product labeling at the recommended dose and approved indication.  Yet, the lowest effective dose is now recommended to gradually increase the hemoglobin concentration to the level sufficient to avoid the need for red blood cell transfusion.  The FDA will continue to assess any new data as it becomes available.

FDA Alert [11/16/2006, Updated 2/16/2007 and 3/9/2007] | Information on Erythropoiesis Stimulating Agents (ESAs) (marketed as Procrit, Epogen, and Aranesp)| www.fda.gov

Remuzzi F, Ingelfinger, JR | Mario Negri Institute for Pharmacological Research, Bergamo, Italy | Correction of Anemia – Payoffs and Problems | N Engl J Med. 2006,  355:2144-2146.

FSGS Clinical Trial Update
Multicenter Study of FSGS in Children and Young Adults

Primary FSGS is a leading cause of end-stage renal disease in both children and adults, with loss of kidney function in 50% of patients over 10 years.  The FSGS Clinical Trial was sponsored by the National Institutes of Health (NIH) in response to this poor prognosis and the need for rigorously-tested treatment modalities.  The FSGS Clinical Trial, which has been featured before on the NephCure website, is a Phase III randomized trial of children and young adults age 2 to 40 years being conducted at over 100 sites in North America.

Children and young adults with nephrotic syndrome have proteinuria, which is the result of tissue alteration (and sometimes scarring) that occurs in the kidney glomeruli.  Most nephrotic syndrome patients of young age have kidney biopsy findings consistent with the diagnosis of minimal change disease.  Typically, these patients will have remission of clinical symptoms after treatment with high doses of the steroid prednisone and they rarely develop progressive disease that leads to end-stage renal disease.

   However, a subgroup of children and young adults with nephrotic syndrome have so-called steroid-resistant nephrotic syndrome and their kidney biopsies show evidence of FSGS.  Patients with this condition do not respond to treatment with the steroid prednisone.  In consequence, the long-term prognosis for this steroid-resistant subgroup is poor because no satisfactory treatment exists for their condition.

   The National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) within the NIH has formed a collaborative network of research centers that is comparing the effects of treatment of steroid-resistant nephrotic syndrome with cyclosporine to treatment with mycophenalate mofetil combined with dexamethasone.  Efficacy of the treatment is being assessed against the goals of  the start of remission of proteinuria after 52 weeks of treatment and sustained remission after 26 weeks off treatment.

   This largest randomized trial on FSGS ever conducted is enrolling subjects aged 2-40 years through February 2008.  To date, 109 patients have been screened and 77 randomized towards the enrollment target of 207 patients.  Patients with FSGS who still want to participate or find the closest participating site should go to the website www.fsgstrial.org or call the toll-free hotline 1-877-622-FSGS (3747).

5-Year Study Compares FSGS-Treatments
Largest Trial of FSGS Ever Conducted Scheduled to End in 2008
Children and young adults with nephrotic syndrome have proteinuria, which is the result of tissue degeneration and scarring that occurs in the kidney glomeruli.

Most Nephrotic Syndrome patients of young age have kidney biopsy findings consistent with the diagnosis of minimal change disease. Typically, these patients will have remission of clinical symptoms after treatment with high doses of the steroid prednisone, and they rarely develop progressive disease that leads to End-Stage Renal Disease (ESRD).

However, a subgroup of children and young adults with nephrotic syndrome have so-called steroid-resistant nephrotic syndrome, and renal biopsies show evidence of FSGS. Patients with this condition do not respond to treatment with the steroid prednisone. In consequence, the long-term prognosis for this steroid-resistant subgroup is poor because no satisfactory treatment exists for their condition.

The National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) has formed a collaborative network of research centers that will compare the effects of treatment of steroid-resistant nephrotic syndrome with cyclosporine to treatment with mycophenalate mofetil combined with oral pulse dexamethasone. Efficacy of the treatment will be assessed in terms of induction of remission of proteinuria after 52 weeks of treatment and sustained remission after 26 weeks off treatment.

This is the largest randomized trial on FSGS ever conducted, and will enroll 207 subjects aged 2-40 years through February 2008. In June 2006, 58 patients had already been enrolled for the trial. Any patients with FSGS who want to participate or find the closest participating site should go to the website www.fsgstrial.org or call the toll-free hotline 1-877-622-FSGS (3747).

Five of the listed clinical trials on novel drugs or drug combinations (Pentoxifylline, Dexamethasone, Candesartan Cilexetil, Fluvastatin, and a combination of Mycophenolate Mofetil and Cyclosporin) are so-called Phase III trials. Phase III trials usually represent a late stage in the drug testing process, in which the study drug or treatment is given to larger groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely. A Phase III trials may be the last stage before an eventual approval by the Food and Drug Administration (FDA), depending on study design and outcome.

In most cases, FSGS and nephrotic syndrome appear either as idiopathic diseases, meaning that their cause is unknown, or as a disorders secondary to another disease, such as infection with HIV. However, there are also numerous forms of FSGS and nephrotic syndrome, for which a known genetic defect is the cause. A prominent example is the Congenital Nephrotic Syndrome of the Finnish Type ( CNF ). In CNF , mutations in the protein nephrin, which is present in kidney podocytes and plays a key role in the process of kidney filtration, are responsible for the development of kidney disease. Since genetic defects – and therefore the associated diseases – are inherited from generation to generation, one refers to these cases as familial, or inherited forms of kidney disease.

It is very likely that in many patients currently diagnosed with idiopathic FSGS the underlying cause of the disease is actually a genetic defect that researchers have not yet been able to identify. This is why the search for novel mutations associated with the development of FSGS remains an important task. The identification of genetic defects is helping scientists to unravel some of the the mechanisms behind the disease and create some tests for the disease-associated mutations. The latter will facilitate the diagnosis of inherited forms of FSGS and lead to better-targeted treatment of patients.

This study will recruit a total of 600 patients divided into 3 groups. Since FSGS is significantly more common among individuals of African descent, group 1 will consist of 200 African-Americans with FSGS, while group 2 will be 200 African-Americans with HIV but without FSGS. Group 3 will be 200 non-African-Americans with FSGS. Researchers will look at certain parts of the genome to detect differences between patients with FSGS and patients without FSGS. A total of approximately 3000 locations on the genome, referred to as genetic markers, will be screened.

The presence of podocytes in the urine, a condition called podocyturia, during glomerular disease has so far been documented by several research groups. It may be possible to utilize this as a biomarker for glomerular disease, meaning that the detection of podocytes in the urine may indicate the presence and severity of glomerular disease.

The detection of podocytes in the urine thus far has been hampered by insufficient methods to identify and quantify cellular fragments in biologic samples. Researchers at the university hospital of the University of Strasbourg, France, have developed a technique to evaluate the number of podocyte cellular fragments in the urine of patients with glomerular disease.

The aim of this French clinical study is to quantify podocyturia during glomerular disease and to study the relationship between podocyturia and other symptoms of glomerular disease such as proteinuria. The study will test whether treatment with angiotensin-2 inhibitors, a common therapy for affected patients, can reduce podocyturia. A total of 20 patients will be recruited for the study, and enrollment is scheduled to begin by the end of 2006.