Note: Letter to the Editor RE this article
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While diabetes and hypertension remain the most common etiologies of kidney disease, the incidence of glomerulonephritis (GN) is on the rise. The increase in the number of people diagnosed with GN is a growing concern among health professionals. In many cases, the etiology of the various types of GN has not been completely elucidated. Common causes of GN include IgA nephropathy, focal segmental glomerulosclerosis (FSGS), membranous glomerulonephritis (MGN), membranoproliferative glomerulonephritis (MPGN), and rapidly progressive glomerulonephritis (crescentic nephritis). All of these conditions have the potential to leave the kidney irrevocably scarred and unable to function. FSGS, in particular, has an especially poor prognosis, with the highest likelihood of progression to end stage renal disease (ESRD).
Not only is FSGS the most deadly of the nephropathies, it is becoming increasingly common. New cases of FSGS continue to rise while the rates of other glomerular diseases such as minimal change nephrotic syndrome (MCNS) and MGN have become stable or fallen. An accurate assessment of rates of FSGS can be difficult, as most children and adults presenting with nephrotic syndrome are not routinely biopsied and an estimate of the rate of incidence is generally extrapolated from clinical reports, registries, and renal biopsy materials. FSGS is the most common cause of kidney failure in children and accounts for about 5% of adult cases of renal failure.1
And while incidence of FSGS continues to grow, few in the alternative medical community are aware of FSGS or understand how to treat it. In 1993 after receiving the diagnosis of FSGS, the author sought in vain an alternative practitioner who was versed in FSGS. Left to her own devices to sort out the often contradictory information on kidney health, the author embarked on a career as a naturopathic physician. 20 years later, little has changed, as few in the field of alternative medicine are familiar with FSGS.
FSGS is a histopathological definition based on cellular changes observed on a biopsy. Presently FSGS is considered an idiopathic condition and may not represent a single disease with one etiology. The histologic features of idiopathic FSGS were first described by Theodor Fahr in 1925.1 It was later identified in a group of children who had died from nephrotic syndrome in 1957. The lesions were "focal," affecting some nephrons and sparing others, and "segmented," scarring one part of the nephron.2 The picture of FSGS on biopsies originally caused it to be referred to as the "flea bitten" kidney.
Structural changes of FSGS include sclerosis of the glomerulus, podocyte erosion, and deposition of extracellular matrix in the mesangial tissue which become solidified. Mesangial hypercellularity and a collapse of the vascular structure servicing the nephrons are observed. There may be IgM deposits or C3 complement. If atrophy and fibrosis of the kidney tubulointerstitium is present, it generally portends a poor prognosis.3
FSGS is four times more common in those with African ancestry, contrasting with IgA nephropathy, which occurs most often in Caucasians and Asians.4 The average age of onset for FSGS is 24, older than MCNS, which is primarily pediatric, but younger than MGN, which strikes primarily those over 40 years of age. Risk factors for FSGS include HIV, heroin use, a family member with FSGS, and a state of chronically overworked kidneys present with chronic conditions such as morbid obesity and diabetes.3
While FSGS is usually considered idiopathic, known causes for it include infection, toxicity, obesity, and genetic mutations. Significant injuries to the parenchymal tissue of the kidney will result in a loss of functioning renal mass and produce a state of hyperfiltration. The remaining, functional nephrons that are struggling to maintain a normal level of filtration are susceptible to FSGS injury. While obesity increases the demands placed on the kidney, it uncommon as a cause of FSGS. Higher rates of obesity do not explain higher rates of FSGS.1
A predisposition to FSGS may begin in utero, as impairment in the process of nephrogenesis will result in fewer layers of nephrons within the kidney and a reduced renal mass. Kidney size is consistently proportional to birth weight, and a low birth weight can be an indicator of reduced filtration capacity. Renal mass later in life will not correspond to filtration capacity, as a reduced number of nephrons will cause glomerulomegaly, as enlargement of the nephrons is a compensation. There is an inverse relationship between the number of nephrons and their size, and enlarged nephrons are susceptible to podocyte erosion and sclerosis.5
It has been suggested that FSGS is actually a progressed form of MCNS, as childhood MCNS may become FSGS.6 Both FSGS and MCNS are associated with TH1 immunity, whereas IgA nephropathy and MGN are associated with a TH2 immune response. The primary difference between MCNS and FSGS is that MCNS does not leave a scar and the nephron can revert to a healthy form while FSGS by definition causes scar tissue. Typically MCNS is responsive to steroid treatment where FSGS generally is not.
Genetic factors associated with FSGS include HLA DR4, a mutation of NPHS2 which codes for podocin and a mutation of ACTN4 which codes for actinin, a structural protein found in the podocyte.3 Immune dysregulation is common in FSGS patients and higher IgG/IgM ratios are found in patients who respond to therapy compared with those who do not.7 Permeability factor, a low molecular weight protein, is also believed to induce proteinuria and injury to the nephron.8
Environmental influences and infection may also predispose toward FSGS. Exposure to free radicals may also be a factor in FSGS, as the albumin leaking through the glomerulus has undergone massive oxidation.9 Another factor may be low vitamin D levels, which are implicated in many autoimmune conditions and may explain the predilection of those with African ancestry toward ESRD, as an increase of melanin requires greater sunlight exposure to maintain adequate vitamin D levels.10
One of the more controversial hypotheses for the origin of FSGS is Simian virus 40 (SV40). In one study 41% of FSGS patients presented with SV40 on cell cultures. SV40 is known to have entered the human population through contaminated vaccines.11 Once infected, the human kidney can become a reservoir for the virus.12
Recently, a group of renal pathologists proposed a standardized pathologic classification system for FSGS. Five categories were defined: collapsing variant of FSGS, tip lesion variant of FSGS, cellular variant of FSGS, perihilar variant of FSGS, and FSGS not otherwise specified (FSGS NOS). The categories of FSGS are used as prognostic indicators, and one patient can show qualities of more than one variant. Of these types of FSGS, the collapsing variant, which is more common among African Americans, has the worse prognosis of them all. 86% percent of patients diagnosed with the collapsing variant of FSGS will proceed to end stage kidney disease and only 14% of these patients will achieve remission.13
Tip lesion FSGS is less likely to affect African Americans, and although it generally causes severe nephrotic syndrome, kidney function is less severely impaired than with other types. Perihilar FSGS, in contrast, presents with less severe nephrotic syndrome but is more likely to show hypertension. Achieving remission with perihilar variant is difficult but kidney function was better preserved. No conclusions have been drawn on the typical course of cellular variant FSGS as it has a low prevalence, while FSGS NOS often shows a clinical course similar to perihilar.13
Another variant of FSGS appears to be C1q nephropathy. Noted for dominant or co-dominant immunofluorescence staining for C1q on a renal biopsy, C1q nephropathy appears to be on the spectrum of MCNS/FSGS. Of 19 biopsies with C1q nephropathy, 17 were determined to be FSGS and two were MCNS. Those patients with tubular atrophy and interstitial fibrosis had the highest rate for reaching ESRD.14
The signs and symptoms of FSGS are the same as any other form of nephrotic syndrome. The patient usually first notes dependent edema, often with swelling of the periorbital area upon awakening. There will be foaminess to the urine with proteinuria and hypoalbuminemia. Low body temperature and chronically feeling cold are common, as a loss of binding globulin in the urine will lower levels of T4 and T3.15 Severe hypercholesterolemia and mildly elevated blood pressure are also typical. Over time there will be bone degeneration, muscular atrophy, increased platelet aggregation, and compromised immunity. As renal replacement therapy is routinely available, the cause of mortality for most of these patients will not be renal failure but secondary heart disease.
For many FSGS patients, renal failure is not the end of the disease for them. FSGS recurs in transplanted kidneys about 30% of the time, sometimes within hours of implantation.16 For those who have had a first transplant fail to FSGS, the rate of recurrence in subsequent transplants is even higher. Factors associated with risk of recurrent disease include: mesangial proliferation in native kidneys in children, an older kidney donor, and rapid progression of the disease to end stage. Surprisingly, a bilateral nephrectomy of native kidneys prior to transplantation does not prevent the spread of FSGS from the native kidneys to the graft, but instead is associated with an increased risk of recurrent FSGS posttransplant.17
Posttransplant FSGS is not only a concern for those who lost their native kidneys to FSGS but de novo FSGS also occurs in grafted kidneys. De novo FSGS can be associated with the nephrotoxicity of cyclosporine or sirolimus, but may simply occur under hemodynamic stress in a kidney in a state of hyperfiltration.18 Recurrent FSGS is typically more virulent than de novo although both will lead to graft failure.19
Conventional treatment for FSGS typically involves an initial 8-week course of prednisone; however, only 20% of FSGS patients will respond to steroids. The next step is usually immunosuppressive therapy with calcineurin inhibitors, cyclosporine or tacrolimus. Despite the nephrotoxicity of these agents, many patients experience a marked reduction in proteinuria. However, patients often become dependent on these medications and relapse after discontinuation of therapy.8
Other immunosuppressive therapies used for FSGS include sirolimus, mycophenolate mofetil, rituximab, and cyclophosphamide. Sirolimus is of limited use for FSGS. Despite some initial evidence that it may be beneficial, sirolimus worsened GFR and did little to improve proteinuria. Mycophenolate mofetil may be of use to patients who do not respond to calcineurin inhibitors and shows promise of reducing proteinuria.8 Rituximab has shown some promise with pediatric FSGS, but in a study with adult FSGS only 3 out of 8 patients responded to rituximab.20 Cyclophosphamides have been used for several decades for FSGS, but side effects of these medications are often severe and the use of cyclophosphamides has largely been replaced with calcineurin inhibitors.
Besides immunosuppressive therapy, conventional treatment also includes blood pressure management and addressing dyslipidemia. Supportive therapy with ACE inhibitors and ARBs can take some stress off the kidneys and decrease proteinuria. Statin drugs such as Lipitor are often used to manage the hypercholesterolemia that accompanies nephrotic syndrome.8
An increasingly common approach to FSGS is plasmapheresis, although it is mainly used to treat recurrent FSGS in transplants rather than in native kidneys. Despite the fact that the permeability factor that incites proteinuria has never been identified, this method of blood purification has shown promise in improving proteinuria. It works best when initiated early, even prophylactically prior to implantation.21
Despite the many treatment options available for FSGS, the disease process is usually only slowed as it advances toward renal failure. Given the poor prognosis, natural medicine has much to offer the FSGS patient with supportive therapy. The author was given a prognosis of renal failure within 2 years of the onset of symptoms, but extended that time to 5 years with the use of natural medicine. (The author was not a naturopathic doctor at that time, only a layperson experimenting.) When FSGS returned immediately after transplant therapy, the author used her research as a naturopathic student to support the new kidney. Graft failure was predicted in a matter of months, but the transplant lasted 6 years in spite of recurrent FSGS.
One of the most promising natural agents for FSGS is Ganoderma lucidum (reishi mushrooms). In a 2004 study, 14 patients who were unresponsive to conventional therapy were treated with Ganoderma and all 14 responded. Proteinuria and endothelial cell toxicity were successfully suppressed in all patients. There was also a restoration of cytokine balance.22 Please note that Ganoderma is not safe for transplanted kidneys and all herbal medications should be presumed unsafe for transplants until proved otherwise.
Another promising agent is antroquinonol, an extract from a mushroom that grows on the camphor tree in Taiwan. Antroquinonol is known to inhibit nitric oxide production and inflammatory reactions. In a 2011 study it was found to attenuate proteinuria and podocyte injury, and reduced oxidative stress, leukocyte infiltration and fibrosis.23
In practice the author uses a variety of anti-inflammatory agents to decrease proteinuria. The efficacy of these agents will quickly become apparent to patients as they notice a marked decrease in the foaminess of the urine. Fish oil is often effective in suppressing proteinuria. EPA/DHA fish oil is preferred, as cod-liver oil may have excess vitamin A and krill oil has a larger amount of phosphorus. Bromelain and quercitin can also help reduce proteinuria. Curcumin is especially useful as an anti-inflammatory and has been demonstrated to support a kidney in a state of hyperfiltration.24
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