Oral Galactose in Children With Steroid Resistant Nephrotic Syndrome
Condition: Focal Segmental Glomerulosclerosis; Steroid Resistant Nephrotic Syndrome
MeSH terms: Nephrotic Syndrome; Nephrosis; Glomerulosclerosis, Focal Segmental; Syndrome
Study type: Interventional

Summary: 
      Focal Segmental Glomerulosclerosis (FSGS) is a devastating kidney disease which is difficult
      to treat and carries a poor prognosis, with 50% of affected children progressing to end stage
      renal disease (ESRD). The purpose of this study is to investigate oral galactose as a benign
      treatment for FSGS in children. The investigators hypothesize that galactose, a simple milk
      sugar thought to bind to the protein factor (FSPF) that causes FSGS thereby inactivating it
      and stopping it from damaging the kidney, resulting in a reduction in glomerular permeability
      to albumin and decrease in proteinuria in children with nephrotic syndrome secondary to FSGS.
    

Detailed description: 
      RESEARCH PLAN

      A: Primary aims:

        1. Determine the effect of 4 months of oral galactose administration on the level of FSPF
           in children with steroid resistant FSGS

        2. Determine the effect of 4 months of oral galactose administration on the first morning
           urine protein to creatinine (urine protein: creatinine) ratio and serum albumin level in
           children with steroid resistant FSGS.

      B: Secondary aims:

        1. Determine the effect of 4 months of oral galactose administration on dose of
           immunosuppressive medication.

        2. Assess first morning urine protein: creatinine ratio, serum albumin level, and change in
           immunosuppression dose at 3 months after discontinuation of oral galactose therapy.

      B.Background and Significance

      Idiopathic nephrotic syndrome (NS) in children is most commonly due to minimal change
      nephrotic syndrome and can be successfully treated with steroid therapy. However 10-15% of
      children with nephrotic syndrome are diagnosed with FSGS, which is resistant to steroid
      therapy and many other immunosuppressive drugs, and is associated with poor outcome.
      Approximately 50% of patients with FSGS progress to ESRD within 5-10 years and in about 30%
      of children, FSGS can recur after transplantation.(1) African-American children are at
      significantly higher risk for FSGS.(2) Recent studies indicate that primary FSGS is a
      heterogeneous disorder caused by genetic mutations in nearly a third of cases and as yet
      undefined immunological defects in the remaining cases.(3) Immune mediated FSGS has been
      associated with a circulating permeability factor, which is thought to increase glomerular
      permeability to albumin, leading to proteinuria and contributes to sclerotic lesions in FSGS.
      Presence of the FSPF is defined as permeability activity >0.5. (4) Current therapies for FSGS
      include plasmapheresis and many immunosuppressive agents that include cyclosporine,
      tacrolimus, mycophenolate mofetil, rituximab, and drugs that decrease proteinuria such as
      angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) with
      inconsistent outcome. Additionally, these drugs have long-term consequences of
      immunosuppression and some drugs such as cyclosporine and tacrolimus affect renal function
      adversely when used for prolonged periods of time. (5) There is an urgent need for
      investigating benign therapies such as galactose. If proven to be useful, it may present a
      safe alternative or an adjunct to currently available therapies.

      Preliminary Studies:

      1. In 2008, Savin et al. showed that galactose, a simple nontoxic sugar, binds with high
      affinity to the FSPF in vitro.(6) They also found that trace amounts of galactose (>10-12 M)
      inhibited glomerular permeability activity induced by FSPF in vitro. This series of in vitro
      experiments also demonstrated that the effect of FSPF activity in serum can be reversed by
      its incubation with galactose or alternatively by pre-incubation of glomeruli with galactose.
      Additionally, the authors describe significantly decreased permeability activity in vivo in a
      single patient with post-transplant FSGS in response to both IV and oral galactose. The FSPF
      activity in this patient decreased progressively during the 4 weeks of galactose ingestion
      (from 0.8 to 0.1), and persisted 4 weeks after discontinuation of oral galactose (0.2). The
      proposed mechanism for this action is that FSPF have galactose-binding sites which interact
      with galactose of the glomerular glycocalyx, activating signal transduction in podocytes.
      Introduction of free galactose may block the FSPF binding sites or alter the tertiary
      structure of the FSPF, thus inhibiting its activity.

      Despite the decrease in FSPF activity in this patient, proteinuria did not improve. The
      authors propose the lack of clinical response may be due to the advanced stage of kidney
      damage at the time of IV galactose therapy, and this patient was already on dialysis at the
      time of oral galactose administration.

      It would be important to study the introduction of galactose early in the course of FSGS to
      determine if it is effective in decreasing proteinuria and delaying the progression of FSGS.

      De Smet et al presented their experience with a case of 48-year old male, with nephrotic
      syndrome secondary to FSGS, treated with oral galactose at 10 gm BID for 6 months, at the
      annual meeting of American Society of Nephrology 2008 (ASN 08, TH-PO-955). Their patient had
      failed to respond to prednisone, cyclophosphamide, mycophenolate mofetil, cyclosporine and
      plasma exchanges. Prior to treatment, the FSPF was detected at 0.87 and urinary protein
      excretion was 4.3 gm/day. After treatment with galactose, the FSPF decreased to 0.09 and
      urinary protein excretion decreased to 0.56 gm/day. The success obtained in this case argues
      for trial in additional patients.

      Methods:

        1. Oral galactose therapy: After obtaining informed consent and assent FSPF will be
           obtained at a baseline to determine eligibility. Blood samples for FSPF will be
           collected in a "red-top" tube (without anti-coagulant), allowed to clot, then spin and
           separate. The serum will be shipped on ice for FSPF analysis to the laboratory of
           Virginia Savin, Medical College of Wisconsin, Milwaukee, WI. All other parameters
           (including weight, height, blood pressure, urinalysis, urine protein: creatinine ratio,
           serum albumin, creatinine, electrolytes, and glucose) will be collected at the same
           visit as part of standard of care. Female participants of child bearing age will be
           given a urine pregnancy test and excluded from the study if pregnant.

           Once patients are found to be eligible, oral galactose will be initiated at a dose of
           0.2gm/kg/dose BID to a maximum of 15 gm BID for a period of 4 months. The prescribed
           dose of galactose powder will be dispensed to subjects in packets, mixed with 4 ounces
           of water, and consumed orally. FSPF will be measured again at week 16. All the other
           parameters will be repeated at 4, 10 and 16 weeks after starting oral galactose. Oral
           galactose therapy will be stopped after 16 weeks. In order to determine the clinical
           significance of the galactose treatment, a set of clinical parameters (weight, height,
           blood pressure, urinalysis, first morning urine protein: creatinine ratio, serum
           albumin, creatinine, electrolytes, and glucose) will be obtained at 12 weeks after
           discontinuation of oral galactose. Measurement of adherence with galactose will be
           estimated by counting the number of galactose doses returned at each subsequent monthly
           visit. Patients will be considered adherent if they have taken >90% of the prescribed
           doses.

        2. Adjunct therapy of nephrotic syndrome: Each patient will remain on his or her baseline
           therapy immunosuppressive therapy with cyclosporine, tacrolimus or mycophenolate
           mofetil. Steroids dose will be tapered to 0.5mg/kg, to a maximum of 40 mg, every other
           day at the time of starting galactose. If patient achieves remission, as indicated by
           negative first morning urine for protein for 3 consecutive days, alternate day steroid
           therapy will be tapered by 0.12mg/kg/dose or by 10 mg/dose, once per week. If patient
           has sustained remission for 1 month, and is off prednisone, the dose of
           immunosuppressive drugs will be lowered by 25% per month until off. BP will be
           controlled to below 95th percentile for height. If patient is on ACE inhibitors or ARBs,
           the dose will stay unchanged during the duration of galactose administration unless
           patient is experiencing side effects of therapy. If additional therapies for control of
           hypertension are needed, they would be chosen from the antihypertensive drugs other than
           ACE inhibitors and ARBs. Diuretics will be prescribed as needed for the symptomatic
           relief of edema. Adjunct therapy medications described in this section are standard of
           care and are not for research purposes.

      Result analysis:

      Each patient will serve as its own control. Results will be considered clinically significant
      if the following criteria are met in response to oral galactose therapy at week 16 and if the
      reduction in urine protein: creatinine and the increase in serum albumin persist at 12 weeks
      after discontinuation of galactose.

        1. Reduction in FSPF to <0.5 or decrease in FSPF by > 0.3

        2. Decrease in first morning urine protein: creatinine ratio by 50%

        3. Increase in serum albumin by >1gm/dl

        4. Decrease in dose of prednisone or other immunosuppressive drugs by 25% Statistical
           Analysis The primary outcomes are the means of paired pre vs. post galactose treatment
           differences in FSPF, urine protein: creatinine ratio, serum albumin and dose of
           immunosuppressive drugs. We will use repeated measures ANCOVA models to estimate each
           primary outcome as the dependent variable while holding constant pre-treatment levels.
           Therefore, the independent variable will be the pre-treatment level of the corresponding
           dependent variable, The model will be used to estimate the mean difference +/- the 95%
           confidence interval (CI) corresponding to the mean level of the dependent variable at
           pre-treatment. We will consider the pre-post difference to be statistically significant
           if the 95% CI around the result fails to include 0 and to be clinically significant if
           it meets the criteria specified above.

      Adequacy of the Sample: We evaluated the effect size difference that could be detected with
      80% and 90% power in a pre-post treatment study of galactose involving 10 patients assessed
      pre-treatment and post-treatment. The correlation between measurements on the same person was
      assumed to be .7 and the two-tailed type 1 error was set at 0.05. The study will have better
      than 90% power to detect effect size differences of 0.6 sd and better than 80% power to
      detect effect size differences of 0.5 sd. These are considered to be moderate effect sizes.

      Research Facilities: The FS permeability factor will be tested in the laboratory of Virginia
      Savin MD (Center for Glomerular Pathophysiology, Medical College of Wisconsin, Milwaukee, WI)
      using previously described methods.(7)

      Risks and Side Effects:

      FSGS is a difficult to treat disease associated with poor outcomes, including progression to
      end stage renal disease. Galactose is a naturally occurring simple sugar and oral galactose
      supplementation has no known side risks or side effects in humans. Patients eligible for this
      study are those who have failed to respond to the current alternative treatments for FSGS,
      which include steroids and other immunosuppressive agents, such as cyclosporine, tacrolimus,
      mycophenolate mofetil, and rituximab. These alternative immunosuppressive treatments have
      many long term complications, some of which include stunted growth, nephrotoxicity,
      hyperlipidemia, and diabetes. There is an urgent need for investigating benign therapies such
      as galactose, which may present a safe alternative or an adjunct to current therapies.

      There are no known side effects of oral galactose supplementation and no reports of toxicity
      with chronic use in humans. The Certificate of Origin for the D-Galactose product from
      FerroPfanstiehl is included in the Appendix and certifies that the D-Galactose to be used in
      our study is safe for human consumption.

      D-Galactose is administered safely in diagnostic testing for both glycogen storage disease
      and cirrhotic liver disease (8) and as sonographic contrast agents, such as Levovist ®
      (Bayer). Galactose has also been successfully administered as a treatment in Fabry's disease.
      (9) In this case report, IV galactose infusions were administered at a dose of 1 g/kg every
      other day for 2 years during which time liver function tests remained normal. Possible
      associations between dairy intake and ovarian cancer has been investigated with inconclusive
      results. A 2006 pooled analysis of 12 cohort studies done by Harvard School of public health
      found no association of intake of dairy foods with ovarian cancer and a statistically
      insignificant increase in risk of ovarian cancer at intakes of lactose > 30 g/d. This study
      involved analyzing surveys of reported dairy intake, but did not account for the presence of
      other factors in milk, such as hormones, that could contribute to ovarian cancer risk (10).
      Another 2005 meta-analysis in the European Journal of Cancer Prevention found no association
      between milk/dairy products or galactose metabolism and ovarian cancer risk. (11) In addition
      to occurring naturally in milk, galactose has been approved by the FDA as a substance
      Generally Recognized as Safe (GRAS) as an ingredient in infant formula and other baby foods
      and pediatric nutrition supplements in the form of galacto-oligosaccharides (a compound made
      of 1 to 7 galactose molecules linked to a glucose molecule at the reducing end).
      (www.fda.gov/food/foodingredientspackaging/generallyrecognizedassafeGRAS/GRASListings/ucm1539
      10.htm)

      Benefits:

      FSGS is resistant to steroid therapy and many other immunosuppressive drugs, and is
      associated with poor outcome. Approximately 50% of patients with FSGS progress to ESRD within
      5-10 years and in about 30% of children, FSGS can recur after transplantation.(1) Given the
      devastating course of this disease and the benign nature of the proposed galactose treatment,
      the anticipated benefits far outweigh the risks. If effective, galactose supplementation
      could stop the progression of FSGS, limiting glomerular damage and preventing progression of
      the disease to ESRD. The potential benefit of preserving kidney function and preventing the
      need for dialysis or transplantation is significant for both participants in this study and
      for other children with FSGS who may benefit from galactose therapy in the future.
    

Intervention name(s): D-Galactose
Intervention type(s): Drug
Intervention description(s): Oral galactose will be initiated at a dose of 0.2gm/kg/dose twice daily to a maximum of 15 gm BID for a period of 4 months. The prescribed dose of D-galactose powder will be dispensed to subjects in packets, mixed with 4 ounces of water, and consumed orally.
Other intervention name(s): Galactose
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Nephrotic syndrome; Focal Segmental glomerulosclerosis; FSGS; Minimal change; Steroid resistant; Pediatric; Proteinuria; Galactose; FSPF