Blog from the Guest Lecture Series at East Carolina University – Brody School of Medicine

Lecturer: Gerald Appel, MD
Blogger: Tejas Desai, MD

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Calcification in Chronic Kidney Disease – What’s New in Phosphate Binders?

Dr. Appel started with the NEJM article from 2010. This article reviewed oral phosphate binders in CKD. Historically, phosphate binders were used to control hyperparathyroidism, but recent data now strongly suggests that phosphate binders should be used to mitigate vascular calcification. Vascular calcification corresponds to increased death and may correspond to the use of calcium-based phosphate binders. Thus far, there are no randomized trials that show that lowering phosphate increases survival — it is simply a correlation.

The DCOR study (n = 2100 patients) is the only study that had sufficient power to detect a difference in mortality based on the type of phosphate binder used. This study compared sevelamer against calcium-based phosphate binders (calcium carbonate or calcium phosphate). Primary analysis revealed no significant difference in mortality. Dr. Appel believes that the secondary analysis showed (rather than suggested, as the article states) that sevelamer is superior in patients over the age of 65. If you received a calcium-based phosphate binder, your survival (at the end of 3 years) was no different than if you received sevelamer. However, in patients over age 65, calcium-based binders had a higher mortality than those taking sevelamer. Unfortunately, the DCOR study can be interpreted in many ways, depending on which end points you choose to believe, especially because conclusions can be based on economics.

In the US, dialysis patients spend about 13 days hospitalized per year (data from the NKF meetings in Orlando in 2009). In a secondary analysis of the DCOR Trial, 10% less hospitalizations per year and 12% less hospital days per year occurred in the sevelamer group. In other words, one would avoid 119 hospital days if 75 dialysis patients were on sevelamer than a calcium-based phosphate binder. Extrapolated to the entire US population on dialysis (n = 360,000), we would avoid 581,000 hospital days and maintain 249,000 in-center dialysis days. Financially, for a dialysis unit, sevelamer would be the better phosphate binder.

The conclusion of the 2010 NEJM article was that a calcium-based phosphate binders are recommended as first line agents because they are the least expensive. Dr. Appel believes that avoiding hospital days and maintaining in-center dialysis days would be more cost-effective. In addition, he believes the litmus test in deciding on which binder to use should be based on what we would choose for a family member.

Dr. Appel turned his attention to binder characteristics. Calcium carbonate and acetate are effective but are absorbed, contribute to the calcium-phosphate product, and have no lipid-lowering effect. Calcium-magnesium combinations are also used, but not widely. Lanthanum is absorbed and is accumulated in the bone (see 2010 NEJM article). Sevelamer is effective, not absorbed, lowers lipids (up to 30% LDL lowering), and does not contribute to the calcium-phosphate product. However, lipid-lowering is not likely to mitigate mortality (see 4D, AURORA, and SHARP Trials).

Phosphate binders have also been studied in in non-dialysis CKD patients. 1000 VA patients were investigated over 3 years — treatment with phosphate binders in CKD III and IV patients was associated with lower mortality. Dr. Appel believes this is the future in phosphate binders: starting early to prevent the long-term vascular calcification damage seen in CKD V and ESRD patients.

Renvela versus Renagel in slowing the progression of CKD: renvela raises the bicarbonate because it is bicarbonate-based. A RCT of 134 patients with CKD and bicarbonate 16-20 mEq/L were given bicarbonate and the rate of decline of creatinine clearance was slower than in the control group. 9% of the renvela group had rapid progression to ESRD versus 45% in the control group. Experimental data in animals suggest that sodium bicarbonate acts on endothelin in interstitial cells and interstitial fibrosis.

In a study by Don Wesson in KI in 2010, patients with hypertensive nephropathy were randomized to receive either, placebo, sodium chloride, or sodium bicarbonate for 5 years. 40 patients in each arm, 66% were African-American. All arms achieved equal BP control. Sodium bicarbonate slowed progression of CKD the most (less albuminuria, lower urinary endothelin levels, lower cystatin C levels, and lower creatinine decline). Simply administering bicarbonate, regardless of whether you raise the serum bicarbonate level, can slow the progression of CKD.

Both PTH and FGF-23 increase in early CKD. FGF-23 is produced by osteocytes and is a phosphaturic hormone. It blocks the reabsorption of phosphate in the proximal tubule and downregulates production of 1,25 vitamin D. Higher FGF-23 levels correlate with vascular calcification, CKD progression, and mortality. In a 6-week study of 40 patients with CKD III or IV using calcium acetate or sevelamer, sevelamer lowers PTH and FGF-23 more than calcium acetate.

Updates in Glomerular Disease

In this portion of the presentation, Dr. Appel focused on studies presented at the ASN as well as studies coming out of the Glomerular Center at Columbia University.

Lupus Nephritis — Induction Therapy
The ALMS Trial looked at 370 patients who had either aggressive WHO class III or IV. It was an international study, with 33% of patients from China, 33% in South America and Europe, 33% from the US. The goal was to determine if mycophenolate could be used as induction therapy, when compared against cyclophosphamide. At the end of 9 months, patients who responded were re-randomized to maintenance therapy with either mycophenolate or azathioprine (The ALMS-Maintenance Trial; yet unpublished).

Mycophenolate and IV cyclophosphamide were equivalent as induction therapy modalities in every renal and non-renal biomarker. Superiority did not need to be shown in the mycophenolate group because of the significant toxicities from IV cyclophosphamide.

Only 14 deaths in 370 patients. Six of the nine deaths were in a single center in China. There were no deaths in the mycophenolate group in Europe and the US. All other adverse events were non-significant.

Lupus Nephritis — Maintenance Therapy
The ALMS Maintenance trial (unpublished) looked at all responders to the induction therapy – 227 patients in total. Regardless of the induction therapy used (mycophenolate or IV cyclophosphamide), patients were randomized to azathioprine or mycophenolate for 3 years. Patients in the mycophenolate group had a significant less rate of treatment failure (double with the azathioprine group). Renal flares and creatinine doubling were higher in the azathioprine group. All end points were improved in the mycophenolate group. Failure to respond in the maintenance phase with azathioprine was 32% versus 16% in the mycophenolate group. The superiority of mycophenolate did not depend on the type of induction therapy used or the racial background of the patient.

One death in 227 patients in the ALMS-Maintenance Trial was in the azathioprine group from an automobile accident.

IgA Nephropathy – Pathophysiology
A large number of patients with this disease have an abnormal IgA molecule. The defect occurs at the hinge region — patients have less galactose residues at this region of the molecule. Most IgA patients have galactose-deficient IgA molecules. However, simply having this deficiency is not sufficient to make the diagnosis currently.

One main question is how much the biopsy findings contribute to the prognosis of IgA nephropathy. Currently, the new classification of IgA nephropathy uses the Oxford Classification. A summary of the Oxford Classification is below:

  1. mesangial hypercellularity – 0 (absent) or 1 (present) point
  2. endocapillary proliferation – 0 or 1 point
  3. segmental sclerosis – 0 or 1 point
  4. tubulointerstitial fibrosis – 0, 1, 2 points
  5. crescents did not matter because the pathologists could not agree

The higher the score, the worse the prognosis. At Columbia, tubulointerstitial fibrosis was the most important pathologic finding that influenced prognosis; proteinuria was the most important clinical finding that influenced prognosis.

IgA Nephropathy – Therapy
Steroids work in IgA nephropathy. A Chinese study looking at 63 patients from age 18-65 with at least 1 gram of proteinuria and an estimated GFR at or above 30 cc/min were given a 6-month tapering dose of prednisone with ACE-inhibitor versus ACE-inhibitor alone. The former group had a lower rate of 25% GFR decrease and 50% increase in creatinine and a greater reduction of proteinuria.

In an Italian study, 97 patients with over 1 gram of proteinuria were given ramipril versus ramipril + prednisolone for 6 months. At the end of 8 years, 1 patient of 48 developed ESRD in the prednisolone group versus 8 of 49 patients in the ramipril-only group. Eight-year renal survival in the prednisolone group was 97% versus 70% in the ramipril-only group.

At Columbia, patients with over 1 gram of proteinuria received every-other-day steroids at 120 mg x 2 months, 100 mg x 2 weeks, 80 mg x 2 weeks, 60 x 2 weeks, then 40 mg until 6 months were over (in total). Twenty-five patients were assessed using this regimen. The entering creatinine was the most important factor in determining if steroids would work. There is a “point of no return” beyond which steroids will not lead to remission. Dr. Appel is now thinking about starting steroids at 500 mg of proteinuria rather than waiting for 1 gram of proteinuria and worsening renal function. (This data will be presented at the International Society of Nephrology Meetings in Vancouver, 2011).

A randomized trial conducted by Dr. Appel looked at mycophenolate versus placebo in IgA nephropathy & showed no difference in progression to ESRD or rate of worsening renal function. The average entry creatinine was 2.4 mg/dl, suggesting that there is a true “point of no return”. (Citation: J Am Soc Nephrol. 2003;14:753A).

Focal Sclerosis
Myosin heavy chain 9 (MYH9) is a protein found in the podocytes. Patients with HIV nephropathy and focal sclerosis have a large amount of MYH9. African-Americans with focal sclerosis have the abnormal MYH9 (e1 allele) compared to African-Americans that are normal. However, the genetic predisposition for focal sclerosis is not MYH9, but the apolipoprotein 1 gene (chromosome 22) adjacent to it. Apolipoprotein 1 confers resistance to African trypanosomiasis (sleeping sickness). It is thought that focal sclerosis originated from a location in Africa where trypanosomiasis is endemic. Therefore, the leading theory on why African-Americans have a high predisposition for developing focal sclerosis is that there is a genetic protective measure against an infectious illness; similar to what one sees with sickle cell anemia and malaria. It is not known what apolipoprotein 1 does to predispose patients to focal sclerosis.

An NIH trial of 138 patients, 97% of patients under the age of 19, were randomized to cyclophosphamide or mycophenolate if steroids failed to improve focal sclerosis. There was no difference in therapy. All 138 patients underwent genetic testing; the results are pending.

Membranous Nephropathy – Pathophysiology
One of the largest questions is the content of the electron deposits in membranous nephropathy. Most patients diagnosed with membranous undergo a rigorous malignancy workup, which will no longer be the case in the future.

The phospholipase A2 receptor is the antigen in the electron deposits. Patients with idiopathic membranous nephropathy have IgG4-phospholipase A2 complexes in the basement membrane. Dr. David Salant’s work shows that 70-80% of patients with idiopathic membranous nephropathy have circulating antibodies against phospholipase A2, where as patients with secondary membranous have 0% antibodies. Therefore, if patients have antibodies against phospholipase A2, regardless of their age, they most likely have idiopathic membranous and an extensive tumor workup is not needed. This test is anticipated to be available in 2012.

Phospholipase A2 can be followed over time to determine the course of membranous.

Dense Deposit Disease (type II membranoproliferative GN)
DDD is due to activation of the alternate complement pathway. Anti-C5 antibody blocks the alternate pathway and development of the membrane attack complex. In Italy, there is one patient who has been successfully treated and 6 patients at Columbia who are improving. Anti-C5 antibody is already FDA-approved for paroxysmal nocturnal hemoglobinuria, in which it blocks the alternate complement pathway.

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