Daily Blog from the NKF’s Clinical Meetings in Orlando, FL

Day 5

IgA Nephropathy

Presenter: Gerald Appel, MD (Columbia University – New York Presbyterian Hospital)
Reporter: Hsiao Lai, MD (East Carolina University)

Stronger recommendation for use of steroids along with ACEi/ARB/salt restriction in patients presenting with abnormal renal function, significant proteinuria and/or concerning biopsy (50 %+ crescents), or in patients with normal renal function with persistent proteinuria following ACEi/ARB therapy of 3-4 months. CSA not recommended based on current data. One study showed a benefit with MMF, second study showed negative effect — as a result, no strong recommendation at this point.

He recommends the use of the Oxford Classification for IgA for grading pathologic findings, but did not associate specific therapy plan or interpretation with score range, so I am not sure how clinically useful this is aside from reminding us what to look at on biopsy.

Oxford Classification: Scale 0-5
Mesangial cell hypercellularity (0 if less than 50 %, 1 if greater than 50%)
Endocapillary proliferation (present = 1, absent = 0)
Segmental glomerulosclerosis (present = 1, absent = 0)
Tubulointerstitial fibrosis (50% = 2)
No criteria for crescentic disease in this classification, but should take into account if ≥50% crescents

Membranous Glomerulonephritis
Presenter: Fernando Fervenza, MD (Mayo Clinic)
Reporter: Hsiao Lai, MD (East Carolina University)

For patients with persistent proteinuria (greater than 8 grams/day):
Ponticelli protocol (Methylprednisolone + cyclophosphamide with maintenance steroids) still works! – he recommends at least a year of maintenance steroids, but smaller methylprednisolone bolus doses.

CNI’s also work, but take a longer time to achieve remission and inevitably relapse once therapy stopped.

MMF + high-dose prednisone works with same number of remissions as the Ponticelli protocol, but 90% relapse once therapy stopped. MMF monotherapy is not effective (AJKD 2007).

Rituximab: small study 20 patients who had been refractory to multiple immunosuppressive therapies had good response: 4 complete, 12 partial, 1 limited 2 failure, 1 relapse. Antiphospholipid antibodies (anti-PLA2R) levels may be a good marker of response to rituximab therapy.

Focal Segmental Glomerulosclerosis
Presenter: Jeffrey Kopp, MD (NIH/NIDDK)
Reporter: Hsiao Lai, MD (East Carolina University)

Emphasis on clinical factors: age at presentation, race and family history to see if they fit into any familial or genomic classification as this will affect response to therapy and decision to try cytotoxic therapy. Biopsy appearance can also be helpful. Tip lesions and perihilar variant tend to be responsive to steroids. Collapsing lesions- poor prognosis and should start with aggressive therapy (prednisone + CSA).

Prednisone + MMF a few pediatric studies show benefit, but no studies in adults.

Rituximab in recurrent FSGS may have a benefit.

Workup and Management of Nephrolithiasis
Presenter: Not Available
Reporter: Hsiao Lai, MD (East Carolina University)

Not much new here. Here is a quick review:

1. Calcium phosphate stones are still on rise
2. Reemphasis on salt restriction
3. HCTZ if there is a problem with hypercalciuria and normal to low serum calcium levels
4. Citrate can be used, but may increase urinary pH, unclear benefit/risk ratio
5. Reemphasis on repeated 24-hour urine collection for lithogenic factors, volume pre- and post- intervention.
6. questionable role for Renvela

Calcium Oxalate stones: dietary contribution usually small, but still should screen for excess intake of any particular food type or group. Do not restrict dietary vitamin C, but no vitamin C supplementation.

Interesting Poster Abstracts
Reporter: Hsiao Lai, MD (East Carolina University)

BARD: Bardoxolone Methyl an antioxidant inflammation modulator molecule with similarities to olive oil is being investigated in Phase2b trials in patients with T2DM and CKD eGFR 20-45 ml/min/1.73m2. BARD activates Nrf2, a transcriptional regulator, through Keap1. Nrf2 upregulates antioxidant and detoxification pathways (glutathione) and suppresses NF-κB. Preliminary data with 52 wks of treatment show dose-dependent improvement in eGFR up to 7-9 ml/min, (OR 1.38 and 1.6) with concurrent improvement in phosphorus, BUN, uric acid. –→ ?? Maybe something we could use also for IgA nephropathy?

HbA1c in CKD: it is correlated with glucose control in all stages but the strength of correlation decreases with increasing stage of CKD. They propose looking at gluc*gfr, but did not compare strength of this marker to HbA1c as far as I could tell.

Undetected MI in patients with CKD: Interesting study → they went into homes of ~20,000 people and did EKGs, labs and interviewing. Increase proportion of undetected MI (Q waves on EKG with patient denying hx of AMI) vs. detected (patient denies any knowledge of MI) with advancing stage of CKD. Higher risk of mortality associated with undetected vs. detected MI.

Day 4

ANCA Vasculitis

Presenter: Stan Nachman, MD
Reporter: Kenar Jhaveri, MD (North Shore – LIJ Health Systems — Hofstra University)

Review of Major Trials:

1. MEPEX trial: JASN 2007 showed that for patients with ANCA vasculitis and Creatinine > 5.8 and on dialysis, plasmapheresis was helpful in taking them off dialysis and for renal recovery
2. CYCLOPS trial: Large trial that compared oral vs IV cytoxan in ANCA vasculitis and there was no difference in end points for renal outcomes but there was less cumulative dose of cytoxan in IV dosing and less side effects.
3. CYCAZAREM trial: compared changing to Imuran after 6 months of induction with PO cytoxan to continuing cytoxan PO for 12 months, no difference in remission.
4. RITUXVAS:- RCT (small) IV cytoxan to Rituxan + initial 2 months of cytoxan IV — no difference in remission. More adverse events in rituxan arm
5. RAVE:- Rituxan + azathioprine for maintenance vs IV cytoxan plus azathioprine, induction part completed:- similar rates of remission and no major advantage with rituxan
6. NORAM:- compared Methotrexate in lieu of cytoxan, more relapse with Methotrexate

In terms of maintenance, two trials, one comparing MMF to AZA showed AZA to be safer and less side effects.

In summary and in my opinion, the best treatment is IV cytoxan for 6 months followed by AZA maintainance.

(See also: The Netherlands Journal of Medicine 2010, Volume 68, No. 2, 62-7)

Tumor Lysis Syndrome
Presenters: Ali Abu Alfa, MD; Ahsan Ejaz, MD; Scott Howard, MD
Reporter: Kenar Jhaveri, MD (North Shore – LIJ Health Systems — Hofstra University)

Take home points:

1. A new definition of TLS has been developed using the Cairo – Bishop criteria. The patient has to meet 2/4 laboratory criteria and 1/3 clinical criteria.
The criteria are:

Lab–> Uric acid > 8 or 25% increase from baseline, K > 6 or 25% increase, Phos > 4.5 and calcium < 7 and again 25% change from baseline

The clinical criteria:–Creatinine greater than 1.5, cardiac arrythmia and seizures

2. Pathogenesis:- Uric acid nephropathy, non-crystal related uric acid disease, calcium phosphate crystals and volume depletion
3. An old tool to help diagnose was urine uric acid/creatinine ratio greater than 1.0
4. If Urine pH is too low, you form uric acid related damage; if too high, calcium phosphate related damage
5. NaHCO3 infusion has no role as such given point 4 and is not recommended.
6. Forced diuresis is allowed as long as patient is euvolemic
7. Patients can be stratified as to the likelihood of developing TLS and AKI based on pretreatment levels of uric acid:

a. Low risk patients:- Clinical judgement and fluids, no potassium/phosphate reduction
b. Medium risk patients:- same as above + daily oral allopurinol
c. High risk patients:- same as above + rasburicase x 1 w/wo hemodialysis

Day 3

Diabetic Nephropathy

Presenter: Multiple
Reporter: Hsiao Lai, MD (East Carolina University)

This was a nice review and interpretation of studies regarding the use of ACE-inhibitors, ARB’s, and strict glycemic control.

Studies that address the use of ACE-inhibitors or ARB’s for the prevention of diabetic nephropathy:


The speakers concluded the following from the data presented in the aforementioned trials: There is no proven benefit in decreasing mesangial volume or preventing microalbuminuria in most cases. Although these drugs do ameliorate retinopathy. The only exception is trandolapril, which may prevent the development of microalbuminuria.

ARB’s and ACE-inhibitors can prevent progression to overt nephropathy and a greater benefit may be seen in higher doses. The IDNT trial suggested no benefit but rather more progression of hypertensive nephropathy by using ARB’s or ACE-inhibitors versus diuretics. However, this trial did not measure proteinuria.

Intensive glycemic control (to a hemoglobin A1c of less than or equal to 6.5%) in th elderly population had no benefit compared to standard controls and may indicate a greater risk of cardiac events and all-cause mortality. The speakers attribute this to a higher incidence of hypoglycemia. They recommended to adhere to current guidelines. In earlier stages of diabetes and in younger patients there may still be a benefit for intense glycemic control — this was shown in a small United Kingdom study, but admittedly, more studies are needed.

Massey Distinguished Lecture – Bundling of Services
Presenter: Allan Collins (University of Minnesota)
Reporter: Hsiao Lai, MD (East Carolina University)

Key Points Before Bundling:

Dialysis procedure and staff fee,
Standard dialysis labs, and
All other externals billed separately

Key Points After Bundling:

Extended labs,
EPO, IV iron, oral iron, and vitamin D, antibiotics reimbursement changes,
Will give more reimbursement for admissions for catheter-related infections,
Sliding reimbursement over the first 3 months post-initiation of dialysis

The new bundling has areas of deficiency. Those mentioned specifically are:

CKD screening,
Stage 4 CKD education

Presidential Address
Presenter: Bryan Becker, MD
Reporter: Hsiao Lai, MD (East Carolina University)

The President addressed the goals and role of NKF, as well as the progress we have made as a nephrology community

National Kidney Foundation Goals:

1. prevention CKD,
2. improve health and well being of patient and family (patient centered)
3. increase availability of organs for transplantation

Apparently, we have made a record attendance level this year, which is 60th anniversary of the NKF.

Programs/Things to watch out for:

KEEP- Early intervention,
Healthy People 2010, and
The newest guidelines from KDIGO-2

Hot Topics – Phosphorous and Chronic Kidney Disease
Presenter: Multiple
Reporter: Hsiao Lai, MD (East Carolina University)

Speakers discussed the role of phosphorus in vascular calcification. Phosphorus is an independent predictor of increased cardiovascular disease risk even at “normal” phosphorous levels. A reduction in phosphorus is associated with a decline in cardiovascular disease risk.

The speakers support non-calcium based binders above calcium-based binders, but I would interpret this with caution. However, for patients with known vascular calcification or calcification elsewhere, non-calcium based binders may be a good alternative.

Treatment of bone disease, especially osteoporosis, is still unclear. DEXA scans are less helpful because they are less accurate with later stages CKD and ESRD. Bone biopsies done before the start of any therapy would be better than the DEXA, but there is still no good safety and efficacy data. However, if the patient is in the early stages CKD, manage them as you would other high-risk patient populations with screening tests and therapies.

Strengths and Drawbacks of Current Immunosuppressant Agents
Presenter: Ray Bloom, MD (University of Pennsylvania)
Reporter: Hsiao Lai, MD (East Carolina University)

The speaker lightly touched on current/prior regimens – and emphasized the results of three trials looking at withdrawal of Cyclosporine (CSA), Sirolimus(SRL) vs Calcineurin inhibitors(CNI), and Steroid withdrawal/avoidance regimens

CAESAR is a randomized open label European trial in which all 3 arms received IL-2R induction, and then received either looking at

1) normal CSA dosage,
2) low dose CSA, or
3) CSA withdrawal at 6 months

Although there was no difference found in graft function between the 3 arms, the CSA withdrawal arm had an increased rate of rejection.

SYMPHONY has 4 arms:

1) low dose SRL,
2) standard dose CSA,
3) low dose CSA, and
4) low dose Tacrolimus

At 12 months, there was ~40% rejection rate with SRL regimen compared to 20% in CSA arms, compared to 10% low dose tacrolimus. Also the lowest eGFR was seen in SRL arm at completion

5-year double blind randomized controlled trial with early steroid withdrawal (withdrawal at 7d vs. slow taper to 5 mg at 6 months). There was no difference in weight gain or cardiovascular profile. There was a higher rate of acute rejection in the early withdrawal arm and also increased rate of chronic allograft dysfunction. Overall, there was similar rates of graft survival in the withdrawal vs avoidance groups.

The speaker’s personal take is to avoid Sirolimus in general due to the SYMPHONY results, along with the many side effects. Something new to me was the decreased gonadocyte function found with Sirolimus use (this was mentioned by an audience member). A consensus was to use Sirolimus in very specific patients with good or fairly good graft function, low underlying immune risk, and no proteinuria.

Finally, new immunosuppresive alternates that we will be hearing about in the future include:

Everolimus: – an mTOR inhibitor; similar side effect profile to rapamycin but with shorter t1/2; possibly decreases post-transplant malignancy; as with rapamycin, increased rejection rates compared to CNI’s. FDA approval pending in 2 – 3 weeks.
Belatacept: blocks co-signal for T-cell activation; better cardiovascular risk profile and renal function than CSA; increased risk for PTLD and therefore should not be used in EBV naive patients.
Voclosporin (ISA247): new calcineurin inhibitor; structurally analogous to CSA; main side effects are hyperglycemia and hyperlipidemia; chronic allograft nephropathy is an issue with this drug.
Sotrastaurin (AEB071): protein kinase C inhibitor; problems with increased rejection rates when used in CNI-free MMF+ regimens; may be an option to lower CNI dose.

Key Point: Although we have improved our early 1-year graft survival rates and decreased early rejection rates, we have not improved t1/2 of kidney allografts. However, the presenter showed current LRD kidneys with ~15 yr lifespan which I thought was an improvement.

Day 2

Obesity and Kidney Transplantation

Presenter: Not available
Reporter: Kenar Jhaveri, MD (North Shore – LIJ Health Systems — Hofstra University)

Take home points
1. Low BMI 30 are both associated with worsening graft survival
2. Why does obesity affect transplant outcomes: The risk factors after few studies have been:

increased insulin resistance, increased BP, hyperlipidemia, increased proteinuria and development of NODAT

3. There has been a higher incidence of acute rejection in high BMI patients? The reason: obesity has been associated with mild continuous chronic inflammation and increased proteinuria.
4. Should obese patients be trasnplanted? Yes as a comparative study showing how they do on dialysis still shows they do better on transplant. Yes, when compared to non obese patients getting transplanted, the risk is low, the overall benefit vs dialysis is more.
5. Should their immunosuppresion be treated differently? No real headway. When compared steroid free vs steroid + protocols in obese patients, no difference was noted in outcomes.

HIV patients and Kidney Transplantation
Presenter: Not available
Reporter: Kenar Jhaveri, MD (North Shore – LIJ Health Systems — Hofstra University)

Take home points
1. Nice site for reference is www.hivtransplant.com
2. A large NIH sponsored study basically showed that the outcomes of large number of patients when compared to non hiv patients transplanted was no different.
3. The 3 year follow up showed no major difference in graft survival
4. HIV disease didn’t progress either, perhaps because they didn’t get induction therapy or they were carefully selected patients or there is data that almost all immunosuppresive drugs we use has anti HIV viral activity from cellcept to CNI to sirolimus
5. The major problems people run into these transplants are drug toxicities as anti retrovirals have significant effect on CNI levels and high doses of CNI and increased intervals are needed.
6. There is usually more rejection in these patients,perhaps because of point number 5, but also perhaps because they don’t get much induction
7. Some centers are using induction with thymo, but their acute bacterial infection rates are high. Ideally, a anti CD20 induction is a good choice.

Dual Liver and Kidney Transplantation
Presenter: Not available
Reporter: Kenar Jhaveri, MD (North Shore – LIJ Health Systems — Hofstra University)

1. When to do both and when to do just Liver? It’s hard to figure this out as most of the kidney damage in liver associated kidney injury is ischemia and we don’t have good markers
2. A good strategy suggested was using biopsy as a guide and using the Interstitial fibrosis, tubular injury as a tool for seeing if they need a SLK or just a liver transplant.
3. When this strategy was used in some centers, and crt compared after going ahead with a respective transplants ( SLK or just liver), crt were 1.2 at 6 months in both groups.
4. Most common biopsy finding: ischemic ATN, followed by other primary GNs, (MPGN, IgA, FSGS, TMA) and vascular disease
5. If the patient has ESLD and is on dialysis < 6 weeks, perhaps just a liver is fine but otherwise might need a SLK. But with the biopsy method, we might achieve more accuracy

Day 1

Gifford Hypertension Symposium – Novel Cardiovascular disease Biomarkers

Presenter: Stanley Hazen, MD (Cleveland Clinic)
Reporter: Hsiao Lai, MD (East Carolina University)

An interesting presentation on the use of MPO as a novel CVD biomarker. MPO has been linked to vulnerable atherosclerotic plaque development and accelerated atherosclerosis in mice. In one study researchers found the use of elevated MPO plus calcification score on Cat Scan was highly predictive of cardiovascular events.

Other markers, such as Troponin I levels or hsCRP have been found to be predictive of later CV events. Dr. Hazen proposed a 3 step potential treatment algorithm for subclinical myonecrosis and inflammation detected by a panel of:

hsCRP, MPO and Troponin I

in the setting of negative traditional clinical markers (eg LDL, troponin I less than 0.03)

MYH-9 Associated Kidney Failure in African-Americans
Presenter: Barry Freedman, MD (Wake Forest University)
Reporter: Hsiao Lai, MD (East Carolina University)

Researchers have identified MYH-9 as a common kidney failure gene through admixture mapping. Admixture mapping looks for genetic associations by comparing gene frequency in separated populations following mixing. MYH-9 is a likely etiology for rapid progression to renal failure in African-Americans with nephropathy from diverse etiologies such as HIVAN, “hypertensive or non-diabetic ESRD”, FSGS.

The investigators feel that MYH-9 alone can account for the excess risk for nondiabetic-induced end-stage renal disease in the African-American population.

Odds Ratio for renal failure in African-Americans with MYH-9 compared to without is 5,
Odds Ratio 7.7 in European americans with MYH-9 than without, but this occurs in much lower frequency.

Symposium on Hyponatremia
Presenters: Richard Sterns, MD and Joseph Verbalis, MD (Georgetown University)
Reporter: Hsiao Lai, MD (East Carolina University)

The key learning points from the session:
Goals for correction of symptomatic acute hyponatremia

1st 6 hrs: ~6meg/L
1st 24 hrs: 6-8meq/L
1st 48 hrs: 18meq/L

According to the presenters, normal saline is not recommended any more.

Hypertonic saline: hot shot boluses or 3% HS are recommended for acute hyponatremia with severe neurological symptoms:

seizure, coma/stupor, respiratory arrest

Otherwise with mild or moderate symptomatology, vaptans are a good option. Vaptans would correct a little slower, but there is less risk of overcorrection and demyelinating lesions.

Fluid restriction for chronic mild hyponatremia with no symptoms is still appropriate.

Reintroduction of mild hyponatremia should be attempted in cases of overcorrection of hyponatremia with worsening mental status and may improve clinical findings.



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