15th International Conference on Dialysis sponsored by the Renal Research Institute from Rio Grande, Puerto Rico

Table of Contents

  1. The MONitoring Dialysis Outcomes (MONDO) initiative
  2. Nutritional Resilience – A Novel Concept
  3. Ports for Vascular Access in Dialysis
  4. Extracorporeal Method to Reduce Inflammation in Acute Sepsis
  5. HIF-1 Stabilizer Drugs for the Treatment of Anemia
  6. Remote Ischemic Pre-conditioning for Cardioprotection
  7. Approach to Renal Biopsy
  8. New Approaches for Idiopathic Nephrotic Syndrome
  9. Roles of FGF23 in Mineral Metabolism and Cardiovascular Disease in CKD
  10. Optimal bicarbonate levels in HD and PD
  11. Living Kidney Donors and Measurable Risk
  12. Latest RCTs in hemodiafiltration

The MONitoring Dialysis Outcomes (MONDO) initiative by Len Usvyat of the Renal Research Institute & Fresenius Medical Care
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MONDO is an international consortium of dialysis providers that contribute data to understand outcomes in ESRD patients. Its genesis first began in 2009 after Blood Purification 2009 27:38-47 highlighted the negative outcomes in US dialysis patients. The MONDO researchers wanted to know if similar negative outcomes were seen in non-US ESRD patients. Thus the official MONDO consortium began in the summer of 2010. The data collected by MONDO is from 38 countries from 2000 an updated annually. As of 2012 there are ~150,000 patients in the database with over 30 million different data points (observations). Noticeably absent in the MONDO database are patients from continental Africa and south Asia and Australia.

One of the first things that we have learned from MONDO are the events that occur before patient death. A total of 41,903 deaths were studied through the MONDO database. Serum albumin level drops significantly leading up to death in patients from all continents at the approximate same rate (1st derivative). This decline accelerates at about 20 weeks before eventual death. Nex, the intradialytic weight gain actually declines around 10-20 weeks before eventual death. Finally, pre-dialysis systolic BP also declines within 5-10 weeks before eventual patient death. Indeed the rate of decline of pre-dialysis systolic BP is the same for patients in all continents. Finally, serum CRP levels increase at the same rate 10-20 weeks before eventual death. The data from this observational study will appear in a Kidney International 2013 issue.

This is interesting observational data because it may lead to the development of prognostic indicators that clinicians can use to help patients deal with end-of-life issues. MONDO is also looking at serologic predictors of hospitalization, such as albumin and hemoglobin levels.

Nutritional Resilience – A Novel Concept by Franklin Maddux of Fresenius Medical Care
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Nutritional competence cannot be measured by looking at one marker, though many people simply use albumin. Anywhere from 18-75% of dialysis patients experience protein-energy easting (KI 2008). Though the relative risk for mortality if albumin is low is 0.8, there are other markers with greater accuracy. Nevertheless, Dr. Maddux shows us a number of synthesized data all revolving around albumin levels.

From RRI data (n = 3054), those who survive in the first year of hemodialysis have an increase in albumin while those who die don’t. Nutritional resilience should not just focus on the level of albumin but the rate of change of albumin (1st derivative). 47,269 incident HD patients who survived for more than 1 year were analyzed to determine what the determinants are for having a positive rate of rise of albumin. The probable causes include higher enPCR, pre-HD weight increase and a neutrophil:lymphocyte ratio (as a surrogate marker of inflammation).

Dr. Maddux focuses on the large data set from MONDO to identify determinants of poor nutrition. One can make the argument that this is only an initial first step as the data is observational and the marker being used to assess nutrition, albumin, isn’t an accurate identifier of poor nutrition.

Ports for Vascular Access in Dialysis by Dr Frank Prosl of Duke University
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Dr Prosl starts out with a history of the high costs of placing and maintaining hemodialysis access. In fact, he suggests that the guidelines for creating/using AVFs is now under question. Interestingly, the authors of Kidney International 2012 82:623-625 recommend a randomized trial to compare AVF to AVG to tunneled catheters because 1) no such trial has been done and 2) we have automatically concluded that AVFs are the best access w/o these randomized trials. These authors are concerned about the negatives of AVFs, namely the rate of primary failure, risk of aneurysms and bleeding. Dr Prosl indicates that AVFs have additional shortcomings, including greater pulmonary hypertension and greater cardiovascular effects. Dr Prosl is basing a lot of his statements based on Kidney International 2012 82:623-625 , including that the infectious rate of tunneled catheters is decreasing with the greater use of aseptic techniques and antibiotic locks. In CJASN 2011 6: 1996-2002 the Mayo Clinic analyzed their patients with AVFs. Only 1/3 of AVFs were usable for dialysis.

Dr Prosl indicates that he and another partner have been developing a modified catheter system where the catheter is inserted into the SVC (as is currently done). The distal end of the port (closest to the provider) is embedded under the skin (unlike current catheters). Pictures are not provided as they are not published.

Extracorporeal Method to Reduce Inflammation in Acute Sepsis by Rodney Kenley of Aethlon Medical Inc.
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Mr Kenley begins by stating that he is the President of Aethlon Medical and is company has been awarded a defense contract on the treatment of septic wounded soldiers by using extracorporeal therapies. He will be providing a literature review of the data surrounding sepsis and extracorporeal therapies.

The data regarding the superiority of intermittent hemodialysis versus continuous renal replacement therapies is inconclusive. Most of the literature suggests that the 2 modalities are equivalent in septic patients. Mr. Kenley then turns his attention to high cutoff membrane CVVH (which is a membrane whose permeability is increased). There is better clearance of interleukins but greater removal of antibiotics and proteins. He does’t mention any trials that have used high cutoff membrane CRRT in septic patients, however.

Attention is then turned to hemoperfusion with polymyxin B. These trials are very small but suggest an improvement in blood pressure, dopamine use, and oxygen index (P/F ratios). Specifically, the EUPHAS Trial looked at 64 patients in Italy to polymyxin B hemoperfusion versus control (not defined by the presenter). The 28-day survival was better in the hemoadsorption group (p 0.03). In the EUPRHATES trial, 360 patients are enrolled to look at the 28-day mortality. This trial has not been completed.

There are now a 4 cytokine-adsorbing columns, with the CytoSorb Cytokine Extractor as a common column. A clinical trial in Germany looked at 43 patients (25 control, 18 treated) showed an improvement in 28-day mortality (no reference listed).

Leukocyte modulation is a technique whereby the membrane that binds leukocytes before returning blood back to the patient, thereby decreasing inflammation that is commonly associated with traditional hemodialysis. Some studies have shown an improvement in 60-day mortality and need for continued dialysis in patients with acute renal failure. Again no references provided.

HIF-1 Stabilizer Drugs for the Treatment of Anemia by Dr K Peony Yu of FibroGen
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Erythropoeisis is regulated through hypoxia inducible factor (HIF). By stabilizing HIF, it can enter the nucleus and stimulate transcription of mRNA that will increase endogenous erythropoietin. HIF-PHI can stabilize HIF; one in particular is FG-4592 (produced by FibroGen). GlaxoSmithKline has GSK 1278863 and Akebia has AKB-6548. All three are in phase 2 studies with only FG-4592 in a phase 3 study. The mechanism of physiologic adjustment of erythropoiesis at high altitude is the same as that when FG-4592 is administered. Dr Yu then shows observational data that patients living at high altitudes have lower risk of death, hypercholesterolemia, and cancer; she seems to be suggesting that perhaps the use of FG-4592 would also achieve these benefits, though that’s a really big stretch.

In a phase 2 trial, FG-4592 was given to HD patients versus standard ESA therapy to maintain a hemoglobin of 9-13. In this 6 week study, there was a dose-response to the rise in hemoglobin. Indeed, the hemoglobin levels steadily rose with regular administration of FG-4592 while hemoglobin decreased over time with regular administration of ESA (though she does not show data about iron stores over time). Dr Yu even mentions that there were no serious cardiovascular effects with the use of FG-4592, although the duration of this trial was only 6 weeks. In another study, oral FG-4592 given over 19 weeks led to a more stable hemoglobin level than ESA. Indeed FG-4592 is equally as effective when used in conjunction with oral iron or IV iron, unlike ESA (TH-OR096 at Kidney Week 2012).

Dr Yu indicates that the limits to ESA effectiveness is systemic inflammation, as measured by CRP. With FG-4592, CRP levels don’t affect its ability to raise hemoglobin levels. Moreover, the rise in hemoglobin at 12 weeks with FG-4592 is similar to that with ESA that occurs in 24 weeks (TH-OR096 Kidney Week 2012).

In CKD 3 and 4 patients (JASN 2011 22:196A), whether FG-4592 is administered by a weight-based formula or a standard dose of 50 mg or 100 mg, the rate of rise and terminal hemoglobin levels at 16 weeks were the same. In a subgroup analysis, patients receiving FG-4592 three times a week had a lower blood pressure and lower cholesterol. Both of these effects disappear once FG-4592 is discontinued.

Another concern with ESA use is thrombocytosis –> thrombosis. With FG-4592 use, the rise in hemoglobin did not increase platelet count (but this was a subgroup analysis).

Per Dr Yu, the advantages of FG-4592 include: can be orally given, mimics body’s own erythropoiesis, and lowers blood pressure and cholesterol. To this date, there are no serious adverse effects attributable to this drug. There is also no evidence for an increase in thrombosis as measured by platelet count.

FibroGen and Astellas are working together on a phase 3 study on FG-4592 in anemic CKD patients.

Remote Ischemic Pre-conditioning for Cardioprotection by Dr Chris McIntyre of the University of Nottingham
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In the 1980s (Murray 1986) it was learned that if you made an organ ischemic before a major ischemic event, the organ would be able to sustain the damage from that major event (ischemic preconditioning). In the 1990s, it was learned that preconditioning did not necessarily need to affect the organ in question. McClanahan 1993 and Gho 1996 used the kidney and intestine, respectively, to show demonstrate this idea. In addition there was a 65% reduction in heart attacks with lower limb ischemic preconditioning (Birnbaum 1997 and Oxman 1997). In the 2000s, ambulatory blood pressure cuffs were used to induce ischemia to mitigate heart attacks and strokes. This is known as remote ischemic preconditioning (RIPC) (Hausenloy 2008).

In Yetgin 2012, this meta-analysis has shown a general favor towards remote ischemic preconditioning by measuring biomarkers such as CK, troponins, and NGAL. Hemodialysis patients are subjected to recurrent dialysis-induced end organ ischemic injury, making RIPC very interesting in this patient population. Dr. McIntyre mentions that patients with AVFs have a reduction mortality that is not just due to lower risk of infection. The AVF itself may be inducing ischemic preconditioning (in the distal portion of the limb) not seen with catheterized patients. Questions in RIPC include the dose response of inducing ischemia, how often to dose RIPC techniques, and what is the minimum and maximum RIPC dose that results in the desired effect.

Approach to the Renal Biopsy by Dr. Agnes Fogo of Vanderbilt University
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Dr Fogo first starts with some normal histology. Normally, there about 3 mesangial cells in the mesangium. Capillary loops are all open. She shows a silver stain that clearly highlights open capillary loops with thin basement membranes. A normal EM showing the homogenous basement membrane and well defined structures.

Fogo will focus mostly on the glomerulus such as podocyte and GBM injury. We start with a thick GBM with proteinuria. She shows a light microscopic slide with a thick non-smooth GBM on silver stain. Spicules are evident on the silver stain, which are considered deposits. on IF, the entire glomerulus lights up with a granular pattern. EM shows subepithelial deposits. Diagnosis = membranous nephropathy.

Now we have a patient with irregularly thickened GBM. Silver stain shows irregular feathery extrusions. EM shows fibrils, randomly arranged. Congo red stain shows bright green. Diagnosis = amyloid (not specified as primary or secondary).

Another thick GBM on a PAS (appears as a pink area that is thick, drawn with a felt-tip pen rather than a fine point pen). The arterials show hyalinosis (both afferent and efferent) and the mesangium is expanded. The EM shows a thick GBM w/o deposits. Diagnosis = diabetic nephropathy.

Now we have a patient with proteinuria and hematuria and segmental sclerosis. This is seen in FSGS of various subtypes (which are clinically important) but not always. Fogo shows an IF with mesangial pattern of positivity: diagnosis = IgA nephropathy.

Fogo now talks about crescents. Crescents can occur in almost any disease. Crescents have a half-moon shape that occur because of a reaction to a rupture of the glomerulus. Crescents are almost always secondary, so be sure to look for the underlying renal disease that led to their formation. Crescents are divided into cellular, fibrocellular, and fibrous. The former are acute, the latter are chronic changes

Now onto the double contour basement membrane. The EM clearly shows cells interposed between the true and false basement membranes.

New Approaches to Idiopathic Nephrotic Syndrome by Dr Gerald Appel of Columbia University
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Will focus on 3 drugs: rituxan, ACTH, and eculizumab and as they are used in FSGS, Membranous nephropathy (MN), DM.
Rituximab is FDA approved for rheumatoid arthritis and ANCA + vasculitis. It is a half-mouse half-human monoclonal antibody. As a result, Appel always co-administers solumedrol with it to prevent any reactions to the mouse-portion of the molecule.
ACTH not only stimulates endogenous steroids, but the it binds to the podocyte through the podocyte-specific melanocortin receptors.
Eculizumab is a humanized monoclonal Ab that acts against C5. It is approved for paroxysmal nocturnal hemoglobinuria and atypical hemolytic-uremic syndrome.

First, we start with FSGS. The new test for FSGS is suPAR. A number of cells express uPAR and shed it into the bloodstream –> suPAR. This molecule binds to the podocyte and changes glomerular architecture. In Nature Medicine 2011 17:952 the suPAR levels are much higher in FSGS than MN. In terms of treatment, we still start with steroids and we have good data for calcineurin inhibitors. In KI 2011, CsA reduces proteinuria more than MMF in steroid-resistant FSGS patients aged 2-40 years. In JASN 2012 23:1117, for steroid-resistant FSGS patients, rituximab versus calcineurin inhibitors, the former did not have any good effects compared to the latter. When looking at ACTH in patients with steroid-resistant and calcineurin-resistant FSGS patients, proteinuria drops at a median time of 6 weeks.

In IgA nephropathy, we have a new marker: galactose-deficient IgA molecules. This is found in IgA patients and their relatives. In KI 2011 80:79 this is clearly shown. Why do the patients have disease and their relatives remain healthy despite both having galactose-deficient IgA? It is thought the patients develop antibodies against the galactose-deficient IgA that makes them have disease, whereas their relatives do not form those antibodies (JASN 2012 23:1579). Another theory is that there is a considerable greater amount of oxidative stress in those patients who ultimately develop disease versus their relatives (CJASN 2011 6:1903).

In MN, the phospholipase A2 receptor is likely the antigen that, combined with its respective antibodies, comprise the basement membrane deposits. In secondary MN patients, the amount of phospholipase A2 receptor found is 0%. According to KDIGO, the Ponticelli protocol is still considered the first line for therapy. In a JASN 2012 article by Ruggenenti, rituximab is touted as a first line therapy for MN — Appel disagrees with this idea. His primary problem is that the study is not randomized and 67% of the patients in the study were new onset (never had any prior therapy). The MENTOR Trial is currently underway to evaluate rituximab verses CsA in MN as a first line therapy (JASN 2012 23:1-2). in AJID 2006 by Ponticelli, idiopathic MN patients were divided to receive ACTH versus steroids + CYC. The former group had a similar degree of complete and partial remissions as the standard group.

Now onto C3 glomerulopathies. Dense deposit disease is really not MPGN type 2. DDD has no IgA or IgG on IF — only C3. If you have an MPGN, consider the CJASN 2011 6:1009 classification scheme. MPGN with positive Igs are Ig-mediated. W/o Igs, the disease is complement-mediated (DDD or C3 glomerulonephritis). This is important to know because of the potential therapeutic benefit of eculizumab (an antibody against C5). In CJASN 2012 7:748, patients with C3 glomerulopathy who failed multiple drugs previously had good responses with eculizumab. We now need a randomized controlled trial, which are being conducted by Alexion and Novartis.

Roles of FGF23 in Mineral Metabolism and Cardiovascular Disease in CKD by Dr Myles Wolf of the University of Miami
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FGF-23 was first discovered as the use of hypophosphatemic disorders (both genetic and acquired). FGF-23 increases urinary phosphate excretion and inhibit production of vitamin D levels and stimulate vitamin D degradation –> severe hypophosphatemia. FGF-23 is secreted by both osteocytes and osteoblasts (AJP-Endocrinology Metab 2003 Vol 285). FGF-23 is a bone-derived hormone that regulates phosphate and vitamin D production.

FGF-23 requires klotho as a co-receptor to exert its function, in particular in the kidney. Every cell expresses FGF-23 receptors, but its selective function is mediated by the presence of klotho, which is found in select tissues, like the kidney. Phosphate intake, high levels of vitamin D and PTH all are stimuli for FGF-23 production. We now believe that an increase an FGF-23 is the earliest alteration of disorder of mineral metabolism (as high as at GFRs of > 60) (Wolf M. JASN 2010). If one neutralizes FGF-23 in a CKD patient, 1,25 vitamin D levels return to normal w/o any change in the GFR.

In Gutierrez NEJM 2008, the odds ratio of mortality increases with rising levels of FGF-23. Indeed this relationship holds true when we look at the crude data or adjusted data. This is in contrary to phosphate levels (Block JASN 2004) where mortality is increased with high phosphate levels but only after you make multivariate adjustments. From the CRIC study, there is concentration-dependent increase in mortality with rising levels of FGF-23 in early CKD patients (Isakova JAMA 2011).

FGF-23 is also a marker of increasing left ventricular mass index (LVMI) (Faul J Clin Invest 2011). In fact, there is some data to suggest that FGF-23 actually has a direct role in increasing LVMI, not just an association. This action is independent of the presence of klotho as the heart and cardiac myocytes do not express klotho. Thus, the idea that FGF-23 exerts effects only in the presence of klotho is falling out of favor.

The story for FGF-23, however, isn’t always negative. There is data to suggest that the presence of FGF-23 helps in mitigating vascular calcification. In a reanalysis of the CRIC data, at any level of coronary artery calcification (CAC levels > 0, > 100, > 400, or > 800), there is no association with levels of FGF-23 but significant association with phosphate levels (Scialla Kidney Int’l 2013).

Optimal bicarbonate levels in HD and PD by Dr J Burkhart of Wake Forest University
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Dr Burkhart starts off by indicating that patents on PD and HD should have the same target bicarbonate levels. Specifically, the target pH should be the same, but we really only measure bicarbonate as the surrogate marker. It’s important to have a higher bicarbonate to prevent a number of complications including protein wasting and accelerated demineralization of bone (Mehrotra Semin in Dialysis 2010). Most of the data comes from FMC and DOPPS datasets and almost all show an association between lower bicarbonate levels and increased mortality. In fact, there is even more limited data looking at bicarbonate levels and mortality in PD patients. Randomized trials will be needed to move away from simply associative data and towards confirmatory cause-effect data.

Near the end of the presentation, Burkhart explains why some individuals want different target bicarbonate levels based on the type of dialysis. Specifically, PD is continuous which could make the bicarbonate target different than the intermittent HD modality. Second, bicarbonate levels are measured from the venous circulation in PD patients, whereas it is mixed arterial-venous in HD patients. Perhaps this is a reason for different bicarbonate targets. Third, there is greater potassium shifting in hemodialysis than in PD which could also mean having a different target. Again, Burkhart believes that the target levels should be the same in both modalities of dialysis.

Living Kidney Donors and Measurable Risk by Dr Warren Kupin of the University of Miami
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We take a great deal of time in caring for the kidney transplant recipient. However, we don’t have formalized obligations to the kidney donor. In fact we don’t even have a national donor registry. Since 2000, the number of cadaveric and living donors has stabilized. Indeed in the US in 2012, the number of living donors is the same as it was in 2000. Over the last 7 years, the number of living donors has decreased to levels seen in the year 2000. In Europe, there has been a slight increase in living donors in the past 12 years. Of the 98 countries that perform kidney transplants, 52% have a > 50% of their transplants from living donors. The only group in the US that has shown an increase in living donations are in the elderly (65-70 years of age). All other groups (by age) have decreased their living donation rates.

This drop in rates of living kidney donation is very worrisome. Pre-emptive transplantations result in greater survival for the recipient than if they had been on dialysis first. However, < 10% of all pre-emptive transplants come from cadaveric kidneys. Thus, living donations are needed to achieve the best survival for the recipients. Currently, Dr Kupin cannot explain why living donation rates have decreased.

Although paired exchanges, ABO-incompatible living donations, and altruistic donations are increasing, in total they represent a single-digit percentage of the total number of yearly transplants. Therefore, we cannot rely on these options to improve kidney transplantation. The risks to living donors include: higher risk of hypertension, CKD, and cardiovascular risk. However, not all centers inform the donors of these risks (NDT2008 23:3316). And there is one particular risk that is worth remembering: pregnancy after living donation. Data from the University of Minnesota show an odds ratio of 5.6 for developing pre-eclampsia after living kidney donation.

Over 95% of donor surgeries are performed laparoscopically, with only < 5% of donors requiring re-hospitalization. The mortality rate for the donor is 3.1/10,000 donors, which hasn't changed in the last 15 years (JAMA 2010 303:959). This mortality rate is lower than that for cholecystectomies or appendectomies. Unfortunately, African-American donors have the highest risk of death (7.2 deaths/10,000 donors) — the highest of any racial/ethnic group of living donors.

Today, because there are less living donors, especially from the young age group, surgeons are now taking anybody, including older donors. 60% of transplant centers have no upper-age limit for living donation (CJASN 2011 2887). Since 1999, people with BMI’s > 30 and > 35 are increasingly being accepted as living donors. There is also a greater number of living donors from those with controlled hypertension (ACKD 2012 19:212). More and more “medically complex” individuals are being accepted as living donors (AJT 2008 8:2062).

Latest RCTs in hemodiafiltration by Dr Bernard Canaud of the Fresenius Medical Care – Germany
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Hemodiafiltration (HDF) is a combination of diffusive and convective clearances. Dialyzers that have high internal resistance (long length, small fibers) one gets a huge amount of back ultrafiltration (low convective clearance). Canaud recommends a low-resistance dialyzer to achieve proper convection. In HDF, once can have pre- or post-dilutional fluid administration. Post-dilution is recommended because it allows for the greatest clearance of blood before it returns to the patient. Convective dose is a linear function of the ultrafiltered volume (NDT 2009 15:49).

The DOPPS study (KI 2006 69:2087) first explored the use of convective clearance and showed a risk reduction for mortality of 75%. There are 5 RCTs, all from Europe, comparing HDF (+ convection) to HD (- convection) alone. All of these studies follow the patients for a mean of 2 years and look at either all-cause mortality, cardiovascular mortality (CV), or both. In the CONTRAST study (JASN 2012 23:1087), there was no difference in survival or CV risk in either group. In secondary analyses, serum phosphate levels decreased more in the HDF group. In the Italian C/D study (JASN 2010 21:1798), HDF reduced intradialytic hypotension by 50%. Again, no difference in mortality. In the Turkish HDF study (NDT 2012 1-11), there was no difference in survival between both groups but subgroup and secondary analyses show a risk in CV events in the HDF group. The ESHOL study (J Nephrol 2011 24:196) results are pending but will be published in JASN in 2013.

In fact, of the 4 reported studies, any positive effect on survival or CV outcomes has been seen only through secondary analyses (none through the primary analysis).



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