Blogs from the 44th annual American Society of Nephrology Kidney Week 2011 Meetings in Philadelphia, PA.


  1. President’s message – open plenary
  2. Leptin and biological basis for obesity – State of the Art Lecture
  3. Microangiopathic Syndrome in Pregnancy
  4. Lupus Nephritis in Pregnancy
  5. Diabetic Nephropathy in Pregnancy
  6. Recent Advances in Physiology of Osmosensitivity of Neurons
  7. CNS regulation of cell volume
  8. Osmotic Demyelination Syndrome
  9. Biomaterials and biotechnology: From delivery of angiogenesis inhibitors to the development of controlled drug delivery systems and the foundation of tissue engineering – State of the Art Lecture
  10. Membranous Glomerulonephritis and treatment with steroids, cyclophosphamide, and calcineurin inhibitors
  11. Membranous Glomerulonephritis – Upcoming Therapies
  12. Simultaneous Kidney-Pancreas Transplantation
  13. Simultaneous Kidney-Liver Transplantation
  14. Simultaneous Kidney-Heart Transplantation
  15. Alternatives to Urea Clearance
  16. Catheter-induced inflammation in dialysis – pathogenesis and clinical implications
  17. Encapsulating Peritoneal Sclerosis

President’s Message – Opening Plenary Session [Return to Contents]
Presenter: Joseph Bonventre, MD PhD (Brigham and Women’s Hospital)
Blogger: Tejas Desai, MD (East Carolina University)

The 44th annual ASN meeting started out with the President’s address. 12,500 registrants are attending this year’s conference, with more registrations to come.

In this year’s address, the President has focused on the 9 challenges facing the ASN. They are: 1) research funding, 2) healthcare reform, 3) workforce issues, 4) lack of one voice, 5) fragmentation, 6) globalization, 7) public awareness of kidney diseases, 8- social media/IT, and 9) the industry/physician relationship. He proceeds to discuss each challenge and the “countermeasures” that the ASN is taking.
Health care reform, Public Awareness, and Social Media/IT
One of the largest reforms currently underway is the shift from the individual physician to large central entities, such as accountable care organizations (ACO). The ASN will be tackling this issue and provide better education to their members about this shift. In addition, the ASN has visited Capitol Hill to lobby for lifetime immunosupporession for kidney transplant recipients and to sustain graduate medical education (GME) dollars.
Public awareness about kidney diseases has to increase. In the WHO’s 2008 list of the top non-communicable diseases, chronic kidney disease didn’t even make that list. To increase public awareness, the ASN has changed its annual meeting from RenalWeek to KidneyWeek. The ASN will be increasing its social media presence (Facebook, Twitter) to also increase public awareness.
Workforce, Fragmentation, and Research Funding
The percentage of US medical graduates entering nephrology has been steadily decreasing since 2002. The ASN feels that the decision to pursue a career in nephrology occurs during medical school and not internal medicine residency. However, the President did not outline the strategies being executed to attract medical students to nephrology. Rather, he announced that, for the next 5 years, the ASN has committed funding of $50,000 for up to 2 years of original research for 10 fellows.
Nephrology itself has become fragmented, with many areas of focus, such as onco-nephrology, geriatric nephrology, or critical care nephrology having been “ceded” to other specialties. The President indicated that the ASN will have to “reclaim” these areas of study in order to re-enrich the field of nephrology – though he did not offer specific strategies to achieve this goal.
Industry/Physician Relationship
The President was brief in his description of this challenge. The key points were that 73% of funding in the US goes to industry, with only 13% going to academia. Both numbers are more favorable in the European Union (63% and 26%, respectively). He did not provide specifics of how this balance can be readjusted in favor of academia.
Lack of one voice
The ASN is now reaching out to various patient-centered and volunteer organizations, such as the American Association of Kidney Patients (AAKP), the National Kidney Foundation (NKF), the American Nephrology Nursing Association (ANNA), among other groups to unify the nephrology voices and make a stronger push for favorable reforms in Washington, DC.
The two countries with the largest research and development dollars are the US and China, but only China is increasing its number of publications (the US, in contrast, is having a decrease in nephrology-related publications). Moreover, articles that have a diversity of authors are gaining more citations than those authored by individuals from the same country. The ASN will be supporting the globalization of nephrology research by providing the newly created Mitch Scholars Program – a program that will provide free membership to all fellows in Latin America.
That concludes the blog of the opening plenary session. Many things to look forward to and many challenges to overcome was the theme of this year’s presidential message.

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Leptin and biological basis for obesity – State of the Art Lecture [Return to Contents]
Presenter: Jeffrey Friedman (Howard Hughes Medical Institute and Rockefeller University)
Blogger: Tejas Desai, MD (East Carolina University)

This year’s State of the Art Lecture focused on leptin and the genetics of obesity. Obesity is one of the most inheritable traits at 0.8-0.9 (closer to 1.0, the more likely the trait is inheritable). For comparison, obesity is more likely to be inherited than diabetes, alcoholism, or heart disease. Only individual height (0.9) is more likely to be inherited than obesity. As such, there is likely to be a genetic explanation for obesity amongst the environmental and behavioral influences.
Leptin is a gene, whose correspondingly named protein product is produced by adipose tissue in a manner directly proportional to the amount of fat (fat mass) present. Leptin is a major molecule in the homeostatic mechanism that tells the brain how much to eat; more on that later on.
Dr. Friedman goes on to talk about the early days of linking obesity to genetic factors. Stephen O’Rahilly, a physician in the UK, noted a 4-year old child of 90 lbs who was pre-diabetic. He postulated that the young child had a deficiency in leptin – perhaps as a result of extensive consanguinity in the child’s family. As a result, the brain was unaware of the amount of fat mass in the child and resulted in uncontrollable eating. To prove this, he administered recombinant leptin and by the age of 6, the child had lost much of his weight and was no longer pre-diabetic.
Leptin levels tell the brain, specifically the neurons that control eating, when to stop caloric intake. The greater the fat mass, the more leptin produced and the greater the inhibitory signal to stop eating, unless there is a defect in either leptin production or leptin sensitivity in the brain. For example, patients with lipodystrophy have a congential loss of adipose tissue. As a result, leptin levels remain low and the patient continues to eat. In such patients, the ingested fat, while not stored as adipose tissue, is stored in other organs, namely the liver leading to hepatic steatosis. Such steatosis can be revered with the administration of recombinant leptin.
Dr. Friedman makes the case that adipose tissue is more than just fat – it is an endocrine organ that has a significant role in maintaining body weight.
Obesity is not a decreased leptin state. Obesity is more likely to be a condition in which there is a defect in leptin signaling, particularly in the brain. High doses of leptin (0.3 mg/kg weight/day) can result in greater than 5% weight reduction in about 35% of obese patients. Perhaps these high doses, which is difficult to administer pharmacologically, can overcome the signaling defect.
Finally, 80% of serum leptin is eliminated by the kidney. There is evidence that impaired kidney function prolongs the half-life of leptin. One wonders if this is an explanation for why ESRD patients, who have no renal function, becoming increasingly “malnourished” as they continue on renal replacement therapies.

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Microangiopathic Syndrome in Pregnancy [Return to Contents]
Presenter: Fadi Fakhouri, MD (affiliation unknown)
Blogger: Tejas Desai, MD (East Carolina University)

The lecture starts with some introductory facts about acute kidney injury (AKI) and microangiopathy (TMA): maternal mortality from AKI was 31% in the 1970’s, but down to practically 0% in the 1990’s (in the Western World; mortality is certainly above 0 in developing countries). Preeclampsia and eclampsia are the most common causes of AKI in pregnancy – up to 35% of all pregnancy-AKI etiologies.
Dr. Fakhouri then proceeds to discuss the new classification of thrombotic microangiopathies. He supports a 2-model classification of 1) ADAMTS13-deficiency-associated TMA versus 2) Complement-dysregulation-associated TMA. Each class has its own unique features and specific therapeutic strategies, which he will touch on briefly in this lecture.
In pregnancy, TMA’s occurring in the second or third trimester is usually due to ADAMTS-13-deficiency. The standard treatment for such pregnant patients is plasma exchange (TPE). However, for those patients who are refractory to TPE, rituximab has been used safely, as shown in the RITHA-13 study. The FDA classifies rituximab as a class C drug in pregnancy. It appears that the threshold of ADAMTS-13 deficiency is 10%. For those patients who have a history of TMA and become pregnant, Dr. Fakhouri recommends performing prophylactic TPE to increase ADAMTS-13 levels to above 10%. This is because the recurrence rate of TMA in pregnant patients with ADAMTS-13 levels less than 10% = 34%; if greater than 10%, 4% recurrence rate.
Complement-dysregulation-associated TMA’s usually cause post-partum TMA. In these patients, data suggests that ESRD will be reached within 6 months. For such patients, one must not necessarily wait for genetic testing to identify the specific complement gene that is dysfunctional before starting therapy. Eculizumab is a drug with great promise for this type of TMA, by inhibiting the cleavage of C5. The regimen that Dr. Fakhouri recommends is that which is used for the treatment of paroxysmal nocturnal hemoglobinuria (PNH): 900 mg q-week for 4 weeks, then 1200 mg q 2 weeks. Unfortunately, there is limited data elucidating the duration of treatment. He recommends following disease progression clinically as well as CH50 levels (they should be less than 20% if the drug is optimally blocking the complement cascade).
Finally, he ends his lecture by briefly touching on the HELLP syndrome. Traditionally, HELLP has been considered a form of TMA, though kidney biopsies of patients with HELLP show glomerular endotheliosis or ATN, both of which are reversible and may be the main factors why AKI can reverse once the HELLP is treated. However, liver biopsies seem to show evidence of TMA. As a result, there is a debate of whether HELLP truly is a TMA in the kidney.

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Lupus Nephritis in Pregnancy [Return to Contents]
Presenter: Vesna Garovic, MD (Mayo Clinic)
Blogger: Tejas Desai, MD (East Carolina University)

Dr. Garovic starts by reminding us that the most important influence on kidney disease progression in a pregnant patient is the degree of renal dysfunction (or function, depending on how you view the world) at the time of conception. There are limited adverse effects when the creatinine at conception is 1.4 mg/dl or lower. However, when the creatinine at conception is 3.0 mg/dl or higher, there is significant risk to fetal viability and maternal morbidity.
She concludes with a case of a pregnant female with antiphospholipid syndrome (APS) and a history of strokes (CVA) who became pregnant against medical advice, and ultimately suffered loss of her baby and her own life. She makes the case that such patients (APS + CVA) have an absolute contraindication to becoming pregnant. Those patients should strongly consider surrogacy in order to have a good outcome for both the patient and the fetus.

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Diabetic Nephropathy in Pregnancy [Return to Contents]
Presenter: Elizabeth Mathiesen, MD (University of Copenhagen)
Blogger: Tejas Desai, MD (East Carolina University)

Dr. Mathiesen starts by listing the prognostic indicators for pregnancy in patients with diabetic nephropathy – preeclampsia, kidney function at the time of conception, the need for dialysis, and, interestingly, the degree and stability of diabetic retinopathy. Prognosis is improved if proteinuria is less than 3 g per day, if serum creatinine is less than 124 umol/l, if there is stable visual acuity, and, most importantly, if high blood pressure is controlled. Diabetic nephropathy pregnant patients are thought to have a higher risk of developing ESRD in their lifetime, but this is not the case. Data show that risk is comparable to the development of ESRD in diabetic patients who are not pregnant.
Her most impressive data shows that intense blood pressure control, even in pregnant patients in whom diabetes is not intensely controlled (A1c’s around 7-8%), increases the likelihood of a full-term birth. Thus, it appears that in diabetic pregnant patients (with or without diabetic nephropathy), the main risk factor remains blood pressure and not diabetic control.

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Recent Advances in Physiology of Osmosensitivity of Neurons [Return to Contents]
Presenter: David Cohen, MD (Oregon Health Sciences University)
Blogger: Tejas Desai, MD (East Carolina University)

Dr. Cohen began his lecture by showing us a slide of serum osmolarities among different species. What’s remarkable is that all the mammals on the slide have a serum osmolarity close to approximately 300. It would appear that the mechanisms used to regulate osmolarity are similar across mammals. The focus of the talk is on such mechanisms, mostly studied in animal models, with some crossover into our species.
The lamina terminalis (LT) is the key sensor of systemic osmolarity. It sits in the brain, just anterior to the third ventricle. Functional MRI images show that activity in the LT is increased when the sensation of thirst is present and when arginine vasopressin (AVP) is released. A number of receptors/channels sit in the LT, some of which were discussed in this lecture.
TRPV4 is the first channel protein that Dr. Cohen discussed. It is an osmosensor and in knockout mice, the loss of this channel leads to diminished thirst, water intake, and as a result, increases in serum osmolarity. In humans, the P19S polymorphism of the channel is present (TRPV4P19S). Its activity is also dependent on serum tonicity. A similar protein, TRPV1, is found in the LT and also has osmosensing characteristics. Knockout mice of this channel (TRPV1 -/-) suffer a similar fate as TRPV4 knockouts.
Additional channels still under investigation are NALCN and the NaX channels. The former is a non-selective cation channel in neurons that plays a role in maintaining serum Na+ in mice. The latter is a channel in glial cells (known as NaV2.1 in humans) that influences the appetite for sodium in mice.

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CNS regulation of cell volume [Return to Contents]
Presenter: J. Verbalis, MD (Georgetown University)
Blogger: Tejas Desai, MD (East Carolina University)

In this lecture, Dr. Verbalis aimed to explain some of the adaptive and de-adaptive mechanisms occurring in neurons during water stress. He started off with a slide showing the powerful effects of the brain’s compensatory mechanisms against changes in cell volume. Acute changes in brain cell volume leads almost universally to stupor/coma (near 100%); chronic changes in brain cell volume, when adaptive mechanisms have had time to kick in, drops the probability of stupor/coma down to 6%.
A number of adaptive mechanisms exist in neuronal cells to mitigate cell swelling in hyponatremia. These mechanisms mainly rely on the extrusion/degradation of cytosolic osmoles. In the brain, such osmoles are of 2 types: electrolytes and osmolytes. In the former, Na+, K+, and Cl are actively pumped out of the cell. Electrolytes account for about 67% of the intraneuronal osmoles, and amongst these 3, brain chloride (Cl) is the electrolyte that is pumped out in greatest percentage. How are these ions eliminated from the cytosol? The answer isn’t well understood, but may have something to do with intracellular Ca2+. While Na+, K+, and Cl are actively pumped out of the cell, Ca2+ enters the cell in a manner that is proportional to the degree of cell swelling (or cell stretching). Stretch-activated channels (SAC’s) are activated in direct proportion to the degree of cell swelling, which causes an influx of Ca2+. What happens inside the cell, and how Ca2+ plays a role in eliminating intracellular Na+, K+, and Cl, is unclear.
Osmolytes make up the remaining 33% of intracellular osmoles, and consist of creatinine, glutamine, glutamate, taurine, and inositol (to name a few). Rather than active elimination from the intracellular space, these osmolytes are degraded via mechanisms that aren’t clearly understood. Dr. Verbalis showed a series of graphs indicating the drop in concentration of each of these osmolytes as serum Na+ levels dropped (hyponatremia). These adaptive mechanisms require time (days) in order to be fully effective, but when they are completed, the patient is able to survive. However, fine neurologic testing (specifically, fine motor skills) during periods of severe hyponatremia indicates that an osmole-depleted brain is not a normal brain. Dr. Verbalis emphasizes this point a few more times – osmole-depleted brains appear to be normal, but in fact are “quasi”-normal and can be excited with the mild external stimuli (such as mild hypoglycemia, mild hypoxia).
One final mechanism that is involved in regulating brain cell volume is the extrusion of water from within the cell. The main channel in the brain is aquaporin-4 (AQP4), found both at the blood-brain and brain-CSF interfaces. AQP4 channels allow for bidirectional movement of water; once open, water moves through these channels in a manner predicted by the osmotic pressure gradient. Thus it is not exactly clear what deleterious effects these channels can have on brain cell swelling when they are not functioning correctly (that is, open channels when they should be closed).
De-adaptive measures are simply the reversal of the above-mentioned adaptive mechanisms. This mechanism requires days to occur and is primarily dependent on the regeneration of osmolytes. One question that was not answered in this lecture is why de-adaptive measures rely heavily on the regeneration of osmolytes rather than the influx of electrolytes, given that osmolytes account for only 33% of the intracellular osmoles. Are these osmolytes, collectively, contributing to the intracellular osmolarity to a greater degree than the electrolytes, despite being quantitatively lower in concentration? This would be tough given that Na+ is a powerful contributor to intraneuronal osmolarity.
Finally, Dr. Verbalis broached the topic of chronic hyponatremia (for 3 months or longer). He showed data from his lab of the effects on bone. Many forget that 33% of total body sodium is stored in bone and that osteoclasts have a sodium sensing feature, akin to calcium sensing. Mice who live with hyponatremia for months have significant bone demineralization (as shown on DEXA scanning). These osteoclasts sense a deficiency in total body sodium (for an unclear mechanism given that the initial insult in hyponatremia is excess water and not necessarily a reduction in total body sodium) and release bone-stores of sodium. The kidney, however, detects the increase in total body sodium and affects a natriuresis. As a result, a vicious cycle begins with an increasing amount of bone sodium released from the bone. According to Dr. Verbalis, the chronic hyponatremic mouse is the most striking animal model for osteoporosis known thus far.

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Osmotic Demyelination Syndrome [Return to Contents]
Presenter: Richard Sterns, MD (Rochester Medical Center)
Blogger: Tejas Desai, MD (East Carolina University)

Dr. Sterns started his lecture with the risk factors for osmotic demyelination syndrome (ODS): 1) chronic hyponatremia, 2) malnutrition, 3) hypokalemia, 4) serum [Na+] less than 105 meq/l, 5) too fast a correction of hyponatremia. Interestingly and perhaps frightening, the clinical symptomatology and radiographic findings of ODS are delayed by 2-3 days. Thus one gets the impression of clinical improvement while, in reality, the situation is deteriorating towards ODS. He did not focus on any earlier warning signs/symptoms of ODS.
Where did the 1 meq/l/hour correction of [Na+] come from? Evidence shows that a correction of 2.8 meq/l/hour portends a 20% risk of ODS, while 1 meq/l/hour portends less than 5% risk.
Thus far, the only effective management of ODS (other than prevention) is to reinitiate hyponatremia using free water with or without dDAVP infusions. Studies from Sugumura in Japan initially showed some therapeutic effect against ODS using dexamethasone (of note, recent data from this group suggests minocycline may have a therapeutic effect as well).
Finally, how does hypokalemia induce ODS? This question was only superficially answered – K+ infusions in hypokalemic patients will cause a rapid intracellular shift of that K+. This occurs at the expense of Na+ exiting the cells. In effect, K+ infusions increase serum [Na+], and since this can’t be controlled or regulated tightly, there is a risk of rapid [Na+] correction resulting in ODS.

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Biomaterials and biotechnology: From delivery of angiogenesis inhibitors to the development of controlled drug delivery systems and the foundation of tissue engineering – State of the Art Lecture [Return to Contents]
Presenter: Robert Langer, ScD (MIT)
Blogger: Tejas Desai, MD (East Carolina University)

A great lecture by one of the fathers of bioengineering and drug delivery systems. Dr. Langer provided the audience with a stimulating overview of three key areas that he has (or had) been working on during his career:
1) discovery of angiogenesis inhibitors,
2) development of drug delivery systems, and
3) tissue engineering.

His lecture did not go into many details in each of these 3 areas. Key points from the lecture include:

1. early on in the 1970’s many scientists believed that anti-angiogenic factors could not be delivered via polymer-based delivery systems because they a) were too big to fit inside, b) would react with the polymers, or c) the polymers would not degrade at a predictable and controllable rate so as to prevent toxicity. These ideas were all disproved by Dr. Langer’s work.

2. controlled delivery systems are based on polymers of different chemical and thermal properties. However, Dr. Langer did not go into much detail as to the nature of these polymers, or even how they were considered or discovered. He did show a cool video from the television program NOVA, which depicts, in lay terms, how such delivery models are built. The program, Making Stuff: Smarter, featured Dr. Langer’s work. You can view it here (minute 40:36).

3. Dr. Langer’s lab has done quite a bit in tissue engineering. While he showed many pictures and videos related to this work, the one organ that he did not touch upon, was the kidney. No mention was made about engineering nephrons, ureters, the bladder, or the entire kidney. I found that ironic considering that he was giving a talk to nephrologists.

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Membranous Glomerulonephritis and treatment with steroids, cyclophosphamide, and calcineurin inhibitors [Return to Contents]
Presenter: Michael Choi, MD (Johns Hopkins University); Introduction by Claudio Ponticelli, MD
Blogger: Tejas Desai, MD (East Carolina University)

Dr. Claudio Ponticelli began the session with brief statistics about membranous glomerulonephritis (MGN). 20-30% undergo spontaneous remission, 20-40% have persistent proteinuria but stable creatinine, and 30-50% will progress towards ESRD or death from complications of severe proteinuria. The current and well established risk factors for progression of MGN to ESRD are:
1) increased age,
2) superimposed FSGS,
3) increased creatinine at the time of diagnosis,
4) increased interstitial lesions on kidney biopsy, and
5) elevated proteinuria levels at the time of diagnosis.

Specifically, regarding proteinuria: if it is between 4-8 g per day for 6 months or longer, 55% of patients will develop ESRD within 10 years. If it is greater than 8 g per day for 6 months or longer, 66-80% will develop ESRD within 10 years.

Dr. Choi began by discussing the use of steroid monotherapy in the treatment of MGN. The classic investigation, using prednisone 45 mg/meter squared every other day for 6 months showed no significant improvement than placebo. Subsequent studies have also indicated that steroid monotherapy is not useful in MGN treatment.

He then discussed the classing “Ponticelli” protocol, in which patients were placed into 2 cycles. Cycle A = methylprednisolone (MP) 1 g x 3 days, then 0.5 mg/kg/day orally in months 1, 3, 5 + chlorambucil 0.2 mg/kg/d in months 2, 4, 6. Cycle B: methylprednisolone (MP) 1 g x 3 days, then 0.5 mg/kg/day orally in months 1, 3, 5 + cyclophosphamide 2.5 mg/kg/d po in months 2, 4, 6. In both cycles, there was an equivalent number of complete and partial remissions (CR and PR). Importantly, only 50% of patients responded by 6 months. The additional respondents were identified another 6 months later. Dr. Choi emphasized that unlike other glomerulonephritides, such as ANCA-associated vasculitides, MGN treatment is slow; one should not expect immediate results and should be willing to wait (for up to 24 months) before labeling a patient as “treatment failure”.

He then moved onto cyclosporine (CsA) therapy. In one trial, CsA was added to prednisone and compared to prednisone alone (CsA: 3.5 mg/kg/d for a level of 125-225 at 26 weeks + 0.15 mg/kg/d prednisone versus prednisone alone). The CsA group did remarkably better than the prednisone monotherapy group, but 50% of patients relapsed one year off therapy.

What about tacrolimus? In another study, tacrolimus monotherapy (0.5 mg/kg/d x 12 months for a level of 3-5 + 6 month taper) versus prednisone monotherapy showed increased CRs and PRs. Similar to CsA, however, there was a 50% relapse rate after 1 year of discontinuation of the drug.

What about tacrolimus (0.1 mg/kg/d + prednisone 1 mg/kg/d) versus CsA (100 mg/d x 4 months) + prednisone (1 mg/kg/d)? CRs and PRs are the same.

Finally, Dr. Choi provided his recommendations for the treatment if MGN:
1) oral prednisone/IV MP + oral cyclophosphamide because it has the best efficacy with lower adverse effects than with chlorambucil
2) alternatively, if cyclophosphamide toxicity is unacceptable, try oral prednisone + CsA x 6 months or tacrolimus monotherapy x 6 months, but continue the calcineurin inhibitor (w/o prednisone) for an additional 6-12 months with a taper of 50% every 4-8 weeks.

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Membranous Glomerulonephritis – Upcoming Therapies [Return to Contents]
Presenter: Fernando Fervenza, MD (Mayo Clinic); additional commentary by B. Haraldsson, MD (University of Gothenberg)
Blogger: Tejas Desai, MD (East Carolina University)

In this session, most of the focus was on 2 particular drugs: rituximab and recombinant ACTH.

The theory behind the potential effectiveness of rituximab has to do with the deposition of IgG in the basement membrane by B-cells. Rituximab is an inhibitor of B-cell activity, and thus should be effective against MGN. In a small study of 20 patients, rituximab at 375 mg/meter squared given every week x 4 weeks to patients with a mean creatinine clearance of 72 ml/min and mean proteinuria of 12 g (55% of which failed some form of “initial therapy” previously), 17 patients had either CR or PR at 24 months (only 2 patients had relapse at 24 months).
Dr. Fervenza indicated that his group is actively recruiting patients for a randomized controlled trial of rituximab versus CsA, with the primary endpoint of CR or PR at 24 months.

ACTH trials are extremely small, and either compared to either placebo or just ACE-i/ARBs. The real robust data is yet to be published. However, the notion that ACTH could improve MGN through its stimulation of endogenous steroid production is unlikely to be the mechanism of action (given that steroid monotherapy has been shown to be ineffective). Dr. Haraldsson expanded on the mechanism of ACTH by indicating that it acts on a renal-specific melanocortin receptor, MC1R. In animal studies, agonism of this receptor decreases oxidative stress — perhaps elucidating the manner in which ACTH exerts its effect independent of steroid production.

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Simultaneous Kidney-Pancreas Transplantation [Return to Contents]
Presenter: Alexander Wiseman, MD (University of Colorado)
Blogger: Tejas Desai, MD (East Carolina University)

The consideration of a dual kidney-pancreas transplant (SPK) will depend on a balance between the beneficial effect of euglycemia versus the detrimental effects of an additional surgery. While studies have shown that SPK transplants improve diabetic control and diabetic lesions, these studies are small and uncontrolled.

The Collaborative Transplant Study looked at 15,000 type 1 DM patients from 1984-2007. It showed that patient survival was greatest in those receiving SPK, follwed by liver donor kidneys (LDK), and then deceased donor kidneys (DDK). However, and quite importantly, it took 10 years for the survival in SPK recipients to equal (and then exceeed) that of LDK recipients. This is important because most pancreas transplants don’t last for 10 years (the half-life is a lot less, though Dr. Wiseman did not give a value). In addition, if the pancreas transplant were to fail, the patient survival of an SPK patient drops down to that seen in DDK recipients.

Dr. Wiseman’s group analyzed this data further, and looked at the difference in patient survivals in a shorter time period (84 months). The following are hazard ratios for patient death, compared to SPK’s:
SPK, with pancreas function (P+) —
LDK 1.48
SPK, P- 2.39
DDK 2.0

Since patient survival, both at 10 years and even as short as 84 months, is driven by pancreatic function, what are the factors that influence pancreatic graft survival? Donor-specific factors include: age (older is worse), BMI (higher is worse), DCD status (+ is worse). Recipient-specific factors include: BMI > 30 (HR graft loss 1.4), prior dialysis (HR graft loss 1.41), age > 45 (HR graft loss 1.68).

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Simultaneous Kidney-Liver Transplantation [Return to Contents]
Presenter: Randall Detwiler, MD (University of North Carolina – Chapel Hill)
Blogger: Tejas Desai, MD (East Carolina University)

Simultaneous liver-kidney (SLK) transplantations is primarily driven by the need for a liver. Thus, the traditional rules governing kidney transplantation do not apply. The need for a liver transplant is determined by the MELD score. In 2002, the MELD score was incorporated as the guideline for determining liver allocation. Since that time, the liver transplant waiting list has decreased, but the number of liver transplant or SLT surgeries have not. In addition, there appears to be significant geographic variability in the number of SLTs performed (highest in region 7, lowest in region 4).

It is not entirely clear why there is such geographic variability. UNOS has tried to implement allocation guidelines to limit such variability. The latest US Consensus Conference has provided the following guidelines for automatic SLKT procedures:
1) ESRD patients with cirrhosis and portal hypertension or a hepatic vein wedge pressure > 10
2) ESLD patients with an eGFR < 30
3) ESLD patients with AKI that requires renal replacement therapy for 8 weeks or longer (and this includes hepatorenal syndrome patients)
4) ESLD patients whose kidney biopsy (either percutaneously or via the transjugular approach) shows at least 30% interstitial fibrosis or 30% glomerulosclerosis.

Finally, for those cirrhotic/ESLD patients with concomitant underlying chronic kidney disease, a true biochemical assessment of their renal function may require GLOFIL testing (iothalamate testing) rather than serum creatinine measurements. The reason: creatinine production and metabolism is significantly altered in these patients with poor liver function and decreased muscle mass.

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Simultaneous Kidney-Heart Transplantation [Return to Contents]
Presenter: Maryl Johnson, MD (University of Wisconsin)
Blogger: Tejas Desai, MD (East Carolina University)

Heart transplant recipients who require renal replacement therapy immediately post-transplant have much poorer outcomes than those who are dialysis-independent. Data from UCLA between 1994-2001 showed that post-heart-transplantation, 41% of patients died early on if dialysis was needed, versus 3% if dialysis was not needed (“early on” was not clearly defined by the presenter).

UNOS data from 1998-2007 show that heart transplant patients versus simultaneous heart-kidney (SHK) patients have equivalent survival (provided that the former group does not require post-transplant dialysis).

Dr. Johnson showed a number of information-dense figures which are difficult to blog about. The general idea, however, is that kidney transplantation should be performed with the heart if there is any possibility of immediate post-operative renal replacement therapy.

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Alternatives to Urea Clearance [Return to Contents]
Presenter: J. Bargmann, MD (affiliation unknown)
Blogger: Tejas Desai, MD (East Carolina University)

Dr. Bargmann started off by making it clear that kT/Vurea is not a correct measure of dialysis adequacy. To support this claim, she provides various pieces of evidence. The most compelling reason is that the weekly kT/Vurea in PD patients is lower than that in HD patients, yet survival rates are approximately the same. How can it be that a lower kT/Vurea in PD leads to the same mortality rates as HD?

Rather, a proper measure of dialysis adequacy ought to take into consideration the removal of three classes of uremic toxins: 1) water-soluble low molecular weight substances (like urea), 2) middle molecular weight molecules (like B2 microglobulin), and 3) protein-bound molecules (like p-cresol). Conceivably, kinetic modeling for these 3 classes of uremic toxins would provide a more clearer picture of dialysis adequacy than simply focusing on one category.

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Catheter-induced inflammation in dialysis – pathogenesis and clinical implications [Return to Contents]
Presenter: Edwina Brown, MD (Imperial College)
Blogger: Tejas Desai, MD (East Carolina University)

Biofilm is the accumulation of microorganisms that are adherent to the catheter material. It accounts for approximately 80% of infections and are, themselves, resistant to antimicrobial agents. Biofilms are found in all catheters, including peritoneal catheters, and including those catheters that are not thought to be infected (that is, in patients who do not display signs/symptoms of a catheter-related blood stream infection). Biofilms of both PD and HD catheters are generally made of Staph. aureus. Moreover, biofilms have been found in dialysis tubing, though Dr. Brown did not go into this into any great detail.

Inflammation due to the catheter could be due to both the presence of the biofilm or the catheter material itself (usually polyethylene). There is a considerable amount of data that show worsening of inflammatory markers in patients with vascular catheters (low albumins, elevated CRP’s, low hemoglobins). PD catheters also increase peritoneal inflammation, as evident in animal studies showing a thickening of the peritoneal membrane within 4 weeks of catheter insertion. However, such inflammation is usually restricted to the peritoneum. The Global Fluid Study showed no changes in the [IL-6] (an inflammatory marker) in patients with PD catheters for months.

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Encapsulating Peritoneal Sclerosis [Return to Contents]
Presenter: Peter Blake, MD (University of Western Ontario)
Blogger: Tejas Desai, MD (East Carolina University)

Encapsulating peritoneal sclerosis (EPS) is a rare condition, that is most directly related to time on peritoneal dialysis. Despite its rarity, there is currently a preoccupation with EPS in Europe. Dr. Blake emphasized that this preoccupation, which he cannot explain, is actually leading to less utilization of PD as form of renal replacement therapy. Thus, he presented data to help “set the record straight” regarding EPS.

EPS is a clinical syndrome with symptoms of gastrointestinal obstruction + confirmation of calcifications and encapsulation of the intestines. Simply having GI obstruction or peritoneal calcifications is insufficient to make the diagnosis and leads to over diagnosis. EPS usually develops 4-7 years post-PD initiation, on average. It is rare to occur within the first 3 years of PD. Interestingly, this once universally fatal disease isn’t such anymore; 50% of patients survive. This, however, is unlikely to be due to new therapeutics to prevent or treat EPS, but rather due to earlier detection of more milder cases of EPS — a lead-time bias in essence.

He concluded his session by re-emphasizing that there really is no reason why EPS should dissuade a physician or patient from choosing PD. In his experience with PD patients, he has had only 1 patient with true EPS based on the true definition (and that patient has successfully been changed to HD).

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