Blogs from the 45th annual American Society of Nephrology Kidney Week 2012 Meetings in San Diego, CA.
- President’s message – Open Plenary
- Tolerance and Kidney Transplantation
- Sonography of the Kidney
- CT and MR of the Kidneys
- Nuclear Imaging
- Gadolinium and Complications
- Are CKD Patients Attaining Therapeutic Targets?
- Case Management of Patients with CKD
- Is More Better? How Often Should ESRD Patients on Hemodialysis Be Seen?
- Disease Management in ESRD Patients
- The Challenge of Phosphorus Control and Adherence in Maintenance Dialysis Patients
- Clinical Outcomes in Dialysis Patients Related to fluid Intake, Nutritional status, Dietary Protein, and Phosphorus Intake
- Tailoring Phosphate Binding Therapy to Reduce Pill Burden and Improve Adherence
- First Six Months: Induction Therapy for Proliferative Lupus Nephritis
- Renal Glucose Transport — Man to Molecule
- Pharmacological Management of the Cardiorenal Syndrome
- Ultrafiltration in the Cardiorenal Syndrome
- Cancer Screening in ESRD
- HIV Associated Glomerular Disease
- HCV Associated Kidney Disease
- Hyponatremia due to Congestive Heart Failure
- Sepsis and AKI: The Kidney as Target and Amplifier
- Genetic Responses in Polycystic Kidney Disease correlate to AKI
This year marks the final year of Dr. Ron Falk’s tenure as ASN President. His plenary session focused on achieving a “cure” for kidney disease. The plenary session began with a historical view of dialysis. Back in 1967, Dr. Carl Gottschalk (of UNC) helped author the Report on the Committee on Chronic Kidney Disease (link). In it, Dr. Gottschalk mentioned a number of ideas and goals that Dr. Falk touched on in his presentation.
First, the Gottschalk report discussed the ultimate need for a cure to kidney disease. Back in 1967, the most common cause of kidney disease was infection. Dialysis, which was recommended by the Report, was expressly viewed as a temporizing measure towards kidney transplantation. “Cure”, considered a “restoration of health” by Dr. Falk, is something that the nephrology community has strayed away from in recent decades. Indeed surgeons and oncologists are more likely to focus on “cure” than nephrologists; an idea that reenergized Dr. Falk. Dr. Falk encouraged all nephrologists (and perhaps even all health care providers) to focus on the “restoration of health” and cure kidney disease.
The Gottschalk report also mentioned that a balance would be realized between the treatment of kidney disease and knowledge. In both areas Dr. Falk insists that we must do more. Treatments of kidney disease have lagged, especially in an era when academia and industry have not worked closely because of conflicts of interest. Both academia and industry must re-double their respective efforts to work together in order to expand our knowledge of and find treatments for kidney diseases.
Finally, the Report also mentions a key goal of training the newest generation of nephrologists. To that end, the ASN is now offering 5 new research training grants for young investigators. The goal is to raise $20 million for these grants, with $14 million already raised in < 1 year (the largest is a $10 million contribution by Fresenius).
Dr. Sachs starts off this State-of-the-Art lecture by mentioning the need to identify how tolerance develops. The 2 big complications of kidney transplantation are 1) chronic rejection and 2)complications from drug therapy. Both could be mitigated by developing tolerance, but < 5% of kidney transplant patients ever develop spontaneous tolerance.
Tolerance can develop in 2 ways: 1) central tolerance, in which there is clonal deletion of cells in the thymus, and 2) peripheral tolerance, in which matured cells are eliminated from the systemic circulation. In both cases, chimerism (transplanting both the kidney and bone marrow of the same donor, after high dose irradiation to the recipient's bone marrow, to the latter) can help promote tolerance. Dr. Sachs went on to describe 3 clinical trials that have shown promising results.
1) ITN NKD01 link): a trial that looked at multiple myeloma patients who suffered from ESRD and needed both a kidney and bone marrow transplant. In these patients (n=6), high dose irradiation to the bone marrow allowed for a bone marrow transplant along with a kidney transplant from the same donor.
2) ITN NKD02 (link): this trial looked at patients who did not have multiple myeloma (and thus, did not necessarily need a bone marrow transplant) (n=5) but received both donor kidney and bone marrow. This chimerism was lost after 1-2 weeks but 4 of the 5 patients were maintained on no immunosuppressive medications.
3) ITN NKD03: this trial expands on ITN NKD02 by recruiting patients from more sites.
All-in-all, Dr. Sachs’ experience shows that chimerism results in 70% of patients becoming tolerant and only 20% losing their kidney allograft within 3 years.
Sonography of the kidney can reveal critical information of 1) renal parenchyma, 2) the urinary space, 3) masses, and 4) renal vasculature.
Renal Parenchyma: Renal ultrasonography can elucidate kidney size, shape, cortical thickness and echogenicity. Size is directly proportional to the height of the patient, but is conventionally thought to be between 10-12 cm. Width of the kidney, while measured often, is clinically not relevant. Most adult kidneys have a uniform shape. Unlike neonates that have a lobular or globular kidney shape (normal), adults lose this shape. If, however the lobular appearance is seen in an adult kidney, it would suggest scar tissue and chronic disease. Cortical thickness is measured from the renal capsule to the base of the renal pyramid; normal is about 5-9 mm. Although it is difficult to measure (because the pyramids are sometimes hard to identify), cortical thickness is the best assessment for the presence of CKD. Finally, echogenicity is a qualitative measure of how much sound is reflected. The more sound reflected, the more scar tissue (CKD) of inflammatory cells (ARF) in the kidney and the whiter it appears.
Urinary Space: Filling defects are commonly due to kidney stones. Stones are easily identified by their hyperechoic nature and the resulting lack of sound transmission deep to the stone (resulting in a shadow). The subsequent proximal hydronephrosis can also be seen with ultrasound, but keep in mind that 1) not all stones are seen, especially if there is overlying bowel, and 2) not all dilated ureters are due to hydronephrosis (pregnancy, diuresis, stents all cause dilation of the ureter w/o mechanical obstruction).
Masses: Ultrasound is excellent at discriminating between fluid-filled (e.g., cysts) and solid masses. Simple cysts are thin walled, w/o internal septations or echoes, and w/o calcifications. Complex cysts are characterized by the opposite. Whether simple or complex, all cysts cause distal enhancement. This feature is not seen in solid masses, which makes it a good discriminating feature. Nevertheless, ultrasonography should not be used as a screening tool for solid masses.
Renal Vasculature: Peak systolic velocities of the renal artery are difficult to calculate with ultrasonography unless you have an experienced ultrasonographer. That’s because the angle of the sound plays a large role in this calculation. On the contrary, the resistive indices of the interlobular arteries can be calculated easily regardless of the angle of the sound because you are comparing velocities, and not measuring an absolute velocity.
CT and MR are useful to evaluate renal cysts that have a Bosniak score (a href=”http://radiology.rsna.org/content/226/1/47.full”>link of 3 or 4. The CT scan uses Hounsefield Units (HUs) to quantitate the relative liquid content of a mass. Cysts, which are fluid-filled, have low HUs (0-5). Masses with more solid components and/or greater vascularity (both of which are features of malignancy) will have greater HUs. While MR also differentiates the relative liquid content, it does so in a qualitative manner.
Once you’ve determined that the mass has more solid features, you need to determine if there is enhancement. Enhancement is the most important factor in identifying malignancies. For CT, iodinated contrast is needed to determine enhancement, while MR can measure the amount of water that can diffuse through tissue. With CT, enhancing lesions light up (appear bright) and have high HUs. With MR, lesions that allow water to diffuse easily (less solid in nature) appear bright.
Nuclear medicine scanning (commonly referred to as a MAG-3 scan) is excellent at determining glomerular or tubular function. 99-Technetium is the radioactive agent that is coupled to either DTPA (100% filtered, 0% secreted by the tubules) or MAG-3 (97% secreted by tubules, 3% filtered by glomerulus) depending on the structure you wish to analyze. Nuclear medicine images of the kidney are taken from the posterior view, so the right kidney is on the right side of the image. Scanned images then measure the number of radioactive counts over time in each region of interest (renal artery, cortex, renal pelvis, proximal ureter, distal ureter, bladder). These pictures over time can help you determine if there is poor uptake, obstruction, or both.
Dr. Swaminathan’s lecture was very interesting as he showed data to suggest that patients at increased risk for nephrogenic systemic fibrosis have higher ferritin levels, receive higher ESA doses, and have greater abnormalities in calcium-phosphate product. Specifically, it seems that skin biopsies of NSF patches are filled hemosiderin-filled macrophages. A 2007 JASN (link) study suggested that iron mobilization results in a dissociation of gadolinium from its chelating agent, causing deposition of gadolinium into the skin. In animal studies, administration of iron with gadolinium increases skin fibrosis, which can be reversed with iron-chelator therapy.
From NHANES 2005-2010:
13.1% of people have CKD
8.5 % have CVD
9.3% have DM
Top 3 adverse effects of CKD:
From KEEP data, risk of death in the CKD population is 16x greater than that of advancing to stage 5 CKD
Reference to Go et al. NEJM 2004; 351:1296-1305 – increasing CV disease with reduction of GFR across stages of CKD
Odds of Awareness, Treatment and Control of Complications of CKD – Snyder et al, 2008
Snyder JJ, Collins AJ. KDOQI hypertension, dyslipidemia, and diabetes care guidelines and current care patterns in the United States CKD population: National Health and Nutrition Examination Survey 1999–2004. Am. J. Nephrol. 2009;
Major KDOQI points:
-Manage dyslipidemias –
-Monitor/manage disturbances of mineral metabolism
-Get and influenze immunization
-See a nephrologist
KDOQI – less than 130/80
KDIGO 2012 HTN guidelines – less than 140/90
HTN in CKD from NHANES data from ADR 2012
-about 75% measured/treated
-Only approx. 25% aware, treated and controlled
KEEP data across stages of CKD – approx. 20% were aware, treated and controlled
Current ATP-III classification; (ATP-IV is eminent)
67% of NHANES population above target
-1/3 were unaware
-1/3 were aware, treated and controlled
-Less patients with eGFR 30mg/gm
SHARP simvastatin + ezetimibe vs placebo – across all ranges of pre-dialysis CKD there was benefit to treatment
-approx. 50% of CKD pts at goal A1C less than 7%, aware, treated and controlled
-? target overaggressive, so KDIGO recommends target of approx. 7% to prevent or delay progression of the complications of diabetes. Pulling back on the goal a bit.
Of patients with medicare claims and a dx code of 585.3 or higher in 2009, only 50-60% of these patients were referred to a nephrologist (same as % referred to a cardiologist). Need to further educate primary care physicians about timing of referral.
CKD is complex but co-exists with many other conditions, so develop optimal models of care that lead to good outcome for individuals, healthcare systems and and society
The Chronic Care Model developed by The MaxColl Institute (ACP-ASIM Journals and Books)
CKD is a chronic illness
-Define CKD in a consistent manner
-Consider development of care models specific to
b)Unique conditions (transplant, GN, other)
-Recognize complexity, need for integration and specialization
-Philosophy: Longitudinal, regular, multidisciplinary, integration of services
Team + nephrologist better than nephrologist alone (Canadian and Italian data)
? Multidisciplinary Clinics (patient goes to DM clinic, CKD clinic, lipid clinic, Cardiology Clinic vs just go to one clinic that is multidisciplinary).
Asked audience to raise their hands – most see their dialysis patients 4x/month – few see their dialysis once a month. I wonder if those who raised their hands see the patients themselves, or they were answering for themselves and their surrogate extenders (my commentary)
Since 2004, income (reimbursement) based on frequency of visits
– 2004 69% billed 4x/month
– By 2006 72% billed 4x/month
– Who took the burden of care after the policy care? Claims data does not answer this question for the visits that are not comprehensive visits (by the physician)
– From 2003 to 2004, median provider reimbursement per patient, per month increased from $248.50 to $276.90
– Medicare capitation changes from 2003 to 2004 reflected 13% increase in patient visits
– BUT is this reducing death and hospitalization? Slinin et al study (ASN 2012) – For hospitalization costs – $230/month or $2800.00/year savings but not lower mortality. So medicare pays providers more for outpatient dialysis care reimbursement but this reduces hospitalization cost so net even for medicare costs
ESRD population ideal for Disease management:
– Complex, multiple comorbidities, high morbidity/mortality
– CMS ESRD Managed Care Demonstration: improved QOL, improved processes of care, but no reduction in hospitalization at any site, and reduction in mortality at only one site, plus financial loss by medicare despite capitation
Design of the ESRD Disease Management Demonstration (3 areas or DMO=disease management organizations, evaluation period: January 206 to December 2008). 2 of the DMOs are ongoing, one is no longer functioning
o In-person f/u, telephonic f/u, home weight monitors by DMO C
o Areas in addition included pharmacist involvement, immunization rates, DM management, advanced care planning, free oral nutritional supplementation to improve nutritional markers and patient outcomes for albumin less than 3.8
o Compared survival, hospitalization, cost etc in the DMOs vs fee-for-service
• Results mixed based on the DMO, but 2 had improved survival compared to fee-for-service.
• Overall reduced hospital admissions but total hospital days and length of stay were longer; the reduced hospital admissions really came from only 1 of the 3 DMOs; DMOs did better in utilization of outpatient physician visits, SNF stays and ED visits
• The demonstration cost medicare 13.4% more than fee-for-service (FFS)
• Combining all disease management organizations, the estimated savings per patient per year was $500.00 per patient
o Is care coordination enough? Do we also need concrete intervention like DMO C who aggressively targeted albumin less than 3.8 and provided free supplements at this point to optimize nutrition. DMO C was really the DMO responsible for the reduced hospitalizations and overall cost savings
From DOPPS, 40-45% of dialysis patients in US have goal phosphorus
Why aren’t we doing well?
– High protein diet
– Food additives
– Phos absorption is poorly regulated
– Vitamin D
– Release from bone in severe secondary HPT
– Pill burden
– Tolerance of binders
– Inadequate removal of phosphorus by conventional dialysis
Let’s assume we can get phosphorus controlled – will we impact mortality? Yes, but this is a “qualified yes”
Needs for the future:
– Clarify ideal phosphorus – KDIGO says get it “normal” – what does that mean?
– Need evidence-based rather than opinion-based guidelines
– Better understand fully the benefits of lowering phosphorus
– Introduce more effective means of lowering phosphorus
Clinical Outcomes in Dialysis Patients Related to fluid Intake, Nutritional status, Dietary Protein, and Phosphorus Intake by Kamyar Kalantar-Zadeh, MD, MPH, PhD from UC-Irvine
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Critique this blog
Which of the following is/are the strongest predictors of death in dialysis patients?
Look at changing weight over 6 months:
– Patients who lose weight and he has to decrease the dry weight, they do poorly
– Patients who cramp and have gained weight and he has to increase the dry weight, they do well
Overnutrition is a killer, but takes 10, 20 or 30 years
Undernutrition kills you quickly (i.e. cancer) and will kill your patient before overnutrition is relevant
Which is the following is the strongest predictor of better survival in dialysis patients?
1. Higher Hgb
2. Lower serum phos
3. Higher serum albumin
4. Lower serum calcium
Serum albumin >3 is associated with significant increased mortality. If albumin drops by 0.1 or 0.2, mortality goes up by 100% or so.
What is the recommended dietary protein intake in dialysis patients?
1. 0.3 to 0.4 gram per kg ideal body weight
2. 0.6 to 0.8 gram per kg ideal body weight
3. 0.9 to 1.1 gram per kg ideal body weight
4. 1.1 to 1.3 gram per kg ideal body weight
5. >1.5 gram per kg ideal body weight
Mortality is quite high when protein intake is low.
nPNA estimates daily protein intake
Now let’s connect it all together:
– Phos comes from protein
– KDOQI conflict – low phos diet is good AND high protein diet is good
– Phos/Protein ratio (P-to-P ratio)
o Egg whites 1.4mg phos/gm protein
o Egg yolk 24mg phos/gm protein
o Small study by dietician – given egg white based supplement they can lower phos
– BUT Highest dietary phos = highest mortality
– Phos from Plant vs Animal Protein (Kalantar-Zadeh et al, CJASN 2010.; Noori et al, IJKD 2010)
– Organic phosphate is found naturally in foods and is largely bound to proteins, which impair phos absorption
o Plant proteins like nuts, beans, chocolate
o Animal proteins like fish, meat, chicken
– Inorganic phosphates = additives and preservatives:
o Extend shelf life, improve color, enhance flavor, retain moisture and are not required for food manufactures to list on the food item
o www.foodadditives.org – search food additives and they try to convince you why phosphorus is good
– Sullivan C et al. JAMA 2009;301(6):629-35 – Educating CKD stage 5 patients on the avoidance of phosphorus-containing foods can lower serum phosphous
– The lower your income, the higher your phosphorus
– The more educated you are, the lower your phosphorus
– Cupisti et al, J Ren Nutrition 2012 (e-pub) – measuring phos that is added to food
– Next question: should serum phosphorus be controlled by decreasing dietary protein in dialysis patients?
o We may not help our patients by doing this, we may hurt them
o Pt’s who can get phos down and protein up, have best survival (so far observational studies only)
o DON’T BE PROUD OF THE PHOSPHORUS OF 3.2 BUT YOU ARE STARVING YOUR PATIENT TO DEATH!
– Any phos binder is better than no binder Kovesdy et al, AJKD 2010
– Does higher pill burden = higher volume
o Each pill = 55cc water
o Need more attention on dietary non-protein restriction (fast food and additives)
o Protein intake should be liberalized (?)
o More attention to the phos-protein ratio
Lots of attendance today and yesterday at the CKD-MBD (mineral bone disorders) talks, people recognize this is an important topic. We need to:
o Prevent symptoms: brown tumors, other bone complications, calciphylaxis
o Prevent parathyroid hyperplasia
o Slow progression of vascular calcification
– We have convincing observational data re: increased phosphorus and increased mortality
– More recently, lots of excitement about FGF-23
o Association with FGF-23 and mortality and multiple populations: dialysis, pre-dialysis CKD, transplant and healthy population
– KDIGO and KDOQI both have strong guidelines in this area with KDIGO focusing more on trends
– So guidelines say control phosphate, medical directors say get your phosphorus in line because our unit doesn’t look so good…
– Recent review by Tonelli M et al NEJM 2010 (nice diagram re: phos handling)
– Various dialysis modalities remove phosphate differently; also depends on starting phosphorus
How efficient are binders in terms of classes?
o This is a complicated question to answer
o Recently there has been some smart work in this area: Daugirdas JT et al Semin Dial, 2011
• Came up with a relative phosphate binding coefficient (RBPC)
• Calcium carbonate RBPC of 1.0
• Aluminum RBPC of 1.5
• Sevelemar RBPC of 0.75
• Lanthanum carbonateRBPC of 2.0
o Then they came up with a phosphate binding equivalent dose (to gm of Ca CO3)
• i.e. 500mg lanthanum can bind 45mg phosphate – see Daugirdas article for more
Effect of health literacy and numeracy – Cavanaugh KL et al JASN 2010; Green JA et al CJASN 2011
o Patients knowing their phosphate
o Navigating the health care system
• Dealing with prior authorizations
• Avoiding donut holes
o Patients soliciting advice from the nutritionist
o Change dietary skills
o Remember to take medications
What is compliance?
o Taking 80% of pills
• In CKD studies compliance = 50%
• In ESRD studies = 38%
• In binder studies, big reason of poor compliance is gastrointestinal intolerance
KDIGO and uptodate both recommend – glucocorticoids combined with either cyclophosphamide or MMF for induction
Where do these recommendations come from?
1. Euro-Lupus Nephritis Trial (Houssiau et al, Arthritis Rheum, 2002)
– Multicenter, prospective, 90 patients with proliferative LN
– High dose IV CYT (monthly x 6 months + 2 quarterly pulses) vs low dose IV CYT (fixed pulse dose of 500mg Q 2 weeks x 6 doses)
– Freedom from renal flares identical
– Less infection in low dose group
– Now 10 year f/u available
o Identical Cr at 1.0mg/dL
o Essentially identical proteinuria at .5-.6gms/day
o Cumulative CYT dose less in low dose group
o Very good clinical results in the long-term
– Cautious about:
o Largely Caucasian – can you apply this to Hispanics and AA patients?
o Moderately severe LN – can’t really apply this to abundance of crescents and Cr of 3-4
o Longterm IS (GC and other IS)
o They required ACE-I and/or ARBs
o Done at referral centers
2. Ginzler trial – Ginzler E, Appel G et al, NEJM Nov 2005
– Young ~31-32y/o
– 1/3 or more African American
– More CR with MMF, more CR+PR with MMF
– Creatinine and proteinuria comes down with both
– Renal flare and renal failure not statistically significant in terms of differences
– Problems with study – crossover design – if failing at 3 mos could go to other therapy; all U.S., no info about maintainance
3. ALMS trial
– RCT MMF vs IVC in severe LN, 1/3 Asia, 1/3 US+Canada, 1/3 South America
– 53 to 56% had CR
– MMF was not superior to CYT but was similar
– Cr and proteinuria improved similarly
– All lab markers improved similarly (alb, C3, C4, dsDNA)
– Adverse events were exactly what you would expect: more diarrhea with MMF (28%), alopecia with CYT (35%
– Mortality similar – only 4.9% with MMF and 3% with CYT (not statistically significant – 6 of the 9 deaths on MMF were in China and 5 of the 6 were at a single center in China)
– This induction trial led into a 3 year maintenance trial
4. LUNAR trial
– Rituximab vs IV placebo – all on MMF + steroids
– Largest randomized, placebo-controlled trial to evaluate rituximab in LN
– At 52 weeks, no response in 54% in placebo and 43% in Ritux group (not statistically significant); can’t really draw firm conclusions based on trends.
– Subset analysis (not pre-specified in design); might be more response in African Americans, also slightly improved response in Hispanics
– IV CYT and MMF overall appear equivalent in inducing remissions
– IV CYT by the Eurolupus protocol uses overall les CYT with equal results to the older NIH regimen (Caucasion in Eurolupus)
– The role of rituximab is unproven
– CNIs should be considered as add on to other therapies
– Newer agents may have a role but need to prove themselves in RCTs
This was a fascinating translational research lecture by this year’s Homer Smith award recipient. Early on in his career, Homer Smith noted that the nephron was able to fully absorb all the glucose it filtered. In addition, he noted that the drug “phlorizine”, first identified in 1855, could increase renal excretion of glucose by some unknown mechanism. In the 1960s, Robert Crane proposed that glucose absorption occurred through an active co-transport process with sodium. Dr. Wright became fascinated with renal glucose transport and in 1984, his work led to the discovery of the sodium-glucose co-transporter (1 and 2) in the proximal tubule of the nephron. This transporter would allow the kidney to reabsorb all the filtered glucose, against its concentration gradient, but allowing sodium to be reabsorbed down its concentration gradient. This co-transport was further elucidated by Dr. Wright to be the key mechanism by which the kidney reabsorbs filtered glucose.
Why is this important? It turns out that mutations in the SGLT-1/2 receptor gene causes tremendous loss of renal glucose. However, these patients are completely asymptomatic and do not have any increased risk of developing kidney disease. Interestingly, patients with these genetic mutations are thin and highly unlikely to develop diabetes mellitus. Indeed in diabetic rat models (JCI p1510), drugs (like phlorizine) inhibit SGLT-1 function and decrease serum hemoglobin A1c levels.
These findings have led drug companies to investigate a total of 21 new non-insulin-derived drugs to antagonize SGLT-1/2 receptor activity and help treat diabetes mellitus. One such drug, dapagliflozin, reduced A1c by a full 1%, facilitated weight reduction, but did not cause any hypoglycemic adverse events (Lancet 2010 p2223). These findings are very interesting and promising because they suggest that a non-insulin-dependent mechanism exists to help treat diabetes mellitus.
Five drugs that antagonize SGLT-1/2 are currently in phase 3 trials and another 2 have been submitted to the FDA.
There are many changes occurring in the study of preeclampsia (PE). For starters, the diagnostic triad of hypertension, proteinuria, and edema will be changing. Edema is no longer in the diagnostic criteria for PE, and proteinuria will soon be falling out as well. This just leaves hypertension, which studies show is not correctly measured in pregnant patients (PRAM Study), as the only criteria for diagnosis (for now). A promising diagnostic tool is the biomarker soluble FMS tyrosine-like kinase 1 (sflt-1). To understand how sflt-1 is used as a biomarker, we first have to understand what it does.
The normal pregnancy is marked by increased angiogenesis in the placenta. When the normal pregnancy is about to be completed, anti-angiogenic factors, like sflt-1 or sEng, are secreted to curtail angiogenesis and facilitate labor. Normal pregnant patients will express sflt-1, but at low levels and late in the 3rd trimester. PE patients, however, express sflt-1 much earlier (late 2nd/early 3rd trimester) and significantly higher levels. This feature makes sflt-1 measurement a possible diagnostic tool for detecting PE, especially since proteinuria and edema are no longer part of the diagnostic triad.
A study in AJOG 2010 showed that the sflt-1/PiGF ratio of 85 or greater has an ROC AUC of 0.99 for diagnosing PE (PiGF is a pro-angiogenic factor that is reduced in PE patients). It is only a matter of time before we begin using this biomarker to diagnose PE (rather than clinical findings).
However, since sflt-1 over-expression is the reason for why PE occurs in the first place, therapy of PE that targets sflt-1 may have promise. Unfortunately, pharma companies hesitate to test any new drugs on pregnant patients (the last drug tested and released by pharma companies was oxytocin in the 1970s). Therefore, one must look to remove sflt-1 rather than neutralize it with antibodies or other molecules. Here there is promise in a resurrected old therapy: lipoprotein apheresis. In lipoprotein aphresis, columns of negatively charged particles are exposed to the blood of PE patients and bind to the extremely positively charged sflt-1. These columns, when used at regular intervals during pregnancy, can maintain a steady low level of sflt-1 and prolong gestation (RAAPID Trial in Circulation 2011). Prolonged gestation is key as both speakers mentioned repeatedly that fetal outcomes improve greatly the longer the gestation period.
Dr. House reviewed a trial data to help us understand the evidence behind the use of certain medical therapies for the cardiorenal syndrome. The first trial, DOSE-HF, studied low-dose diuretic versus high-dose in both bolus and continuous infusion administrations. The study concluded that there was no difference in low- versus high-dose diuretics or infusion versus bolus in the primary endpoint.
Trials such as SOLVD, Val-HeFT, CHARM, CONSENSUS indicate that ACEi and ARB improve cardiac function and overall mortality from cardiac disease, but they don’t look at renal-specific endpoints such as time to doubling creatinine or progression to ESRD.
A new drug, LCZ696, is being studied in the PARADIGM-HF and PARAMOUNT trials (Lancet 2012 p. 1387). LCZ696 is a nephrilysin inhibitor, which ultimately allows the increase of endogenous natriuretic peptides and natriuresis as a result. The PARAMOUNT trial compared LCZ696 to valsartan: LCZ696 arm showed a reversal in cardiac re-modeling and an improvement in NYHA score. PARADIGM-HF trial, not yet published, compares enalapril to LCZ696 on mortality and renal function (2* endpoint).
BAY 94-8862 is a non-steroidal highly selective mineralocorticoid antagonist (stronger than eplerenone). It is currently being studied in the ARTS trial and results are pending.
This was an extremely informative lecture by Dr. Kazory. There has been a tremendous push in Cardiology and the cardiology literature to begin using dedicated ultrafiltration machines to achieve a faster and more controlled natriuresis in acutely decompensated heart failure (ADHF) patients. Studies such as JACC 2005 p2043 and Br Heart p534 indicate a faster and predictable rate of fluid removal with ultrafiltration (compared to diuresis with loop diuretics), improved removal of sodium and limited hypokalemic episodes.
Trials such as UNLOAD (JACC 2007 p675) have compared ultrafiltration to IV diuretic therapy in ADHF patients over 3 months and have shown a decrease in the number of rehospitalizations (down 53%) and length of stay in a rehospitalization (down 62%) in the UF arm.
While the cardiology world seems to sold on the idea of using ultrafiltration over diuretics, there are a number of unanswered questions that Dr. Kazory brings up.
1. are there any reno-protective effects of using UF over diuretic therapy? There is limited evidence to answer this question since almost all of the trials are managed by cardiologists who look at renal endpoints in secondary analyses only. The one study that is worth mentioning is in Cong Heart Fail 2008 p298 which showed a decrease in renal function in the UF arm, but again it was not the primary endpoint.
2. is there an impact in long-term mortality with UF? Cardiology studies show decreased mortality in the short term (90 days) but there are no studies that look at mortality at 6 months or even a year. So we really don’t know if UF will actually help change the course of disease or if it just helps in the short term.
3. is it cost-effective? Here the data is very sketchy because most of it is unpublished (personal communications). Therefore, Dr. Kazory was unable to make a conclusion about cost effectiveness.
4. are there any guidelines for initiation or discontinuation of UF, the optimal UF settings, who should be performing UF (cardiologists versus nephrologists)? The jury is still out on this (depending on whom you ask, of course) but the CARRESS-HF trial will hopefully have some answers (J Cardiac Fail 2012 p176)
One of the landmark studies looking at cancer screening in ESRD patients came from the Lancet in 1999. These investigators followed 831,804 ESRD patients from 1980-94 and found that the relative risk for renal cell carcinoma (compared to the general population) was 3.6.
bladder/ureteral cancer —– RR 1.5
thyroid cancer —– RR 2.3
cervical cancer ——- 3.6
multiple myeloma —– 4.0
There was no statistically significant increases in the RR for lung, breast, and colon cancer when compared to the general population.
So why are some cancers more likely to develop in ESRD patients? For renal cell carcinoma, the answer lies in the development of acquired cystic kidney disease, which itself increases the risk of malignancy. Nephron 1991 shed some light by suggesting that there might be a detection bias, since the initiation of chronic hemodialysis may be the first time that a patient receives extensive medical evaluation. There may also be impaired immunity causing an increase in oncogenic infections (EBV, HPV) or the association of kidney disease and HBV or HCV may cause an increase in other malignancies.
As a cause of death, females over the age of 50 studied in an Archives of Internal Medicine 2006 paper had a 5 year survival of only 25%. But when one looks at the risk of death for an ESRD patient over the age of 65 to a normal renal function patient over 65 but with either breast or colon cancer, the ESRD patient (w/o cancer) has a greater mortality then either the patient with breast or colon cancer. It seems that simply having ESRD puts you at a higher risk of death than 2 of the most common cancers in America; perhaps due to the tremendous increase in cardiovascular risk that overshadows the risk of death from malignancy.
While the diagnostic accuracy of pap smears is not affected by having ESRD, the same is not true for fecal occult blood testing (FOBT) or PSAs. Non-malignant conditions such as gastritis or angiodysplasia, found frequently in ESRD patients, provide many false positive FOBTs. Free PSAs are dialyzable, thereby iatrogenically lowering the total concentration in the serum. However, just like in the general population, there is no clear answer as to whether PSAs should even be checked.
The bottom line for cancer screening is that most ESRD patients won’t live long enough to reap a benefit from the screening process. Cancer screening only adds 1.3 days of extra life in a dialysis patient over 30 years. Most ESRD patients won’t live for an additional 30 years to see the extra 1.3 days of benefit because of the overwhelming risk for cardiovascular mortality. Cancer screening, therefore, would only be useful if there was a good chance the ESRD patient could receive a transplant.
HIV patients are living much longer since the advent of antiretroviral therapy (ART). As a result, HIV is now considered a chronic condition. As such, there are a number of kidney conditions that arise from being chronically infected with HIV. Classic HIV-associated nephropathy (HIVAN) is very common in African Americans (90%), produces large echogenic kidneys, and leads to rapid ESRD. Histopathologically it appears as collapsing FSGS with tubular microcyst formation. Thankfully, HIVAN can regress is appropriate antiretroviral therapy is initiated.
A new entity is HIVICK (HIV-immune complex kidney disease). The exact pathophysiology is not understood and it’s even unclear that it is directly related to HIV infection, but HIVICK is seen in a number of patients with HIV. Stay tuned for more information about this entity as research is underway.
Although a lot of attention is paid to HIV, the incidence and prevalence of HCV is six times (6x) greater than that of HIV (in the US). A large percentage of HCV-infected patients suffer from extra-hepatic manifestations (about 35-40%). The most common extra-hepatic manifestation is vasculitis, with 81% being small-vessel vasculitis mediated by cryoglobulins and 19% affecting the medium-sized vessels through non-cryoglobulinemic immune complexes.
Of the patients who have HCV, 40-50% will have cryoglobulins (cryocrit > 2%) but only 10% will be symptomatic. Interestingly, those patients that have symptomatic cryoglobulin vasculitis, there is a higher risk of lymphoma. Indeed a number of studies have showed such a higher risk that physicians are beginning to consider cryoglobulinemic HCV as a pre-malignant condition.
Treatment of HCV is aimed at preventing liver disease, vasculitis (the most common extra-hepatic manifestation) and lymphoma. The mainstay of therapy is interferon alpha (IFN-a). Endogenous interferon is suppressed by HCV, thereby allowing it to survive. Administering supplemental IFN-a can help kill the virus. However, IFN-a takes about 6 months to work, so if the patient is having active disease, another therapy will have to be added. At this time, the evidence suggests that rituximab can have immediate effects at lowering HCV activity.
TPE (plasma exchange) is, interestingly, not a first line therapy for cryoglobulinemic HCV, but mainly used for life-threatening situations.
Hyponatremia is a common electrolyte abnormality in CHF patients and is associated with worse outcomes. Dr. Palmer’s talk addresses mortality associated with hyponatremia, management of hyponatremia in CHF with Tolvaptan, and ideal dosing of diuretics.
A prospective study of 98,411 patients revealed incidence of hyponatremia (Na <135 Meq/L) as 14.5% among all admitted patients. In multivariate adjusted models, hyponatremia was associated with higher mortality but once hyponatremia resolved there was a significant reduction in mortality and morbidity. Am J. Med.122:857-865, 2009.
Overall, poor outcomes with hyponatremia are echoed in patients with CHF. The incidence of patients admitted with hyponatremia in CHF patient’s ranges from 11.5 to 27%. The development of hyponatremia during hospitalization was also associated with higher mortality and morbidity. J Card Fail 18:620-5,2012
As with other causes of hyponatremia, in CHF, the water intake exceeds the renal water excretion. Vasopressin (AVP) plays an important role in regulation of plasma tonicity. The effect of vasopressin depends on the location and type of receptors. Among the receptors V1a, V1b and V2, renal effects of vasopressin including free water absorption are carried out through V2 receptors located in the renal collecting ducts. Dr. Palmer comments on the established association of elevated AVP and NYHA class IV to discuss the role of AVP antagonists in treating hyponatremia and volume overload in CHF patients.
Dr. Palmer describes the 5 types of Cardiorenal syndrome with emphasis on the classical presentation CHF exacerbation. The classical Type 1 cardiorenal syndrome presents as low cardiac output and low renal perfusion. Venous congestion plays a key role in reduced renal perfusion since eGFR correlates to central venous pressure rather than ejection fraction. Clinical cardiology 34:113-116,2011.
SALT-1 and SALT-2 studies have established the role of Tolvaptan in treating hyponatremia in CHF patients. Results show that Tolvaptan significantly improves and maintains Na levels in patients in two groups with Na levels <135mEq/L and <125 mEq/L. N Engl J Med. 2006;355:2009-2112.
Internists and cardiologists often face a dilemma in the course of the treatment of CHF exacerbation- choosing the appropriate dose and avoiding renal injury. Dr. Palmer answers the question.
“In patients with decompensated CHF, what is the optimal way to administer loop diuretics?”
DOSE (Diuretic Optimization Strategies Evaluation) Trial answers this concern by comparing low dose (IV dose = home PO dose) vs. high dose (IV dose= 2.5x home PO dose). Results show high dose was superior in net fluid loss, symptomatic relief-reduction in dyspnea, reduction in pro BNP and reduction in adverse events. The trial also established that there was no difference in outcomes with continuous vs. bolus dosing of diuretics. However it is also established that diuretics cause an elevation of Cr, reduction in eGFR and electrolyte disturbances, which cannot be ignored.
Dr. Palmer increases the curiosity about the use of other agents.
“ Are there differences in the renal function and hemodynamics when weight is reduced to the same extent by a loop diuretic as compared to a V2 antagonist?”
Diuretic effect of Placebo vs. Tolvaptan vs. furosemide was compared in dogs using urine volume, urine osmolality, free water clearance, urine Na and K excretion, change in AVP, aldosterone and epinephrine as parameters. The result was astonishingly supportive of Tolvaptan as an effective agent with free water clearance, minimal change in Cr, electrolytes, low incidence of azotemia and no increase in aldosterone with its use. Cardiovasc Drug Rev 25:1-13, 2007.
Dr. Palmer concludes with emphasis on Tolvaptan as an agent for CHF.
AKI most common causes:
40% of hospital AKI is from ICU setting
Definition: Severe sepsis = sepsis + organ dysfunction or hypotension
We have seen some improved outcomes over recent years in this population likely due to decreasing incidence of over-ventilation and replacement of large volume normal saline rescuscitation with sodium bicarbonate or lactated ringers.
Severe sepsis more common in:
elderly (age over 65 yrs)
co-existent chronic condition (cancer, CHF, CKD, HIV)
CKD is the 4th most common underlying disease and a cause for increased mortality with sepsis
1/3 of patient mortality is early, within the first week from multi-organ failure
2/3 of patient mortality is after the 1st week
(* late mortality mechanism: immunosuppression with secondary bacteria infection eg.
PNA or reactivation of latent viruses)
Refining Animal Models of Sepsis:
Model 1: Aged cecal ligation puncture Mouse sepsis model
— 1st 6 hrs well
— After 6 hrs they get sick –> polymicrobial infection –> increase in proinflammatory cytokines –> multiorgan injury –> reproducible AKI with tubular vacuolization on responsive to TNFα blockade
— 24-48 hrs splenic apoptosis with high mortality
Model 2: Uterine ligation E coli infection Mouse model
— In this model as in human sepsis older animals did worse
Existing paradigm of Sepsis informed by the research in his lab:
— initial events unlikely to be sequential
— late events may be more important than previously thought
Early Events: Phagocytes take up bacteria through Scavenger type B receptors rather than classical phagocytic receptor –> Toll-like Receptor (TLR) Activation –> immune activation –> splenic apoptosis –> circulating microparticles that mediate DIC and transfer sepsis
Late Events: HMGβ1 release
Blocking Scavenger receptors:
↓TNF, IL6, IL10
↑neutrophil infiltration and bacterial killing
ultimately increased survival, decreased morbidity and mortality in mouse model
Targets for therapy:
TLR inhibition (use of chloroquine)
αMSH analogue (AP214, longer half life now in phase 2 trials)
Bone marrow stromal cells – track to lungs and interacts with macrophages to
shift the cytokine balance, acts “at a distance”
Calpains- calcium activated cystine protease
— Increase inflammation and lymphocyte apoptosis
— Regulate pathogenic pathways
— Decrease splenic apoptosis
— Decrease circulating microparticles which promote DIC
some common biological process activated as in AKI/CKD
HMGβ1: high morbility group B1, made in spleen, autocatalytic,
Folic Acid CKD mouse model:
— AKI: increase of TNF, IL6, IL10, VEGF (acute early dz), HMGβ1 (late dz)
Targets for intervention:
— VEGF (early, 0-6 hrs)
— HMGβ1 (late, ?)
ARPKD 1:20,000 live births
Model: cpk mouse with close phenotypic appearance to ARPKD with disruption of cystine gene or primary cilia protein. Investigator crossed B6-cpk mouse with CAST mouse, which apparently allowed them to produce mice with variable pace of cystogenesis.
Traditional view of cystogenesis:
— epithelial cell dysfunction –> cyst growth and fibrosis
abnormal proliferation, differentiation, apoptosis
cell transport abnormality + ECM abnormality
New addition to this paradigm is upregulation of cyst growth by stress, ischemia and trauma leading to innate immune response which triggers vascular dysfunction feeding back into cyst growth. They propose this process can be down regulated by NGAL and TNF inhibition
Genome wide analysis was performed on mice with severe cystogenesis to obtain gene transcript data. Identified genes with differential expression and grouped the biological processes regulated by genes with highest up regulation. Found 3 major biological pathway involvement:
— inflammation –> innate immune response –> complement activation with acute phase response
— oxidative stress –> innate immune response
— vascular dysfunction
These findings triggered them to look at biological processes associated with AKI. They compared existing transcriptome functional annotations for AKI to those that they found for cpk kidneys.
In same manner they looked at genes differentially expressed in AKI and found strong overlap in biological pathways in AKI and cpk
Looking at genes most overexpressed at 36 hrs post ischemia they identified a few candidate genes for therapeutic targets:
— navcr1 (him1?)
— Lipocalin2 (NGAL)
— Hmox1 (hemoxygenase1)
Similarly they identified biomarker candidates expressed prior to the injury marker:
— MCP1 – cc12 gene
— CD14 – an early monocyte marker – very strong correlation
— 14 Other macrophage markers coincided with 25 highest candidate genes
Macrophage depletion has been shown to inhibit cyste growth in pkhd1-cre mice (JASN 2011. 22:1809-14) (link).
Macrophages form 2 populations M1, M2:
M1: Cc13, Cc19, Cc10, iNos, IL1ra, IL2ra, IL18ra, ifng
M2: Arg1, ccl17, CD163(haptoglobin receptor), Mr1 (Mannose receptor), F13a, Fcer1g, IL4ra, IL10ra, IL13ra, Saa3)
Many of the M2 markers were correlated, but none of the M1 markers. M2 correlates with macrophages in latent activation phase.