January 22, 2013 | Leave a Comment
5th Annual International Pediatric Nephrology Fellows Conference from Rio Grande, Puerto Rico
Acute Dialysis Pearls by Dr. T Bunchman of VCU
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The conference starts with Dr. Timothy Bunchman from VCU Peds Nephrology. Visit pcrrt.com for more information.
Case 1: A 15 year old female (71 kg) with new onset IDDM and has developed oliguria AKI with a K of 6.3 and Na of 175 (uncorrected), BUN 90, glucose 1300. FIO2 70%. The typical pediatric emergency. Everyone agrees she needs dialysis but her complicating factor is severe hypernatremia. (hyperosmolarity). The osmolarity of a PD solution is around 290-340 depending on the glucose concentration. For HD and CRRT, the osmolarity is around 285. The patient in this case has an osmolarity of > 400 and simple dialysis will lead to death from cerebral edema. Although HD would be the most efficient form of dialysis (compared to PD or CRRT), it may be the wrong choice in this patient given the huge discrepancy in osmolarities. Efficiency of HD = 30-50 liters/hr; PD 0.5-2 liters/hr, and CRRT 0.1-8 liters/hr.
To challenge the audience, Dr. Bunchman wants the group to write a 1) PD prescription, 2) HD prescription, and a 3) CRRT prescription in 3 minutes.
PD prescription by the audience: 4.25% dianeal solution with 0 potassium, continuous exchanges with 0.5-1 liter dwell volumes. Dr. Bunchman agrees with a continuous modality to change her osmolarity slowly – he suggests 24-30 osm drop per day (2* the change in sodium concentration, which is about 10-12 meq/L/day).
HD prescription by the audience: Blood flow of 150-200 ml/min (lower blood flows for more inefficient dialysis), dialysate flow rate as low as possible, a membrane that is the smallest possible (for low convective clearance). Change the sodium bath to as high as possible (limited by the conductivity of the machine). Dr. Bunchman also suggests a mannitol infusion.
CRRT prescription by the audience: Dr. Bunchman says either CVVHD or CVVH is equivalent in pediatric patients. Blood flow of 100 ml/min was chosen by the fellows (but this may clot the filter), with a dialysate flow rate of 1000 ml/hr based on a BSA of 1 meter squared. The fellows want to add 2 meq/l of K to the dialysate along with citrate because of the low blood flow. The group is satisfied with the dialysis sodium concentration of 134 meq/l. .
In reality, Dr. Bunchman performed CRRT on this patient with an additional sodium of 60 meq/l for a total sodium bath of 200 meq/l (400 osm bath). This was performed over 5 days and she did not experience any permanent neurologic sequelae. The take home point: the patient needs a replacement therapy that is inefficient using insulin to bring the K down.
Dr. Flynn asks Dr. Bunchman to speak about mannitol. It represents an osmolar load, similar to infusing 3% saline. Pediatric nephrologists don’t advocate mannitol because it has been implicated in causing neurologic sequelae.
Finally, Dr. Bunchman mentions in passing that another way to increase inefficiency is to run the blood and dialysate flow con-currently (instead of counter-currently).
Case 2: 4 year old child (20 kg) s/p stem cell transplant develops gram negative sepsis, oliguric, 20% volume overload, PEEP 10 but 90% FIO2, pH 7.18, K 6.8, BUN 85, and BP 80/40 on norepinephrine. Dr. Bunchman concedes that the patient requires RRTx, but what modality and prescription? Same 3 groups contemplate for 1 minute.
PD prescription by the group: 1.5% dianeal solution w/o heparin in the solution with small dwell times (fast exchanges). Of note, there is no risk of systemic heparin intoxication if you instill heparin intraperitoneally. Remember that PD solutions have lactate in them, which could keep the patient acidotic.
HD prescription by the group: Use an 11-french vascular access; add an additional vasopressor like dopamine (Dr. Bunchman disagrees with dopamine as it as fall out of favor), blood flow as low as possible (50 ml/min) because of the already low BP, dialysate flow 300 ml/min (choosing a less efficient mode because it is the patient’s “first run”); use heparin for anticoagulation. Overall, perform an inefficient form of dialysis because of worry of hypotension and clearing the norepinephrine. Dr. Bunchman indicates it is reasonable to worry about clearing the norepinephrine.
CRRT prescription by the group: perform both convective and diffusive clearances – convective to clear middle molecules which are facilitating the sepsis, and diffusion to clear smaller molecules. Dr. Bunchman agrees with the premise for convection. Access size would be dependent on whatever the surgeon provides, with which Dr. Bunchman totally disagrees. He recommends at least an 8-french in the IJ position. Blood flow of 100 ml/min with dialysate flow of 1 liter/hr dialysate and 1 liter/hr replacement. Keep in mind that the net solute clearance of a small molecule, like urea, is practically the same if you have a 2 liter/hr convective clearance or 2 liter/hr diffusive clearance, or 1 and 1 (as the fellows recommended). Fellows continue with a citrate-based anticoagulation strategy, with which Dr. Bunchman agrees.
Pediatric Nephrol 2008 p625-30: A great paper that suggests improved clearance of IL-8, 10, 18 using convective clearance in septic patients.
Vasopressor activity works better with improvement in acidosis. Since norepinephrine has a low molecular weight and limited protein-binding, effective dialysis would remove some of the norepi. Thus, those fellows who had a concern about drug clearance were right. Thus other vasopressors will be required at least in the very near term until you correct the patient’s pH. Dr. Bunchman doesn’t usually add a second vasopressor immediately upon the start of RRTx but will monitor the patient. He may even administer sodium bicarbonate acutely to raise the pH faster.
Case 3: 17 year old female on lithium who had a poly-pharmacy overdose. Found down with a Cr of 2.0, AST of 2400 and toxic lithium levels (with EKG changes). 30 seconds to write a prescription.
PD prescription by the fellows: no role for PD in this patient! Dr. Bunchman agrees.
HD prescription by the fellows: the indication for dialysis is that she is symptomatic (EKG changes) and cannot excrete the lithium via the kidneys or liver. Dr. Bunchman asks about standard versus high-flux. High flux has a greater membrane porosity. He recommends the high-flux dialyzer but keep in mind that Lithium levels rebound quickly because of their movement out of the cells.
CRRT prescription by the fellows: Use convective clearance for lithium toxicity, with which Dr. Bunchman agrees.
Finally, charcoal is not recommended anymore for many poisonings. He recommends visiting www.extrip.org that looks at the best modalities for treating poisonings.
Glomerular Disease Pearls by Dr. C Nester of the University of Iowa
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Dr. Nester starts out with the nephritic syndrome, which is characterized by 1-2 grams of proteinuria in 24 hours. Many can have hematuria with RBC casts, pyuria, hypertension, and/or fluid retention. They can be grouped into acute, chronic, and rapidy progressive. From 2011 USRDS data, all GNs seem to be stabilizing at a prevalence of about 15,000-25,000 cases per million population.
The most common primary GN causing ESRD in the peds population since 2004 is FSGS with IgA as the second most common. SLE nephritis comprises the most common secondary etiology of GN-induced ESRD.
Case 1: A 14 year old presents with brown urine 14 days after being started on augmentin for a sinusitis infection. In addition she has an upset stomach and can’t take PO for 6 days. Urine microscopy shows dysmorphic RBCs with granular casts. 2.9 grams of proteinuria with a Cr of 2.4. Her Cr was 0.6 a few days ago. Dr. Nester asks the audience what they will find on the biopsy.
Next step by the fellows: get some basic labs; get a head CT because of the sinus congestion; manage the hypertension. Dr. Nester chooses to ask a more detailed history including a family history. She would also admit this child because of the strong chance of having a rapidly progressive GN (defined as a Cr that’s going up fast).
Dr. Nester recommends immediate biopsy (including on the weekend) because of the rapid nature of the disease. In addition, the fellows recommend empiric treatment with steroids at the minimum. The fellows are worried about GPA, post-infectious GN, IgA nephropathy and/or HSP (because of the stomach complaints) and lupus nephritis. Since lab studies were requested, the audience recommends complement levels, ANA, anti-dsDNA, ANCAs and anti-GBM. Cryoglobulins, HIV, and HBV/HCV are less commonly ordered in the pediatric population. Dr. Nester emphasizes the history because there are many infections associated with GNs.
Dr. Nester asks the fellows what they would see on the biopsy. Most fellows agree that crescents will be seen on light microscopy. Dr. Nester walks the audience through the most likely histopathologic findings in each microscopic type (light, immunofluorescence, and electron microscopies).
This patient was given the diagnosis of post-infectious GN after receiving 2 empiric doses of solumedrol. Her biopsy was consistent with acute tubular necrosis (ATN). Dr. Nester recommends supportive care and stopped solumedrol after 3 doses. The ATN developed probably because of significant volume losses (diarrhea) and poor PO intake.
Dr. Nester now turns her attention to C3 Glomerulopathy, which is her area of research. This entity displays a predominance of C3 in the immunofluorescence. This is an alternate complement pathway mediated renal disease whose pathology is not clearly understood. C3 nephropathy is subdivided into 2 types: 1) dense deposit disease (type 2 MPGN), and 2) C3 glomerulonephritis (e.g., CFHR5 nephropathy). Dr. Nester is convinced that many patients with post-infectious GN who develop chronicity probably have a C3 glomerulopathy. The most scary feature of this condition is that it can recur in the transplant allograft.
80% of dense deposit disease has C3Nef factor. 45% of C3 glomerulonephritides have C3Nef factor.
The rules for transplantation change at the 18th birthday. Hint Hint — list every child before they are 18 years of age.
Current time thresholds are as follows: if age 0-5 years, wait time around 6 months, 12 months for kids aged 6-10, and up to 18 months for kids aged 11-17. Share-35 is an initiative to prioritize children who need transplants by giving them allografts from donors under the age of 35. Wait time, however, is regional (11 regions in the US). Nationally, since the implementation of Share-35, median wait times have decreased for 0-10 year olds, but regionally there are differences. By regions, region 11 (NC, SC, TN) have decreased their median wait times since 2004 (Share-35 implemented in September 2005).
Dr. Andreoni now talks about the details of the wait list. You can list a person at any age, but they may not accrue “time” unless they are advanced CKD or ESRD. A child can accrue time from the time they are listed as opposed to when they develop advanced CKD. In fact, UNOS data (2011) shows that 33% of kids are listed when not on dialysis; only 20% are listed when their GFR is > 30; 18% of pediatric patients receive pre-emptive transplants.
Even in children, living-donor half-lives are better than deceased donor half lives. This is important because after the implementation of Share-35, living donations dropped and deceased donations increased. This means that kids are receiving a kidney as their first transplant that won’t last as long as before Share-35.
A few technical issues: pediatric patients receive adult kidneys, usually anastamosed to the great vessels rather than the iliac vessels to avoid lower extremity claudication. Many times, the pediatric native kidney must be removed to make room for the allograft. It’s not absolutely necessary to place a ureteral stent but most surgeons do to minimize post-operative bstruction. The ureter is shortened so that it requires less blood supply (most of the ischemia occurs at the distal portion).
From 2005-10, the incidence of first acute rejection is higher for deceased donor than living donations starting at 12 months post-transplant. After 12 months, the incidences increasingly widen between the 2 types of donations.
Hyperacute rejection occurs in the operating room but should be completely avoidable with a proper crossmatch. Hyperacute rejections occur because of preformed antibodies (and thus is totally humoral). MHC is on chromosome 6 (class 1: A, B, C; class 2: DP, DQ, DR). There is also a minor histocompatibility complex (miH) that can cause rejection over time. MHC class 1 are on all nucleated cells. MHC class 2 are found only on antigen presenting cells.
Blood typing is a component of the crossmatching process. Class 1 and 2 MHCs are also matched. Also look for anti-donor antibodies or donor specific antibodies (DSA). These are non-HLA antibodies.
Blood type A is a bit special. Most people are A1 (85%). Non-A1 antigens are in lower density and not has immunologic. Because of these 2 features, non-A1 donors can work with group O or B recipients as long as the recipient has low titers (< 1:8) of anti-nonA1 antibodies.
How do we test for the presence of anti-HLA antibodies? Previously PRAs were done — a cytotoxic assay against the cells from the population. PRA testing is now outdated. Flow cytometry (luminex) is the current testing of choice to determine which allele is the culprit. The flow is resulted in a cPRA (calculated PRA). OPTN.gov can tell you cPRA or the likelihood (percentage) that the established donor pool- specific recipient combination will have a positive crossmatch (meaning the donor cannot give a kidney to the recipient).
Dr. Andreoni now turns his attention to immunosuppressants in pediatric transplant recipients. Data is from www.srtr.org. Most use a T-cell depleting agent like thymoglobulin or campath (rare use) or IL-2R blocker (simulect) as induction agents. Steroids are also considered an inducing agent along with tacrolimus. All recipients are placed on valganciclovir except for those transplants that are D-R- for both CMV and EBV. TMP/SMX is used for PCP prophylaxis for all patients regardless of CMV/EBV status. Most kids don’t receive rapamicin. Nevertheless, Dr. Andreoni recommends that we become familiar with all the drugs because we never know when we need to change or if we will be institutionally limited.
Now onto the kidney allocation process. Historically, you received pouts for the number of HLA matches (2 points for each HLA match), 1 point for every year you wait, and 4 points based on your PRA. Now, allocation process prioritizes anyone who needs a multi-organ transplant (e.g, heart, liver, liver, pancreas). 2 points maximum for HLA matching (only DR), 0-4 points for a cPRA >=80, and still 1 point/year waiting. Share-35 is will be changing to KPDI 0.35. In fact, ECD kidneys will now be determined by the KDPI rather than age, HTN, DM alone.
Nephrotic Syndrome by Dr. D Gipson
Nephrotic syndrome has a prevalence of about 16/1,000,000. Approximately 80% are responsive to steroids. There is a high financial cost for treating kids with nephrotic syndrome: in 2009, $146 million for all hospitalizations (on an average per individual, about $28K per hospitalization).
In a biopsy cohort back in 1978, 77.1% of patients 1 year of age with proteinuria had FSGS at all age ranges (1-5; 6-10; 11-15; and 16-19 year olds). Interestingly, lupus membranous disease increases starting at the age range of 6-10.
The leading cause of ESRD in pediatric patients is becoming cystic kidney disease since 1996 (USRDS ADR 2011). Not all countries have seen the conversion from genetic conditions to cystic kidney disease.
Dr Gipson now turns her attention to FSGS and why the outcomes are poor. This is probably because FSGS is not a single condition yet we treat it as one disease. Turns out, there is only one risk factor that we know upfront, before the start of our initial evaluation: their race (specifically if they are African-American).
Dr. Gipson now turns her attention to NEPTUNE (Nephrotic Syndrome Study Network). NEPTUNE was initiated to establish multi-disciplinary research and education platform for nephrotic syndrome. NEPTUNE is trying to increase translational research in FSGS, MN, and MCD. It is a prospective longitudinal study.
Hypertension by Dr. J Flynn of the Northwest Dialysis Clinics
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The casual office BP measurement is generally inaccurate. The technique is often performed incorrectly (using the diaphragm when you should be using the bell). There is “terminal digit preference” which occurs because the scale is in even numbers (there is no such BP as 137/95). BP varies during the day as well and their is an “accommodation effect” that occurs after serial BP measurements in the office.
Ambulatory BP monitoring (ABPM) is a procedure in which the patient wears a monitor which records the BP at regular intervals over 24 hours. These monitors usually capture 50-75 readings in a 24 hour period. These devices are devoid of terminal digit bias, observer bias, and allows us to detect circadian variation of BP. White NEJM 2003 showed that ABPM has a role in treating adults with HTN (it correlates with and predicts adverse cardiovascular and renal outcomes). Trials such as CKiD and ESCAPE also show a value for ABPM.
CKiD study (JASN 2010 21:137) showed that 40% of kids had masked hypertension (office BP normal but ABPM abnormal). LVH was common in children with confirmed or masked hypertension. There is an odds ratio of 4.1 of ABPM being a predictor of LVH. In a different set of data from the CKiD study (Hypertension 2012 60:43), as the GFR decreased the more likely a patient would have an abnormal ABPM. Patients treated with an ACE inhibitor were 89% more likely to have a normal ABPM than those not on ACE inhibitors.
In the ESCAPE study (NEJM 2009 361:17), 385 kids studied prospectively in Europe. Treatment arm was ramipril at fixed dose and then randomized to conventional versus intensified BP management. The latter group did not progress as rapidly to a 50% decline in GFR or ESRD as the conventional group over 5 years.
In Ped Transp 2011 15:635, LV mass decreased in patients who had ABPM measurements as well as carotid intimal-medial thickness after 5 years of monitoring.
There is a lot of clinical terminology in an ABPM measurement. The mean BP is an average for a specific time period or for the whole 24 hour period. The BP load is the percentage of readings above a specified threshold ( 10% dip is considered normal). Reversed dipping is when the sleep BP is higher than daytime — the most common examples are in kidney transplant patients (this could be due to short-acting BP medications taken only in the morning). Both diabetes and autonomic dysfunction will usually not cause a BP dip. There are also many research terms like morning surge (change between lowest BP at sleep and the BP upon awakening) — morning surge has been linked to stroke in adults. Hyperbaric index is the area under the curve above a pre-selected BP threshold. AASI is the ambulatory arterial stiffness index which isn’t explained by Dr. Flynn.
BP Loads are important because the greater the load, the more likely there is a secondary cause of hypertension (Flynn 2002). However, BP Load is not validated in children.
A special mention of white coat hypertension. This is a BP level > 95th percentile in the office whose BP is normal outside of the clinical setting. 30-40% of children with confirmed office HTN actually have white coat HTN. The higher the BP in the office, the less likely the patient will ultimately have white coat HTN.
Masked hypertension is when a patient has normal office BP but high ABPMs. Masked hypertension is associated with increased cardiovascular risk, whereas white coat hypertension is not. In Hypertension 2005 45:493, 8% had masked hypertension at the mean age of 10.2. Most of these patients were overweight and greater frequency of parental HTN.
Hypertension 2008 52:433-451 provides guidelines on how to interpret ABPMs in children by height. Dr. Flynn indicates that height is a more important determinant of BP than age.