Wednesday, December 28, 2011
Does this differ from what's been going on in practice for the last 10-15 years? A quick look at the USRDS shows that back in 1996 less than 20% of patients started dialysis with an eGFR of greater than 10 ml/min/1.73m2. In stark contrast by 2009 a full 20% were starting with an eGFR of over 15 ml/min/1.73m2 and greater than 50% were starting above the 10 ml/min/1.73m2 mark.
Why the heck did this happen when uremic signs and symptoms, at least in the IDEAL trial, in general seem to occur at GFRs below 10 ml/min/1.73m2?
A variety of explanations have been put forward (well reviewed by Rosansky and colleagues here and here). A commonly proffered argument is that perhaps uremic signs and symptoms are occurring earlier in our aging and increasingly ill population. However, in a study of 2402 nursing home residents who initiated dialysis, the authors found that seven signs and symptoms commonly associated with declining kidney function, such as volume overload and cognitive or functional decline, accounted for less than one third of all cases of early dialysis initiation including less than half of all cases of early outpatient dialysis initiation, suggesting that dialysis initiation may be primarily prompted by laboratory values in a large number of patients.
Regardless of the reasons, the trend is clear, early start was the rule rather than the exception building through the late 90s into the 2000s.
What has this meant for patients and US societal economic cost? A very nice paper from O'Hare and colleagues tells part of the story, using information from a large integrated health care system in Seattle, the group was able to estimate the rate of eGFR decline prior to the onset of dialysis in a subset of patients. This in turn allowed them to predict how many additional days on dialysis patients spent in 2007 versus 1997 by looking at the mean eGFR at time of dialysis initiation in patients listed in the USRDS and then back calculating (this relied on the assumption that the rates of decline were similar in these groups).
These estimates showed that dialysis was initiated on average of five months earlier in 2007 compared to 1997 and almost 8 months earlier in patients over 75! Doing some back of the envelope calculations the group guessed that early initiation in the US had cost an additional $1.5 billion dollars during 2007. This is slightly higher but similar to the over $1 billion dollar additional yearly cost estimate made using slightly different assumptions by the AJKD editorialists for the economic analysis of the IDEAL trial (this was the US estimate - the IDEAL trial was conducted in Australia and New Zealand).
Given that early initiation of dialysis in asymptomatic closely followed patients has no proven benefit (and may even be harmful if you look at recent retrospective data) part of our charge as emerging nephologists is helping to reverse this expensive and unhelpful trend.
(Photo: Stanford Chapel at Night)
Sunday, December 25, 2011
Thursday, December 22, 2011
Tuesday, December 20, 2011
A nice example of this literature was published this past month in CJASN by a group from Cincinnati examining 3679 diabetic veterans over an average followup of about 5 years looking at how hospital acquired AKI, defined using AKIN criteria, influenced the development of stage IV CKD and mortality. Individuals with less than 3 outpatient serum creatinine measurements or eGFRs of less that 30 ml/min/1.73m2 where excluded from the study.
Hospital acquired AKI occurred in 29% of the cohort and in the vast majority of cases, 88%, was of mild severity (AKIN stage I) with only 12% of cases in AKIN stages 2 and 3. The group was unfortunately unable to capture data on the need for inpatient dialysis. Of those who developed hospital acquired AKI, 23.4% went on to develop stage IV CKD as compared with 10.4% of hospitalized patients who avoided AKI. Hospital acquired AKI was a significant risk factor for the development of stage IV CKD with HR of 3.56.
As with severe dialysis requiring AKI, these less severe cases of AKI were also significantly associated with mortality with 38% of the patients who developed hospital acquired AKI dying by the end of the study period as compared with 24% of the hospitalized patients who did not develop AKI.
Interestingly the group looked at individuals who developed multiple episodes of AKI and with each episode up to 3 there was an approximate doubling of the risk for developing stage IV CKD. It was additionally notable that the hazard ratio for AKI was similar to that of proteinuria, a well known risk factors for CKD progression.
So how should the post hospital followup of these less severe cases of AKI be handled? Some have asked whether these patients should be seen by nephrologists, however given the already strained capacity of many renal clinics this would seem difficult to achieve. More practically, educating housestaff and primary care physicians on the importance of AKI as a risk factor for CKD and encouraging them to refer when CKD becomes present seems more achievable. In addition, in integrated systems such as the VA these patients could be followed remotely and brought into nephrologic care when our services are of value to the patient.
Sunday, December 18, 2011
The course took place on the coast of Maine at the MDIBL, a place with great historical and modern day significance for renal physiology. George Dorr, who founded Acadia National Park with John D. Rockefeller, had the foresight to recognize the potential value of the island for the scientific community. He offered land for two labs, the MDIBL and the Jackson Laboratory (which also continues to operate on the island with tremendous success). The MDIBL is where E. K. Marshall discovered and described active tubular transport in the goosefish in the 1920’s. It is where Homer Smith wrestled with the concepts of clearance, GFR, and effective renal blood flow and worked out calculations based on his studies in marine animals. He did ground breaking experiments in the lab and wrote a number of manuscripts and books in his cottage on the campus describing these fundamental concepts. For 35 years, he spent his summers working at the MDIBL. Roberts Pitts called this time the “Smithian Era of renal physiology”. Homer Smith brought many others to the island to work on renal physiology, and over the years a number of important discoveries have been made at the MDIBL. The lab continues to be a place of excellence, active in research.
The annual course brings fellows back to this historical place and places them under the mentorship of a distinguished faculty. Mark Zeidel serves as the course director and every year he brings in a remarkable faculty from across the country to distill fundamental concepts of renal physiology in a historical and comparative context. They do this by dividing the course up into six modules. Each fellow participates in three of the six modules with each module lasting for two days. The modules split the kidney up into functional units beginning with the glomerulus and continuing on through the proximal tubule, the loop of Henle, and the distal tubule. They also covered salt and water homeostasis and renal genetics. On the first day of each module, we worked with the faculty in the lab performing experiments using classic physiology model systems such as the toad bladder, the shark rectal gland, the zebrafish, and the xenopus oocyte. We developed a presentation based on our experiments to share with the group on the morning of the second day of each module. Even though we only work with three of the modules each year, we learned what the other groups were doing through the peer presentations. The afternoons after the presentations were spent exploring the island and Acadia National Park. There were organized outings for hiking, biking, and kayaking. We finished the week with a big lobster bake at a park on the seawall.
I have had the great pleasure of attending the course each of the last two years, participating in all six modules. I told my wife when I got home each time that I felt like a kid at camp. Only instead of the usual camp games, we were playing with kidneys and urine. These were tremendous experiences that I will carry with me throughout my career in nephrology. It was great to meet and work with faculty and fellows from across the country. I came away with an enhanced understanding of physiology and a renewed enthusiasm for all things renal. As you make your schedules out for next year, I would encourage you to consider setting aside some time to attend next year’s course, September 2-9.
Posted by Michael Hovater MD
Sunday, December 11, 2011
Originally Posted by Nate Hellman
Friday, December 9, 2011
Treating hypertension on pregnancy sometimes feels a little like going back in time. As Nate posted previously, the list of anti-hypertensives that are considered safe in pregnancy is relatively short – first line agents include labetalol, hydralazine, methyldopa and some calcium channel blockers, while beta-blockers and diuretics are relatively contraindicated and ACEi and ARBs are definitely contraindicated. ACEi have been associated with a constellation of fetal injuries when used in later pregnancy while a study published in 2006 suggested that they were associated with fetal malformations when used in the first trimester. Given the prevalence of hypertension in the general population and the ubiquity of ACEi, this lead to some understandable anxiety about whether these classes of drugs should be prescribed at all to women of child-bearing potential.
However, two recent studies published in the BMJ and the Journal of Obstetrics and Gynecology have challenged this orthodoxy. The first is a large registry study while the second is a meta-analysis of all studies of ACEi in early pregnancy. These two large studies found that although the risk for fetal malformations was higher than controls with first trimester use of ACEi, there was a similar increased risk associated with the use of any other class of anti-hypertensive and in women with untreated hypertension. There was no excess risk of ACEi over these other groups. This suggests that it is the hypertension itself that is causing the increased risk of malformations rather than any effect of an individual medication. It is important to note that the previously documented association between fetal malformations and the use of ACEi in the second and third trimesters was confirmed in the BMJ study. This indicates that the drugs are not safe for use throughout pregnancy and should be stopped when a woman becomes pregnant. That said, it should bring some relief to mothers who have conceived while taking an ACEi that they have not done any inadvertent harm to their children.
I recommend this excellent editorial on the topic
When recommending OTC medications, it is important to suggest therapies based on patient symptoms, drug interactions and adverse effect profile. Below a summary of safe drugs to use in this population according to symptoms:
Relief of non-productive cough:
Dextromethorphan is a cough suppressant with no reported drug-interactions with immunosuppressant medications. Caution should be exercised in liver transplant patients as dextromethorphan is metabolized by the CYP450 2D6 isoenzyme.
Codeine is typically used as an opioid analgesic but is also used as a cough suppressant in combination products. In patients with low GFR, doses should be reduced (25% - 50% reduction) due to potential for accumulation of metabolites.
Relief of congestion and productive cough:
Guaifenesin is an expectorant with no significant drug-drug interactions, although caution is recommended in renal transplant recipients and in patients with decreased renal function as it is hydrolyzed to a renally eliminated metabolite and high doses of guaifenesin have been rarely associated with urolithiasis.
Antihistamines including diphenhydramine (1st generation) and loratidine (2nd generation) are used for relief of symptoms such as cough, watery eyes, runny nose and sneezing.
Caution should be advised in the following settings: patients on calcineurin inhibitors as antihistamines decrease gastric motility; patients with renal dysfunction due to urinary excretion of antihistamine metabolites (extend dosing interval); liver transplant patients due to hepatic metabolism; and lung transplant patients as antihistamines thicken bronchial secretions and can cause respiratory depression.
Don't forget about nonpharmacological therapies, which can be safely utilized to provide relief for cold symptoms: saline sprays, vaporizers and humidifiers.
The following medications are NOT recommended: Pseudoephedrine, Phenylephrine, Oxymetazoline and NSAIDS (Advil, Aleve, Ibuprofen, Motrin, Excedrin, Midol). Patients should be informed to carefully read product ingredients as combination therapies could contain these agents.
Thursday, December 8, 2011
Think we missed a story? Nominate it in the comments to this post and we'll put it up for readers to vote on.
Wednesday, December 7, 2011
An 18 year-old girl with end stage renal disease secondary to focal segmental glomerular sclerosis had a double cuff flex neck peritoneal dialysis (PD) catheter uneventfully inserted in order to begin dialysis. Ten days after this procedure, following successful post-operative catheter flushes, she presented with new, intermittent, sharp, right-sided abdominal pain with catheter flushes. Over the next week, she went on to experience progressive peritoneal filling difficulties that required curtailing planned treatments. She was otherwise asymptomatic and, when not on dialysis, reported feeling well. An abdominal x-ray revealed that her catheter had migrated into the right flank, and her dialysis treatments did not improve after recombinant tissue plasminogen activator or an intensified bowel regimen. Her PD catheter was capped, and she was instructed to present for surgical repositioning of the catheter the following day.
In the operating room, the peritoneal catheter was found to be in the right lower quadrant as expected and initially appeared to be surrounded by only inflamed omental remnants. Further dissection of the omentum away from the catheter, however, revealed multiple dense adhesions, including a small loop of bowel and a markedly inflamed appendix, encircling the PD catheter. These adhesions were lysed, freeing the PD catheter from the appendix. After a pause to discuss these findings with her mother, the surgeon proceeded to perform a previously unplanned appendectomy. The PD catheter was relocated to the pelvis and flushed with ease.
This case highlights a rare but previously documented cause of PD catheter obstruction: appendiceal entrapment. However, this case has a few significant differences from the literature. First, and most notably, the patient’s pathologically-confirmed appendicitis did not present with signs or symptoms consistent with this disease (fever, localized abdominal pain, elevated WBC). Catheter obstruction and malposition were our only clues, and even en route to the OR, both the medical and surgical teams believed this to be a simple case of catheter malposition, perhaps with an element of omental adherence. Second, this case questions the current literature’s suggested management of surgical peritonitis, which centers around catheter removal and dialysis interruption. HS’s catheter was left in, and her pain, catheter flows, and dialysis treatments dramatically improved post-operatively. Perhaps the most important lesson that I take away from this case, though, is to quickly consider the more rare surgical causes of PD catheter obstruction and even peritonitis when conventional medical treatments fail.
Posted by Matt O'Rourke
Sunday, December 4, 2011
In addition there are many other renal diseases that can be associated with HIV infection, its treatment or associated conditions. An interesting review can be found here.
Below are some of the differentials on that long list:
Many of the anti-retrovirals have been associated with nephrotoxicity in various forms. Further information can be found on previous posts.
Similarly, various antibiotics and other anti-microbials used to treat or prophylaxis this population must be kept in mind (e.g. Bactrim, amphotericin, pentamidine etc.). Another potential problem over the longer term is the diabetogenic potential from various protease inhibitors.
Co-infection with other diseases, particularly HBV and HCV should be investigated. This opens a whole other list of differentials in terms of renal disease – e.g. membranous associated with HBV and syphilis; cryoglogulin and membranoproliferative disease associated with HCV. An immune complex mediated disease with predominance of IgA has also been described, as have various forms of lupus like clinical cases.
One other rare consideration is thrombotic thrombocytopaenic purpura, which may result from HIV induced endothelial injury.
Just some of the differentials to keep in mind when asked to see a patient with kidney disease and HIV infection.
Thursday, December 1, 2011
Two examples of such compounds are indoxyl sulfate and p-cresol sulfate which are produced by colon microbes from tryptophan and phenylalanine/tyrosine, respectively. In the ongoing search for the medley of true uremic toxins (remember that urea, produced from protein metabolism in the liver is at worst only mildly toxic) compounds such as indoxyl sulfate and p-cresol sulfate are potentially toxic candidates.
In an interesting study recently published in JASN a group from Stanford examined the profile of plasma solutes in normal subjects and dialysis patients with and without colons. As expected, HPLC assays revealed that indoxyl sulfate and p-cresol sulfate were nearly absent in dialysis patients without colons in contrast to solutes like urea that were present in equal amounts in both the colon intact and absent groups.
In addition, mass spectroscopy revealed a number of other known and unidentifiable solutes in significantly higher concentration in the dialysis patients with colons when compared with normal subject and dialysis patients without colons. This suggests that we are just at the beginning of understanding the contribution of the colonic microflora to uremic toxicity.
As suggested at the end of the JASN article, a deeper understanding of our micorflora's contribution to uremic toxicity could allow us to explore the health benefits of reducing the production of toxic solutes by nutritional, probiotic, or pharmacologic means.
Friday, November 25, 2011
The molecular weight of sodium chloride is 58.4 mg/mmol (23.0 mg/mmol from sodium and 35.4 mg/mmol from chloride) hence there are 154 mmol of sodium chloride in the one liter bag of normal saline.
9000mg/58.4mg/mmol = 154 mmol
As there is one molecule of sodium and one molecule of chloride in each molecule of sodium chloride (commonly referred to as salt) there are 154 mmol of sodium in the one liter bag or 3542 mg (well above the daily recommended 2300mg).
Now some craziness: average sea water is 3.5% sodium chloride (there are multiple other ions at much lower concentrations) meaning 35 grams of salt per liter of water!
This leads to some interesting phenomena. Check out this recent BBC time lapse video of something called a "brinicle."
In arctic waters the formation of surface ice forces solutes out of the newly formed solid and into "brine channels" which contain super concentrated sea water. As the concentration of solutes rises the freezing point of the solution drops and the density increases.
This cold dense super concentrated sea water descends towards the sea floor. The distribution of the brine channels can be such that the super concentrated sea water comes out in columns. As it does less concentrated water with a high freezing point around it freezes. When the column reaches the ocean floor the water flows with gravity to the lowest point, freezing everything in its path including animals.
So what sort of salt concentration is this "super concentrated sea water" at? The lowest recorded temperature of sea water I could find was negative 2.6 degrees C. Calculating backward from the freezing point depression equation and assuming all solute in sea water is sodium chloride...
Change in freezing point of solution = KF · m · i
KF = the cryoscopic constant, which is dependent on the properties of the solvent = 1.853 kg/mol for water
m = mol of solute per kg of solvent
i = the van 't Hoff factor (number of solute particles per mol) = 2 for NaCl
2.6 = 1.853 * m * 2
2.6 = 3.706 * m
0.702 = m
0.702 mol/L or 702mmol/L of sodium chloride
58.4 mg/mmol * 702mmol/L = 40,997mg/L or 41g/L or 4.1% sodium chloride
That super concentrated sea water makes our 3% "hypertonic saline" look like weak tea!
Wednesday, November 23, 2011
Recently there was a very interesting series in three parts in the online magazine Slate.com concerning the use of mice and rats as surrogates for humans in animal studies. Anyone who has worked with mice in the lab is aware of the conditions that they are generally kept in – they live in small cages with limited opportunity for exercise and have an unlimited food supply. The inevitable consequence of this is that the majority of lab mice and rats are overweight – if not obese. What does this mean for their ability to serve as appropriate controls?
As detailed in an article in PNAS last year, laboratory rodents “metabolically morbid”. They are overweight, insulin-resistant, have premature cardiovascular disease, are prone to infection and cancer and appear to be more likely to develop degenerative neurological disorders. Overall, when you think about it, they aren’t very representative of healthy humans at all. This has major implications for medical research. Laboratory mice as currently bred are cheap, reproduce rapidly and are easily manipulated genetically. Any changes to feeding regimens and exercise availability are going to significantly increase costs associated with their use so there is a trade off between practicality and the unquantified effect that using these obese animals may be having on the results of our experiments. It must be pointed out, however, that most research on mice uses animals that are young and have not had time to become particularly overweight such that this would not apply to all mouse models.
It’s a fascinating topic and the sheer number of citations that the PNAS article has accrued already indicates that others recognize that this is a potentially serious issue. Comments are welcome,
Saturday, November 19, 2011
1. Abstract: [FR-PO1777] Urinary Content of Plasmin(ogen) and Activation of ENaC Current by Urine Resides during Remission of idiopathic Nephrotic Syndrome. Buhl et al.
The same group from University of Southern Denmark who published the original plasmin study came back again and presented more evidence for their hypothesis. They took spot urine samples from 20 children with active idiopathic NS and compared them to urine samples obtained after remission in the same patients. Urine samples were analyzed for plasmin and plasminogen concentrations and urinary protease activity. Urine plasmin and plasminogen concentrations (normalized to urine creatinine concentration) and urine protease activity were found to be significantly higher in the active phase of NS in comparison to the remission phase. Not only that, the urine samples obtained in the active phase were able to evoked stronger ENaC currents than the urine samples obtained in remission phase.
2. Abstract: [FR-PO1776] Preeclampsia Is Associated with Significant Urinary Excretion of Plasmin(ogen) and the Ability of Urine To Activate ENaC In Vitro. Buhl et al.
The same group above also did another study where urine samples from 16 preeclamptic patients and 17 normotensive, non-proteinuric pregnant women (control) matched on age and gestational age were compared. Urine was analyzed for plasminogen and proteolytic activity. ENaC currents after exposure to urine was monitored in M1 cells by whole cell patch clamp. Urine plasminogen concentration (normalized to urine creatinine concentration) and proteolytic activity were increased in the urine of preeclamptic patients but not in controls. What is more, a significant positive correlation was found in the preeclamptic group between urinary plasmin(ogen) and diastolic blood pressure. The ability of the urine samples from preeclamptic patients to evoke ENaC current was abolished by amiloride to a lower level than the controls, suggesting that there might be small amounts of plasmin (ogen) present in the urine under normal conditions. The authors speculated that this might have a natural anticoagulant effect in the urine.
3. Abstract: [FR-PO1779] Nephron Expression and Distribution of the Plasminogen Receptor, PLG-RKT, and Colocalization with ENaC and uPAR, in Murine Kidney. Nangia et al.
Dr. Parmer’s group at UCSD has identified the presence of a novel Plasminogen Receptor (PLG-RKT). This PLG-RKT, apparently colocalizes with urokinase, and ENaC on the apical surface of the distal nephron, and all of these are present in an orientation to promote Plasminogen activation and ENaC processing. They actually found that urokinase was also present in the proximal tubule but in a less prominent way than in the distal nephron. The significance of the latter is unknown. Therefore, the machinery for sodium retention is present even under normal conditions.
Thursday, November 17, 2011
Since moving to Baltimore, a city with a large African-American population, earlier this year, I have had the opportunity to see several interesting patients with sickle cell SS disease and renal complications. Here is a mention of some of the kidney abnormalities that occur with SS disease, as well as some of the clinical manifestations.
The underlying pathology of renal sickle cell disease seems to be from microvascular hypoxemia: when red blood cells acquire a sickle shape and obstruct capillary flow, microinfarcts, chronic ischemic injury and medullary hypoxia can occur. Hemosiderin deposits can also be seen on biopsy. Sequelae can include:
1) hyperfiltration. Hypoxia can lead to increased prostaglandin release, which increases GFR. NO synthase may also be upregulated.
2) increased proximal tubular function. The exact causes are unknown, but the proximal tubular upregulates secretion of creatinine, as well as resorption of phosphorus. Thus, creatinine-based estimations of GFR may overestimate renal clearance in sickle cell patients.
3) microalbuminuria. Unclear if this is secondary to ischemia, or if hyperfiltration plays a role. Can progress to overt proteinuria over time. It is interesting to note that parvovirus B19 has been implicated as a cause of nephrotic syndrome in SS disease patients.
4) hyposthenuria. Otherwise known as inability to concentrate or dilute urine; possibly due to impaired water ADH response, although another possibility is that enhanced clearance of interstitial solute washes out the medullary concentration gradient.
5) impaired distal tubular function. Cause unclear. Can lead to decreased distal H+ and/or K+ secretion, and lead to an imcomplete distal RTA.
6) hematuria. Probably from capillary microinfarcts.
7) renal papillary necrosis. From medullary ischemia.
A collapsing form of FSGS as well as MPGN have been reported in conjunction with SS disease.
Amazing (and awful), that a single genetic mutation can cause so much renal havoc!
Submission Deadline: Extended to December 9th, 2011
Submit abstracts online here.
Wednesday, November 16, 2011
The UK Renal Association (RA); the professional body for UK nephrologists and renal scientists, has recently started a website to foster discussion of interesting cases (There is also a link in the sidebar). The site remains embryonic whilst a development strategy is debated, but the RA would be very gratfeul for feedback and some comments/discussion of the cases.
Monday, November 7, 2011
Thursday, November 3, 2011
All are more than welcome to attend, so whether you're an interested reader, a past, present or budding blogger, or just want to forget about how badly your poster went, drop in and say hi. If more than 100 people show up, Gearoid has promised to perform his famous "string dance", although that may not be an incentive for everyone.
RFN are planning to maintain an active presence during the meeting, follow our twitter feed for updates. So come along, get involved, and look forward to meeting up in Philly.
Tuesday, November 1, 2011
Cardiac and renal involvement usually manifest after the first or second decades of life. Fabry’s nephropathy initially presents as proteinuria or isosthenuria, later progressing to renal insufficiency. By age 35 years, half of male Fabry’s patients have proteinuria, and by age 50, about half have developed ESRD. While some female heterozygotes develop renal insufficiency, they do so less frequently, and rarely progress to end-stage disease.
Biopsy findings in Fabry disease show lysosomal inclusion bodies containing glycolipid material in visceral epithelial cells, most prominently podocytes. “Zebra bodies”, inclusions of ceramide material in lysosomes, are often seen in the podocytes. Vascular sclerosis along with other chronic changes such as interstitial fibrosis and tubular atrophy are also commonly seen. Fabry’s can be diagnosed definitively by various serum tests measuring the alpha-galactosidase A activity. Sequencing of the GLA gene, mutations of which are known to cause Fabry’s disease, can be helpful in assessing female family members for presence of a carrier state.
Currently, two formulations of recombinant purified alpha-galactosidase A exist, although only one (Fabrazyme, alpha-galactosidase A alpha) is on the market in the U.S. While trials have not been effective in reversing renal damage in ESRD patients, they have shown a significant slowing in the rate of EGFR decrease in patients with mild renal dysfunction (EGFR > 55 mL/min). Despite the inability to rescue kidney function in our dialysis patients, however, screening plays a vital function in establishing family inheritance patterns—and identifying the next generation of Fabry’s patients in the early stages of disease. So, in younger male patients with ESRD of unclear etiology: ask about Fabry’s symptoms, screen them, and help to increase Fabry’s awareness and diagnosis!
Originally posted by Lisa Cohen
Monday, October 31, 2011
Saturday, October 29, 2011
A number of years ago, I was at a lecture given by a transplant surgeon from London. He was discussing the dangers surrounding living unrelated kidney transplantation and he told the story of a member of a royal family, of a country that will remain nameless, who had come to London to get a transplant from his cousin. The cousin did not speak any English and, in fact, spoke a very obscure dialect so the translators had been provided by the Prince rather than the hospital. The night before the operation, the transplant fellow was doing his rounds and stopped to talk with the cousin. By coincidence, he was from the same area as the donor and started talking with him. It turned out that the donor was a private in that nation’s army and had no idea what he was doing there. Of course, the transplant was cancelled.
I was reminded of this by the case of Levy Izhak Rosenbaum (previously mentioned in a post by Nate) who pleaded guilty this week to three sample charges of organ trafficking. He was selling kidneys to wealthy Americans for over $100,000 each and allegedly paying donors in Israel around $10,000 for each kidney. He is likely to spend the next 20 years in prison.
Iran is currently the only country where it is legal to pay donors although it was legal in India until 1994. There are very short waiting lists in that country as a result although, as you might expect, there is very little intra-family donation because of the ready availability of organs from unrelated donors. The Declaration of Istanbul stated unequivocally that transplant tourism and organ trafficking are unethical and lead to exploitation of the poor but this certainly has not ended the debate. Last year, there were a number of posts on RFN on this very topic with some impassioned debate.
One of the key arguments in favor of allowing payment for donation is the lack of adverse outcomes for donors but many programs still do not monitor long-term outcomes, although it must be said that most published data suggests that it is relatively safe. However, any operation carries some risk and it is inevitable that a portion of these donors would die in any given year. Remember that donation carries no medical benefit for the donor.
This is a very difficult ethical topic and I don’t know what the correct answer is. My own bias is that it should not be allowed and I think it would take a lot to convince me otherwise. This particular case is interesting because the concept of organ trafficking is usually discussed in the abstract in the US but this shows that it is certainly going on here and care must always be taken if there is any suspicion of money changing hands.
In a related case, 3 Brazilian doctors were convicted this week of removing organs from patients in a public hospital for use in an expensive private hospital. The patients, with the collusion of a neurosurgeon, were diagnosed with brain death and the doctors were convicted of murder. There were allegations of payments being made although these were never proven. The complexity of this topic is shown by the fact that it took 25 years for this case to come to a conclusion – the original operations occurred in 1986.
Friday, October 28, 2011
1) water passes through filters for particle removal
2) it then passes over activated carbon, which removes chlorine and chloramines
3) next is a cation exchange resin that serves to “soften” hard water, i.e. exchange Ca and Mg for Na
4) then: reverse osmosis. Pressure is applied to the water and pushes it over a polyamide or cellulose acetate membrane. This process rids the water of organic matter, bacteria, and endotoxins.
5) next step: deionizers, resins that remove cations and anions.
6) water is then irradiated to kill any remaining pathogens.
7) then it is ultrafiltered to remove any remaining bacteria, viruses, and pyrogens.
Water is then continuously circulated to avoid stagnation, and siphoned off to different dialysis stations during treatment.
If you see the following signs in patients at a particular dialysis unit, consider the following water treatment problems:
Anemia- aluminum, chloramines, copper, zinc
Bone disease- aluminum, fluoride
Hemolysis- chloramines, copper, nitrates (3 C's from Nate's prior post)
Hypertension- calcium, sodium
Hypotension- bacteria, endotoxins, nitrates
Metabolic acidose- low pH, sulfates
Nausea/vomiting- bacteria, endotoxins, low pH, nitrates, sulfates, zinc
Many thanks to Dr Coyne for the shameless pirating of several of his slides.
Originally posted by Lisa Cohen
Wednesday, October 26, 2011
A patient presented to the outpatient service with progressive renal insufficiency and sub-nephrotic range proteinuria. He had a long history of CMML with few blasts in his bone marrow aspirate but a peripheral white cell count that was persistently in the 40s. There are many ways in which leukemia can cause renal dysfunction the commonest being infiltration of the kidney, tumor lysis, acute or chronic TMA and toxicity related to the treatment including chemotherapy and radiotherapy. It was not initially obvious what the specific cause of the renal impairment was in this case so he was referred for a renal biopsy.
CMML (chronic myelomonocytic leukemia) is classified as a myelodysplastic/myeloproliferative disorder as it has characteristics of both and primarily is a disease of the elderly. It is characterized by the presence of increased number of peripheral monocytes and usually causes renal damage through infiltration or amyloid deposition. Under normal circumstances, monocytes and macrophages produce lysozyme. This protein is stored in these cells and used to lyse the cell walls of certain bacteria. In some patients with CMML, there is marked overproduction of lysozyme some of which is released into the circulation. It is subsequently filtered by the glomerulus and then reabsorbed by proximal tubular cells where it causes direct toxicity. There may also be an effect related to the fact that it is positively charged thus leading to potassium wasting. Interestingly, previous case reports have found that lysozyme is the predominant protein found in the urine of patients with this disorder and measuring urine and serum lysozyme levels could obviate the need for a renal biopsy in some cases.
The figure above is taken from a case report of lysozyme nephropathy, showing the normal appearing glomeruli, degenerative tubules and many protein reabsorption droplets on EM. Panel C shows strong staining for lysozyme in proximal tubular cells by immunohistochemistry. Treatment is generally supportive and aimed at treating the underlying disorder, thus reducing the production of lysozyme
Monday, October 24, 2011
This is a question we face quite often in the Nephrology clinic when we are commencing patients on high dose steroids for glomerular and other systemic inflammatory diseases.
I came across a couple of interesting retrospective studies while trying to find some evidence to help guide the decision-making process.
The first study analyzed 116 cases of pneumocystis pneumonia in non-HIV infected patients. The major common exposure was steroid treatment in the month preceding presentation (90.5% of patients) – the median dose was equivalent to 30mg prednisone for a median of 12 weeks before presentation.
The second reported risk factors in 41 cases in a French centre. Mortality was 29%; 85% had received steroids at a median daily steroid dose equivalent to 15mg prednisone. Only 17% had received prophylaxis.
The third used a matched case-control type analysis in patients with SLE – they reported 15 cases of pneumocystis infection; risk factors for infection compared to 60 matched controls included higher disease activity, renal involvement and higher mean cumulative steroid dose (49 vs 20mg/day; p<0.01).
Finally a Cochrane review of RCTs of prophylaxis against PCP (versus none/placebo/non-PCP agents) suggested that prophylaxis was warranted when the risk of PCP infection is higher than 3.5% for adults – the authors suggested this included the following groups – “recipients of solid organ or allogeneic bone allografts for the first 6 months after transplant and, for the latter, throughout the period of immunosuppression, as well as in patients with acute lymphoblastic leukemia and Wegener granulomatosis”
There are a number of factors to be considered when trying to answer this difficult scenario – the dose of steroids used, the duration of treatment, use of other immunosuppressive drugs (i.e. the net state of immunosuppression), medical co-morbid conditions and infection history.
Many experts suggest prophylaxis for patients with rheumatological diseases requiring treatment with ≥20mg prednisone for greater than one month when used in combination with another immunosuppressive drug. Overall the pros and cons of PCP prophylaxis must ultimately be judged on a case-by-case basis.
Tuesday, October 18, 2011
However if we use the evidence available to us, there are certain protocols which are specific to certain diseases. Not everything responds to steroids--for example, while it is reasonable to attempt a course of steroids alone for FSGS, there is good data to suggest that steroids alone does NOT have an effect in individuals with isolated hematuria from IgA Nephropathy.
One of the landmark protocols for glomerular disease is the so-called "Ponticelli Protocol", used in the treatment of idiopathic membranous nephropathy. The 1992 NEJM paper describes the randomization of a group of patients with biopsy-proven membranous nephropathy to one of two regiments: (a) a 6-month course of steroids alone, or (b) a 6-month course of alternating monthly steroids and chlorambucil. The rate of remission was significantly lower in the steroids/chlorambucil group, thus giving rise to the first effective therapy for this disease.
In present day nephrology (at least at the fellowship program at which I am training) chlorambucil is seldom used--too many side effects (e.g. bone marrow suppression)--and instead a different cytotoxic agent--namely cyclophosphamide (Cytoxan) is used. A typical regimen (the "modified Ponticelli protocol", JASN 1988; 9:444) is shown below:
Months 1, 3, and 5: Solumedrol 1000mg iv daily x 3 days then prednisone 0.4 mg/kg/d x 27 days.
Months 2, 4, and 6: CTX 2.5mg/kg PO daily x 30 days.
Originally posted by Nate Hellman
Monday, October 17, 2011
As I passed the doorway the attending at the head of the group spun on his heal, looked at me dramatically and asked, "what illness was that man suffering from?"
I wracked my brain, "had his hands looked arthritic? Did he have a chest tube?" I had no idea and shrugged.
"That," the attending declared, "was Heavy Chain Disease!" The team chuckled and moved on and I sighed and tried to remember what Heavy Chain Deposition Disease (HCDD) was. In the October issue of AJKD there's a nice case series of HCDD that had me reliving that day of internship.
HCDD falls under the banner of Monoclonal Ig Deposition Diseases (MIDD). There are three major types of MIDD, Light Chain deposition disease (LCDD), Light and Heavy Chain Deposition Disease (LHCDD) and HCDD. In the July NephSap on Renal Pathology (which is a must read if you haven't seen it yet) it's stated that 80 to 90% of MIDD cases are LCDD, 10 to 20% are LHCDD and less than 5% are HCDD with just 27 cases identified by the AJKD authors.
HCDD is characterized by glomerular and tubular basement membrane deposition of monoclonal heavy chains without associated light chains. In terms of the types of Ig that have been described IgG related disease has been most commonly reported with rare reports of IgA and IgM.
Clinically most patient's with HCDD present with hypertension, progressive renal failure, nephrotic range proteinuria and microhematuria. In the AJKD article the authors note that a conclusive diagnosis of a plasma cell dyscrasia was made in all cases of IgA related disease but in just 19% of IgG disease. They speculate that the reason for this is that the conformational abnormality of the monoclonal heavy chain in IgG disease is such that it has a very high avidity for renal parenchyma so that even small quantities produced by a clinically undetectable population of cells is enough to cause HCDD. The single case report of IgM disease did not have an associated plasma cell dyscrasia.
The predominant pattern seen on light microscopy in HCDD is nodular glomerulosclerosis and of note all the cases of IgA related disease additionally had crescents. Nodular glomerulosclerosis has its own interesting differential diagnosis that has been previously reviewed on RFN. Check out the nice table below on the subject from JASN.
Immunofluorescence is negative except for occasional complement deposition along with the pathologic heavy chain and electron microscopy shows fine, granular, punctate electron dense deposits that lack fibrillary structure (see Emily's great review of Organized Deposition Diseases for more on fibrillary deposits). The deposits are seen in the inner aspect the of the GBM, mesangium, outer tubular basement membranes and vessel walls.
Now if the attending hits you with a bad pun post call, you'll 1) be ready for the pun and 2) be ready to dazzle and amaze with knowledge about HCDD.