Saturday, July 28, 2012

Enteric Hyperoxalosis following Roux-En-Y Bypass

Recently, I evaluated an older gentleman with diabetic nephropathy who had undergone a living related kidney transplant from a family member. He underwent Roux-en-Y bypass with an approximate 80 lbs. weight loss prior to his transplant to achieve a BMI of 30. His post transplant allograft function was initially stable with a serum creatinine of 1.5 mg/dl.

Approximately 1.5 years after his transplant he was lost to follow up and ceased his surveillance laboratory testing. He then developed worsening edema and fatigue and returned to our center for evaluation of his symptoms. On routine laboratory testing his serum creatinine was elevated at 6.8 mg/dl. He underwent an ultrasound guided transplant biopsy which revealed the findings seen in the biopsy on the left.

Pathology noted severe chronic interstitial fibrosis with evidence of oxalate deposition (shiny deposits under polarized light) within his allograft supportive of secondary oxalate nephropathy. Secondary oxalosis can occur from either high oxalate consumption (e.g. mega-doses of vitamin C, large consumption of star fruit or rhubarb) or increased enteric absorption of oxalate from either malabsorption or alterations in enteric flora (see nice editorial in the July 2012 nephsap).

In this particular case, enteric hyperabsorption following Roux-en-Y bypass was suspected as the underlying cause of the secondary oxalosis. In a case series performed at the Mayo Clinic Roux-en-Y bypass resulted in enteric fat malabsorption (from 4 grams per day to 9 grams per day, normal reference 2-7 grams/day) and an increase in serum oxalate levels for 12 months, the length of the evaluation. Urinary oxalate levels were also elevated, and enteric hyperabsorption was shown by providing an oxalate load and demonstrating an increase in serum oxalate levels.
Our patient was found to have severe fat malabsorption by timed fecal fat quantification with elevated serum and urinary oxalate levels.  Unfortunately given the chronicity of renal injury, recovery of his allograft was unlikely and he restarted maintenance hemodialysis. 

Author: Erik Lum, MD

Thursday, July 26, 2012

Image of the Month

A man in his early 60s was being treated for metastatic adenocarcinoma of the lung for 2 years. Recently, he had  been complaining of increasing hemoptysis and a PET CT was performed which showed progression of his disease. He presented to the ED with general malaise, edema and abdominal bloating. His creatinine had increased from a baseline of 1.0 to 1.5mg/dl and he had >10g urinary protein daily. A renal biopsy was performed. Light microscopy revealed thickened basement membranes with some double-contour formation but no definite "spikes" Immunofluorescence showed dense granular staining for IgG along the capillary loops with some minor staining in the mesangium. The diagnosis was early secondary membranous glomerulopathy most likely related to the progression of his malignancy. An EM image is shown below (Click to enlarge)
Subepithelial deposits typical of membranous nephropathy are easily seen in the image (A). The overlying podocytes are damaged and the foot processes are effaced. The lower part of the image (B) shows an area at the junction of the capillary loop and the mesangium. Here, a deposit is also present but it appears that the overlying glomerular epithelium degenerated and is sloughing into the lumen. This is likely due to complement activation and the formation of membrane attack complexes induced by the presence of the deposits and is thought to be the cause of the severe proteinuria seen in this patient. It is important to note that this is not associated with inflammation because the complexes are out of the reach of inflammatory cells which is not the case where subendothelial deposits predominate. This case was not entirely typical because there were occasional subendothelial deposits noted throughout the glomerulus although they were few and their significance was uncertain. 

Thanks to Dr Bijol for the Image

Tuesday, July 24, 2012

Upcoming Open Door Forum: Improving Care for Medicare Beneficiaries with ESRD

An interesting opportunity to learn about and contribute to the healthcare dialogue...

"On Tuesday, July 31, the Centers for Medicare & Medicaid Services (CMS) will host an Open Door Forum for individual input on ways the Innovation Center can develop and evaluate new models of payment and service delivery to reduce program expenditures, while improving the quality of care for Medicare beneficiaries living with End Stage Renal Disease (ESRD).

Information and perspective provided by patients, providers, caregivers, suppliers, payers and researchers could provide vital insight to inform the design of innovative models to reduce program expenditures, while improving the quality of care for these beneficiaries.

In this Open Door Forum, we hope to hear from all interested stakeholders. On the call, CMS staff will provide a brief introduction and then open the phone lines for members of the public who wish to contribute to the dialogue concerning new payment and service delivery models to reduce program expenditures, while improving the quality of care for the ESRD population.

WHEN: Tuesday, July 31, 2012 | 1:00 PM - 3:00 PM ET

WHERE: No prior registration is necessary. Call the number below 5-10 minutes before the beginning of the Open Door Forum.

(866) 501-5502 | Conference ID: 99562870"

Monday, July 23, 2012

"Prophylactic" dialysis before cardiac surgery

This has been discussed between the renal division and the cardiac surgery division in my institution. We know that AKI post cardiac surgery is an independent prognostic factor for mortality (Am J Nephrology 2010 31 408). It’s a big deal! But what can we do about it?
The etiology for AKI post cardiac surgery is multi-factorial but one of them is the length of time on cardiopulmonary bypass. Postulated mechanisms are the inflammatory response, ischemia, micro-embolization of gaseous particles, etc. (Perfusion 2006 21 209). One may then wonder if off-pump CABG would prevent post-op AKI and reduce mortality.
The answer comes from a recent study (NEJM 2012 366 1489) showing that the off-pump CABG group had fewer episodes of AKI (defined as a creatine rise of more than 0.3 mg/dl), 28% v. 32% (p = 0.01). However, the 30-day mortality was not different between off-pump and on-pump CABG... It is speculated that this may be due to intra-operative hypotension, technical issues, etc.
What about the CKD patients who are yet to be on dialysis? Would they benefit from “prophylactic” dialysis? Well, this is a controversial topic with only 3 studies looking into it… 1 is from West Virginia and 2 are from Turkey. Here’s the summary of each study.
The 2 of them showed a benefit on mortality (the single most important quality the surgeons are looked upon), hospital stay and post-operative complications.
However, each study has flaws. All of them are single-center, 2 of them are not randomized, and 1 of them is retrospective. AKI was not defined well and there is a bias that creatinine rise will be masked in patient who received dialysis. Their indications for post-op dialysis are not the standard. No difference was observed in terms of likelihood of requiring long-term dialysis.
I don’t think we have good evidence to support prophylactic dialysis. In my institution, we ended up dialyzing a couple of patients at a request from cardiac surgeons. As always, we need better studies. And if there is a potential benefit in prophylactic dialysis, the question would be what the benefit is due to (ultrafiltration versus clearance).
Posted by Tomoki Tsukahara.

Wednesday, July 18, 2012

When IgA-ttacks!

To many of us IgA nephropathy (IgAN) is a disease to be watched and monitored.  Most cases of IgAN in which the clinical course is aggressive occur with one of two atypical presentations:

1. Acute kidney injury (AKI) and macroscopic haematuria or
2. Nephritic syndrome or RPGN with a crescentic nephritis on biopsy

The first thing to say is that both of these presentations are rare. Whilst visible haematuria coinciding with mucosal infections is a well-known feature of IgAN, development of coincident acute kidney injury is uncommon.  In fact, the largest published case series with this presentation I could find included only 38 patients.  With regards to crescentic nephritis, it is instructive that the recently produced Oxford classification of IgAN study found so few patients with a severe crescentic nephritis (median % gloms with crescents 9%) that the authors were unable to include crescents as having “independent value in predicting renal outcome.”

The AKI seen with visible haematuria is often due to tubular injury from intra-tubular erythrocyte casts and a possible direct nephrotoxic effect of haemoglobin.  The key issue in these patients is not so much treatment, which is through general supportive measures, but ensuring that protracted or repeated AKI is not due to a crescentic IgAN.  As a result, the recently published KDIGO glomerulonephritis guidelines recommend that any patients with known IgA exhibiting AKI and visible haematuria who fail to show improvement of kidney function after 5 days should undergo repeat renal biopsy.

Crescentic IgAN (defined as RPGN with crescents in >50% of glomeruli seen in the biopsy) although rare has a poor prognosis: end-stage renal disease in 75% of one cohort at 10-year follow-up.  The KDIGO guidelines suggest on the basis of low quality evidence initial treatment as for ANCA vasculitis with steroids and cyclophosphamide.  Interestingly, no suggestion is made for maintenance therapy in these cases.

I have only ever seen a single case of severe crescentic IgAN and no cases of AKI with visible haematuria.  However, I think it’s important to know some details about these presentations.  In the near future I’ll look at Henoch-Schonlein nephritis and that most thorny of issues in IgAN; who to treat with immunosuppression outside of an RPGN presentation.

Monday, July 16, 2012

Hyperammonemia in Myeloma: Dialyze?

 A middle aged man with IgG kappa multiple myeloma previously treated with bortezomib and lenalidomide presented to the hospital with altered mental status. He had completed chemotherapy months prior to presentation. Shortly after being admitted, he progressed to obtundation associated with tachypnea and a profound respiratory alkalosis requiring intubation for airway protection. His initial arterial blood gas at the time of intubation revealed a pH of 7.35, an undetectably low pCO2, and a bicarbonate of 14 (on concurrent labs) with an anion gap of 14. Mechanical ventilation was initiated with a minimal amount of pressure support. All subsequent blood gases demonstrated a pH greater than 7.55 with ongoing respiratory alkalosis. The anion gap normalized. Intensive work-up of the altered mental status resulted in the sole finding of hyperammonemia with a serum ammonia level of 100 umol/L. There was no liver injury evident on labs. Lactulose was initiated to treat the elevation in ammonia with no improvement noted.

We were consulted regarding the possibility of dialysis to correct the hyperammonemia. 

Do we need to correct high ammonia levels?

Hyperammonemia carries a significant morbidity and mortality, and patients frequently require ICU-level care for encephalopathy. With acute presentations of hyperammonemia, levels of ammonia greater than 200 umol/L are associated with cerebral edema and herniation due to cerebral dysautoregulation. In the presence of chronic hyperammonemia, compensatory increases in ammonia metabolism by the muscles and hepatic and splanchnic vascular beds may blunt symptoms. Interestingly, arterial, venous, and brain levels of ammonia typically do not correlate in patients with chronic hyperammonemia but have a better correlation in acute hyperammonemia. In our patient, we did not check arterial ammonia levels to look for a correlation.

Why is our patient hyperammonemic?

Ammonia is produced primarily in the gut as a product of protein breakdown and bacterial metabolism, and it is broken down primarily in the liver. Increased production of ammonia can occur in the presence of protein breakdown from GI bleeding. In patients with liver failure who are already predisposed to having high ammonia levels, GI bleeding is a known risk factor for the precipitation of hepatic hyperammonemic encephalopathy.

Our patient had no laboratory evidence of liver dysfunction. He had recently suffered an episode of GI bleeding from a bleeding mechanical abnormality seen on EGD that was corrected. Perhaps this could have been the inciting factor for the elevated ammonia, but the patient's ammonia levels remained elevated throughout his hospital stay despite termination of the bleeding.

Inborn errors of metabolism can be considered, but most of these present in childhood. However, urea cycle disorders can be unmasked in adulthood by medications, protein intake, and infections. The drugs most likely to be involved include salicylates, valproate, carbamazepine, sulfadiazine, pyrimethamine, glycine, and TPN. None of these were implicated in our patient. Urea-splitting organisms and herpes infection can also raise ammonia levels. Neither were present.

Alas, multiple myeloma can be a cause of hyperammonemia. Rising beta-2 microglobulin levels in the absence of acute kidney injury in our patient suggested worsening myeloma off of chemotherapy.

Hyperammonemic encephalopathy in multiple myeloma

In vitro, myeloma cell lines secrete ammonia into culture medium in greater amounts than other hematological malignant cells. This may be due to excess protein synthesis in myeloma cells. In vivo, the exact mechanism for hyperammonemia in multiple myeloma patients is unknown.

It is important to rule out hypercalcemia and hyperviscosity as causes of altered mental status in patients with multiple myeloma before encephalopathy is attributed to elevated ammonia levels. In our patient, calcium and viscosity levels were checked and found to be normal.

In a published review of 27 cases of hyperammonemic encephalopathy in multiple myeloma patients, depressed levels of consciousness were noted to occur at ammonia levels ranging from 35 to 39,342 umol/L. The degree of ammonia elevation did not appear to correlate with death (if one ignores the outlier of 39,342) but in all cases where the patient's ammonia level did not improve, death was the unfortunate outcome. Presenting symptoms included respiratory alkalosis, asterixis, myoclonus, hallucinations, and hyperdynamic heart failure. Of the 27 reported cases, 4 patients received dialysis (3 HD, 1 PD) and 9 received ammonia-lowering medications such as antibiotics, lactulose, carnitine, and flumazenil. All patients received chemotherapy.

Should we dialyze our patient?

In drug intoxications associated with hyperammonemic encephalopathy, dialysis serves a definitive role in clearing the toxin and correcting the hyperammonemia. However, in cases resulting from malignancy, the answer is less clear.

Of the 4 patients who received dialysis in the study described above, 3 survived. Of the remaining 23 patients who were not dialyzed, 12 survived. Ammonia levels decreased in all 4 patients who received dialysis and in 19/23 patients who did not undergo dialysis. This suggests that dialysis plays perhaps only a minor role in lowering ammonia in this patient population. Given the potential for harm associated with dialysis catheter placement, we felt that the risks outweighed the unclear (if any) benefits of dialysis.

Our patient received steroids and further chemotherapy. Interestingly, administration of steroids can raise ammonia levels in the short term because of increased catabolism. Ammonia levels fluctuated wildly but improved slightly. The patient was extubated succesfully. His mental status improved but not to baseline. He continued to have a respiratory alkalosis at the time of discharge. 

Ammonia: Chicken, Egg, or Bystander? 

In hepatic encephalopathy, it is well known that ammonia levels do not correlate with the degree of encephalopathy. For this reason, following ammonia levels after initiating treatment is discouraged. The same may be true here. Perhaps ammonia is the cause of the encephalopathy; perhaps it is a biomarker of disease; perhaps it is an innocent bystander. Further study is needed to elucidate this as it may clarify the role of dialysis as a treatment for hyperammonemia in myeloma.


Friday, July 13, 2012

Venus, Sjogren's and the Kidney

The Williams sisters put yet another Wimbledon doubles tittle into their trophy case over the weekend.  This, just hours after Serena had won the singles competition.  Pretty impressive.

In reading the coverage I learned that during the last year Venus had been diagnosed with Sjogren's syndrome (I know, I know, old news to those paying attention).  There was no mention in any of the reports that Venus has had any kidney problems, her main issues have apparently been with severe fatigue and joint pains.  Although we usually think of dryness in the eyes and mouth when we hear Sjogren's syndrome there are a number of potential renal tip offs to the diagnosis...

Interstitial (and sometimes glomerular) Disease

Interstitial nephritis - Typically mild but can progress to ESRD in rare cases.  In a Mayo Clinic case series 46% and 25% of patients with Sjogren's syndrome who underwent kidney biopsy had chronic or acute interstitial nephritis respectively.  Only one of the 24 patients biopsied had ESRD and this was from a total case series of 7276 patients (there may have been some additional cases of ESRD lurking in the cohort who didn't get biopsied as they didn't have complete clinical data on all the patients).

Glomerular disease - Less common than interstitial disease but does occur. Associations with MPGN (often in association with cryglobulins), FSGS, Membranous and minimal change have all been reported. 

Tubular defects

Distal renal tubular acidosis - An unexplained distal RTA is a invitation to investigate for Sjogren's.  Patients with distal RTAs are prone to nephrolithiasis (typically calcium phosphate stones) and nephrocalcinosis.  Severe associated hypokalemia can also occur with flaccid paralysis having been described as a presenting symptom.

Although the cause of distal RTAs in most patients with Sjogren's syndrome is unknown a few patients have been described who have an absence of the H-ATPase pump on intercalated cells in the collecting duct.  Another hypothesis is that Sjogren's leads to autoantibodies directed against carbonic anhydrase II thus leading to the generation of less protons for excretion.

Proximal RTA and full blown Fanconi's syndrome have also been described.

Nephrogenic diabetes insipidus - Urinary concentrating defects are not uncommon in patients with Sjogren's.  As an example, in an Italian series 21% of patients were noted to have an abnormal urinary concentrating ability.  The cause of this tubular defect is again unknown but histologically clusters of lymphocytic infiltrate can sometimes be seen around collecting ducts which could theoretically interfere with the actions of ADH.

Hypokalemia - This can occur in the absence of RTA and is thought to be due to tubular damage induced sodium wasting with subsequent increased distal sodium delivery.  In the distal nephron increased sodium delivery drives potassium loss in exchange for sodium.  This effect may be amplified by volume depletion with subsequent increased aldosterone levels which again drive sodium absorption and potassium loss.

Thursday, July 12, 2012

Urea and Hyponatremia

Urea is a hyponatremia treatment long forgotten in the United States. Chronic SIADH is usually managed either by vaptans or a combination of fluid restriction, salt and furosemide. However, vaptans are very expensive and few patients can afford it. In a recent Belgian article, the use of urea as a comparable, cheaper alternative is being advocated.

What do we know about urea? It is a very cheap powder (< $0.50/30 gram) that works by increasing free water excretion through osmotic diuresis. Shown below is the solute excretion as a determinant of free water excretion.
Free water clearance = solute excretion/Uosm x (1 - Uosm/Posm)
Physiologically it makes sense, but does it really work? In this article, 13 patients with SIADH were tried on vaptans (satavaptan or tolvaptan) for 12 months. Then vaptans were discontinued for 8 days and urea was started after ensuring that their Na level came down. The result? It worked as well as vaptans! Side effects included hypernatremia and gastric irritation but no osmotic myelinolysis has been reported with urea. It does not cause volume overload (unlike salt), hypokalemia (unlike diuretics), or uremia. You will not become uremic even if your BUN is 100 after you take urea (but you will be urinating a lot!).
So why are we not using it? Are you a fan of bitter drinks? We know Belgians are (great beer there!). In Belgium, only about 15% of patients discontinue to take urea due to its taste. In Canada, Dr. Bichet tried it himself (mixed with orange juice) and wrote it does not smell of anything but the bitterness is strong. On this side of the border, Dr. Berl wrote that it is rarely compatible with North American palate.
That being said, it may be a time to use urea again as a comparable, cheaper alternative for hyponatremia treatment. Across the Pacific (in Japan) there is a proverb “good medicine tastes bitter”. 

Posted by Tomoki Tsukahara

Wednesday, July 11, 2012

Too much protein

An internal medicine resident was presenting a consult to our team on a patient with nephrotic-range proteinuria. During his presentation, he stated that he had already ruled out amyloidosis because the patient had a negative SPEP and UPEP by immunofixation.

To evaluate the validity of his statement, we need to go back to pathophysiology to review the mechanism of amyloidosis.

Amyloid is a pathologic proteinaceous substance, deposited in the extracellular space in various tissues and organs of the body in a wide variety of clinical settings. Under light microscopy, with hematoxylin and eosin staining, amyloid appears as an amorphous, eosinophilic, hylaline, extracellular substance that, with progressive accumulation, encroaches on and produces pressure atrophy of adjacent cells. By electron microscopy amyloid is seen to be made up largely of continuous, non-branching fibrils. This electron-microscopic structure is identical in all types of amyloidosis.

The two major kinds of amyloidosis are:

1)     Primary amyloidosis (AL) (Amyloid Light chain)
The AL protein is made up of light chains, mainly composed of λ light chains or their fragments. Its deposition is associated with certain forms of plasma cell tumors.
Diagnosis: With the use of immunochemical techniques, monoclonal immunoglobulin is found in the serum or the urine in nearly 90% of patients. If you add the serum-free light-chain assay, an abnormal result is found in 99% of patients. A biopsy of an affected organ is usually diagnostic also.
Treatment: Debatable
Patients with severe organ dysfunction should receive repeated cycles of Melphalan/Dexamethasone as first line therapy. Patients with less severe organ dysfunction may benefit from high Dose melphalan followed by stem cell transplant as the first line therapy. For patients with relapsed disease, the use of alternative regimens (thalidomide, lenalidomide, cyclophosphamide, or bortezomib) is a reasonable approach that is growing in popularity.

2)     Secondary amyloidosis (AA)
AA fibrils are derived by proteolysis from a larger precursor in the serum called SAA (serum amyloid–associated) protein that is synthesized in the liver under the influence of cytokines such as IL-6 and IL-1. The production of SAA protein is increased in inflammatory states as part of the “acute phase response”; therefore, this form of amyloidosis is associated with chronic inflammation. However, increased production of SAA by itself is not sufficient for the deposition of amyloid. You need to have an enzyme defect that results in incomplete breakdown of SAA, thus generating insoluble AA molecules.
Diagnosis: Biopsies of accessory salivary glands, abdominal fat, and rectal mucosa yield positive results in 50% to 80% of patients. Kidney biopsy is positive in almost 100% of symptomatic patients.
Treatment: Treat the underlying source of inflammation. Eprodisate is a member of a new class of compounds that inhibits polymerization of amyloid fibrils potentially slowing the decline in renal function

Getting back to the resident, I think his statement would be correct in AL (primary amyloidosis), but not valid if the patient has AA (secondary amyloidosis).

Posted by Tarek Alhamad

Saturday, July 7, 2012

Allowing Altruistic Donors to be Altruistic

If you were embarking on a search to find and interview the healthiest individuals on the planet, speaking with kidney donors would be a great place to begin. People who have donated one of their kidneys share many traits in common. They have incredible compassion, mental strength, and are willing to undergo a major operation that carries a rare (but not zero percent) risk of complications to benefit a friend, a family member, or in some cases, a complete stranger. But even all these traits do not qualify a person to become a kidney donor.

As nephrologists, our duty in evaluating prospective kidney donors is to identify any potential health problems that may put the donor in harm's way. A prospective donor that is too young may not have accumulated the chance to develop certain diseases, making donation risky. A donor that is too old may carry excessive surgical risks, making the donation procedure unsafe. An intensive search for malignancy and transmissible diseases is required because of the risk to the donor and the potential recipient. Any history of kidney problems, including microalbuminuria, proteinura, a family history of kidney disease, and recurrent kidney stones, precludes kidney donation. A myriad of other considerations are also made by the transplant team, including a careful psychiatric evaluation of the donor and a number of blood tests, evaluating for ABO compatibility and HLA matching, which lead to possibilities of direct donation, paired exchange, or transplant chains outlined in this blog post.

Unfortunately, there is one risk whose occurrence is difficult to predict and whose impact is impossible to quantify: loss of health insurance. Described in this New York times article is the case of a father who donated his kidney to his daughter who had lost her renal function in the face of lupus nephritis. While he gained the chance to make an impact in his daughter's life, he lost his health and life insurance despite appeals from his nephrologist stating that his remaining kidney was healthy.

The Affordable Care Act recently upheld by the Supreme Court will protect people from being denied health insurance because of pre-existing conditions beginning in 2014. However, it will not prevent insurance companies from raising premiums on patients they consider higher risk, which may include kidney donors despite numerous prospective studies with long-term follow-up attesting to the safety of undergoing a uninephrectomy.

It is not clear how we can accurately assess the risk of insurance loss or rise in premiums for prospective donors, but one thing is clear. We need to allow altruistic donors to be altruistic.

Posted by Karandeep Singh

Friday, July 6, 2012

Publish or Perish

In academic medicine we are all aware of the pressure to publish, and the metric by which many judge the quality of the papers that are published by a given author is the impact factor of the journal in which their papers appear. The impact factor of a journal is simply the average number of citations per article divided by the total number of “citable articles”. This method of assessing the quality of journals has become increasingly important over the last 20 years and has led to some changes in publication practices. For example, reviews tend to get cited more often than original research papers which is why review journals often have a relatively high impact factor (e.g Current Opinions in Nephrology and Hypertension in our field). Case reports, in contrast, rarely get cited and as a result, journals have moved away from publishing case reports and towards publishing reviews.

Ten years ago, Thomson Reuters (who generate the impact factors) realized that some journals were gaming the system to increase their citation count by publishing review articles and editorials that would preferentially cite papers published in their own journal. TR changed their algorithm to detect this kind of behavior and it is much less common as a result. Which brings me to this great website: Retraction Watch. This is a site which details on a daily basis papers which have been retracted from the literature for various reasons some sinister and some more innocent. Yesterday, they reported on the case of a series of articles retracted for citation manipulation which resulted in 3 journals losing their impact factors for this year. The articles were review papers which almost exclusively cited papers in another journal called “Cell Transplantation” and the authors were editorial board members of this journal. All in all, if these papers were excluded from the citation record, the impact factor of this journal would decrease from 6.2 to 4.1 for last year! This is a great post detailing the whole saga.

See here for a paper detailing the history of the impact factor.

Of course, we in the nephrology world would never get caught up in something like this…