Bury it!

One of the issues that we come across repeatedly in the clinic is the timing of access insertion. We all want to avoid the use of catheters and so we refer patients early (when possible) for fistula formation. This is a bigger problem when your patient wants to start PD. You don’t want the patient to have the catheter placed too early because then they will be unnecessarily exposed to the risk of infection. At the same time, you don’t want to wait too long and get to the stage where the patient requires urgent HD (and often, once they start HD it is difficult to make the transition to PD). I saw a patient in the clinic a few weeks ago that fits this bill perfectly. He is an otherwise healthy man in his 60s who has a very active life and a full-time job. His creatinine had been stable for 2-3 years but climbed rapidly earlier this year and we thought he would need to start soon. However, his creatinine stabilized again and he is feeling well so we have him in a holding pattern with regard to the PD catheter insertion. Our surgeon suggested implanting a buried PD catheter, a technique that he has just started doing in our institution.

For this technique, the catheter is buried subcutaneously at the time of insertion. Then, when the patient is ready to start dialysis, the subcutaneous portion is externalized and the catheter can be used straight away. This can be done in the dialysis clinic and does not require a trip to the OR. Thus, a catheter can be inserted months (or even years) prior to use and the problem of timing is dealt with very elegantly. Recently, a paper was published which described the experience of the University of Denver where they have been using this technique as standard since 2000. In total, 134 catheters were implanted in that time. The period prior to externalization varied between 2 and 788 days with an average of 40 days. There was no relationship between catheter embedment time and the risk of catheter failure. 90% of catheters worked immediately and of the remaining 13 catheters, 12 were easily corrected laparascopically. Only 1 patient failed this technique and required transition to HD. This seems like a great technique and I look forward to seeing the results here over the next few months.

See also this earlier paper in KI about the experience with the use of buried catheters in Ottawa.

To biopsy or not to biopsy

Diabetes is a common cause of CKD and the prevalence of diabetic nephropathy is increasing. A question that sometimes arises in the clinic is when it is appropriate to biopsy a patient with a presumptive diagnosis of diabetic nephropathy and are there any signs that may suggest that there is an alternative diagnosis. It is reassuring that recent data have suggested that renal biopsies in low-risk patients are associated with a very low risk of adverse consequences but I still don't think that anyone would recommend biopsying all patients who present with diabetes and CKD.

So how do you decide who to biopsy. It has been suggested in the past that the presence of hematuria was associated with a lower incidence of true diabetic nephropathy while diabetic retinopathy suggested the opposite. A study was recently published in the Journal of Diabetes Investigation which looked at the results of renal biopsies in patients with diabetes. In total, 55 patients with T2DM were included in the study. These were not random patients with diabetes; all of them had a clinical course which suggested that an alternative diagnosis might be present. 30 of the patients had true DN while 25 had no evidence of diabetes. Of these 13 had IgA nephropathy. One patient had a crescentic GN. The duration of diabetes was not a good predictor of the likelihood of DN. This is not altogether surprising when you consider that this is duration since diagnosis and the patients may have had diabetes for signficantly longer without being aware. Poor glycemic control and the presence of diabetic retinopathy were significantly associated with a higher likelihood of DN. No patient in the non-DN group had diabetic retinopathy which again goes to show the usefulness of this examination in stratifying patients with presumptive diabetic renal disease. This goes to show that the advice that we have been getting in the past is good - the absence of diabetic retinopathy should make you suspect an alternative diagnosis.

One interpretation of this study is that patients with atypical presentations and diabetes should have a biopsy because there is a good chance of an alternative diagnosis. Another, more conservative interpretation is that even in patients where there is a high pre-test probability of a non-diabetic lesion, the majority of patients will have diabetic nephropathy and in those that don't the treatment will most likely be the same in any case.

eJournal Club

CJASN eJC Article of the Month, 2012-08-15 Prevalence and Factors Associated with Hyperkalemia in Predialysis Patients Followed in a Low-Clearance Clinic "Pantelis A. Sarafidis, Rochelle Blacklock, Eleri Wood, Adam Rumjon, Shanique Simmonds, Jessica Fletcher-Rogers, Rachel Ariyanayagam, Aziza Al-Yassin, Claire Sharpe, Katie Vinen" Join in the discussion online at ejc.cjasn.org ©American Society of Nephrology

A few months ago, CJASN introduced a new feature called eJournal Club. This is a means by which fellows (and others) can review papers and communicate directly with the authors. The idea is that perhaps these papers could be discussed in local journal clubs and then any questions or concerns that arise could be answered by the authors. It's an interesting idea that to my mind is a big improvement on the traditional model of letters to the editor. At the moment, the paper is chosen by the editors each month but the plan may be for this to change in the future if there is sufficient interest.

This month's paper is a study of the factors that are associated with hyperkalemia in patients attending a low clearance clinic in the UK. The main finding of the paper is that eGFR is the best predictor of the likelihood of being hyperkalemic. In the univariate analysis, patients with hyperkalemia were more likely to have a low serum bicarbonate or be on sodium bicarbonate treatment. However, in the multivariate analysis these were not significant. Looking at the analysis, the cut-off for bicarbonate in the LR was greater than or less than 25 mmol/L while the mean values in both groups were lower. I wonder, if they had run this as a continuous variable in the LR or chosen a lower cut-off for bicarbonate, if it wouldn't have been significant. This is a question that I can now ask the authors. This is free to all - you do not need to be an ASN member or a subscriber but you do need to register your email address with the ASN. The PDFs of the article and accompanying editorial are provided also.

I think this is a great use of new media and we will be referring to it monthly.

Pathology Image of the Month

A 47 year old man with ESRD secondary to a chronic TMA presented 3 months following a renal transplant with a rising creatinine (1.44 mg/dl from a baseline of 0.9 mg/dl). His prograf level had ranged from 5-7. His flow XM was positive although no donor-specific antibody was detectable on a single antigen bead. His H&E stain is seen below.

He has a moderate interstitial infiltrate. (A) marks an enlarged, abnormal nucleus with a Cowdry type B inclusion. These inclusions can be seen both in adenovirus infections and in patients with BK nephropathy. (B) marks a lymphocyte in the proximal tubular epithelium – tubulitis. The absence of significant necrosis makes adenovirus less likely and, given the recent history of a renal transplant, the likeliest diagnosis therefore is BK nephropathy.

This image shows immunohistochemical staining for BK (SV-40) in the renal cortex. There is some cytoplasmic staining in surrounding tubules. However, this is non-specific. There is intense staining in the nuclei of infected cells (which are also enlarged relative to the non-infected cells) and this is highly specific for BK-virus infection.

The final image is a EM image of an infected cell. Because BK-viral infection tends to be focal, it is unusual to actually see this appearance on EM. There is the appearance of a crystalline array of viral inclusions and in BK-virus, these tend to the in the range of 40-50 nm in size. In contrast, the inclusions in patients with adenovirus tend to be larger.

(Click any image to enlarge)

More Fruit Please

Current Opinions in nephrology and hypertension has an excellent review this month on the rationale for bicarbonate treatment to slow the progression of CKD. The original data animal data was derived from the 5/6 nephrectomy model where rats fed with an acid chow developed metabolic acidosis and had relatively rapid GFR decline that could be ameliorated by giving the rats sodium bicarbonate. Interestingly, switching them to a low-acid, soy-based diet had a similar effect suggesting that simply reducing net acid intake is just as effective. The same group developed a 2/3 nephrectomy model in rats where they did not develop acidosis but the decline in renal function could still be slowed by treatment with bicarbonate. Current guidelines in humans suggest that patients should be prescribed bicarbonate when the TCO2 is less than 22 but recent studies have suggested that even above this level, patients with a reduced GFR may have net acid retention in the kidney with a potential for consequent renal injury that could be prevented by alkali treatment. This, of course is balanced by the fact that we do not want to give large quantities of sodium to patients with CKD.

One suggestion is to look closer at the diet of patients with CKD. The biggest source of dietary acid is animal protein and reducing meat intake will reduce overall acid intake (in contrast, we all see elderly malnourished patients on dialysis with high pre-dialysis bicarbonate levels that is actually a negative prognostic sign). The DASH diet is high in fruits and vegetables and is already a first line treatment for hypertension. Because it has a high component of fruits and vegetables, it has a high alkali content and could substitute for exogenous bicarbonate treatment in some patients. The trade-off is that it is also high in potassium and this would need to be carefully monitored in patients with a low GFR. The take home for me is that this explains, at least in part, the deleterious effects of a diet high in animal protein in patients with CKD and that we can potentially treat acidosis in these patients without resorting to large quantities of oral sodium bicarbonate. See this previous post on the benefits of bicarbonate therapy in patients with mild CKD.

Combo

Azilsartan medoxomil is a relatively new angiotensin receptor blocker and a study was recently published in Hypertension which compared the combination of two different doses of this drug with chlorthalidone against olmesartan in combination with hydrochlorothiazide for the treatment of stage II hypertension. Both combinations were effective at treating hypertension although the reduction in systolic blood pressures was significantly higher in both azilsartan medoxomil/chlorthalidone arms. There was very little difference between the higher and lower doses of azilsartan medoxomil in terms of effectiveness but there was a higher incidence of adverse effects (mostly dizziness/hypotension or an elevated creatinine) in the high dose group.

This begs the question whether the increased effectiveness of the new combination was due to the effect of the azilsartan medoxomil or the chlorthalidone. Chlorthalidone and hydrochlorothiazide have never been directly compared in a randomized trial and this study is unlikely to ever be done because it simply is not cost effective. However, there is a growing consensus that chlorthalidone is the more effective drug for the treatment of hypertension and prevention of secondary events. Add this to the fact that the majority of patients are on suboptimal doses of hydrochlorothiazide and there is an argument that we should be starting patients primarily on chlorthalidone (if not switching existing patients). To give the authors of this paper their due, they did not gloss over this fact and included a paragraph in both the introduction and discussion about the relative effectiveness of chlorthalidone vs. hydrochlorothiazide and suggested that this could have contributed to the increased effectiveness of their combination drug.

I believe that we should always try to give patients as few tablets as possible and as a result, there is a certain logic to combinations of ARB/ACEi + thiazide diuretics. This is the first ACE/ARB that has been combined with chlorthalidone in a single pill and it may be an attractive option for that reason. See this review about the relative benefits of chlorthalidone vs. hydrochlorothiazide (although these authors did not think that the evidence was sufficient to argue convincingly for one over the other), and this previous post by Lisa about the relative efffectiveness of the two drugs.

It's a pity that this study was not done as a direct comparison of two ARBs in combination with chlorthalidone as it would have been easier to judge the relative merits of the drugs without this significant confounding factor.

Myeloma Cast Nephropathy: New treatment possibilities

There are a laundry list of renal complications in multiple myeloma that have been previous reviewed on RFN.  Myeloma cast nephropathy is one of the most frequent, being found in approximately a third of patients in autopsy series.  Acute kidney injury is a common presentation of myeloma cast nephropathy with a variable amount of proteinuria.  As a tubular interstitial lesion with intact filtration barrier lower levels of albuminuria are typically present however large amounts of serum free light chains can be present leading to the classic findings of a negative urine dipstick (which detects albumin) with high levels of proteinuria by quantitative evaluation (stay frosty medical students, your intern is just itching to pimp you on this one).

On light microscopy diffuse tubular damage resembling ATN is seen along with distinctive distal tubular casts (in contrast to light chain fanconi syndrome where intracellular proximal tubular deposits are seen).  These casts often have sharp edges, a tendency to fracture (image on the left) and frequently have adherent neutrophils, monocytes or multinucleated giant cells around their periphery (image on the right).

Two papers from a group in Alabama shed light on the mechanism of formation of these casts and new potential treatment strategies.  It has long been known that the casts are composed of light chains bound to Tamm-Horsfall protein.  What the group first showed is that the CDR3 region on free light chains is the critical determinant of the binding with Tamm-Horsfall protein.

In their more recent paper, they report the development of a competitive inhibitor of the light chain Tamm-Horsfall protein interaction by blocking the Tamm-Horsfall protein binding site.  In a rodent model, in which human serum from patients with multiple myeloma was used to induce myeloma cast nephropathy they demonstrate the ability of the inhibitor to prevent both the histologic changes of myeloma cast nephropathy as well as AKI.

The inhibitor was infused just four hours after the serum containing light chains so future studies will need to examine situations that more closely mimic human disease in which presentation to care is delayed for much longer periods of time.  Despite this, the study adds to our understanding of the mechanisms on AKI in patients with myeloma casts nephropathy and provides a new avenue for investigation of treatment of renal disease in patients with myeloma casts nephropathy independent of chemotherapy.

Images from the recent NephSap Pathology edition.

Conference Review: Renal Biopsy in Medical Diseases of the Kidneys

I'm not a huge conference goer.   I've been to ASN a few times and have made a brief appearance at the Advanced Nephrology for the Consultant down in San Diego but otherwise haven't seen much of the conference circuit.  But when I got the Columbia flyer for the Renal Biopsy in Medical Diseases of the Kidneys a few years ago I knew it was going to be something I'd have to eventually check out.  It features the core of the GN clinical and pathology brain trust lecturing on what they know best: what GNs look like and how to manage them.  Falk and Jennete on ANCA, Appel and D'Agati on SLE, Rennke on, well, anything.  So this summer I finally got myself organized and funded and took the trip out to Manhattan to see the show.

First, a few general comments.  Staying in Manhattan is expensive.  Like $400 a night expensive.  The conference had a block of rooms reserved at hotel called the Lucerne for $200 a night.  I procrastinated and called the hotel after the deadline listed in the flyer and was politely told that all the rooms were gone and I could now book one for $440 a night if I was interested.  I declined and luckily had a family member take mercy on me and allowed me to stay with them on short notice.  If that hadn't come through I was ready to book a room through Airbnb which, if you haven't used it, is a cool site where you can find locals renting out space in their homes for cheap.

Second, it is hot and humid in Manhattan in the summer. Crazy hot. Bring wardrobe accordingly. I scuttled between air conditioning on the subway, lecture hall and my hosts place the whole week (I know, soft Californian behavior).

Third, take advantage and see Manhattan. I channeled my inner intern and skimped on sleep to hit the conference then experience the city.  Well worth it.

As for the conference it is certainly one of the best I've ever been to.  It's truly education focused, the talks are given in series rather than parallel like some of the big conferences so you're never at risk for missing anything.  The speakers are, for the most part, amazingly clear and avoid the common sin of nerding out on their own particular pet projects but rather focus on big picture relevance.

It's fun watching the older and younger members of the team interact as they clearly like each other and have a great back and forth.  You also get a sense of how some of the younger faculty like Glenn Markowitz, Andrew Bomback and Leal Herlitz are coming into their own and making their marks on the GN world.

The group aren't afraid to give their opinions when it gets to the grey areas.  Who doesn't want to hear how Gerry Appel manages not so clear cut cases of Lupus Nephritis?

Lots of path slides, which for those like myself about to take boards, is great review.  The faculty clearly take pride in their lectures and are up-to-date current in their lectures with recent literature incorporated.  Lots of interested cases discussed.  Very nice syllabus with all slides included.  If they want to kick up their game they could go for online access to high res versions of the path slides - though many of them you can find in the recent NephSap renal path edition.

My inner intern unfortunately caught up with me on the last day and I missed Saturday morning and had to catch a flight out before the path and case workshops in the afternoon.

My only gripe would be the daily supplied lunch - terrible.  I bailed and braved the heat to find something good to eat, which was actually a lot of fun.  All in all a wonderful conference that I highly recommend.  I kept up a pretty good twitter feed of pearls from the first three days of lectures which you can check out here.

A unified view of abnormal sodium regulation in the nephron

Summer has come to the northern hemisphere and it is time to praise our kidneys for all the hard work of preserving the intravascular volume. Although only 30% of Na reabsorption takes place in the distal nephron, this is the place for most common genetic diseases causing abnormal sodium handling:

What are the responsible proteins for these diseases?

1. Bartter syndrome: Na reabsorption decreases via NKCC2 due to defects in NKCC2, ROMK and basolateral Cl channels or from an overactive basolateral CaSR.

2. Gitelman syndrome: Na reabsorption decreases due to a reduced number of NCCs on the luminal membrane.

3. Pseudohypoaldosteronism type 1: Na reabsorption decreases due to the defects in ENaC or mineralocorticoid receptor.

4. Liddle syndrome: Na reabsorption increases due to a higher number of ENaCs on the luminal membrane (they are spared from ubiquitination).

5. Gordon syndrome: Na reabsorption increases due to a higher concentration of NCCs on the luminal membrane (defects in WNK4 or overactive WNK1). More recently, mutations were discovered in the genes encoding KLHL3 and CUL3 proteins.

CUL3 is a component of ubiquitin ligase and KLHL3 is its partner (expressed in the DCT). It is speculated that the defects in these proteins may change the distribution of NCC.

Is this clinically relevant?

In Gordon syndrome, these mutations can occur de novo and are encountered more frequently (47% for KLHL3 and 32% for CUL3) than those involving the WNK kinases (13%). It appears that they are under-diagnosed and some of the cases of RTA type 4 with hypertension could be caused by them!

50 years after Bartter syndrome was described, the work on mechanisms responsible for abnormal Na regulation in the nephron continues…

Posted by Tomoki Tsukahara MD 

 

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

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

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"

"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.

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.

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.

References

1. Clay AS, Hainline BE. Hyperammonemia in the ICU. Chest. 2007 Oct;132(4):1368-78.

2. Lora-Tamayo J, Palom X, Sarrá J, Gasch O, Isern V, Fernández de Sevilla A, Pujol R.‏ Multiple myeloma and hyperammonemic encephalopathy: review of 27 cases.‏ Clin Lymphoma Myeloma. 2008 Dec;8(6):363-9.‏

3. Furer V, Heyd J. Hyperammonemic Encephalopathy in Multiple Myeloma. Isr Med Assoc J. 2007 Jul;9(7):557-9.

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.