Do hibernating bears urinate?

And now for a discussion of a burning nephrology question: what happens to a bear's renal function when it goes into hibernation? (Thank my brother for raising the question while he was a medical student.) The simple answer to the headline question is: no, they do not. The details behind what does happen to renal function and nitrogenous waste disposal in hibernating bears is unfortunately not fully worked out yet, but what is known is a fascinating example of adaptive physiology.

Bears hibernate in spans of a few weeks to several months, depending on the species, the weather, and available food stores. During that period, their metabolism drops to about a third of normal. There is a shift away from protein and carbohydrate metabolism toward fat breakdown. These processes result in a few notable changes in renal function: creatinine rises (from an average of 1-1.5 mg/dL to 3 mg/dL, thought to be due to decreased renal perfusion), and urea:creatinine ratio falls (as a result of decreased protein metabolism). A small amount of urine, about 100 mL, is produced, and the water and nitrogenous breakdown products are reabsorbed through the bladder. How does this happen? No idea. Urea is degraded, again by an unknown mechanism: one theory is that urease-producing bacteria in the gut aid in breakdown. Nitrogen is also thought to be shunted toward protein anabolism. The amazing result is that blood from hibernating bears does not contain an elevated level of urea, uric acid, amino acids, or ammonia. They replenish the water lost via respiration via lipolysis, where water is an end product. Interestingly, despite increased fat metabolism, bears do not develop a ketosis. Again, not sure why (may be related to increased glycerol metabolism).

So, next time you see a bear foraging through garbage pails, or sniffing around your campsite, remember: he may be looking for food, but he does not need to find the latrine.

Post obstructive diuresis

Urinary tract obstruction is a frequent occurrence in the hospitalized setting. Thankfully, after relief of the obstruction a vast majority of patients have complete recovery of kidney function. However, a few patients will have marked polyuria (>4-5L per day) after release of bilateral obstruction. This is termed postobstructive diuresis. There are several physiologic and pathologic factors that lead to the development of this condition.



Physiologic factors

1. Excess sodium and water retention
2. Accumulation of urea and other non-reabsorbable solutes resulting in an osmotic diuresis.
   

Pathologic factors

1. Decreased tubular reabsorption of sodium secondary to altered expression of proximal and distal sodium transporters.
   
2. Inability to maximally concentrate urine, secondary to a decreased medullary concentrating gradient, leading to decreased response to ADH
3. Increased tubular transit flow time reducing equilibration time for absorption of sodium and water.
4. Increased production of prostaglandins immediately following relief of obstruction.
   

Patients who develop post obstructive diuresis need to be monitored closely. Especially if the patient is unable to eat and drink on their own. Once the accumulated excess of sodium and water has been excreted, severe volume contraction and hypokalemia can occur. It is important to monitor urine output closely in this setting. Once the patient has diuresed to the point of euvolemia, fluid replacement should be administered as needed to prevent volume contraction. This is done by replacing 75% of the urine losses with 0.45% NS. This condition is usually self-limiting and resolves over several days to a week. Persistent polyuria beyond a week is often due to overzealous volume repletion.

Something fishy?

A 30-year-old man was admitted to our hospital for evaluation of lung nodules detected during pre transplant evaluation for his stage V chronic kidney disease (CKD). Sounds routine, but what caught me completely clueless was when I was told that he had CKD due to lecithin:cholesterol acyltransferase (LCAT) deficiency. A prominent physical finding on meeting him was the presence of bilateral peripheral corneal opacities at such a young age. On questioning, the patient reported that he was diagnosed with this condition on family screening after his father died following massive myocardial infarction due to dyslipidemia at the age of 35. A nice case report from KI can be found here or from NDT here.

Familial LCAT deficiency is a rare but possibly under diagnosed autosomal recessive disorder reported in families of European ancestry and is characterized by

1. Dyslipidemia – extremely low HDL levels (less than 10 mg/dL), increased cholesterol: cholesterol ester ratio with elevated triglycerides and total cholesterol.
2. Presence of corneal opacities giving the fish eye appearance.
3. CKD with proteinuria by 3rd-4th decade. Biopsy findings typically include - mesangial matrix expansion and foamy appearance of the glomerular basement membrane (GBM) on light microscopy, lipid droplets in the mesangial matrix, GBM and podocytes on electron microscopy with foot process effacement and segmental or global sclerosis eventually.
4. Mild hemolytic anemia.

Briefly, LCAT is an enzyme synthesized in the liver and primarily bound to HDL. It plays a prominent role in esterifying the cholesterol in the HDL thereby creating a concentration gradient for the cholesterol to move out of tissues thus helping HDL to function in reverse cholesterol transport (from tissues to liver). In patients with the LCAT deficiency, HDL-C maturation does not occur as unesterified cholesterol remains within the tissues and an abnormal lipoprotein called lipoprotein X (unesterified cholesterol and lecithin) is formed in the blood from the surface of chylomicron remnants not metabolized due to this enzyme deficiency. These lipid accumulations within the tissues explain the classic findings in these patients.

Although the mechanism of kidney injury is unknown, it is believed to be likely due to direct injury to the glomerular filtration barrier from the lipid deposition and/or inflammatory response due to lipoprotein X mediated monocyte recruitment and eventual glomerulosclerosis.

In our patient the diagnosis of LCAT deficiency was made by measuring the plasma assays for LCAT at the age of 6yrs. He had albuminuria by the age of 16 yrs but was lost to follow up and later presented with chronic kidney disease and nephrotic range proteinuria. He subsequently underwent renal biopsy that showed the above classic histological findings. He now has stage V CKD and is later scheduled to undergo live unrelated kidney transplantation. Liver transplantation is also being considered to decrease his risk of recurrence following transplantation.

Although this case is unique and perhaps rare, it highlights the importance of family history and careful physical examination particularly in patients with unexplained nephrotic syndrome. Next time, in such situations look closely into the eyes, you may find something fishy.

Viresh Mohanlal, MD

Image Credit to Tara Lemana

Epo: The honeymoon is not over

Having just returned from my own honeymoon, I was taken by this recent hypothesis-piece by Fishbane et al. They have made some observations on the natural history of untreated renal anemia from examining the placebo arm of the recent TREAT RCT. Briefly, placebo-treated patients in TREAT received rescue therapy with Epo only if their Hgb levels fell to less than 9.0 g/dl; Epo was discontinued and patients returned to placebo as soon as their Hgb levels rose above this level. By this design, the placebo arm of TREAT sheds light on a very conservative approach to anemia management in pre-dialysis CKD.

Interestingly, analogous to patients with newly diagnosed type 1 DM who commonly experience a sharp reduction in their insulin requirement after initial presentation, there appears to be a similar “honeymoon period” after initial presentation with renal anemia, during which the hematocrit stabilizes or even increases (see figure) without treatment. An explanation may be that CKD patients presenting with an acute event such as infection may experience an abrupt, transient, decline in serum erythropoietin levels, and worsening of anemia. As they recover from the presenting event, serum erythropoietin levels and Hgb may also improve. However, this improvement would be masked in patients already initiated on maintenance outpatient Epo.


Many Nephrologists feel as though they are stuck between a rock and a hard place when it comes to Epo administration post-TREAT. This observation may encourage them to hold their nerve in CKD patients who initially appear to require Epo, as the anemia may well improve given time, at least in the short term. Of course, most patients with progressive CKD (save those perhaps with APCKD) will ultimately develop intractable anemia. A further RCT is required to know how to treat them, perhaps with a “TREAT placebo arm” vs. “no Epo at all” design. Perhaps, it could be called the DIVORCE trial (Darbepoetin Intermittently Vs Observation in Renal anemia of CKD).

My head feels like it's about to explode

In a previous post I discussed the relative rates of infection and graft failure of femoral and jugular dialysis catheters. As a follow-on I wanted to talk about another potential complication of catheters.

Recently one of our patients had been having trouble with her AVF. She had it for 9 years and had multiple previous revisions and angioplasties of recurrent subclavian and brachiocephalic stenoses. She was admitted for insertion of a bovine interposition graft and the following day she had a tunneled RIJ catheter inserted as a bridge until the AVF could be used again.

The following day she presented to the ED with dyspnea, tongue and facial swelling. A laryngoscope found laryngeal swelling and she was intubated emergently. She had a CT neck which is shown below:





(Click image for larger view)

She previously had received radiotherapy to her neck for a SCC of unknown origin which had left her with no jugular vein on the left and chronic supraglottic edema. Shortly after insertion of the line, a clot formed in her RIJ proximal to the catheter which, in the absence of a LIJ led to a SVC-like syndrome. She was treated with intravenous heparin and eventually removal of the catheter.

Catheter-associated thrombosis is surprisingly common. Prior to the 1990s the most popular route for inserting temporary dialysis catheters was the subclavian vein but this was increasingly recognized to be associated with subclavian thrombosis and stenosis. As a result, most lines are now inserted into either the jugular (preferable) or femoral veins. Up to 25% of patients with femoral lines develop associated thrombus which can be asymptomatic but may also present with signs of DVT or PE. But what about jugular lines? According to this study of 143 prevalent dialysis patients with RIJ tunneled dialysis catheters, 26% were found to have a catheter-associated thrombus while 62% of these had a complete occlusion of their RIJ. None of these were symptomatic.

So what can you do about this? In one way, ignorance is bliss. Given that they are usually asymptomatic, in the absence of catheter dysfunction, we should probably do nothing as if you removed every line simply because of the presence of an asymptomatic thrombus, you would run out of access site very quickly. Perhaps the lesson is this. In patients with previous surgery/radiotherapy to the neck or with multiple previous catheter insertions, determine the anatomy prior to inserting a new line so that any future complications can be anticipated and dealt with promptly.

Doc, I am very sensitized! (part 2)

Let’s continue our discussion from our last blog about sensitized kidney recipients. In summary, we have this 60 yo man interested on a second transplant. He has a high PRA (98%) as well as anti-HLA Abs against his only potential donor (his son).

So, what is his best option? His best outcome would be to obtain a kidney from a donor that he does not have any HLA Abs against (DSA). If he waits in the deceased donor list, this might take many years based on his elevated PRA (most kidneys from the population will have HLAs that he is sensitized to). Similar problem would be faced by enlisting on a paired kidney donation (PKD) program, since he will likely be sensitized to most of the donors. However, this has a great potential in near future since the larger the size of the enrolled pool of recipients, the greatest the chance of success in finding a donor.

Finally, we could attempt to desensitize our kidney recipient so that he could get a kidney from his son. The best predictor of success in desensitizing a patient is his titers of DSA. The general literature suggests that the higher the titer the lower the success in obtaining a negative crossmatch pretransplantation (ultimate goal). There are two major protocols of desensitization:

-high dose IVIG (2g/kg)
-Plasmapheresis associated with low dose IVIG (100mg/kg).

The goal of desensitization is to decrease the number of circulating DSA and decrease the production of these Abs, preventing hyperacute rejection in the immediate posttransplant period and minimizing the risk of subacute antibody-mediated rejection (AMR). Plasmapheresis (TPE) is able to remove physically the antibodies, however is associated with great rebound of antibodies if used alone. IVIG is effective in reducing anti-HLA Abs, through multiple hypothesized mechanisms (Figure above). There has been no randomized trials comparing both protocols, however a retrospective analysis suggested that combination of IVIG with TPE might be more effective in desensitizing patients. Even though both protocols are able to reduce hyperacute rejection and decrease DSA in most patients, they are not effective in patients with high titers of DSA and they are still associated with high prevalence of AMR (20-50%) after transplantation. The presence of AMR significantly decreases long-term graft survival . Moreover, the combination TPE and IVIG is impractical for deceased kidney transplantation, leaving high dose IVIG as the only option for those patients without potential living donors. Finally, Rituximab has been added in some protocols with some good additional results.

In our patient, the DSA titers were low at 1:4 and repeat DSA was 82%. Our recommendation was to enlist him on a paired kidney donation as well as deceased donor list (he gets extra points for his high PRA). We would also start preparing him for a potential desensitization in case no donors were available in the PKD program. A combination of TPE and low dose IVIG is used in our center and we estimate a minimal of 4 TPE before obtaining a negative AHG-CDC crossmatch (based on titers). Immunosuppressive drugs are started 4 days prior to potential tx day. Lastly, we would also perform a minimum of 3 sessions of TPE after tx with IVIG, followed by monitoring for DSA. Based on our own’s center data, we expect a good short-term outcome on his case with ~90% graft survival on the first year after transplant. Long-term is still suboptimal due to high degree of AMR with all available protocols, but with better survival then staying on dialysis.

Secondary forms of hypertension

Lisa Cohen recently summarized rare "genetic" forms of hypertension including Liddle's syndrome and PHA type II (Gordon's syndrome).

I want to summarize other causes of "secondary" hypertension which are not inherited (at least not typically in a Mendelian transmission) and which are potentially "fixable".

These phenotypes are distinct from primary hypertension which affects the vast majority of our patients. Secondary forms of hypertension affect typically less then <5% of patients with hypertension.

In order to identify a reversible cause for hypertension following data needs to be obtained:

• HPI
• Family history
• Physical exam
• Initial labs including Chem7, Lipid panel, Urine analysis, EKG
• Indications for further labs include abnormal initial tests (high Ca++ levels, low K+ levels), abrupt onset of hypertension, young age (<30),>50), hypertension resistant or refractory to 3+ medications, worsening hypertension in a previously well controlled patient, BP >180/110 at onset.
  

The most common forms of secondary hypertension are:

1. Renovascular hypertension
2. Coarctation of aorta
3. Cushing’s syndrome
4. Primary Aldosteronism
5. Thyroid/parathyroid disease
6. Pheochromocytoma

Typically others causes such as CKD or sleep apnea are not considered "secondary" forms of hypertension. Physical and laboratory findings can help and guide in ruling out secondary forms of hypertension: If you find this -> think this !!!

1. Truncal obesity and striae -> Cushing's syndrome
2. Labile hypertension -> Pheochromocytoma
3. Abdominal bruits -> renovascular hypertension
4. Decreased BP and Pulse in lower extremities -> Coarctation of aorta
5. Abdominal flank masses -> Polycystic kidney disease
6. Elevated Crea and/or abnormal UA -> parenchymal kidney disease
7. Hypercalcemia -> Hyperparathyrodism
8. Hypokalemia -> Hyperaldosteronism (also Cushing's syndrome and Pheochromocytoma can present with this).

Last but not least, a few more facts on the three most common secondary forms of hypertension:

1. Renovascular hypertension- Renal artery artherosclerosis (males>50, Fibromuscular dysplasia (females<40),Other (rarer) causes include vasculitis, scleroderma, Takayasu arteritis, etc. - Labs show typically hypokalemia and hyper-reninemic hyperaldosteronism - Screening tests recommended are Doppler US, MRA, CT angio, captopril renogram - Gold standard is arteriography which could show “string of beads” vs. single stenosis
2. Hyperaldosteronism: Aldo causes increased Na+ uptake in distal tubule -> increase in intravascular volume
   -Suspect in patients with unexplained low K+
   -Main causes are adrenal adenomas (~ 70%) and b/l adrenal hyperplasia (~ 25%)
   -Screening by checking stimulated PRA or PRC which will be undectable or low
   -Confirm screening tests with salt/fluid loading -> "elevated" Aldo level will NOT be suppressed
3. Pheochromocytoma:
   -Rare tumors arising from chromaffin tissue of the adrenal gland
   -90% occur in the adrenal medulla
   -10% are b/l, 10% are malignant and 10% are familial!
   -Associated with MEN II
   -Remember that 33-50% of patients have sustained hypertension !
   -Suspect it if refractory to treatment
   -Screen for serum or urine metanephrines
   -CT adrenals or/and MIBG scan (meta-iodo-benzyl-guanidine) to detect tumors

Interventional nephrology in fellowship training

Interventional nephrology is quickly becoming a sought after "subspecialty" of nephrology. However, many training programs do not offer a structured training program (as highlighted in this recent AJKD paper). Traditionally nephrology training is spent rounding in the hospital, clinic or the outpatient dialysis unit. Procedures, like temporary catheters, biopsies etc. are typically performed throughout these rotations. Little time during training is devoted to assessing malfunctioning fistula, grafts or placing tunneled dialysis catheters. As the job market for nephrology continues to be challenging (highlighted by the recent RBT article) having the necessary certification in interventional nephrology can be a valuable asset when applying for jobs. RFN wanted to know how much exposure nephrology fellows currently have in interventional nephrology?

Of the 73 respondents to our poll

• 52% stated that they had hardly any exposure. I'm not terribly surprised by this. Only 11 programs around the country have American Society of Diagnostic and Interventional Nephrology (ASDIN) accreditation. Only 3 of these are affiliated with University based programs. However, several programs offer training that are currently not accredited by the ASDIN.
• 23% of respondents felt that they just had an introduction to interventional nephrology.
• Only 23% indicated that they either had a fair amount (17%) or more than enough (6%) exposure to this growing field.
  

It is clear that finding a program with an adequate amount of exposure to interventional nephrology is difficult.  I will be interested to see how nephrology programs adapt and expand their current training programs to meet the needs of future nephrology fellows. For more information on how to obtain certification visit the ASDIN website (www.asdin.org). Let us know how your program is offering interventional nephrology training.

Genetic causes of hypertension

And now for some board review tidbits! Below are some genetic causes of hypertension attributable to specific gene mutations.

1. Glucocorticoid-remediable hyperaldosteronism (GRE)- Autosomal dominant condition caused by uneven crossing over on chromosome 8. A chimeric protein is created in which the ACTH-controlled promoter for 11 beta hydroxylase is joined to the structural gene encoding aldosterone synthase. Aldosterone is overexpressed, leading to a hyporeninemic, salt-sensitive state of volume expansion. Hypokalemia and metabolic alkalosis may be present. Glucocorticoid administration suppresses ACTH and thus also aldosterone synthase production.
2. Apparent mineralocorticoid excess (AME)- Autosomal recessive disorder characterized by deficiency in 11 beta hydroxysteroid dehydrogenase 2. 11 beta dehydrogenase 2 metabolizes cortisol to cortisone. In states of cortisol excess (here caused by decreased metabolism), cortisol binds to and activates type I mineralocorticoid receptors, causing an aldosterone-like effect. Hypokalemia, hypernatremia and hypertension are seen. Treatment is with dexamethasone, which suppresses endogenous cortisol production.
3. Liddle’s syndrome- Autosomal dominant genetic mutation on chromosome 16 that causes defective ENaC ubiquitlyation and endocytosis, leading to increased ENaC cell surface expression and subsequent increased Na reabsorption. Presents in childhood with hypertension, hypokalemia and metabolic alkalosis. ENaC blockade with amiloride or triamterine plus a low Na diet are the usual treatment.
4. Pseudohypoaldosteronism Type II (Gordon’s syndrome)-Not sure what the inheritance pattern is in this condition. A genetic defect in WNK kinases 1 or 4 causes a hyporeninemic, hypertensive state. The mechanism by which these WNK defects may cause high blood pressure is unclear, but the most common explanation is that the mutations lead to an increase in thiazide-sensitive Na-Cl transporter activity. WNK I inhibits ROMK in vitro, so it may cause decreased K secretion in vivo. WNKs may also increase paracellular Cl transport, which would decrease H and K secretion into the lumen. Treatment is with thiazides.
5. Mineralocorticoid recepator activating mutation- please see the excellent post from June 7 from Mike on this condition, which was the answer to a board review question.

I recommend some nuts

I have a fresh case with great learning points that I would like to discuss today. So I will continue with the management of sensitized patients on my next blog.

Case: This is a 70 yo female with ESRD from diabetic nephropathy underwent a deceased donor kidney transplant (tx) about 4 months ago. Her peritransplant period was remarkable for delayed graft function and a bx at one week after tx showed ATN without no rejection. Four weeks after transplantation, her creatinine reached a nadir of 1.16 mg/dL. At that time, she was noted to have hypercalcemia (10.4 mg/dL) and a phosphate level below assay detection. She denied any weakness, confusion, dyspnea or myalgia.

Discussion 1: Hypophosphatemia is a common complication after kidney tx, affecting more than 90% of patients. It usually regresses spontaneously by 1 year after successful renal tx. In the general population, it can occur by one or more of three primary mechanisms: (1) inadequate intestinal phosphate absorption, (2) excessive renal phosphate excretion, or (3) rapid redistribution of phosphate from the extracellular fluid into bone or soft tissue.

Patients after kidney tx exhibit mainly an inappropriately increased urinary excretion of PO4. This is thought to be secondary to a disorder in the regulation of tubular reabsorption of PO4. Possible factors include: (1) increased PTH level and activity, (2) increased levels of FGF-23; and (3) side effects from immunosuppressive drugs (both high dose steroids and tacrolimus downregulate phosphate receptors on the proximal tubule). The mechanism of PTH and FGF-23 phosphaturia is through a decrease in Na/PO4 cotransporter expression on the apical brush border membrane.

Case cont.: Based on extremely low phosphate levels, she was started on K-Phos neutral 500 mg three times a day. On a routine visit two weeks later, she was found to have a creatinine rise to 3.86 mg/dL. Her only complaint at that time was diarrhea. She was admitted for hydration and possible repeat kidney bx. Her additional labs on admission included calcium 6.6 mg/dL, PO4 5.3 mg/dL, PTH 515 pg/mL, 25-vitamin D 32 ng/mL and FK level 10.5 ng/mL The kidney allograft biopsy specimen showed sequelae of tubular injury associated with extensive deposition of calcium phosphate within the distal tubules!!! So acute phosphate nephropathy (APN), like the ones recently reported with bowel preps!

Discussion 2: In the general population, PO4 repletion is usually recommended when phosphate levels are below 2 mg/dL. The presence of symptomatic complications may warrant more aggressive repletion with IV PO4 therapy. However, oral PO4 supplementation has been linked to increase prevalence of nephrocalcinosis in kidney tx recipients, nonetheless APN is an uncommon complication. In our case, we believe there were multiple factors that triggered the CaPO4 deposition, including: the oral PO4 supplementation (~1,500 mg daily), the volume depletion from diarrhea, the prior tubular injury from ischemia, the high FK level (vasoconstriction and PO4 wasting) and the hyperparathyroidism with urinary PO4 wasting. No FGF-23 was measured but I would antecipate a high level as well. In combination, these factors led to a high urinary PO4 load to a single kidney, which precipitated with calcium in the tubules. There was a concomitant decrease in serum calcium and rise in Cr, which has been classically reported in the older literature to be associated with calcium phosphate deposition and renal failure (figure). In the absence of specific guidelines for kidney transplant recipients, we recommend a conservative management of hypophosphatemia, starting with dietary changes and applying close monitoring in patients on oral supplem. Vitamin D deficiency should also be addressed if 25-vitamin D levels below 30. Finally, the use of cinacalcet in kidney tx recipients in a small short-term trial demonstrated to correct urinary phosphate wasting by mainly affecting PTH levels suggesting a possible role of this drug in management.

PS. High sources of PO4 are almonds, nuts, meats and eggs. A 12-oz Coca Cola has about 68 mg of PO4 and Fruit punch 123 mg.