Noninvasive Control of Uremic Bleeding

We frequently receive requests to dialyze patients with moderate renal failure who are bleeding due to the concern that uremia may be contributing to failure to control blood loss.

Patients with renal failure do have an increased tendency to bleed, usually manifested by prolonged bleeding time. I was recently reminded by one of my colleagues in conference that while dialysis is an option for treatment of uremic bleeding, it is important to recall (ideally prior to placing the large and inflexible central line) that there are several noninvasive medical therapies for uremic bleeding, some of which work quite well and with minimal side effects.

Uremic bleeding is multifactorial, involving dysfunctional Von Willebrand factor, accumulation of many uremic toxins, particularly L-arginine, increased levels of cyclic AMP and cyclic GMP (cGMP) both of which reduce levels of thromboxane A2 (TxA2) and ADP, anemia, which causes platelets to travel midstream through the blood vessels, farther away from the endothelium. Red blood cells also scavenge nitric oxide and release ADP and TxA2. Lower levels of TxA2 and ADP lead to decreased platelet aggregation. Nitric oxide (NO) also plays a central role. L-arginine induces NO synthesis, which stimulates guanylyl cyclase, increasing cGMP levels, and thus decreasing TxA2 and ADP. TNF-alpha and IL 1beta are also increased in uremia, both of which induce NO synthase.

Treatment options for uremic bleeding include: erythropoetin, cryoprecipitate, desmopressin, conjugated estrogens (premarin, explaining the picture associated with the post), and dialysis. Various doses of erythropoetin have been studied, but the success is dependent not on the dosing regimen but the achievement of a hematocrit of 30%. Cryoprecipitate contains factor VIII, vWF, and fibrinogen, likely increasing the proportion of functional clotting factors in uremic patients' plasma. Desmopressin likely releases factor VIII from storage sites, increasing the concentration of factor VIII and minimizing the effect of dysfunctional vWF. The dose is 0.3 to 0.4mcg/kg IV or subcutaneously. It acts within an hour, but tachyphylaxis develops after one dose, likely due to depleted vWF from endothelial stores.

Estrogens can also safely and effectively improve bleeding time in uremic males and females. The dose needed is 0.6mg/kg IV conjugated estrogens over 30-40 minutes once daily for 5 days. The onset of action is about 6 hours, with maximum effect at 5-7 days and a duration of action of 14-21 days. The mechanism is thought to be reduction of L-arginine, which is a precursor to NO. This results in less guanylyl cyclase stimulation and less production of cGMP, leading to increased TxA2 and ADP and improved platelet aggregation. This theory is supported in rat studies. 17beta estradiol given to rats made uremic by reduction of renal mass significantly reduced bleeding time within 24 hours and normalizes plasma concentration of NO metabolites, nitrites and nitrates, and of NO synthase catalytic activity. Endothelial NOS and inducible NOS immunoperoxidase staining in the endothelium of uremic aortas of untreated rats was significantly more intense than in control rats. Uremic rats receiving 17beta estradiol had NOS staining comparable to controls. Estrogens have been used for patients with uremic GI bleeding, with some controversy and a negative RCT in angiodysplasia. Nate Hellman also talked about estrogens in GI bleeding here.

Nature Clinical Practice published a nice review on treatment recommendations for uremic bleeding, with a summary of recommendations and the strength of the evidence behind each recommendation, along with an algorithm for treatment of bleeding patients. Special thanks to Nirupama Ramkumar for finding and summarizing this article in clinical case conference.

Idiopathic MPGN and its subtypes. Or: I'm going to need the whole bottle to get through this

I recently evaluated a young patient for kidney transplant who had been diagnosed at age 13 with MPGN III. He had a slow reacting C3NeF, low C3, normal C4, low terminal complement levels, and by biopsy had paramesangial and subendothelial but no subepithelial deposits. I was confused by the diagnosis of MPGN III, which I understood to be a controversial and exceedingly rare diagnosis. Without subepithelial deposits the histologic pattern was not consistent with my understanding of MPGN III, and my knowledge of the complement abnormalities associated with the subtypes of idiopathic MPGN was vague at best. I decided to read more about the specifics of MPGN III, but instead of instant enlightenment I developed a deeper confusion. This was going to take a while. So I grabbed a glass of wine and kept reading.

MPGN is a progressive form of renal failure defined by histologic features. All forms have diffuse mesangial proliferation and subendothelial extension of the mesangium. MPGN I is characterized by activation of the classical complement cascade by immune complexes. On IF, MPGN I is distinguished by subendothelial deposits of IgG and C3 or isolated C3, with frequent presence of C1q, properdin, and C4. MPGN type I is far and away more commonly a secondary disorder- if MPGN type I morphology is found on biopsy, you should probably not rest until all possible underlying causes have been ruled out. Idiopathic forms do exist, most commonly appearing in childhood and adolescence. With activation of the classical pathway, serum C3 levels are low or normal, C4 levels are low, and CH50 levels are low.

MPGN II (dense deposit disease) is defined by intramembranous, elongated, brightly eosinphilic, variably refractile electron dense deposits that stain positive for C3 and much less commonly IgM or IgG. This is not thought to be an immune complex disease. It is associated with dysregulation of the alternative complement pathway through C3NeF (C3 nephritic factor), which stabilizes and inhibits the inactivation of the alternative C3 convertase C3bBb, resulting in perpetual breakdown of C3 and continuously activated alternative complement pathway. Factor H deficiency or mutation has also been identified as a cause of MPGN II. MPGN II is also associated with acquired partial lipodystrophy and macular drusen, both of which are also caused by activation of the alternative complement pathway. With activation of the alternative pathway, C3 levels are low, C4 levels are normal, and CH50 levels are low.

MPGN type III is thought to be an extremely rare, and possibly not existent (depending on the expert) disease associated with abnormalities of the complement cascade. It appears identical on light microscopy to MPGN I, with somewhat less hypercellularity. On EM there is the additional finding of subepithelial deposits as well as subendothelial deposits and intramembranous interposition of mesangium. It is associated with a slow acting nephritic factor of the terminal pathway(NeFt), which stabilizes a properdin dependent C5 convertase ((Cb3)2BbP)- resulting in persistent activation of the terminal pathway. With activation of the alternative and terminal pathways, C3 levels are low, C4 levels are normal, and levels of C5 through C9 are low. The lack of literature on this disease highlights its rarity.

Here is an excellent review of the pathophysiology, clinical manifestations, and treatment of idiopathic MPGN.

What I've just reviewed makes the differences between MPGN I, II, and III sound very clear-cut, but this is not actually the case. Some cases of C3NeF positive and hereditary MPGN I have been identified, which implies a completely different pathophysiology of disease than classical MPGN I despite the presence of classical MPGN I histology. As a result, there is a movement to reclassify MPGN based on pathogenesis as opposed to histologic criteria. This makes the literature more than a little confusing. In my patient, despite the lack of subepithelial deposits, he fit the diagnosis for MPGN III based on his serum complement profile, with slow reacting C3NeF, low C3, normal C4, and low terminal complement components.

I am also wondering about the risk of recurrence of MPGN in my patient's pending allograft. Idiopathic MPGN I recurs with a frequency of 20-40% and II recurs in about 80-90% of allografts. In pediatric patients, recurrence of MPGN II results in a 15% rate of graft failure at 5 years post transplant. What about MPGN III? I couldn't find anything in the literature. Does anyone out there have any MPGN III transplant patients?

Of side note, HUS and TTP also result from dysregulation of this very same complement cascade at some of the very same locations, and it is worthwhile to review and compare to the pathogenesis of MPGN.

The organization is key

There are a number of glomerulopathies that feature organized deposits of nonbranching fibrils, some more common than others. The diseases make their first major separation into Congo Red positive (amyloid) and Congo Red negative categories. Amyloid fibrils are randomly arranged, and are 8-12nm in diameter. The Congo Red negative fibrillary diseases are more diverse, and since they are more rare but are favored by those who write the boards, I found a review to be helpful. Fibrillary Glomerulonephritis:

• Randomly arranged fibrils 12-30nm in diameter
• Usually polyclonal IgG
• Presents usually with proteinuria. 50% have nephrotic syndrome at presentation.
  
• 50% of patients progress to ESRD within a few years
• Treatment often unsuccessful. Steroids, cytoxan, and rituxan have been used with varying success.
  
• Does not usually recur in transplants
  

Immunotactoid glomerulopathy:

• parallel deposits of straight, hollow-lumen fibrils (microtubules) >30nm in diameter
• usually monoclonal IgG
• usually secondary
• Deposits occur on subepithelial surface of basement membrane, can be indistinguishable from membranous on light microscopy
  
• Presents with nephrotic syndrome, hypertension, hematuria.
  
• Recurs in transplants

Cryoglobulins:

• randomly arranged curved microtubules 25-35nm in diameter

Fibronectin glomerulopathy:

• 10-15nm fibrils
• Hereditary, autosomal dominant
• Presents with proteinuria, hematuria, hypertension
  

Collagenofibrotic glomerulopathy

• Banded collagen fibrils
• Hereditary, autosomal recessive, most cases from Japan
• Presents with edema and nephrotic syndrome
• Progresses to ESRD

Diabetes can also be associated with fibril deposition, usually 5-20nm in diameter. Lupus can cause fibril formation, and these generally are around the same size as the deposits in fibrillary GN and are arranged in a fingerprint pattern.This article contains an outstanding flow chart for the differential diagnosis of glomerular diseases with organized deposits.

For the boards, it may be helpful to remember that the fibril diameter of the more common fibrillary diseases- amyloid, fibrillary GN, and immunotactoid GP are correlated with their position in the alphabet- (A= 8-12nm, F= <30nm, usually 18-20, and I= >30nm, usually 45-55nm).

Doc, this itching is making me crazy

Nearly every time I walk through the dialysis unit at the VA, at least one patient calls me over to tell me that their itchy skin is driving them crazy. Pruritus is a torment to many dialysis patients, and the best I’ve been able to offer to patients as far as management is: come to dialysis, stay the whole time, and watch your phosphorus intake. That’s pretty dissatisfying to many patients, especially when they are already doing all of those things.

More than half of all patients undergoing dialysis complain of pruritus, and the mechanism isn’t really very well understood. Some studies have found no significant difference in serum levels of creatinine, BUN, calcium, phosphorus, alkaline phosphatase, PTH, and hematocrit in patients with pruritus vs without, but the general recommendation is to keep phosphorus and PTH under good control. One study did find a significant difference in the frequency of neuropathy in patients with pruritus, and another found an association with hemoglobin A1c.

Trials investigating treatment options have not yielded a cure, but treatments are out there, and include topical therapies such as emollients, capsaicin, gamma-linolenic acid, and tacrolimus, systemic therapies such as activated charcoal, gabapentin, pentoxyfilline, and thalidomide, and physical therapies like UV phototherapy, electroacupuncture, and renal transplantation. First and foremost, management involves ensuring the patient is adequately dialyzed and their calcium/phosphorus and PTH levels are well controlled. A flow chart (I love flow charts) is found in this article.

In the patient with severe refractory itching, a diagnosis to consider is Kyrle’s disease, or perforating folliculitis. Kyrle’s disease is associated with diabetes and CKD/ESRD- one series found 9 cases in 200 dialysis patients, and is an odd disorder wherein keratin, collagen, and elastic fibers migrate transepidermally. The lesions are small papules that are flesh colored or slightly hyperpigmented. They slowly enlarge with time and each one contains a central, keratotic, slightly depressed core. This core contains a plug filled with keratin, parakeratotic scale, and basophilic debris. The epidermis around the core is thinned, and the plugs can contact the dermis and become inflamed. Treatment is difficult, but some success has been noted with tretinoin creams (though these should be used with caution in dialysis patients due to risk of high vitamin A levels), avoidance of trauma and scratching- ie wearing gloves, trimming fingernails, and transcutanous nerve stimulators. Large lesions can be excised, and phototherapy has been particularly successful for dialysis patients. Occasionally, patients are cured with renal transplantation. I had a patient recently who was severely affected by pruritus and had been treated for everything from scabies to psychiatric disease. We diagnosed her with Kyrle's disease after a skin biopsy, and although the therapies were not immediately effective in eliminating the itching, it was some relief to her to put a name to her symptoms.

Cisplatin nephrotoxicity

Cisplatin was discovered more than 40 years ago, and is still widely used in chemotherapy regimens for many different types of cancer. Its wider use has been limited by toxicities, one of which is nephrotoxicity. Nate Hellman also wrote about cisplatin nephrotoxicity here.

I was recently consulted on an oncology patient with suspected cisplatin nephrotoxicity. The patient had hematuria with dysmorphic red blood cells on microscopy, and I wondered whether this could be a manifestation of cisplatin toxicity. The answer I found was: maybe.

Early clinical manifestations of the renal effects of cisplatin include a uniformly present polyuria. There is early polyuria at about 24-48 hours, which resolves, but is followed by a late phase between 72 and 96 hours after administration. Hypomagnesemia is a common complication and is likely due to a renal defect in magnesium reabsorption. Hypomagnesemia results in secondary hypocalcemia and hypokalemia. An incomplete distal RTA can also occur. The fall in GFR accompanying cisplatin nephrotoxicity is usually seen about 10 days after administration. A nice review of nephrotoxicity is here.

Preexisting kidney disease predisposes patients to nephrotoxicity because about 50% of cisplatin is excreted in the urine 24 hours after administration. Most of that actually appears in the first hour. Platinum is extensively protein-bound, and free platinum is freely filtered at the glomerulus and excreted unchanged in the urine. However, uptake of platinum does occur, primarily in the proximal tubule. When it enters the tubular cell it undergoes biotransformation and leads to apoptosis. The mechanism of renal damage is complex and multifactorial and due to activation of pathways that lead to production of TNF- α and subsequent inflammation. A review of these complex pathways is found here. The proximal tubular damage can result in glucosuria and amino aciduria. The glucosuria may also occur with cisplatin induced glucose intolerance. Salt wasting has also been reported with cisplatin.

Pre-hydration with saline for a goal urine output of 3 to 4L per day, drug dosage decrease (toxicity is generally dose-related), and screening for renal abnormalities are the most accepted ways to prevent nephrotoxicity. Mannitol and furosemide have been studied as preventative agents, but results have not been uniformly promising. Sodium thiosulphate is another potential protective agent, however there is some concern that it may affect the antitumor activity of cisplatin. Liposomal preparations of cisplatin are being studied and may be less nephrotoxic than the original preparations.

Proximal tubular damage, however, doesn’t explain my patient’s dysmorphic red blood cells. Cisplatin has also rarely been associated with a thrombotic microangiopathy that could possibly explain them. TMA is more commonly seen with cisplatin in combination with bleomycin and gemcitabine, but has occurred with cisplatin alone or with other drugs. He did not have schistocytes on peripheral smear and renal dysfunction was mild, so pheresis was not considered. It is possible that he had an underlying glomerulonephritis that was not previously recognized, but given his platelets of 17 and a single kidney on imaging, we didn’t plan to biopsy to find out. He did not receive any further cisplatin.

Emily Petersen, MD

Hyponatremia correction; rule of 6s

Profound hyponatremia of around 100mEq/L or less is a double-edged sword- it’s got to be treated but can be terrifying to treat. The University of Rochester shared their protocol for controlled correction of severe hyponatremia with AJKD in October of 2010.

Hyponatremia with neurologic symptoms needs to be treated promptly but cautiously to avoid overcorrection with associated risk of osmotic demyelination. The most efficient and rapid way to raise sodium levels is to use 3% saline, but this carries a high risk of overcorrection.

The cause of hyponatremia and its reversibility must also be considered when deciding a course of action. In hypovolemia-induced hyponatremia, vasopressin levels decline and sodium levels rise as volume status is restored to normal. When medications such as thiazides and SSRI are discontinued, their effect on sodium levels goes away and sodium levels will begin to rise as the medications are cleared from the body. Similarly, in patients with beer potomania, sodium levels will rise as they begin to take in increased concentrations of solutes.

As reversible causes of hyponatremia are eliminated, vasopressin levels rapidly fall to undetectable levels- causing polyuria. Patients can excrete massive quantities of maximally dilute urine that can increase sodium levels at an unsafe rate of up to 2mEq/L/h. Most patients who present with profoundly low sodium are at higher risk of osmotic demyelination- chronic hyponatremia, sodium less than 105mEq/L, hypokalemia, alcoholism, malnutrition and liver disease all place patients in danger of this complication.

Desmopressin administered q6-8 hours has been shown by this same Rochester group to be effective and more practical than hypotonic fluids in preventing overcorrection of hyponatremia. They administer desmopressin immediately without waiting for the onset of water diuresis, and concurrently administer 3% saline solution. The goal of the use of desmopressin is to maintain constant antidiuresis and a more predictable response to 3% saline. The downside is that it takes longer to correct sodium, leaving the patient on hypertonic saline for a longer time. During this time, water intake needs to be restricted to avoid decreasing serum sodium concentrations. Desmopressin has also been used in a few cases to re-decrease serum sodium concentrations after neurologic symptoms have developed, which was effective in reversing the symptoms.

They recommend correction of no faster than 6mEq/day for patients with severe chronic hyponatremia, with 6mEq in 6 hours on the first day if symptoms are severe. This has led to the rule of 6s.

• 6 a day makes sense for safety
• 6 in 6 hours for severe symptoms and stop (no more correction that first 24 hours)

Also remember:

Potassium administration also has to be taken into account when correcting sodium with the formula:

Serum [Na+] = {Total body exchangeable (Na+ + K+)} / total body water

* Solve for {Total body exchangeable (Na+ + K+)} by multiplying total body water by serum sodium.

* Determine the amount of solute to give to correct to a goal serum sodium level by solving for the goal serum [Na+]

For example:

Current serum Na+ = 100 mEq/L

Goal serum Na+ = 105 mEq/L

Total body water = 50L

100 mEq/L=5000 mEq/ 50L

105 mEq/L= ? mEq/ 50L

105 mEq/L= 5250 mEq/ 50L

To correct sodium to 105mEq/L, 250mEq of combined sodium and potassium should be administered over an appropriate time period (6 or 24 hours based on the rule of sixes above)

Emily Petersen, MD