Thursday, August 28, 2014

Kidney Organ Allocation in the USA - Upcoming Changes!

This is a short video describing the current and new policies regarding deceased donor kidney allocation in the USA. These policies may significantly affect certain groups of patients and physicians must be aware of those in order to best represent their patients. For more details, also check prior blog.

Link for the video here

Hypokalemic Periodic Paralysis

A recent renal consult I encountered was a Cantonese gentleman with a classical symptomatic history for Hypokalemic Periodic Paralysis (HPP). He presented with a serum K of 1.4 mmol/l and profound weakness. Initially beginning in his teenage years, he had intermittent attacks of weakness lasting hours and affecting proximal muscle groups. Emergency department admissions invariably revealed low serum K.
Many of us will know the classical features to look for in the history:
  • High risk Asian and Hispanic population groups, particularly males less than 20 years old.
  • High carbohydrate meals triggering insulin release or  B-adrenergic surge from exercise or volume depletion.
  • Thyrotoxicosis: A major subgroup of patients, usually men. The mechanism is thought to involve a combination of up regulation of Na-K-ATPase, loss of function of the inward potassium rectifying channel Kir2.6, and a feed forward effect in certain variants of the sulphonylurea receptor 1, culminating in dramatic intracellular potassium shifts. It is important to note is that rarely the paralytic episodes can predate the thyroid disease by many years.
The genetics of hypokalemic periodic paralysis have been discussed previously on Renal Fellow Network.

Management: More Questions than Answers
Acute management is relativity straightforward – administration of K, either IV or orally. Case control series demonstrate up to 70% of patients having rebound hyperkalemia of >5mmol/l if  KCl doses of over 90mmol/ are administered. Lower doses may potentially be used if concomitant B-blockade is deployed in conjunction. Oral KCl rescue is more suitable for home use.  As a rule of thumb, 40 to 60 mmol/l of oral  Kraises plasma potassium concentration by 1.0 to 1.5 mmol/L, and 135 to 160 mmol/l Kraises plasma potassium by 2.5 to 3.5 mmol/l.
Besides avoiding obvious environmental triggers, therapeutic interventions and prophylaxis are more unclear. Patients have normal total body potassium with no chronic GI or renal loss, thus the drop in serum levels is mediated via a transcellular shift. Despite this, prophylactic K supplementation remains a traditional cornerstone of therapy, although one would imagine a normally functioning cortical collecting duct should excrete this quite rapidly, particularly with chronic dosing regimens.
The “highest quality” of evidence comes from a Cochrane review of 3 very small studies, the largest examining the utility of dichlorphenamide, a carbonic anhydrase inhibitor, in 34 patients. Self-reported quality of life improved in 15 patients, and attack frequency dropped. This is in line with a more recent study in 2011 which quote a 50% improvement in symptoms in a larger group of patients on dichlorphenamide. This is unusual as the additional HCO3 in the collecting duct should increase intraluminal negative charge, and encourage potassium excretion, as should the volume depletion and increased RAAS activity. Furthermore, volume depletion could theoretically induce increase sympathetic output, worsening K loss. The most plausible explanation I found was a paper from 1975 suggesting the metabolic acidosis induced by the carbonic anhydrase inhibitor buffers the transcellular shift of K+.
Despite aldosterone levels being normal during attacks, reports suggest aldosterone antagonists may benefit patients as a second line therapy via their K+ retaining effects, although their action appears to be opposite to that of dichlorphenamide. It is curious these agents with supposed diametric effects on renal K handling both have positive effects on K balance in HPP.

The most intuitive treatment is B-blockade, demonstrated in a number of series to be effective, but almost always in those whose HPP occurs in association with thyrotoxicosis.

Authored by Eoin O'Sullivan

Sunday, August 24, 2014

mTOR Pathway in Anti-phospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune hypercoagulable disorder characterized by small-to-large vascular (both arterial and venous) thrombosis with end-organ damages, in presence of circulating antibodies against phospholipid binding proteins.

Kidney transplantation in patients with APS is challenging because  post-transplant thrombosis, vascular complications and requirement of anticoagulation during peripoperative period. Let’s start with a brief review of recent advances in transplantation in APS.

For post-transplant TMA due to recurrent APS nephropathy, Canaud et al. recently explored the use of eculizumab. Eculizumab, a humanized mAb that binds C5, prevents cleavage of C5 into C5a and C5b, thereby preventing generation of the membrane attack complex (MAC). At a molecular level, the pathogenesis of endothelial damage in APS is in part via complement activation; C5b-9 MAC deposition on endothelium, leading to cell lysis and/or activation of other proinflammatory pathways, so the use of eculizumab is reasonable. Three patients, maintained with steroids, CNI and MMF, were treated with eculizumab for posttransplant TMA with robust improvement of allograft functions after several doses, and all three patients were successfully withdrawn from maintenance eculizumab treatment after 3-12 months of initial dose. Interestingly, although biopsy showed improved TMA lesions, C5b-9 depositions were persistent for as long as 3 months as “foot prints”. The authors also noticed that eculizumab treatment did not prevent the chronic vascular lesions seen in 12-month protocol biopsies.

Preemptive use of eculizumab in kidney transplant in APS-related ESRD was also attempted in another case series. Three patients, two with CAPS (catastrophic APS), received 1,200 mg of Eculizumab on day 0, 900 mg on POD 1, and weekly thereafter until week 4. After week 5, they received 1200 mg every 2 week. Despite one  biopsy proven cellular rejection successfully treated with pulse steroid, graft function and survival was acceptable without recurrence of APS during follow-up of 6 months to 4 years. In the setting of no specific treatment other than systemic anticoagulation, eculizumab seems potentially promising treatment, however, the sufficient treatment length of this drug needs to be optimized, especially due to high cost. Also, there is no description of immunosuppressive regimen either for induction nor maintenance, and it is unclear these patients were on sirolimus or not.

 In a recent NEJM article, Canaud et al.  indicated the beneficial effect of sirolimus in proliferative vascular changes associated with APS and CAPS, which were not reversed by eculizumab in their previous study. They demonstrated that the chronic vascular changes in APS patients were induced by activation of mTORC via phosphorylation of Akt-S6K pathway, using immunohistochemistry of renal biopsy samples and in vitro signaling studies with HIMEC-1, a human microvascular endothelial cell line, as well as autopsy samples of CAPS. Furthermore, using a cohort of kidney transplant patients with APS (10 treated with steroids+sirolimus+purine inhibitor and 27 with steroids+CNI+purine inhibitor), their nested-case-control study demonstrated that posttransplant allograft functions were better preserved at 144 months post transplant in the sirolimus group compared with CNI group (7 of 10 vs 3 of 27 patients with functioning grafts) and this effect was observed only in patients with APS and not in patients without APS. Other variables including cold ischemia time and immunologic risk profile were comparable between sirolimus and CNI groups. Although this is a relatively small case-controlled study, the use of mTOR inhibitors for the prevention of APS post-transplant seems very promising.

Naoka Murakami

Thursday, August 21, 2014

Renal Function after Off- or On-Pump CABG: CORONARY Trial is next #NephJC

The next Nephrology online journal club (#NephJC) will discuss the results of the CORONARY Trial, presented at the late breaking session at the ASN and published this year in JAMA. The trial compared patients undergoing their first coronary artery bypass graft (CABG) surgery using an off- or on-pump technique. The main study published previously revealed no difference with respect to the composite outcome of 30-day mortality, myocardial infarction, stroke or acute kidney injury (AKI) requiring dialysis. The renal function trial was a prespecified substudy involving 2975 (of a total 4752) consecutive patients enrolled in CORONARY with baseline and post-operative serum creatinine data. The renal substudy patients had similar characteristics to the overall CORONARY population.

Outcomes of Interest:
  • Post-operative AKI was defined as a 50% increase in the serum creatinine concentration within 30 days of surgery (highest creatinine within 30 days was used).
  • Loss of renal function at 1 year = 20% loss in eGFR (using CKD-EPI).
  • Worldwide enrolment with 42% from Asia and the remainder mostly from Europe (21%) and the Americas (<1% were African American).
  • Baseline characteristics of note were a mean age of 68 years, BMI 27, >80% male, almost half were diabetic and a similar number of ‘urgent’ cases between the groups.
  • Almost a quarter had CKD (eGFR <60mls/min) and the mean eGFR was 74-75mls/min in the 2 groups.
  • There were 561 AKI events (median time of 2 days post-op to peak creatinine) with a reduced rate with off-pump (17.5%) V. on-pump (20.8%) surgery (adjusted RR 0.83 [CI 0.72-0.97]; p = 0.01).
  • Mean eGFR at 1 year was 72 mL/min with off-pump and 73 mL/min with on-pump.
  • No significant difference in loss of eGFR at 1 year between off-pump (17.1%) V. on-pump (15.3%) surgery (P = 0.23).
  • Those with CKD derived a greater benefit in reduced AKI with off-pump surgery but eGFR loss at 1 year remained insignificant.
  • Over 200 patients crossed over between the groups (evenly split) and results of the intention to treat were similar to as-treated analysis.
  • Multiple alternative definitions of AKI & loss of kidney function did not alter the main results.
Dialysis requiring AKI has detrimental effects on long-term kidney function. Less severe AKI is more common with major cardiac surgery (only just >1% had AKI requiring dialysis in the original CORONARY trial). It is less clear what effect these more subtle derangements have on long-term function. This study suggests that these ‘mild’ AKI events may not have much longer-term significance, contrary to observational studies [ref, ref]. As pointed out by the authors, this finding has implications for other interventions in mild AKI such as for contrast nephropathy. Does preventing a subtle GFR dip in this scenario have a long-term benefit? The study is limited somewhat by the unique situation studied in the trial (although cardiac surgery provides a very ‘convenient’ insult in which to study AKI). Also, we are relying on serum creatinine and all its limitation to assess kidney function. Moreover, not all eligible patients had creatinine values measured and single measurements and imputed values were often used for the analysis.

This study provides good evidence that off-pump CABG decreases the rate of non-severe AKI but that this does not appear to translate into better renal function at 1 year. When I first heard the results of this study at the ASN (a somewhat deflating session along with lots of other negative/inconclusive Nephrology studies), I was disappointed with the small magnitude of the AKI decrease with off-pump surgery. I had expected the toxic milieu associated with on-pump surgery (aortic cross clamping, exposure to bypass circuit, changes in blood pulsatility) to be associated with much higher rates of AKI, compared to off-pump. The study also questions my preheld assumption that acute drops in GFR, from mild to severe, had a continuous magnitude of impact on long term renal function.
Feel free to get involved by joining the live Twitter chat on Tuesday 26th August at 9pm Eastern using #NephJC. Also, check out for more background and past journal clubs.

Sunday, August 3, 2014

Spironolactone Revisited

As a renal fellow, I have found myself reaching for spironolactone more and more. It is very helpful when treating the patient with resistant hypertension, but it continues to be under-utilized. Aside from the renal-centric effects of aldosterone, there is evidence that mineralocorticoid receptor activation is responsible for pathogenic remodeling (both structural and electrical) after myocardial infarction. In fact, aldosterone is also produced by the heart, and cardiac expression of the mineralocorticoid receptor is increased in the setting of heart failure and MI. Perhaps aldosterone antagonists can reverse the cardiac remodeling, predisposition to arrhythmia, and risk of cardiovascular death we see in our kidney disease patients?

Remember, patients with ESRD do not die from kidney failure per se, but most die from cardiovascular and cerebrovascular disease. We know that spironolactone reduces mortality and hospitalization due to heart failure in patients with reduced LVEF (RALES trial), but we don’t know if these effects carry over to the ESRD population. However, two recent papers caught my eye.
One was recently published in JACC, where 309 patients with ESRD were randomized to spironolactone 25mg once daily or a control group. The primary outcome was a composite of death or hospitalization from cardiovascular and cerebrovascular events, and the secondary outcome was death from any cause. At three years, the treatment group had significantly fewer cardiovascular and cerebrovascular events: 9 patients (5.7%) vs 19 (12.5%) in the control group (Adjusted HR 0.379, p = 0.016). There were also fewer deaths: 10 (6.4%) with spironolactone vs 30 (19.7%) in control group (Adjusted HR 0.335, p=0.003). Out of the 157 patients in the spironolactone group who stopped the drug, 7 developed gynecomastia, 9 had breast pain, and 3 patients had significant hyperkalemia (>6.5 meq/L). Of course, this was a small RCT and not blinded or placebo controlled. If these effects are true, this would yield a NNT of 14 to prevent one cardiovascular or cerebrovascular event and a NNH of 52 to cause one episode of hyperkalemia. 
A similar study published in JASN randomized 158 patients on PD and already on ACE/ARB therapy to 25mg of spironolactone or a control group.  After two years of follow up, the rate of change of LVMI was significantly lower at 6, 18, and 24 months in the spironolactone group. In a subgroup analysis of males who started the trial with LVMI ≤ 50 g/m2, the control group had a significant increase in LVMI over time while the spironolactone treated group was unchanged. Likewise, in males who started with LVMI > 50 g/m2, those treated with spironolactone had a significant reduction in LVMI over time compared to the controls. In this trial, serious hyperkalemia (>6.0) occurred infrequently: 2 in spironolactone group and 1 in control. Gynecomastia was more frequent in the spironolactone group (14.1% vs 2.5%), but some of these patients had their doses reduced or were switched to eplerenone. 
So what does this all mean? It’s exciting to think that mineralocorticoid antagonists may reduce LVH and cardiovascular events in our ESRD population. A larger, placebo controlled trial is needed to confirm these findings since these were small open-label trials. Fortunately this is underway with the ALCHEMIST trial (NCT01848639), which plans to randomize 825 hemodialysis patients to either spironolactone or placebo. In the meantime, it may be best to use spironolactone as an anti-hypertensive agent in a dialysis patient who is low risk for hyperkalemia. For instance, PD patients tend to have have low serum potassium thanks to high clearance. In the PD patients I’ve seen with hypertension and hypokalemia, I have been backing off pure anti-hypertensive agents (like hydralazine) and starting 25mg of spironolactone. These trials suggest that this dose is safe to use in dialysis patients and possibly has some effect in preventing LVH and improving long-term cardiovascular outcomes.

Posted by John Roberts

Wednesday, July 23, 2014

Hyperammonemia - When should we start dialysis?

I would like to discuss a case that I recently saw in renal consult. He was a man in his 60s with history of end stage liver disease who received a liver transplant. His hospital course was complicated by anuric ATN and liver graft failure. As a result, he was started on dialysis on post-operative day 0.  Dialysis was stopped on post-op day 2 due to recovering renal function. On post-op day 3 he became encephalopathic. His ammonia level was elevated to 337 and did not improve with conventional therapy with lactulose/rifaximin. The question was whether to start dialysis or not in spite of his recovering renal function.

Causes: The urea cycle in the liver in which ammonia gets converted to urea is responsible for excretion of waste nitrogen.  Hyperammonemia in newborns is most commonly associated with inherited disorders of amino acid and organic acid metabolism. Causes in adults include Reye’s syndrome, liver failure, sepsis especially infections with urea splitting organisms, high dose chemotherapy, drugs (salicyclates, valproate), gastrointestinal bleeding, multiple myeloma, parenteral nutrition and late onset of urea cycle defects. The latter usually presents with episodic encephalopathy precipitated by metabolic stressors like infection, anesthesia or pregnancy.

Clinical features: Hyperammonemia can be life threatening and if persistent can lead to irreversible neuronal damage. It leads to cerebral edema causing progressive encephalopathy. Respiratory alkalosis is common due to central hyperventilation. Severe hyperammonemia can also cause seizures. An MRI brain is usually consistent with hypoxic ischemic encephalopathy

When to start dialysis? There are no published guidelines for when to initiate dialysis in a patient with hyperammonemia due to urea cycle defects. It is commonly indicated if the ammonia blood level is greater than three to four times the upper limit of normal or greater than 200 micromoles/L. Continuous hemodialysis is started with higher flow rates and is the most effective treatment in rapidly reducing ammonia levels.  Even though ammonia is osmotically active, the rapid removal of ammonia is not associated with disequilibrium syndrome mainly due to two reasons: First, there is a rapid equilibration of ammonia across the cell membrane. Secondly, the total amount in the blood, even in severe hyperammonemia, is only about 200 micromoles. This contributes less than 1 mosm per liter to total osmolality and therefore, even if it were all removed at once, the change in osmolality is too small to make cause disequilibrium. Contrast this with ammonia levels in the urine which are typically in the millimolar range.

The question remains whether to start dialysis in the setting of acute severe hyperammonemia (levels > 200 micromoles/L) and encephalopathy in adults with liver failure and normal kidney function. I was not able to find any literature on it and would like to know what the practice in other institutions is?  I believe since severe hyperammonemia can lead to irreversible brain damage, dialysis should be instituted. See this previous post concerning hyperammonemia in individuals with myeloma.

Posted by Silvi Shah

Tuesday, July 22, 2014

Tick borne diseases for the nephrologist - Babesiosis

The following few posts are a summary of tick borne illnesses that can cause renal failure and/or electrolyte problems. 

First identified on Nantucket Island in 1969 and was initially know as Nantucket fever.

Endemic areas.
CDC map. Reported cases in 2012
Cases have been reported in Europe (Croatia, France, Great Britain, Ireland, Portugal, Spain, Sweden, Switzerland)(Babesia divergens).

The tick.
Ixodes scapularis. The Blacklegged tick.

The pathogen.
Babesia microti and B. duncani (USA). B divergens (Europe). Protozoan parasites infecting red blood cells
Humans are not a natural host. Infection by blood transfusion has been reported.

Incubation period 1 – 9 weeks

Clinical features.
Fever, chills, sweats, Malaise, fatigue, Myalgia, arthralgia, headache, Gastrointestinal symptoms, such as anorexia and nausea (less common: abdominal pain, vomiting)
Dark urine
Less common: cough, sore throat, emotional lability, depression, photophobia, conjunctival injection
Mild splenomegaly, mild hepatomegaly, or jaundice may occur in some patients

Lab features
Haemolytic anemia, thrombocytopenia, renal failure, transaminitis.

Diagnosis - Light microscopy of blood cells, serology and PCR for B. microti or B. duncani

Treatment - Atovaquone plus azithromycin or quinine plus clindamycin orally for 7 to 10 days.
Atovaquone plus azithromycin is preferred as this combination is better tolerated.

The source for this review is mainly from the CDC website as well as various references cited in the posts. The tick pictures provided may differ from what might be found on a bitten human. Ticks become larger and engorged after feeding and will look different.

Thursday, July 17, 2014

The Lone Star Tick

Recently a 65-year-old female was referred to an ED in the state of Missouri complaining of fevers, chills, headache, diarrhea and vomiting occurring over the last week. 3 weeks prior she had received an orthotopic liver transplant. Her post transplant course was unremarkable and she was discharged on prograf 2mf bid, myfortic 360mg bid, prednisone tapering, Bactrim single strength daily and valcyte 450mg od. She also took thyroid replacement, Januvia, warfarin and aspirin. Past medical history included diabetes, heart failure, dysfunctional uterine bleeding, hypothyroid and PUD. She also had CKD with a creatinine about 1.4mg/dl. On examination her Temp was 38.6, HR 110, BP 113/76 and O2sats 99% on RA. She had no nuchal rigidity but reported a sore neck. She had an erythematous area on her lower back. The rest of her exam was normal.

Her initial labs were:
Hb 6.3, WCC 2.7 (94%neuts, 5.8%lymphs), platelets 35
NA 122, K 5.6, Cl 100, CO2 11, BUN36, Creat 2.3, Gluc 173
Arterial pH 7.31, CO2 20, O2 102
AST 52, ALT 41, AP 155, GGT 171, Bili 0.6, Alb 3.3
UA, No blood, 1+protein, 2 rbc, 2 wbc

She had a normal CT brain and was started on multiple antibiotics in the ED.

On further questioning her daughter reported removing a tick from her back after the patient went out looking at deer close to her house.
Lets pretend the daughter brought in a picture of the tick (see above)!

Lab trends; admission to discharge.
Hb 6.3
WCC 2.7                   1.4           0.6           0.5           0.3           1.2           2.4
94%neut                90            91            87            83            60            59
5.8%lym                 6               6.7           9.2           14            16            28
plt 35                       16            18            24            28            26            31
NA 122                    128         132         135
K 5.6                   
Cl 100
Co2 11
Creat 2.3                 2.2           1.8           1.6                                               1.3
Gluc 173
pH 7.31
CO2 20
O2 102
AST 52                                                                                                               31
ALT 41                                                                                                               31
AP 155                                                                                                              249
GGT 171                                                                                                                            
Bili 0.6                                                                                                               0.8
Alb 3.3
No blood
2 rbc
2 wbc
No lumbar puncture was performed.

To summarize, this lady had constitutional symptoms, fever, neurological symptoms, GI symptoms with a rash and a tick bite. She had pancytopenia, transaminitis, hyponatreamia and renal failure.

Her antiproliferative medication and anti-infective medications were held (Myfortic, valcyte and Bactrim).
IV Doxycycline was commenced.
Sodium and creatinine improved and potassium became low, likely due to GI losses.
Interestingly her leucopenia followed the classical pattern of lymphopenia followed by leucopenia and she required G-CSF. Her transaminases were normal at the time of discharge.

Diagnosis = Ehrlichiosis 

The first case of human ehrlichiosis was described in 1986.
The two most important species to infect humans are Ehrlichia chaffeensis which causes human monocytic ehrlichiosis (HME) and Anaplasma phagocytophilum which causes human granulocytic anaplasmosis (HGA). Both of these diseases have the same vector and have very similar clinical and laboratory features. Ehrlichia ewingii is a less common cause of ehrlichiosis than Ehrlichia chaffeensis.
Ehrlichiae are obligate intracellular bacteria found in membrane bound vacuoles in human and animal leukocytes.

The most endemic area is the southeastern USA – ‘the tick belt’. See the CDC map for the endemic regions in the USA. Cases have also been reported in Europe, Africa, South America and Mexico.

The lone star tick (Amblyomma americanum) is recognized by the CDC as the principal vector of Ehrlichia chaffeensis and Ehrlichia ewingii in the U.S.; both disease agents are responsible for causing ehrlichiosis in humans. White-tailed deer are a primary host of the lone star tick and appear to serve as a natural reservoir for E. chaffeensis. The lone star tick is also a vector of Francisella tularensis, causal agent of tularemia. Adult ticks parasistize deer, cattle, horses, feral swine, sheep, dogs, and humans.

Most infections occur in the spring and summer in the USA.

The clinical manifestations in the elderly and immunosuppressed can be very severe but the following are the usual clinical features:

Fever - Some fevers can be protracted over weeks
Malaise, myalgia, headache and chills – 2/3
Nausea, vomiting and arthralgia – ¼ to ½
Rash (Macular, mucopapular, petechial) – 1/3
Meningism – ¼

More rarely – Seizures, coma, renal failure, heart failure and respiratory failure
There has been a single case of myocarditis and multi-organ failure in a healthy adolescent.

Laboratory findings:
Most common triad is leucopenia, thrombocytopenia and elevated transaminases.

Leucopenia. This tends to be caused by lymphopenia initially followed by neutropenia as in this patient.

Elevated transaminases, LDH and Alk phos
Elevated creatinine

CSF, when neurological symptoms
Lymphocytic pleocytosis and elevated CSF protein

Usually by PCR methods. Note this test may not detect the recently reported third species, E. muris, found in Wisconsin and Minnesota.

Differential diagnosis
This can be a difficult diagnosis to make. It is clinically and geographically similar to RMSF. It can also present like mononucleosis, TTP, hematologic malignancy, cholangitis, the early phases of hepatitis A infection. This is especially so in immunocompromised patients whose clinical features may not be as obvious initially. Common transplant drugs such as Bactrim/Septra, valganciclovir, mycophenolate and azathioprine can also cause cytopenias.

Treatment (adults)
Doxycycline 100mg iv or po bid for about 10 days.
Note this will also treat RMSF which is often confused with ehrlichiosis.

Outcomes. Mortality is about 5%. Most commonly due to viral or fungal super-infections (Invasive aspergillosis, candida, HSV).

This interesting case illustrates the difficulty in diagnosing tick borne infections. They can be lethal and severe in our immunosuppressed transplant population and can be a cause of renal failure in any patient. Also of interest in this case is the lymphocytopenic and neutropenic trending that is usually more peculiar to Anaplasma phagocytophilum which causes human granulocytic anaplasmosis (HGA). We did not test for A phagocytophilum as ehrlichae PCR was positive.


A bit of housekeeping here - I noticed that all of our current course announcements were out of date. These have now been updated with the most recent versions of each course including the following courses coming up shortly:

ASN Board Review Course - August 2-8 2014
HD University - August 15-16 2014
Brigham Renal Board Review Course - August 4-8 2014
Medstar Kidney and Pancreas Transplantation Course - October 11, 2014
Ultrasonography for Nephrologists - October 25-26 2014 (which I recently attended and thought was excellent)

All of these courses have substantially reduced fees for trainees.

Here is the list of courses

Edit: Just to mention that the director of the ISHD meeting, John Daugirdas, contacted me and let me know that the new edition of the Handbook of Dialysis will be out later this year. If you were thinking of buying it (and I did in the past), you might want to wait until then.

Wednesday, July 16, 2014

Baclofen in dialysis patients: Just say no!

At our hospital, we started noticing a pattern of admissions among some of our maintenance dialysis patients. In one case, an elderly woman with DM, peripheral arterial disease, and ESRD on thrice weekly hemodialysis was sent to the emergency department from her nursing facility for altered mental status. She was normal three days prior to admission, but when her nurse found her confused and difficult to arouse, they sent her to our ED. We got consulted to continue maintenance dialysis, but we noticed that she had a fluent aphasia and marked perseveration. The rest of her exam and workup was unremarkable.  I immediately called the nursing facility and had them fax over her medication administration record. Lo and behold, three days prior she was started on baclofen 5mg three times daily for complaints of lower extremity leg pain (which was probably her claudication anyway). We diagnosed her with acute baclofen neurotoxicity.

Baclofen is an oral antispasmodic that is used to treat muscle spasticity. Chemically, it is very similar to the CNS neurotransmitter GABA and it acts as an agonist at GABAB receptors, resulting in an inhibitory effect on neurons.  Baclofen is rapidly absorbed after ingestion and 90% of the drug is excreted unchanged by glomerular filtration. Therefore, patients with CKD and ESRD are at significant risk from baclofen accumulation and toxicity. The most common complaints are non-specific: drowsiness, headache, lethargy, nausea or vomiting. However, with a severe overdose, profound CNS depression occurs with respiratory depression, bradycardia, hypotonia, areflexia, myoclonus, or seizure activity.

The importance of baclofen toxicity in patients with renal failure has only recently been described and remains unappreciated by many physicians. El-Husseini et al. compiled a nice series of 41 cases of baclofen toxicity in patients with renal insufficiency. The majority of the patients had ESRD (62.9%) and the remaining either had advanced CKD or AKI. Despite being a small, heterogeneous case series, a few trends were seen. The onset of symptoms typically came two to four days after initiating the drug, and the mean daily dose was 20mg per day.

Since baclofen is small molecule (213 Daltons) and it has a relatively low volume of distribution and low degree of protein binding, it is readily removed by hemodialysis. There are only a few of clearance studies out there, but one report found that 4 hours of HD with a high-flux membrane resulted in a clearance of 120 ml/min, equivalent to a normal GFR! Since we have been more aware of baclofen, we have discovered more cases of neurotoxicity in our ESRD patients. We treat with daily sessions of high-flux HD for at least 4 hours until symptoms disappear. Our patient returned to her baseline after 3 consecutive days of HD. The authors of the case series highlight the lack of official dosing guidelines for baclofen in patients with renal insufficiency. Thus, many providers are unaware that this drug is contraindicated in those with advanced CKD and ESRD. Renal fellows are already primed to check for excessive gabapentin doses and NSAIDS, but I would add Baclofen to the list of drugs that should not be given to any patient with advanced CKD or ESRD.

Posted by John Roberts

Tuesday, July 15, 2014

Lithium and the Kidney: Old Observations & New Insights

Lithium is indispensable as an effective treatment for bipolar affective disorder. However, it has a narrow therapeutic index with desired therapeutic levels between 0.6 and 1.2 mEq/L. Lithium is handled by the kidney (responsible for almost all its excretion) in a manner very similar to sodium. It has a molecular weight of 7 daltons, has a moderate volume of distribution, is <10% protein bound and is therefore readily dialyzable. Lithium may cause of myriad of renal related toxicities, some of which are classic descriptions and some which are less well known. Much of this has been discussed on RFN before (here, here) but I felt a refresher with some additions was due.

Nephrogenic Diabetes Insipidus (NDI)

This is perhaps the best know and most common complication of lithium therapy, with an estimated prevalence of 20-70%. Patients present with polyuria and polydipsia due to a urinary concentrating defect that can lead to volume depletion, especially if access to free water is restricted. Lithium downregulates aquaporin-2, vasopressin-activated water channels expressed on the collecting duct principal cells. It is worth noting that ongoing volume depletion from NDI may aggravate the risk of supra-therapeutic levels and therefore chronic nephrotoxicity. Amiloride may help as it inhibits lithium reabsorption via ENaC in the collecting duct.    

Renal tubular Acidosis (RTA)

Lithium may induce a hyperchloremic non-anion gap metabolic acidosis, analogous to a distal RTA. It is likely due to decreased distal proton secretion. Unlike acidosis associated with amiloride, it is not associated with hyperkalemia probably because of their different effects on distal H+/K+-ATPase function.

Acute Lithium Nephrotoxicity

This may occur as an overdose in newly treated patients or those on long-term lithium therapy. Acute lithium intoxication may cause altered mental status and acute kidney injury. Drugs which decrease GFR (NSAIDs/RAAS inhibitors) may exacerbate intoxication as can thiazides, which cause a natriuresis and a subsequent reabsorption of Na (and lithium). With preserved renal function and mild intoxication, increasing urine output/forced diuresis may be all that is needed. Care should be taken using 0.9%NaCl if hypernatremia from NDI is present. As mentioned above, lithium is readily dialyzable and hemodialysis (ideally using a high flux membrane to aid clearance) is the primary management for severe cases. A lithium level >4mEq/L is considered an absolute indication for dialysis in most cases. A level >2.5mEq/L with severe symptoms, or renal impairment which will slow native clearance, is also an indication. If in doubt, most nephrologists would have a low threshold for dialysis, although it is usually not needed with a level <2.5mEq/L. Drug levels drop rapidly during dialysis but they do rebound so extended and repeated sessions are usually necessary. Continuous therapies are less efficient so are not desirable if severe intoxication is present but may be used if conventional dialysis is not immediately available.

Chronic Tubulointerstitial Nephritis (TIN)

A chronic TIN with interstitial fibrosis and tubular dropout is the commonest pathology seen when patients with lithium and renal impairment are biopsied. Consistent with this is a bland urine sediment with little/no proteinuria being common (although not exclusive-see next section). As nephrologists, our view of the prevalence of lithium induced CKD is skewed. The exact prevalence is difficult to determine but many patients have preserved renal function. The tricky decision is whether (and if so when) to stop therapy? This is rarely a decision the nephrologist can make alone and should be balanced with efficacy of treatment/alternatives available and usually led by the psychiatrist in my opinion.

Nephrotic Syndrome

It is less well known that lithium may be associated with a glomerulopathy. Minimal change disease is most often described but membranous nephropathy and FSGS has also been reported. Cases were considered lithium induced as proteinuria disappeared upon cessation of the drug, and when re-challenged (for psychiatric reasons), the nephrotic syndrome recurred. A series of 24 patients with lithium-induced nephrotoxicity from New York included one quarter with nephrotic-range proteinuria. My initial thoughts were that the FSGS lesions were likely secondary to nephron loss and resulting hyperfiltration injury. However, arguing against this is that presence of FSGS lesions did not correlate with severity of tubulointerstitial lesions. Moreover, there was a high incidence of extensive podocyte foot process effacement, to a degree uncommon in secondary FSGS. The mechanism of glomerular toxicity is unclear.

Renal Cell Tumors

It has recently been reported in Kidney International that chronic lithium use is associated with an increased risk of kidney tumours.  After a mean duration of lithium exposure of >21 years, patients had a significantly higher risk of solid renal tumours compared with gender, age and eGFR matched controls [Standardized Incidence Ratio i.e. ratio of observed-to-expected numbers of renal cancers was 7.51 and 13.69 in men and women respectively]. The tumours were a mixed bag of benign (oncocytomas, angiomyolipomas etc.) and malignant (clear cell, stromal, papillary) lesions. While these results are thought provoking, this was a retrospective study and the design seems open to detection bias in my opinion (were patients on lithium screened more than regular individuals?).


As previously posted, lithium may cause hypercalcemia and stimulate PTH via a variety of postulated mechanisms (see previous post).

Friday, July 11, 2014

Parvovirus B19 and the Kidney

Parvovirus B19 (PVB19) is a small, non-enveloped, single-stranded DNA virus belonging to the Erythrovirus genus, named for their tropism for erythroid precursor cells. It is the only known parvovirus to infect humans. By late adulthood, most people have IgG Anti-PVB19 serology demonstrating previous exposure, often from an asymptomatic infection. However, infection with PVB19 may cause a variety of clinical syndromes including fifth disease (‘Erythema infectiosum‘, a childhood viral exanthem), a polyarthropathy, pure red cell aplasia and hydrops fetalis in utero. The nephrologist may encounter PVB19 in 3 broad settings: 


The incidence of PVB19 infection post kidney transplantation is hard to accurately determine but is likely in the range of 1-10%. Infection tends to occur in the first year and frequently in the first few weeks, suggesting possible donor transmission but the mechanism of infection/trans mission is unknown. Clinical syndromes are mainly acute anemia and chronic pure red cell aplasia, although a pancytopenia may develop. The few cases I have seen have been easy to identify, as patient presented with a profound isolated anemia. The diagnosis of chronic anemia or pancytopenia may be more protracted as these are obviously common post-transplant complications (graft dysfunction; drugs-immunosuppressants, anti-virals, co-trimoxazole, ACE inhibitor; other infections-CMV etc.). Treatment consists of reducing immunosuppression (usually the anti-metabolite) and IVIg. Similar to other viral infections (CMV, Polyoma viruses), there is some thought that PVB19 may be associated with allograft dysfunction or even acute rejection (?injured endothelium exposing previously hidden epitopes; no hard evidence for this however). A case series of thrombotic microangiopathy with PVB19 infection post transplant isolated PVB19 DNA from graft biopsies, however, overall the evidence for PVB19-induced allograft dysfunction is weak at present. 

Glomerular Disease 

PVB19 may cause a variety of glomerular lesions in immunocompetent hosts. These were first noted as associations with PVB19 viremia, however, subsequently viral DNA has been identified in renal cells from biopsy tissue. The most well described pattern of injury is FSGS, particular a collapsing glomerulopathy (see image), where the PVB19 genome has been detected in podocytes and parietal epithelial cells by PCR. Proliferative glomerulonephritis has also been temporally associated with PVB19 infection. A syndrome similar to acute post-infectious glomerulonephritis may occur, displaying hypocomplementemia, endocapillary and mesangial proliferation with subendothelial electron dense deposits. Acute glomerulonephritis may be more common in patients with sickle cell disease after an aplastic crisis due to PVB19. Given the ubiquitous nature of PVB19, it is likely that host factors contribute to why certain individuals manifest glomerular disease, with genetic factors, as always, being implicated. Viral DNA may be found in renal tissue after the acute infection has passed and the glomerular lesions will not necessarily improve with resolution of the infection. 

Dialysis Patients 

Patient with ESRD are considered to be at risk for aplastic crisis due to PVB19, albeit with a paucity of data to support that claim. The presence of abundant immature erythroid cells (due to EPO use), a relative immunosuppressed state and some particular patient populations (e.g. sickle cell disease) lead to an increased theoretical risk of this complication. 

PVB19 may be diagnosed using serology although immunosuppressed patients may not mount an adequate antibody response so PCR viral load is commonly employed. Treatment is non-specific and is generally supportive. IVIg is often used as these pooled preparations have anti-PVB19 antibodies, although randomized controlled data supporting its use is not available. Cutting back immunosuppression in transplant patients may also be of benefit, initially by reducing/stopping the anti-metabolite (logical as mycophenolate frequently induces bone marrow suppression independently). Also, tacrolimus is considered by some to be particularly conducive to PVB19 infection and a switch to cyclosporine may be a next step. 
To summarize, PVB19 is important to the nephrologist from a clinical perspective particularly for its tendency to cause isolated severe anemia (or pancytopenia) in our immunosuppressed patients. It may also cause glomerular disease in immunocompetent patients and should be a differential diagnosis for otherwise unexplained glomerulopathy, especially collapsing FSGS. It also provides clues from a research perspective to mechanism of glomerular disease/sclerosis.