Lenalidomide and its renal toxicities?

Lenalidomide and renal toxicity, can this occur? Most chemotherapy drugs used to treat paraproteinemias are not nephrotoxic. But with renal toxicities such as electrolyte disorders, AIN and perhaps some GNs, anything might be possible. While cause and association cannot always be ruled out, knowing some associations is helpful. Lenalidomide usually is not associated with any nephrotoxic capabilities. In most cases, it has been studied now in patients with severe renal failure as well. In a recent letter to the editor in AJKD, a case of minimal change disease is reported. Interestingly, NSAIDS were also confounding factors but no AIN was found. Prior to this, a case of fanconi syndrome has been reported with lenalidomide as well. When paraproteins itself can cause GN and fanconi syndromes and other electrolyte disorders, sometimes its hard to make a case for the chemotherapy causing the renal damage.

Topic Discussion: Hypercalcemia and leukemias..( not lymphomas)

Classically, one associates hypercalecmia of malignancy with solid tumors such as breast cancer, kidney cancer and so forth. In regards to hematologic cancers, the lymphomas, and myelomas are the two disease states that have shown to have hypercalcemia.

Does AML, ALL and other leukemias have associated hypercalcemia? It’s rare. T cell leukemia classically associated with HTLV-1 has been widely reported and is the most common leukemia to have hypercalcemia. Besides that, the rest of them are 1-2 case reports. NEJM had one of the earlier cases of this association. Recently, childhood ALL was reported with hypercalcemia of malignancy as a result of parathyroid hormone-related peptide and E2A-HLF from translocation 17; 19.  Shu et al discuss the mechanism involved in leukemias and hypercalcemia. Cancer type T cell leukemia has a 50-90% incidence of hypercalcemia and its pthrp mediated or interleukin mediated or perhaps RANKL mediated. Acute non lymphocytic leukemia has a rare incidence but its pthrp and or 1,25 Vitamin D mediated.

International Update on Glomerular Diseases 2013 Talks

This April we had an update on glomerular diseases at our division. The international society of nephrology graciously has displayed few of the talks on their ISN Education website for all for viewing. Have a look at most of the talks from that day.

http://www.theisn.org/glomerular-disease/tags/course-update-on-glomerular-disease/itemid-916

In The News: Androgen deprivation therapy and AKI

Androgen deprivation therapy (ADT) is one of the mainstay treatments for prostate cancer. A recent study in JAMA2013, via a nested case control study show that these agents might be leading to or may be associated with acute kidney injury. Total of over 10,000 patients were looked at and comparing to matched controls, found these agents to be associated with AKI.

What are the different hormone therapies for prostate cancer?

Orchiectomy (surgical castration)

Luteinizing hormone-releasing hormone (LHRH) analogs

These drugs lower the amount of testosterone made by the testicles. Treatment with these drugs is sometimes called chemical castration because they lower androgen levels just as well as orchiectomy.

The LHRH analogs available in the United States include leuprolide (Lupron^, Eligard), goserelin (Zoladex) to name a few.

Luteinizing hormone-releasing hormone (LHRH) antagonists

LHRH antagonists work like LHRH agonists, but they reduce testosterone levels more quickly and do not cause tumor flare like the LHRH agonists do. Degarelix (Firmagon) is an LHRH antagonist used to treat advanced prostate cancer.

Anti-androgens

Anti-androgens block(ADT) the body's ability to use any androgens. Even after orchiectomy or during treatment with LHRH analogs, the adrenal glands still make small amounts of androgens.Drugs of this type, such as flutamide (Eulexin), bicalutamide (Casodex), and nilutamide (Nilandron), are taken daily as pills.

Other androgen-suppressing drugs

Estrogens , Ketoconazole (Nizoral)

The report in JAMA focuses on ADT and its anti androgen effects. During follow-up, the investigators identified 232 cases with a first-ever AKI admission. These cases were compared with controls matched for age, one year since prostate cancer diagnosis, and duration of follow-up. Compared with never use, current use of ADT was significantly associated with a 2.5 times increased odds of AKI.

The association was mainly driven by a combined androgen blockade, estrogen only, and other combination therapies, which were associated with a 4.5 times, 4.0 times, and 4.0 times increased odds of AKI, respectively, in adjusted analyses. Oral antiandrogens only, gonadotropin-releasing hormone agonists only, and bilateral orchiectomy each was associated with about a twofold increased odds. There might be a combined effect as stated by the authors.

One case report of flutamide associated AKI does exists. The case had shown temporal association in a patient with metastatic prostate cancer. No biopsy was done.

Few questions remain?

1.       How come we don’t see this as frequently then? ( or perhaps we are missing it)

2.       What is the biopsy findings of these patients? Is it tubular damage, glomerular damage, - no mention of that anywhere. There might be protective benefits of androgens to the kidneys but there are basic science papers that have shown the opposite as well.

3.       Looking closely at cases vs cohorts in this manuscript, while no p values are provided, there were more percentages of cases with HTN, CAD, CHF, on NSAIDs, antibiotics, Given complex statistical analysis and more sensitive analysis, they were able to still show an association.

4.       Repeat study to confirm this association needs to be done. This is an observational data from outcomes type of research. This deserves a well designed trial to replicate this and see if this clinical holds true.

Teaching resources page

Please see update teaching resources page
http://www.nephronpower.com/p/nephrology-teaching-resources.html

Please comment on any other resources you know

CONSULT ROUNDS: PRES in Pregnancy

                

Posterior reversible encephalopathy syndrome (PRES) is a clinic-neuroradiological syndrome associated with various clinical conditions, presenting with headache, encephalopathy, seizures,
cortical visual disturbances or blindness. Imaging predominantly shows parieto-occipital white matter changes, with vasogenic edema being the most accepted pathophysiology.
Common clinical conditions include hypertensive encephalopathy, renal failure, autoimmune disorders and treatment with immunosuppressant or cytotoxic medications.
Uncommon clinical conditions include acute intermittent porphyria and cryoglobulinemia.

Some of the earlier cases of PRES were seen with SLE patients and in kidney transplant patients the classic association is with CNIs in rare circumstances. Preeclampsia and eclampsia may be the most common  causes of PRES during pregnancy and most cases are managed without neuroimaging, and the incidence remains unknown.  However, it is uncertain whether a cause and effect relationship truly exists between the two or if these represent independent processes with some element of clinical overlap.
By definition, all patients with posterior reversible encephalopathy syndrome have a characteristic MRI pattern with bilateral hemispheric boundary zones of hyperintensities on T2 and FLAIR imaging, with increased apparent diffusion coefficient values, affecting the cortex and subcortical and deep white matter to varying degrees. The pathogenesis of PRES remains unclear, but it appears to be related to disordered cerebral autoregulation and endothelial dysfunction. Cerebral venous and sinus thrombosis (CVST) in the postpartum period is also a common cerebrovascular incident during the puerperium. Clinical manifestations consist of headache, vomiting, focal or generalized seizures, confusion, blurred vision, focal neurologic deficits, and altered level of consciousness. It is in the differential diagnosis when considering PRES in pregnancy in the post partum period.

                                                                               

Image source: radiopaedia.org           

Nephrology Fellows Jeopardy

Check out the above banner for upcoming Mt Sinai Nephrology sponsored  Fellows Nephro-pardy. More details to follow!!

The return of PD: Can PD strike back?

AKI is diagnosed. You need to start dialysis... can you use PD as an option? This was historically done but trends have changed and extracorporeal blood purification( CVVHDF, HD) gets offered only. A recent article in CJASN did a systematic review on this topic.  Based on their analysis, they found 24 studies that was good to evaluate and included 1556 patients.

Brief points
1. 13/24 studies were PD only with pooled mortality was 39.3%
2. In randomized trials, no difference in mortality between PD vs HD for AKI
3. But the trials were significantly had intertrial heterogeneity.
4. Most of the complications with PD were peritonitis
5. Low resource settings and developing countries had more experience on this use than developed countries. Studies from Europe and North America were very low numbers.

Fellowship training in US might play a significant role in this trend we are seeing in US. In US, 30% of new nephrologists felt competent with acute PD compared to 90% of new nephrologists felt competent for acute HD. Few years ago, we had presented an abstract NKF 2011(page 272) on health care professional dialysis choices in case they needed dialysis.  There is scarce data on what a heathcare professional
would choose for themselves. The survey  consisted of seven questions aimed at assessing choice a health care  provider would make for themselves. We posed these questions to  physicians, nephrologists,nurses,dialysis nurses and nephrology fellows  in training. What we found was that  51.2% of health care professionals chose PD to be their choice of therapy. Among those who  chose HD 87% chose one of Home HD modality with only 13%  choosing in-center HD; far from evident in our current US statistics for  ESRD patients. 45.7% chose Nocturnal Long HD(6-8 hr,3 times/wk)
,31.5% Daily Short Home HD(2-3 hr,5-6 times/wk), 9.8% Home HD (3 hr 3times/wk).70.5 % chose a modality based on a belief of better outcomes of one over the modality.57.3% responders reported the
quality of life to be the specific outcome which was better for the  modality they opted for with 35.4% choosing the modality based on better morbidity, mortality and survival data. In center HD was the
modality most health care providers were comfortable discussing with their patients with only 18.7 % being comfortable in discussing PD.

PD needs to strike back!

Topic Discussion: Anion Gap

What are the limitations of the anion gap use? A recent article in CJASN has some key points.

A.Uses of anion gap
1. evaluate met acidosis
2. detect paraproteins
B. Classically AG has been using HCO3, Cl and Na for calculations. Should K be used? The rationale for not using K is because the absolute change in its concentration observed clinically is small. It might be useful if the K is too low or too high. So if K was 7meEg/L, it should be included in the calculation.
C. Based on the research done on what normal AG is, the span of population is from 8-10meq/L.

D. Figge equation: correction for albumin
So corrected AG= anion gap + 0.25 *( normal albumin- measured albumin (g/dl)
E. Interestingly the article points out from their review that the sensitivity of increased anion gap in detecting hyperlactatemia is very poor. Range is from 44% to 78%. If lactic acidosis is suspected, perhaps directly measuring that rather than relying on AG might be useful.
F. Baseline value for individuals AG to optimize the use of the calculation of AG in the detection of acidosis is what the authors suggest.

IN the NEWS: Rejectostix has arrived

A recent article in NEJM discusses using an urine test to detect pre rejection the risk of rejection in a kidney transplant recipient. In a multicenter study, a molecular signature of CD3ε mRNA, IP-10 mRNA, and 18S rRNA levels in urinary cells appears to be diagnostic and prognostic of acute cellular rejection in kidney allografts.
An editorial accompanies it calls this test the " rejectostix". The lead author Dr. Suthanthiran discusses this idea and test on a youtube exclusive interview as well. The team measured the levels of messenger RNA (mRNA) molecules produced as genes are being expressed, or activated, to make proteins. The mRNAs (18S ribosomal (rRNA)–normalized CD3ε mRNA, 18S rRNA–normalized interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA) indicate that killer T immune cells are being recruited to the kidney in order to destroy what the body has come to recognize as alien tissue. The signature test consists of adding levels of the three mRNAs in urine into a composite score. This would be a nice detective tool for the transplant nephrologist. Check out an exclusive interview of the researchers from Cornell.

Is this our future? hope so, if this holds:- no more kidney biopsies. If you know it early on, you can address it sooner... hope to see this in clinical practice.

ACKD: Special Nephrology Education Issue

The Advances in Chronic Kidney Disease (ACKD) has a special issue on education this month. Interestingly there are some articles that might be of interest to many.
The entire issue is two fold- patient education and physician/trainee education.

For patient related education, check out the articles on
1. Acute start dialysis 
2. Health Literacy
3. Patient education in CKD clinic
4. Education of patients with interface with Primary care

For workforce and physician related articles, check out
1. Future of nephrology workforce( a summary of what ASN workforce group has been doing for the shortage)
2. Innovative teaching methods ( courtesy of myself, Matt Sparks and Hitesh Shah)
3.Online learning( a nice summary of nephrology online teaching tools and includes many blogs that are doing educational content. It summarizes the pros and cons of each blog and in addition has descriptive information regarding each one as well. PB Fluids already has a post on this.
4. Tweeting ( NOD takes on this one)
5. Digital media promotion of CKD