Crizotinib and the Kidney

Does crizotinib cause AKI? and is it reversible?

Crizotinib is a ROS-1 inhibitor and acts on anaplastic lymphoma kinase (ALK) to treat non small cell lung cancer.It also inhibits the hepatocyte growth factor tyrosine kinase. Hence, another angiogenesis inhibitor.
In 2011, it was approved for use in NSCLC with abnormal ALK gene mutation. There was some initial concern regarding this agent and renal function. A biopsy proven case of ATN was published not too long ago from France.

A recent analysis from Univ of Colorado looked at 38 patients with NSCLC who got this agent. The mean GFR decreased by 23.9% compared to baseline and most happened in the first 2 weeks of therapy. Pre renal causes were excluded. 84% of the patients recovered renal function back to baseline after cessation of therapy. The investigators thought that the rapid reversibility raised the possibility that this was a tubular creatinine secretion effect rather than nephrotoxic effect. They didn't have biopsy data.

Here is a commentary on this study.

HIV associated TMA: Is this an ADAMTS13 mediated entity or CMV related?

HIV associated TMA was more common in the AIDS era. After advent of HAART therapy, this entity is rare.

Traditional Risk factors are:
Low CD4 count, high viral load, concurrent Hep C and AIDS, blacks

Most secondary causes of TMA, treating the underlying cause or removing the underlying medication would treat the TMA(HUS or TTP variant).
Interestingly, one study looked at TMA from HIV in more detail and the use of plasma exchange. They prospectively looked at biological differences and response to the therapy. Response was much better in the HAART + plasma exchange arm versus HAART arm alone.  Interestingly, 80% of the patients that developed TMA , had either low ADAMTS13 levels or antibodies to them-in which case TPE or plasma exchange would offer benefit. Does HIV modulate ADAMTS13 or lead to inhibition?

Another study looked at the role of CMV viremia for causing TMA in HIV patients. They looked at clinical and pathological data for 29 patients with TMA and HIV infection. The diagnosis of TMA was confirmed by histological examination of kidney biopsy specimens (18 cases). Endothelial cytomegalovirus (CMV) inclusions were associated with TMA in nine of 18 cases, whereas histological examination did not detect CMV in any control specimens (P < .001).  This study using a case controlled method demonstrated a link of TMA and clinical systemic CMV infection by an odds ratio of close to 4.

So lets revise the risk factors for HIV associated TMA

1. Low CD4, high viral load
2. AIDS
3. Blacks
4. Hep C
5. Concurrent CMV viremia
6. ADAMTS13 inhibition or deficiency.

The MORAL of CORAL

The CORAL trial finally has arrived. Stenting the renal vessels has always been a topic of debate.  This is the largest trial to date that directly compared intervention to medical therapy in atherosclerotic renal stenosis.

1. Investigators randomly assigned over 900 patients to either medical therapy or stenting.
2. Cardiovascular or renal events were the end points. - MI, stroke, need for ESRD and or death
3. 43 months of follow up and no different in primary endpoints. No difference in mortality. Blood pressure slight better in stent group
4. Meds that were used in their protocol:- Atacand with or without HCTZ and a combo of CCB and statin.
5. All renal arteries with stenosis >60% or more were treated( prior studies some severe cases were excluded)
6. Close to 50% in both arms had patients with CKD stage 3 or higher( makes it hard to offer stenting already)
7. Looking closely at the data, it appears that there were more strokes in the medical therapy arm but still not statistically significant. Interestingly, more patients reached ESRD in stent arm than medical therapy arm but not statistically significant.
8. Author's recommendation- no significant benefit to stenting in atherosclerotic renal artery disease.

Is this the end of RAS in atherosclerotic renal disease?-I think so!

ANION GAP ACIDOSIS: GOLD-MARK makes a MARK:

GOLDMARK  is the new MUD PILES

A new mnemonic has been created in the last few years for anion gap acidosis. 

Glycols( ethylene glycol, propylene glycol)
Oxoproline
L- lactate
D-lactate
Methanol
Aspirin
Renal failure
Ketoacidosis

Two popular mnemonics were often used to remember the major causes of the high-gap metabolic acidoses. The first is KUSMALE which represents Ketoacidosis, Uremia, Salicylate poisoning, Methanol, Aldehyde (paraldehyde), Lactate, and Ethylene glycol. 

The second is MUD PILES( most popular), spells out Methanol, Uremia, Diabetic ketoacidosis, Paraldehyde, Iron (and Isoniazid), Lactate, Ethylene glycol, and Salicylate.

Why GOLDMARK then? The causes have changed in the 21^st century. We barely see any more paraldehyde any more, neither we see that much Iron and INH related causes.

Newer causes: D-lactate: seen with short gut syndrome( especially after sugary drinks), diabetes can lead to d-lactate as well. Other new causes is pyroglutamic acid ( oxoproline) seen with chronic Tylenol use. Finally, propylene glycol infusion that is usually found in lorazepam, phenobarb and banana bags.

Initially this was proposed in LANCET

Is BK Virus oncogenic?

EBV virus has been associated with PTLD and many other viruses have oncogenic potential. Does a common urological virus such as BK have oncogenic potential in our transplant patients?    

Given its predilection to lower GU tract, cancers of bladder have been reported with BK( just case reports). In the tumor cells, it is possible to detect fragments of the viral genome that could alter the control mechanisms of the cell cycle and DNA repair.

Besides the correlation between BKVN and graft failure, a small number of case reports suggest an association between BKV infection and the development of renal and bladder cancers in renal transplant recipients. Indeed, for more than 30 years, an oncogenic potential of BKV has been observed in vitro and in animal models. In humans, however, the implication of BKV in tumor development is still unclear.

A table in a recent publication summarizes some of the cases. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482068/table/T1/

Interestingly, Lithium has been associated with collecting duct carcinomas due to the mode of it’s action. At ASN this year, the pathologist presented a case of collecting duct cancer in a transplanted kidney in  a patient who was on Lithium and had persistent BK nephropathy. The biopsy showed a tumor burden as well significant BK virus staining. Talk about second hits!

eAJKD and NOD ASN 2013 coverage

Check out some excellent ASN 2013 coverages of top news and abstracts from ASN 2013 Kidney week'

eAJKD blog :http://ajkdblog.org/tag/kidney-week-2013/
Nephrology on Demand coverage: http://blog.ecu.edu/sites/nephrologyondemand/?p=9224

Clinical Case 76: Answer and Summary

A 35 y old male with BMI of 38 has microalbuminuria. He has hyperlipidemia and no history of DM or HTN. What do you do next?

Start ACEI/ARB	8 (10%)
Weight loss and observe microalbuminuria	63 (79%)
Observer microalbuminuria	6 (7%)
Kidney biopsy	2 (2%)

With 79 responses, most of you would just recommend weight loss( given BMI) and observe the microalbuminuria. Close second was starting ACEI/ARB.  Given no DMII or HTN, many thinkers in nephrology on "microalbuminuria" say that observing might be a better option. Chronic illnesses such as obesity, hyperlipidemia, rheumactic illnesses, etc. all can lead to microalbuminuria. In other words, it can thought of as "ESR" test rather than real renal disease. Observing is important as if rises to significant proteinuria, then certain action might be needed ( as new disease might have developed or meds might be indicated). Data on this is still skim and perhaps we shall hear about this soon in the literature.