Topic Discussion: Why does OncoNephrology matter?

Cancer affects the kidney in many ways. Education of the cancer specialists is important. Lately I have felt that the "kidney" has been ignored in many ways in the oncology world.

Recently, a review was published in NEJM on cancer survivorship and how long patients with cancer are living and the non cancer related complications. There was no mention of CKD and kidney related complications. Several studies have shown that CKD is an independent factor for mortality and cancer related mortality in cancer patients.  Few of us wrote a letter to the editor raising this concern. The response from the author was that “ CKD has a high mortality and not specific to cancer survivors”. This is an important message for our heme/onc colleagues to understand that CKD can add to the risk for cancer survivors. Having early nephrology care and co-managing and preparing for CKD related complications is important.

Another important ignored concept in Oncology is lack of studies that include patients with low GFR. In a recent analysis published in JAMA, Eighty-five percent of recent trials of therapies for the 5 most common malignancies (published in selected high–impact factor journals) excluded patients with CKD. This proportion exceeds that observed in cardiovascular trials published from 1985 through 2005. This finding is concerning because it was estimated that 32% of deaths among patients with CKD in 2005-2009 were attributable to malignancy. As a result of trial under-representation, patients with CKD may not be considered for cancer therapies that have potential to improve morbidity and mortality.

Also, most trials used serum creatinine or CrCl thresholds to exclude patients, despite data demonstrating that these are sub-optimal measures of kidney function in cancer patients. Given the availability of more accurate and validated methods for estimating kidney function, the oncology drugs trials cannot just rely on creatinine measurements.

Finally, two recent reviews published in NEJM and JAMA on immunotherapy related toxicities failed to mention renal toxicities. Liver and kidney are two organs that are responsible for most drug metabolisms. Ignoring those side effects is probably not a good idea. Space limitations and % incidence of renal incidence being low were cited reasons for not including renal toxicities.

As a renal community, it is important that we respond back and make sure the voice of the nephrologists is heard as more and more novel agents are in the market to treat cancer.  

IN THE NEWS: Transplantation and risk of death from malignancies

 A recent article in KI looked at death from malignancy after renal transplantation.

Some key findings:

Single center study in England looking from 2001-2012
18% deaths were from malignancy(lymphoma>lung>renal and others)
Age and gender stratified malignancy related mortality risk difference was higher than in transplant compared to general population.
Risk factors: pre transplant history of malignancy, DDRT and age.
Lung cancer was the most common cause of malignancy death in men and lymphoma in women.
There was no significant difference in the rate of cancer-related death or location of cancer with ethnicity in our cohort, although a trend was observed toward less overall malignancy-related death in non-whites versus whites.

Not surprising to find these findings given the nature of immunosuppressive medications and prior hx of malignancies. 

Use of Erythopoiesis-stimulating agents in CKD patients with cancer

A recent review in KI 2014 discusses this very important question we face in day to day care of CKD patients. If they have active cancer and CKD- what do we do? What is the Hgb target? If they had a past history of cancer- what do we do?

Hazzan et al review these exact questions. Few take home points from the review.

1.       Based on review of oncology literature:- there is an increase in mortality risk with ESA treatment in cancer. This risk is clearly when ESA is used outside the realm of chemotherapy and the risk may depend on type of cancer but data is not clear on that part.

2.       ESA and having cancer itself pose a thromboembolic risk as well.

3.       Progression of cancer- data is not sufficient based on Cochrane systemic reviews with use of ESA

4.       What to do with CKD and ESA use when patient also has cancer?

  Active cancer:- prior initiating ESA- use PRBCs and correct all reversible causes. If ESA to be used, the authors suggest a target of 10g/dl ( more conservative) and have to treat under the APRISE REMS program( usually heme/onc has to do this) and monitoring of embolic events.

What to do with CKD and ESA with patient with past hx of cancer?

If cured:- CKD guidelines of anemia management( but on conservative side)

If not cured:- treat as if they have active cancer- target of 10g/dl.

Take a look at an in-depth review of this topic in KI

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.

Adult cancer survivors and risk of kidney disease?

Long term renal toxicities from chemotherapy in cancer survivors is likely to exist. A recent study in CJASN 2013 looked at this very question. Over 700 childhood cancer survivors were reviewed and function was assessed regarding kidney function loss.  Risks were then identified.
What factors were major predictors of loss of GFR later in life after experiencing treatment for childhood cancers?

1. Nephrectomy  ( nephron mass related)
2. Abdominal radiation ( radiation nephropathy complications)
3. High dose ifosfamide exposure ( proximal tubular toxin)
4. High dose cisplatin exposure ( known tubular toxin)

The full study can be found here

ESRD and Solid tumors

There is some data that certain cancers have a higher rate in ESRD patients. The largest series that was studied was a cohort of 831,804 patients. 

The highest risks are observed in

Kidney Cancer

Bladder Cancer

Thyroid Cancer

and other endocrine cancers.

Suggested mechanisms: Viral etiology from underlying immunosuppressed state as being ESRD. 

Acquired cystic disease perhaps leads to the increased risk of renal cancer

Loss of renal function or having kidney disease was also proposed as a mechanism( inflammation?)

Hypernatremia and Acute Myeloid Leukemia

Electrolyte abnormalities have been seen with AML. Severe hyponatremia associated with SIADH secretion has occurred at presentation. Hypokalemia is a more frequent finding at presentation and is related to kaliuresis. Hypercalcemia can occur. Severe lactic acidosis prior to treatment has been reported. Hypophosphatemia as a result of phosphate uptake by leukemic cells can occur. But hypernatremia secondary to a diabetes insipidus (DI) is rare but has been described. 
Interestingly, this phenomenon( mostly central) has been seen with certain cytogenetics in AML.  
It appears that when you have monosomy 7 variant of AML, it can also lead to in some cases a central DI. Sometimes CDI might be the primary event presenting the AML. Prior literature is not clear the association of this and doesn't appear its CNS involvement but perhaps a genetic association.  Literature reveals many abstracts when you google and pubmed this entity. 
Typically,one would think that the combination of DI and AML is associated with structural abnormalities of the neurohypophysis. But there are cases presenting without any abnormalities of the neurohypophysis on radiological scanning and with normal cerebrospinal fluid examination. AML may directly result in dysregulation of transcription factors resulting in development of DI in AML patients.
One study even compared monosomy 7 with DI and AML and without DI, the group with DI had a 
poorer outcome. 
This association is hard to understand and why this is the case?


Ref:
http://www.ncbi.nlm.nih.gov/pubmed/19380027
http://www.ncbi.nlm.nih.gov/pubmed/3319680
http://www.ncbi.nlm.nih.gov/pubmed/1398517

IN THE NEWS:- Renal Cell Cancer Research Update 2011

Renal Cell Cancer(RCC) has been in the limelight recently. Two recent studies provided some interesting links. In a large prospective study, regular use of  NSAIDs was associated with a 51% increased risk of RCC after adjusting for multiple variables, according to a report in Archives of Internal Medicine 2011 issue.
The absolute risk differences for regular users compared with nonusers of nonaspirin NSAIDs were 9.15 per 100,000 person-years for the women and 10.92 per 100,000 person-years for the men. This was an analysis of over >75,000 patients. In addition, longer use of nonaspirin NSAIDs was associated with increasing risk. This is the largest prospective trial to look at this link. 
In another study recently, researchers have identified an association between RCC and multiple myeloma. They looked at over 57,000 patients diagnosed with RCC as a primary malignancy and over 33,000 diagnosed with multiple myeloma as a primary malignancy. The researchers found 88 multiple myeloma cases in the RCC cohort. Multiple myeloma was 1.51 times more likely to be found in RCC patients than in the general population, according to the investigators. They identified 69 RCC cases in the multiple myeloma cohort. RCC was 1.89 times more likely to be present in patients with multiple myeloma than in the general population.

The first study is suggests a link we knew all along but a prospective study confirms it. The second study is novel and not a common association usually thought about. In other words, should we be screening for RCC in MM patients or vice versa?

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/21911634
http://www.ncbi.nlm.nih.gov/pubmed/21091979

IN THE NEWS:- Myeloproliferative neoplasms and glomerular disease

A recent article referenced below in Kidney International Sept 2011 issue reveals a novel glomerular disease associated with myeloproliferative neoplasms( CML, polycythemia vera, essential thrombocytosis, mastocytosis, primary myelofibrosis and other) that usually become AML.

A description of 11 cases showed following characteristics:

1. mesangial scloerosis

2. hypecellularity

3. Segmental sclerosis

4. Chronic TMA findings

5. Intracapillary hematopoietic cell infiltration

6. No signs of immune complex mediated process by EM and IF

The term MPN related glomerulopathy is suggested.  This is interesting to note as clinically I have always wondered about the nephrotic syndrome that is associated with these cases of MPN. In the literature, there is information about the MPGN pattern of injury seen with such cases and perhaps this is just semantics but looking at the findings suggests a thrombotic microangiopathy and MPGN pattern of injury with novel findings mainly of the cell infiltration( which might have been there in prior cases published but not looked for ).

Morphologically, have to be differentiate from diabetic glomerular changes, FSGS, TMA, and immune complex MPGN

http://www.ncbi.nlm.nih.gov/pubmed/21654720

Health News - Research brings new hope of renal recovery for cancer patients

Health News - Research brings new hope of renal recovery for cancer patients

Transplant Tourism and Malignancy

Transplant Tourism does still continue and many patients continue to get kidneys from other countries where it could be commercial possible.  A recent study showed that when groups were compared( tourism kidneys to home country based kidneys):- the graft and patient survivals were equal but the 10 year cumulative cancer risk was significantly higher in the transplant tourism kidneys; especially in the older age group.  What might be contributing to this? - immunosuppresive therapy, difficulty in follow ups and were some of the thoughts mentioned in this article. Check it out

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21270768

Skin cancer and Transplants

Talking to your patients and just educating them regarding regular skin cancer screening might be just enough to raise awareness and prevent skin cancer. Regular yearly dermatology visits for skin check ups are essential for prevention. Check out this latest healhday article.

http://consumer.healthday.com/Article.asp?AID=650075

Quiz 5 Answers

Which one of the following is not a risk factor for PTLD
EBV status of donor/recipient 2 (16%)
Prior malignancy 1 (8%)
"Net" immunosuppresion 1 (8%)
Prior BK Virus infection 6 (50%)
Age 2 (16%)

Most of you got this one right away!
All except Prior BK infection has been associated to be a risk factor for PTLD In kidney transplant recipients
Please review the recent updated PTLD presentation by Arun Chawla for further clarification

http://onlinetransplantcenter.blogspot.com/search/label/presentations

Post Transplant Lymphoproliferative Disorder (PTLD)

View more presentations from Nephrology, NSLIJ.

Risk of PTLD post transplant?

Why and when is someone with a kidney transplant prone to get PTLD?
PTLD is a lymphoproliferative disorder that occurs because of impaired T-cell immunity after solid-organ or allogeneic stem cell transplant. 90% of the time these are EBV associated.


What are the risk factors for development of PTLD?
1. EBV-negative serostatus at time of transplant
2. Mismatching EBV-negative recipients with EBV positive donors
3. Intestinal Transplants have the highest incidence, then heart-lung, lung, heart, liver and then kidney
4. Children
5. Simultaneous CMV infection within 1 year of transplant
6. Certain HLA subtypes.

http://www.ncbi.nlm.nih.gov/pubmed/12621474
http://www.ncbi.nlm.nih.gov/pubmed/14986084