Risk factors for BK virus infection post transplantation

Transplant related risk

1.       Acute rejection episodes

2.       Cold ischemia time( the longer the more likely)

3.       Delayed graft function

4.       Ureteral stent placement

5.       Thymoglobulin induction

6.       Tacro/ MMF based regimen

Recipient related risk

1.       Older age

2.       Male

3.       Non African American

4.       DMII

Donor related risk ( now this is fascinating)

1.       BK Virus + donor

2.       Degree  of HLA mismatch

3.       HLA C7

Apparently there is growing evidence that the donor kidney might be the source of the BK virus.  Pre- transplant BK Screening of donors might identify the risked recipients post transplant.  Recipients of BK + donors developed BK viremia at earlier transplant time-points, had higher viral loads and slower clearing of the virus.  Even a recent study provides more evidence of this concept.

Overall, a nice review of BK Nephropathy was just published in NDT, where these risk factors are summarized.

Topic Discussion: MGUS and kidney transplantation

MGUS is defined as having a monoclonal protein in a small but abnormal concentration( <3g/dl). But the bone marrow doesn’t meet criteria for plasma cell percentage that qualifies for myeloma.  The incidence of MGUS is around 3.2% especially in the age >50 and the incidence rises as you age. Given the number of renal transplants are increasing especially in the age >50, it is evident that this entity comes up now frequently at transplant selection meetings.  What do we do? Is it a risk factor? Should we be worried?

MGRS( monoclonal gammopathy of renal significance) is a term now used to describe entities that have renal damage from MGUS. A recent KI paper sheds more light on the pathology of such cases. High rates of recurrence and the recurrence is early and more severe than in the native kidney. ( 40-60%) if MGUS had presented as MGRS( or some folks might want to call is MGKS).  Risk is especially high when there is a circulating Monoclonal immunoglobulins still around.  Recurrence is early and much more severe than the native disease.

Soltero et al. looked at transplant candidates with MGUS between 2000 and 2007 in a single center study.  MGUS that received a KT were compared with MGUS that were not transplanted.( similar age and CV risks) . Of 1215 KT candidates, 34 were found to have MGUS  (11%). The gammopathy was monoclonal in 76% of the cases. Nine patients with MGUS were transplanted. Following transplantation, the MGUS group had a lower survival than the non-transplanted group. (p = 0.0008).  Follow-up of 18.7 ±  15.4 months, seven patients (78%) died. Causes of death were cerebral abscess, lung cancer, sepsis, melanoma, bacterial meningitis, myocardial infarction. They had requested UNOS database from 1987-2003 and only found two reported cases of MGUS to UNOS.  Hence data might not be possible to be obtained from UNOS as not many centers are asking this information.

There are cases of LCDD, MPGN and proliferative GN with monoclonal deposits recurring after transplant. Most of the cases had untreated monoclonal clones prior to transplantation. They would now be classified as MGRS cases.

Is MGUS a risk factor for development of MM post transplantation?  A study from Mayo Clinic had indentified patients who had MGUS either before or after transplant. Of the 3518 patients who underwent transplantation, MGUS was found in 42 patients( 23 pre and 19 post).  They were followed for 8 years.  17% of pre transplant MGUS patients developed malignancies such as smoldering myeloma and other hematologic cancers.  None of the patients who developed MGUS post transplant progressed to MM.
Another more recent study by the Mayo group looked at newly diagnosed MM cases post transplantation. 7 cases were identified and 4 of them had MGUS pre transplant and two of them had clonal plasma cells in bone marrow. They concluded that MGUS prior to transplant was a risk factor for MM post transplant.

Garcia et al showed recently that MGUS following transplantation is a different phenomenon. It was  >100 times more frequent in transplant patients than in general population. Of their small subset of 11 patients with post transplant MGUS, only one developed PTLD.  In contrast to MGUS  in general population, progression to plasma cell dyscrasias was absent and it’s incidence is unknown A longitudinal study in 55 patients demonstrated that most of the MG reflected transient B-cell monoclonal proliferations, probably due to an immunodeficiency. Usually associated with intense immunosuppression and M protein is usually small and multiple bands.

In summary, MGRS may not be a contraindication to kidney transplantation as risk of dying from their clone is low.  No data to suggest that small B-cell clones are truly curable but there might be a high rate of recurrence in certain types. While LCDD and amyloidosis might have a slower recurrence rate, proliferative GN with monoclonal deposits might be must faster. MGUS might be a risk factor for development of active hematologic disease post kidney transplant.  The decision to transplant might depend on considering the underlying MGRS characteristics, initial therapeutic response, extrarenal manifestations, and the patient’s status. Risk of graft loss, its link with the B-cell clone and the potential need for reintroduction of chemotherapy should be explained to the recipient and the donor.

The field is still unsure on the question asked? 

Nephmadness 2015: A novel theme

NephMadness began in March 2013 as a social media education project of the AJKD blog.  From the beginning, we envisioned NephMadness as an ambitious month long social media campaign, featured in multiple AJKD blog posts that encouraged deep engagement. Two years and still running with power and fuel, the game has become a monster on it's own in the social media world in nephrology.

Welcome to 2015 now. The theme for NephMadness 2015 is nephrology’s connections with other specialties. The 8 topics are  listed below.  A detail account of history of Nephmadness and how to play the game is now available in an editorial in AJKD. In addition, check out www.ajkdblog.com for ongoing details and brackets appearing starting March 1st 2015.

1. Obstetric Nephrology
2. Infectious Disease and Nephrology
3. The Heart and Kidney Connection
4. Nephrology and Nutrition
5. Genetic Nephrology
6. Critical Care Nephrology
7. Nephrology and Vascular Surgery
8. Onconephrology


Let the madness begin!!

Clinical Case 86: Answers and Summary

Which one of the following chemotherapy agents cause solitary hypophosphatemia?(select more than 1)

cisplatin	7 (38%)
sorafenib	2 (11%)
imatinib	7 (38%)
lenalidomide	4 (22%)

While many chemotherapy agents cause electrolyte disorders, hypophosphatemia is a rare occurrence.

Let’s take each chemotherapy agent at a time that is listed above.

Cisplatin classically is known to cause AKI and proximal tubular damage and hypomagnesemia but sole hypophosphatemia is rarely reported. Usually, a classic Fanconi syndrome has been described. 
So, choice A is less likely to cause solitary hypophosphatemia.

Sorafenib, a multikinase inhibitor targeting the c-Kit, RAF, VEGF and PDGF pathways, is approved for the treatment of patients with hepatocellular carcinoma and renal cell carcinoma, with a broad spectrum of activity also including selected sarcoma subtypes, thyroid cancers and melanoma. Sorafenib induces pancreatic exocrine dysfunction, leading to vitamin D malabsorption and secondary hyperparathyroidism. Patients receiving sorafenib can develop hypophosphatemia and vitamin D deficiency.

Of the 4 listed above, imatinib has been most well described with this electrolyte disorder. In NEJM, Berman and colleagues reported their findings regarding the development of hypophosphatemia and associated changes in bone and mineral metabolism in patients with either chronic myelogenous leukemia or gastrointestinal stromal tumors who are taking imatinib. A nice review article discusses the effect of all tyrosine kinase inhibitors such as imatinib and sorafenib and their effects on bone health. By inhibiting platelet-derived growth factor receptors expressed on osteoclasts, these agents cause a subsequent decrease in bone resorption and decreased calcium and phosphate egress from the bone. As a result, PTH levels increase and phosphaturia follows.

Lenalidomide and hypophosphatemia has been described in conjunction with other therapies and sole effect. It appears to be a potential renal loss mechanism. It is hard in this drug as myeloma is the primary cancer and the cancer itself can cause this electrolyte disorder. A Fanconi syndrome has also been described. 

Detective Nephron Returns with a case for you!

Check out in this month's Feb issue of ASN Kidney News; Detective Nephron's next venture

TOPIC Discussion: Hypertension as risk factor for Renal Cell Cancer

We know that smoking increases risk of renal cell cancer. It is interesting to note that a study published more than 10 years ago in NEJM showed the risk of Obesity and HTN as a risk factor for renal cell cancer.

The study had looked at over 300,000 Swedish men who had physical exams done in 1970s and 1990s and followed till 1995.  Renal cell cancer patients were identified and risks were analyzed. Higher body-mass index and elevated blood pressure independently increase the long-term risk of renal-cell cancer in men. A reduction in blood pressure lowers the risk.

While obesity and lot of things are an enigma, the association with HTN is concerning.  Most of the anti cancer agents in RCC are anti VEGF or Tyrosine kinase inhibitors and it is possible that the HTN in this case is might be associated elevations of such factors and leading to renal cancer.  Does HTN leading to CKD then predispose one to getting renal cancer? These are some interesting findings. Nevertheless, it’s an observational study with only Swedish Men and cannot be generalized at all. 

What else is out there regarding this association of HTN and renal cell cancer?

A Japanese study called the JACC study found nine risk factors (i.e., smoking, obesity, low physical activity, hypertension, diabetes mellitus, kidney diseases, beef intake, fondness for fatty food and black tea) in a Japanese population.

Another study done in the US looked at risk factors for RCC. Hypertension, high BMI, and smoking were associated with renal cell carcinoma, but findings generally did not differ by race. Relative to other racial/ethnic groups, blacks had the highest proportion of renal cell carcinoma incidence attributable to hypertension and chronic kidney disease in their study.  Another study published in the Urology journals puts HTN as a risk factor. VITAL study found a significant association of renal cell carcinoma with obesity, smoking, hypertension, renal disease and viral hepatitis.

Now here is a study that doesn’t feel that HTN is a risk factor for RCC.

 It is quite possible that is the constellation of metabolic syndrome that leads to this RCC risk. Given the risk factors that are consistently being similar to risk factors for cardiac disease, it is more likely that the metabolic syndrome might be the major culprit. The rise of incidence in RCC that we have seen in the last 2 decades goes in line with the rise of the metabolic syndrome and obesity. 

CONSULT ROUNDS: AKI in a transplanted kidney

Acute Kidney Injury in Renal Allograft

Simple Pneumonic (SCRI)—Serum CRreatIne—taught to me by Dr Suthanthiran

Structural( hydronephrosis, vascular problems and collections)

Calcineurin toxicity

Rejection and recurrence

Infections( BK, pyelonephritis)