Differentiation Syndrome

I was recently rounding on a gentleman in the ICU with acute promyelocytic leukemia (APL) who, after starting induction therapy with tretinoin (all-trans retinoic acid), developed fever, hypotension, new pulmonary infiltrates with associated respiratory failure and AKI requiring dialysis.  It was suspected that he had developed the differentiation syndrome.

Recall that APL is a variant of acute myeloid leukemia (AML).  APL is typically defined by the presence of a fusion gene linking the retinoic acid receptor alpha gene on chromosome 17 with the promyelocytic leukemia gene on chromosome 15.  Untreated, APL is the most malignant form of AML.  Luckily, it is highly responsive to therapy which usually includes tretinoin.  Tretinoin allows the terminal differentiation of malignant promyelocytes to mature neutrophils.

However, therapy with tretinoin can lead to the differentiation syndrome which was previously known (and posted about by Nate) as retinoic acid syndrome.  Symptoms include fever, edema, pulmonary infiltrates, respiratory failure, hypotension, rash, pleural and pericardial effusions, hepatic dysfunction and AKI.  The differentiation syndrome occurs in around a quarter of patients treated with tretinoin and is thought to be a cytokine release syndrome but autopsy series have also shown infiltration of various organs including the kidneys with myeloid cells.  An interesting case report in AJKD details the enlargement and subsequent return to a more normal size of the kidneys of a patient who developed the differentiation syndrome and AKI which one could speculate occurred as the parenchyma was filled then cleared of cells.

Treatment of the syndrome involves dexamethasone and in some cases holding the tretinoin.  The team caring for my patient had given him steroids and briefly held the tretinoin while providing supportive ICU care with vasopressors, mechanical ventilation and broad antibiotics while cultures were cooking. The infectious workup came back negative his overall status improved, and within a few days he was able to come off of dialysis.

Photo: Jellyfish at the Monterey Bay Aquarium.

Hypercalcemia of Malignancy

Cancer-associated hypercalcemia is the #1 cause for hypercalcemia in the inpatient setting (in the outpatient setting, the main cause is primary hyperparathyroidism). In general, hypercalcemia of malignancy portends a poor prognosis, and there are three main mechanisms by which hypercalcemia can occur:

1. PTHrP (PTH-related peptide): this is the most common cause of hypercalcemia of malignancy, and is sometimes referred to as "humoral hypercalcemia of malignancy." The PTHrP essentially mimics the effects of PTH by virtue of its interaction with the PTH receptor, though since PTHrP is not detected by standard PTH assays the measured PTH level is typically very low. Sending a PTHrP level may be helpful, though in my experience it often takes several days to come back. PTHrP is most commonly secreted by solid tumors, such as breast cancer.

2. osteolytic metastases: this is the 2nd most common mechanism of hypercalcemia of malignancy, and is due to osteoclast-mediated bone breakdown. It occurs in characteristic tumor types, which can be recalled by this nifty mnemonic, "BLT with a Kosher Pickle, Mustard & Mayo":
B = breast cancer
L = lymphoma, lung cancer
T = thyroid cancer
K = kidney cancer
P = prostate cancer
M & M = multiple myeloma

3. tumor production of calcitrol: the mechanism is here is similar to that of granulomatous disease: tumor cells provide enzymatic synthesis of 1,25 OH-vitamin D, the active form of vitamin D, leading to unregulated GI uptake of calcium. It is most commonly seen in Hodgkin's lymphoma and some cases of NHL as well. It can be diagnosed by finding an elevated 1,25 OH vitamin D level in the presence of malignancy.

Very, very rarely one can observe ectopic PTH secretion as a mechanism for hypercalcemia of malignancy.

kappa versus lambda light chains in paraproteinemias

Antibodies are comprised of the structure noted on the left:  they have two immunoglobulin heavy chains (in blue) and two immunoglobulin light chains (in green), covalently linked with one another via disulfide bonds (in red).  The light chains can be one of two types, either kappa or lambda; each individual B-cell (which synthesize and secrete clonal immunoglobulin) expresses either kappa or lambda, but not both, for the entire duration of its lifetime.  

Light chains play an important role in several nephrologic diseases.  They are small enough to be filtered at the glomerulus, but in normal conditions are reclaimed in the tubule.  When the resorptive capacity of the tubules are overwhelmed with extremely large amounts of light chain--as is the situation in paraproteinemias--then the light chains may appear in the urine, and potentially even cause damage as in the cast nephropathy.  Furthermore, certain light chains may accumulate in the glomerular basement membrane, causing glomerular disease (light chain deposition disease, LCDD), and still other light chains may be the underlying cause of AL amyloidosis.  

These different patterns of paraprotein-mediated disease tend to be mediated preferentially by either kappa or lambda light chains:

In cast nephropathy, lambda light chain is the most common.

In light chain deposition disease (LCDD), kappa light chain is the most common.

In AL amyloidosis, lambda light chain is the most common.

The typical kappa-to-lambda ratio in the normal human is about 65:35 (about 1:9), and this ratio is often altered in the above conditions.  It is especially important to look at the K:L ratio (rather than absolute values of K and L light chains) in patients with altered renal function, as the decreased GFR will directly lead to elevation in both K and L light chains.   

On a related note, Waldenstrom's macroglobulinemia is also a paraproteinemia, but rarely causes cast nephropathy or AL amyloidosis.  Interestingly, renal damage in this condition may well be caused by hyperviscosity syndrome.  

T-MINUS 1 DAYS TO THE NEPHROLOGY BOARDS.  GOOD LUCK TO ALL!

Telomeres, Renal Cell Carcinoma, and the 2009 Nobel Prize in Medicine

The winners of the 2009 Nobel Prize in Medicine were revealed today, shared by three Americans: Carol Greider, Elisabeth Blackburn, and Jack Szostak, the latter of whom works at my home institution of Massachusetts General Hospital. The award was given for their work on telomeres, the regions of repetitive DNA which form protective "caps" on the ends of chromosomal DNA, necessary for preventing the degradation of DNA ends. The study of telomeres has implications not only for basic molecular biology, but also for cancer biology: many tumor lines express an enzyme called telomerase, which catalyzes the addition of telomeres onto DNA ends by virtue of a reverse transcriptase-based mechanism, allowing cancer cells to sustain their high rate of cell division.

For instance, in a 1999 KI study by Dahse et al, increased telomerase activity was detected in 55 out of 60 different primary renal cell carcinoma lines.

Differential Diagnosis of Kidney Injury Following Stem Cell Transplant

One of the major medical advances over the past few decades has been the success of stem cell transplants, which serves as a potential cure for many patients with previously untreatable leukemias and lymphomas.  With the expanded use of stem cell transplant, however, has come an increasing recognition that acute kidney injury can be a major complication of this treatment.  

An excellent 2005 review by Humphreys et al in JASN describes some of the most common causes of AKI in stem cell transplant patients.  

The differential diagnosis of AKI in stem cell transplant recipients can be initially categorized by time period following transplant:  that is, AKI developing in the immediate peri-transplant period, the "early period" (e.g., between 10-20 days post-transplant), and the "late period" (after a few  months post-transplant).  

The most common causes of immediate AKI are relatively rare, but include tumor lysis syndrome (which is fortunately becoming less common based on improved monitoring and newer drugs, such as Rasburicase) and toxic effects deriving from the marrow infusion itself--there is evidence that DMSO (an agent used to prolong cell life) can cause hemolysis and resultant AKI, for instance.  

The most common causes of early AKI include standard causes (e.g., pre-renal failure from prolonged vomiting or diarrhea, obstruction, ATN from hypotension, etc) but also includes oncology-specific diagnoses such as vaso-occlusive disease (a subset of hepatorenal syndrome felt to be due to endothelial damage).  These patients are often exposed to known nephrotoxins (e.g.,  amphotericin B, calcineurin inhibitors, iv contrast) which may also be playing a role. Hemorrhagic cystitis (a complication of high-dose Cytoxan often used as a conditioning regimen) can result in obstructive renal failure.  Methotrexate, often used as an agent to prevent graft-versus host disease (GVHD), can cause a crystal-induced AKI.  Patients with profound neutropenia are also at risk for infections (e.g., fungemia, bacterial sepsis) which frequently cause kidney injury.

In terms of late post-stem cell transplant causes of kidney failure, the main offender here is calcineurin inhibitor toxicity.  In general, this affects individuals who get allogeneic stem cell transplants much more so than autologous transplants, as only the former generally require immunosuppressive agents such as CNIs in order to prevent GVHD, and helps explain why the rate of kidney injury is greater in allogeneic recipients compared with autologous ones.  Many patients develop a low-grade thrombotic microangiopathy felt to be multifactorial in etiology which includes prior irradiation exposure causing endothelial damage, CNIs, and GVHD.   

Bence-Jones Protein

I had always assumed that the "Bence-Jones" protein--essentially, the demonstration of monoclonal light chains on urine protein electropheresis (UPEP)--was named after two doctors, Bence & Jones.  However I recently found out that actually it was named after a single individual:  Henry Bence Jones, a famous British physician and chemist.  In 1848, he was cited as the driving force for the investigation of an unusual chemical analysis discovered in the urine of a patient with myeloma in a paper titled "On the microscopical character of mollities ossium" (mollities ossium was the name for myeloma, which at the time was thought of as a bone disease based on the osteolytic bone metastases which resulted).  In this paper, he described the appearance of a precipitate which occurred when the urine was heated to 50-60 degrees, disappeared when boiled, and reappeared again when the urine cooled--this substance is now known to be the same urine light chains which result in cast nephropathy.

According to this brief biography of Henry Bence Jones, he published on a variety of topics including renal calculi and gout, and was an early proponent of the urinalysis (both urine microscopy as well as chemical analysis of the urine) in diagnosis.  He was also apparently the physician for Charles Darwin, and published the then-definitive biography of the physicist Michael Faraday.   

Genetics of Wilms Tumor

Wilms Tumor--named after the German surgeon/pathologist Max Wilms (pictured at left)--is an embryonal tumor that derives from developing kidney tissue. Wilms was the first to postulate that tumors may arise from precursor cells which arise during development, and indeed study of the molecular pathways active in these "nephroblastoma" shed light on normal kidney development.

There are several genes associated with patients with Wilms Tumor. Here are some of the main ones:

1. WT1 is a transcription factor and considered a tumor suppressor gene. Mutations in WT1 account for between 10-15% of sporadic Wilms tumor. It interacts with p53, a classic tumor suppressor involved in a wide variety of cancers. Denys-Drash Syndrome, a familial and severe form of Wilms tumor, is usually caused by congenital WT1 mutations.

2. beta-catenin is a key component of the canonical Wnt signaling pathway, long known to be a key player in kidney development. Interestingly, most patients with WT1 also have gain-of-function point mutations in the beta-catenin gene which result in increased stability of the beta-catenin protein and subsequent unregulated Wnt signaling.

3. WTX is mutated in a different subset of patients than those with WT1 mutations, and is found on the X-chromosome.

4. BDNF (brain-derived neurotrophic factor): mutations in this growth factor are postulated to result in the WAGR Syndrome--a constellation of symptoms that includes Wilms Tumor along with aniridia, GU abnormalities, and mental retardation.

5. BRCA2: interestingly, mutations in the well-known breast cancer-susceptibility gene can also lead to Wilms tumor.

Serum Free Light Chain Assay

The dilemma:  there are a subset of patients with some type of paraproteinemia--e.g., light chain deposition disease or amyloidosis, for instance--which are NEGATIVE by SPEP & UPEP.  When there is renal involvement, the diagnosis can potentially be made by renal biopsy. But since we can't always be as invasive as we'd like to be, don't forget about the serum free light chain assay.  

Measuring serum free light chains relies on an assay which quantitates light chains NOT bound to heavy chain. In this 2003 Am J Clin Pathol study by Abraham et al, serum free light chains was found to be much more sensitive than either serum or urine immunofixation, and was successful in identifying several patients with AL amyloidosis who had undetectable paraproteins by SPEP & UPEP. 

Of note, serum light chains are cleared renally--so patients with reduced GFR will have increased values of both kappa and lambda light chain. Thus, for patients with CKD it is essential to look at the kappa:lambda free light chain ratio in order to detect a paraproteinemia. 

The Erythropoietin Receptor

As we all know, erythropoietin is secreted predominantly by the kidney (85% from the kidney, 15% from the liver) in response to hypoxia and its function is to stimulate erythropoiesis in the bone marrow.  What  is the receptor on which erythropoietin works?  

The Epo receptor is a member of the cytokine receptor family expressed on the cell surface of erythroid precursors.  Although the Epo receptor itself does not have kinase activity, it is bound by the tyrosine kinase Jak2, also called Janus kinase 2.  The activation of downstream transcription factors by Jak2 (e.g., the Stat family of transcription factors) results in accelerated erythrocyte maturation.

Interestingly, a common mutation in the Jak2 gene (V617F) accounts for the majority of cases of polycythemia vera--the hematologic condition in which there is a primary elevation in the hematocrit which can result in thrombotic complications.  These patients have a low circulating EPO level, but as the EPO receptor is constitutively active, there is always accelerated erythropoeisis.  

How much Cytoxan is too much?

Cytoxan is a very potent but also potentially toxic medication used for a variety of immune-mediated (and nephrology-relevant) diseases. It is often classified as a "cytotoxic agent", as it works as an alkylating agent that explains its utility also as a chemotherapeutic agent.

Because it is traditionally used at very high doses in oncology as compared with nephrology, the risk of side effects is dramatically increased in oncology patients. However, the risk of malignancy--most notably bladder cancer, but also leukemias and non-melanoma skin cancers--is still present in nephrology patients treated for conditions such as lupus nephritis or ANCA-associated vasculitis. How can you minimize this risk?

A 2008 study by Faurschou et al looked at a cohort of 293 patients diagnosed with Wegener's granulomatosis, many of which were treated with cyclophosphamide. They found that the risk of bladder cancer or leukemias was elevated for those explosed to a cumulative dose greater than 36 grams, but there was no increased risk of either cancer for those with a cumulative dose less than 36 grams. A cumulative dose of 36 grams would correspond to taking Cytoxan 100mg a day for 1 year. The authors also report that patients developed bladder cancer between 6.9 - 18.5 years after cyclophosphamide exposure.

One strategy for giving Cytoxan in Wegener's that I have seen used quite often is giving Cytoxan and prednisone when the disease is initially diagnosed for a period of 6 months--then transitioning to, say, steroids and azathioprine. This way, the Cytoxan can be used to get the disease under relative control without causing the dramatically increased risk in cancers, and still could be used a 2nd time if there is another serious flare in the future. Also, because the appearance of cancer is relatively delayed, one may be less hesitant to use Cytoxan for longer periods of time in the elderly.

A Few Post-Transplant Lymphoproliferative Disorder Facts

Heard a case in Renal Grand Rounds this morning regarding an elderly (72 year-old) 1st-time cadavaric renal transplant recipient who presented during his 3rd month post-transplant with fever, an elevated creatinine, and a CT scan showing mediastinal lymphadenopathy. An extensive infectious diseases workup was performed. The patient was CMV negative and his donor was CMV positive. However, while the patient was also EBV negative, his donor was EBV positive. A renal biopsy demonstrated that the patient had an EBV-positive lymphoid infiltrate, consistent with post-transplant lymphoproliferative disorder. The patient was appropriately treated with a reduction in immunosuppression and R-CHOP chemotherapy, but unfortunately he had a number of medical complications and passed away in the midst of treatment.

The case highlights a few interesting aspects of PTLD. First, the vast majority of PTLD cases arise from EBV infection, and of these the majority derive from the recipient, as opposed to the donor. Second, you have to be careful with overimmunosuppression of patients in this category: elderly individuals who are EBV-negative. This patient was given a fairly potent immunosuppression regimen of thymoglobulin, MMF, and tacrolimus, though in retrospect perhaps thymoglobulin could have been avoided. Finally, although PTLD is traditionally thought of as a complication of renal transplant which occurs after 6 months, it is certainly possible for the disease to occur earlier.

cisplatin-induced acute kidney injury

At the Brigham and Women's Hospital & the Dana Farber Cancer Institute, there is an ongoing trial of using pneumonectomy and injected, heated cisplatin into the pleural space for patients with malignant mesothelioma, a condition with an overall poor oncologic prognosis and limited treatment options.  Apparently this technique has had some success, but not surprisingly, it results in many renal consults to the Nephrology Fellow as a very substantial percentage of patients have significant acute kidney injury and many require dialysis.  Unlike standard chemotherapy where cisplatin may be held once renal toxicity has occurred, the injected cisplatin has a very slow, continuous absorption and therefore there is no opportunity for reversal once this sets in.  

The mechanisms of cisplatin-induced acute kidney injury are still being worked out but generally result in tubular toxicity (ATN).  Both necrosis as well as apoptosis appear to be involved, according to this recent KI review article on the topic.  

Cisplatin falls under the category of platinum-containing alkylating agents.  Related drugs include carboplatin and oxaloplatin, which still have some renal toxicity but substantially less than cisplatin.  

Pure Red Cell Aplasia

One of the rare but serious side effects of recombinant erythropoietin therapy is the possibility of pure red cell aplasia, an autoimmune condition in which antibodies against erythropoietin result in T-cell-mediated destruction of erythroid precursors.  It may be recognized by an escalating EPO requirement and need for transfusions despite adequate iron stores.  It has been reported much more frequently in Europe (with a formulation called Eprex, not used in the U.S.) and is thought to be at least partially due to the practice of subcutaneous administration there rather than in the U.S. where intravenous EPO therapy, for reasons of reimbursement, is the rule.  The diagnosis of pure red cell aplasia requires a bone marrow biopsy which demonstrates a lack of erythroid precursors with a preservation of megakaryocyte and myeloblast lineages; in a recent case at our hospital one of the major manufacturers of EPO products was contacted and performed an assay looking for EPO-specific antibodies.  Being a rare condition, there is limited data on how best to treat acquired pure red cell aplasia, but standard practice currently consists of withdrawing EPO and giving a course of immunosuppressive therapy with Cytoxan and prednisone.

  

There are other causes of pure red cell aplasia:  a genetic condition (Diamond-Blackfan Syndrome) as well as other forms of acquired disease, which include leukemia/lymphoma, viral infection (e.g., hepatitis C, HIV, parvovirus B19), or drugs.  It may also be a prodrome to a full-blown myelodysplastic syndrome.  

Waiting Times for Potential Kidney Transplant Recipients With History of Cancer

I saw a patient in the renal transplant clinic today for evaluation to get onto the kidney transplant list, as he is just around the corner to starting dialysis (actually, he may actually start tonight since his routine labs came back with a K of 6.9...). 

His chronic kidney disease was thought secondary to (a) long-standing hypertension, and (b) a history of bilateral partial nephrectomies for a history of bilateral renal cell carcinomas which were diagnosed about 4 years ago.  

Given this patient's history of cancer and the possibility of recurrence, should this patient be recommended to go onto the kidney transplant list?  How long does he need to wait?  Could the administration of immunosuppresant medications really result in decreased immune surveillance of cancer cells which could potentially result in earlier recurrence of metastatic disease?

  

These are all good questions, and there seems to be a relative lack of data.  According to one seasoned renal transplant doctor I spoke with today, if there is any increased likelihood of cancer in these patients (other than skin cancers or PTLD), it is likely small and not a reason to postpone transplant; the main reason in his mind for waiting to ensure a lack of cancer recurrence is to minimize the likelihood that the patient would need to undergo toxic chemotherapy or a major surgery which could interfere with the graft function.  In addition, there is also the issue of wanting to preserve a scarce resource (donated kidneys) for patients who will benefit from them the longest.  

Nonetheless, the American Transplant Society (ATS) has come up with a list of guidelines for "waiting times" after being treated for various cancers before one should be considered for kidney transplant.  To generalize:  breast, colorectal and melanoma cancers have a recommended waiting time of 5 years unless they are early stage; most other cancers (e.g., renal cell cancer, leukemia, lung cancer, prostate cancer, etc) have a waiting time of only 2 years.  Non-melanoma skin cancers (basal cell, squamous cell) are generally not a reason for delaying kidney transplant as they are generally treatable.  

ATRA Syndrome

The M3 subtype of acute myelogenous leukemia--also known as acute promyelocytic leukemia--is one of the most responsive forms of leukemia, as the addition of all-trans retinoic acid (ATRA) is known to overcome the maturation block in affected lymphocytes. 

While this is generally good news for leukemia patients with M3 disease, about 5-25% of patients get an ATRA-induced systemic illness termed "ATRA Syndrome".  Symptoms are widely variable but can include fever, interstitial pulmonary infiltrates, pleural/pericardial effusions, and (the reason for its inclusion in this blog), acute renal failure.  The topic has been a relevant one for me as there are currently two patients on the Renal Consult service I saw today with ATRA-induced renal failure.  The mechanism is unknown but is posited to be due to mass release of cytokines by affected APL cells.  It can be treated by holding the ATRA and administering corticosteroids.  

Case of Hyperammonemia & Fanconi's Syndrome

Quick case summary as presented in Renal Grand Rounds today:  A 54 year-old man presents with altered mental status, a sky-high ammonia level (>200) and anemia requiring blood transfusion.  Other unusual lab values include hypophosphatemia and hypokalemia with a significant non-anion gap metabolic acidosis.  Subsequent workup reveals 3+ glucosuria and aminoaciduria.  What's the underlying diagnosis?

This patient had multiple myeloma, as revealed by an M spike on serum protein electrophoresis. The diagnosis can explain all the major aspects of his presentation:

-myeloma is the cause of his anemia.

-myeloma is a cause of hyperammonemia (plasma cells for whatever reason have the ability to produce large amount of ammonia)

-myeloma and other paraproteinemias are a major cause of adult-onset Fanconi's Syndrome, which this patient has, as demonstrated by his aminoaciduria, glucosuria, phosphaturia, proximal renal tubular acidosis.  

gemcitabine-induced thrombotic microangiopathy

Another oncologic medication with a specific renal side effect is gemcitabine (Gemzar), a nucleoside analogue used with frequency to treat cancer of the lung, pancreas, breast and colon to name a few.  

Gemcitabine can cause a thrombotic microangiopathy, having been reported at an incidence of 0.31% according to a paper by Humphreys et al (in Cancer 2004).  It should be considered in any cancer patient receiving this medication with new onset renal failure, hypertension, or thrombocytopenia.

Bilateral Renal Cell Carcinomas

The case: a 50-ish yo woman, normal baseline renal function, and a history of nephrolithiasis x 2 episodes presented with gross, painless hematuria. She was initially thought to have another stone event, but she had no significant flank pain. Ultimately she underwent CT imaging which revealed bilateral renal masses suspicious for renal cell carcinoma.

Fortunately, there was no evidence of metastatic disease, and she underwent a R total nephrectomy followed by a partial L nephrectomy, leaving her with about 1/4 of her original nephron mass. Pathology reveals a clear cell-type RCC in both biopsy specimens. Her Cr remains in the 1.0-1.2 range. A question is raised as to why she developed two separate RCC's.

There is an interesting differential diagnosis of bilateral RCCs which includes some interesting genetic syndromes, the most common of which is von Hippel Lindau Syndrome, an autosomal dominant inherited gene caused by mutations in the VHL gene. Because the VHL gene is a tumor suppressor gene, there are other tumors which may occur in these patients, including pheochromocytomas and hemangioblastomas, among others. Specifically it is the clear cell RCC which occurs in VHL Syndrome. Other genetic disorders causing RCC's include Hereditary Papillary RCC (caused by mutations in the c-met gene), Tuberous Sclerosis (more likely to cause benign angiomyolipomas, but can result in RCCs), Hereditary Leiomyoma and Renal Cell Cancer Syndrome, and the Birt-Hogg-Dube (BHD) syndrome (resulting in chromophobe RCCs).

Despite these numerous possibilities of mutations causing RCC, a 1998 study revealed that amongst patients with bilateral RCC who underwent extensive mutation screening, only 12% had a hereditary form of RCC whereas the remaining 88% had "sporadic", bilateral RCCs.

Side-Effects of Cytoxan

Welcome to Cytoxan (cyclophosphamide), one of the most versatile (albeit toxic) medications in the nephrology world. Its mechanism of action is as an alkylating agent; it induced alkylation of DNA in actively proliferating cells, which explains its use as a chemotherapeutic as well as an immunomodulatory agent. Its use in renal disease includes lupus nephritis, nephrotic syndrome of several types, ANCA-associated vasculitides, and many others.

However, it has several side effects to be aware of. Some of the main ones are listed here:

1. Hemorrhagic Cystitis: one of the metabolites of Cytoxan, acrolein, causes bladder irritation and can result in hemorrhagic. The risk of this complication can be limited by the concomitant use of mesa, which accumulates in the collecting system and binds/inactivates acrolein.

2. Infertility: this can occur in both men & women; men are encouraged to do sperm-banking before receiving Cytoxan while women may be offered Lupron therapy in an attempt to chemically suppress the ovulatory cycle for the time they are on the medication.

3. Alopecia: like many of the side effects associated with Cytoxan, this one is rare at the doses given for renal disease, which are typically much smaller than those given for oncologic disease.

4. Increased Risk of Infection/Leukopenia.

5. Nausea/Vomiting.

6. Increased risk of Malignancies in the future: especially bladder cancer.

7. SIADH: rare but possible.

Post-Transplant Lymphoproliferative Disorder

Post-transplant lymphoproliferative disorder (PTLD) occurs in < 1% of kidney transplant recipients, but can often be a serious complication. In essence, PTLD is a form of lymphoma which occurs due to decreased immune surveillance as a result of the immunosuppression used to prevent allograft rejection.

The pathophysiology of PTLD is intimately linked to the Epstein-Barr virus (EBV--pictured on the left attaching to a host cell), a member of the gamma herpesvirus family. It attaches to B-cells and in the absence of immune surveillance may result in hyperproliferation of B-cells leading to a lymphoma. Most often the disease is a systemic one with extensive lymphadenopathy and involvement in multiple solid organs. However there are variants of the disease in which the sole manifestation is within the transplanted kidney itself. The infected cells are almost always from the recipient as opposed to being from the donor.

PTLD is best treated by withdrawing immunosuppresion--often by completely removing CNI inhibitors & MMF while continuing low-dose prednisone. In addition, rituxamab (a monoclonal antibody against CD20, a B-cell antigen) has been noted to have a positive effect (which makes sense since this is almost always a B-cell lymphoma). Chemotherapy such as the CHOP regimen are reserved for patients with PTLD with more worrisome lymphoma-type features.