Plasma Cell Dyscrasias and Kidney Transplantation- a consensus report

A multidisciplinary consensus report by specialists in nephrology, hematology/oncology, and pathology addresses the complex intersection of plasma cell dyscrasias (PCD), such as multiple myeloma, AL amyloidosis, and monoclonal gammopathy of renal significance, and end-stage kidney disease (ESKD), exploring candidacy and strategies for kidney transplantation. 

Patients with PCD face disproportionately high rates of ESKD, severely impacting survival and quality of life. Although a kidney transplant can offer meaningful benefits, its use has been historically limited by concerns regarding disease recurrence and suboptimal outcomes. In light of evolving PCD therapies that improve disease control and extend survival, a collaborative expert panel evaluated current evidence to redefine selection criteria and care pathways for PCD-ESKD patients eligible for kidney transplant. 

Key recommendations emphasize achieving and confirming robust hematologic response before kidney transplant, tailoring immunosuppression to balance rejection risk with infection and recurrence, and adopting biomarker-driven risk stratification. The report also emphasizes the importance of ongoing multidisciplinary collaboration and targeted post-transplant surveillance tailored to PCD. 

One classic example of this is PGNMID or C3GN, which has a high recurrence rate post-transplant. Below is a potential pre-transplant treatment strategy to prevent recurrence. 

Together, this consensus guidance aims to broaden kidney transplant access for patients with PCD-ESKD while safeguarding graft survival and long-term outcomes.

Guest Post by Naoka Murakami, MD

Concept Map: TMA and Cancer

 

Created using biorender.com 

Topic Discussion: Pseudo AKI with anti cancer agents

Legend: AKI, acute kidney injury, MATE, multidrug and toxic compound extrusion; OAT, organic anion transporter; OCT, organic cation transporter

As of April 2024--most updated data on anti-cancer agents and Pseudo-AKI.

Several classes of cancer treatments are associated with pseudo-AKI.  Providers must be aware of this phenomenon, as pseudo-AKI can lead to temporary stopping and even permanent discontinuation of life-saving treatments. When patients present with increases in serum creatinine while on these drugs, checking a serum cystatin C level may help differentiate true AKI from pseudo-AKI.

Shruti Gupta and Kenar Jhaveri 

Consult Rounds: Hypophosphatemia and Tumor Genesis Syndrome

What is this entity? Tumor Genesis Syndrome compared to Tumor Lysis Syndrome.

Tumor lysis syndrome (TLS) is a critical medical condition that can arise in leukemias and lymphomas either as an initial presentation or after the initiation of anti-neoplastic treatments. Conversely, tumor genesis syndrome (TGS) is a rare occurrence associated with specific malignancies, particularly those characterized by a high neoplastic burden with rapid proliferation, resulting in the excessive uptake of phosphorus from the serum and leading to hypophosphatemia. Interestingly, a subset of patients may experience a combination of TLS and TGS concurrently, resulting in hypophosphatemia instead of the hyperphosphatemia typically seen in TLS.

From a nephrology perspective, this presents a potential differential diagnosis in leukemic patients. Differentiating hypophosphatemia from TGS is crucial, especially when considering other causes of severe hypophosphatemia related to neoplasms, such as tumor-induced osteomalacia. In this scenario, increased fibroblast growth factor-23 production leads to renal phosphate wasting, mimicking the hypophosphatemia seen in TGS.

In their literature review, Chan et al. highlighted an uncommon presentation involving severe hypophosphatemia, hypokalemia, acute renal failure, and acute respiratory failure in a 16-year-old patient with acute leukemia and significant leukocytosis. Conversely, Zakaria et al. reported a case of a 14-year-old boy with acute T-cell lymphoblastic leukemia who exhibited normal serum biochemistry except for marked hypophosphatemia and elevated LDH levels. Intriguingly, the child showed no symptoms related to low phosphate levels. Additionally, Radi and Nessim described a case of severe hypophosphatemia in an 82-year-old patient with lymphoma, attributing the cause to neoplastic intracellular phosphate uptake. Similarly, Aderka et al. presented a case of a 49-year-old patient with acute myelogenous leukemia experiencing hypokalemia, hypocalcemia, and severe hypophosphatemia (<1 mg/dL) leading to extreme weakness. The hypophosphatemia developed post-chemotherapy initiation and blast lysis, mainly due to the excessive phosphate uptake by leukemic blasts. Recently, another case was described with normal potassium and calcium levels, and despite very low phosphate levels, the patient did not show signs of acute respiratory failure. Additionally, low glucose, elevated LDH, and in some cases elevated lactate may be noted, which may or may not be directly related to TGS but could be a separate effect of leukemia.

Tumor Genesis Syndrome is a rare syndrome that needs to be considered in the differential diagnosis of hypophosphatemia. 

CMML and the Kidney

 

This figure summarizes the various glomerular, reno-vascular and tubulointerstital disorders seen with Chronic Myelomonocytic leukelmia ( recent review in Kidney Medicine by us)

In the NEWs- New Myeloma Working Group Update-- Myeloma related renal disease management

 An important guideline/recommendation was published in Lancet thismonth. This is an evidence based summary by the International Myeloma Working Group on myeloma related kidney disease. A must read!

Here is a summary of the findings

1.      Diagnosis is important- the serum free light chain becomes the corner stone of diagnosis. An algorithm below summarizes the novel way of looking at it. All patients with multiple myeloma and renal impairment should have serum creatinine, estimated glomerular filtration rate, and FLCs measurements together with 24-h urine total protein, electrophoresis, and immunofixation. If non-selective proteinuria (mainly albuminuria) or involved serum FLCs value less than 500 mg/L is detected, then a renal biopsy is needed.

2.      How high is the involved FLC—can tell you if this is cast nephropathy vs looking for a glomerular process. In addition – the urine protein being selective vs non selective can aid in overflow proteinuria vs a true glomerular process.

3.      Kidney biopsy is NOT required but may be recommended if suspicious of cast nephropathy is high. Although recent studieshave shown that the IFTA and number of casts presents on renal bx can predictrenal outcomes.

4.      The IMWG criteria for renal response was recommended( change in eGFR)- see table below. This is used for many studies and validated.

5.      Supportive care and high-dose dexamethasone are required for all patients with myeloma-induced renal impairment( fluids, correction of hypercalcemia, avoiding NSAIDS)

6.      Mechanical approaches do not increase overall survival( plasma exchange- data is in the non bortezomib era, and HCO dialyzer- two RCTs showed no benefit).

7.      Bortezomib-based regimens are the cornerstone of the management of patients with multiple myeloma and renal impairment at diagnosis. New quadruplet and triplet combinations, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, improve renal and survival outcomes in both newly diagnosed patients and those with relapsed or refractory disease. The panel suggested to Start Daratumumab + Bortezomib + Dex early and then add IMiD starting cycle two once renal function has stabilized.

8.      Carfilzomib should not be first line in patients with CKD as risk of TMA( first time someone mentioning this)- glad the toxicities are being considered.. But then again- is the incidence of TMA from carfilzomib that high- I don’t think so.

9.      Dose adjustments are discussed for all anti Myeloma agents and their potential nephrotoxicities- mainly the TMA from carfilzomib. There are other renal toxicities of other agents as well not mentioned here.

10.    Conjugated antibodies, chimeric antigen receptor T-cells, and T-cell engagers are well tolerated and effective in patients with moderate renal impairment

11.   Finally, with improved survival in myeloma, when should we consider kidney transplantation in pts. with ESKD? Should we use sustained MRD-negativity to select transplant candidates? What about the MGRS patients?—the consensus was 2 years of disease free state. But low level evidence.. I have seen sooner in most cases. Overall their outcomes are not great when compared to non myeloma ESKD. 

Consult rounds: Hyperammonemic encephalopathy in the setting of myeloma

Can paraproteinemia cause an elevated ammonia level?

While liver disease and certain medications are known to cause hyperammonemia, myeloma is a rare cause of hyperammonemia. One of the first cases published on this topic was back in 2002 in NEJM.

Here are some cases published in the literature.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891795/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891795/

https://www.amjmed.com/article/S0002-9343(03)00630-2/fulltext

https://diagnosticpathology.biomedcentral.com/articles/10.1186/s13000-022-01285-6

https://pubmed.ncbi.nlm.nih.gov/35871579/

 

 A retrospective study shed more light. In this study of individual patients diagnosed with ammonia related disease from myeloma was evaluated( 27 patients), interesting findings were noted. The mean age was 76 years with a 5:1 male-to-female ratio. All had stage III based on the International Staging Scale (ISS). Bone marrow biopsies demonstrated 54–98% (mean 69%) plasma cell infiltration. IgA subtype was the most common. The mean ammonia level was 113 umol/L. No intracranial processes were detected on imaging. Three patients had improvement in mental status and decreased ammonia levels after chemotherapy; the other three patients declined further interventions. Inpatient mortality was over 66%. 

    The authors also did a MEDLINE search revealing 20 articles originating from the United States and Japan detailing a total of 32 patients who were diagnosed with myeloma induced hyperammonemic encephalopathy. The mean age was 52 years  with an equal distribution between men and women. The average ammonia level amongst these patients was 121 umol/L with as high as 299umol/L.  All these patients had stage III disease by the ISS or the Durie-Salmon system. IgG was the most common subtype at 44% (n=12), followed by IgA with 37% (n=10), light chain multiple myeloma with 11% (n=3), and IgD with 7% (n=2). Of the 25 patients that received chemotherapy, 15 (60%) survived until discharge. The inpatient mortality was 40% (n=10). Those patients who did not receive chemotherapy had a lower rate of survival at 25%.

Some studies report beneficial effects in using hemodialysis to remove excess ammonia. Several others suggest that the initiation of aggressive chemotherapy is the most effective measure to achieve normal ammonia levels and clinical improvement.  Mechanism of this association is still unclear. 

It is important to consider myeloma as a cause of hyperammonemia.

Concept Map- Immune checkpoint inhibitors and AKI- biomarkers

 

As of 2023, this is the most updated bio-markers that have been studied at single centers around the world for AKI associated with ICI therapy. 

References:

Tertiary lymphoid structure signatures are associated with immune checkpoint inhibitor related acute interstitial nephritis

Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis

AKI in patients with immune check point inhibitors

Biomarkers, Clinical Features and rechallenge for ICI related renal immune related adverse events

Cytokines and immune cell phenotypes in AKI associated with ICI

Differentiating acute interstitial nephritis from ICI from other causes

Concept Map: Kidney Involvement in Erdheim Chester Histiocytosis

This concept map in inspired by work in this paper by Chazal et al in Kidney International

 

Concept Map: Onco-HTN( cancer therapy related HTN)

 

Based on a recent AHA scientific statement, a concept map on onco-HTN

New Combined Glomerular Diseases and Onco-Nephrology Fellowship at Northwell

Northwell Nephrology is offering both a traditional two year general nephrology fellowship as well as a new fellowship that includes a third year fellowship specializing in glomerular diseases and onconephrology. The traditional two year fellowship can be applied for through this link

The new expanded third year is through the prestigious Northwell Nephrology Galdi Fellowship in Onconephrology and Glomerular Diseases. This fellowship offer a year of intensive training in these two important subject areas.

A candidate for the Galdi Fellowship will have completed internal medicine residency training, a general nephrology fellowship and demonstrate the highest level of performance and scientific and clinical potential. Candidates for the Galdi Fellowship would be carefully vetted based upon academic and other indications suggesting that advanced training as a Galdi Fellow would enable their ability to become one of a select few international leaders in glomerular diseases and onco-nephrology. The Galdi Fellowship will last for one academic calendar (July through June) year.  A new fellow will be recruited each year.

Training in glomerular kidney diseases is through the Northwell Nephrology Center for Glomerular Diseases directed by Drs. Kenar Jhaveri and Purva Sharma. The fellow will work in the Glomerular Disease Center and be exposed to all aspects of glomerular disease management including a rotation with Division of Rheumatology for extra training in SLE and ANCA vasculitis. The fellow will also have the opportunity to participate in ongoing clinical trials in glomerulonephritis at the Glomerular Disease Center. 

Onconephrology overlaps to an extent with glomerular diseases. Fellows gain experience both in the clinic and hospital with world renowned leaders Rimda Wanchoo and Kenar Jhaveri. Rotations will also include with hematology and oncology teams dealing with multiple myeloma, renal cell cancer and bone marrow transplant services. In addition, the fellow will have rotations with our nephropathologists as well.

 Currently we are accepting applications from current nephrology fellows or recent graduates for the Galdi Fellowship for start date of July 2023. In addition we are accepting applications from internal medicine residents for the general nephrology fellowship starting July, 2023 with a third year Galdi fellowship starting in July, 2025.

For inquiries regarding the advanced fellowship program, please email Dr. Kenar Jhaveri at kjhaveri@northwell.edu 

          Galdi fellowship website 

The application should include
1.      CV of the applicant
2.      Two recommendation letters (one must be from the Nephrology Program Director of Chief)
3.      A Personal Statement on the reasons for joining this fellowship.

In the News: WhatsApp in Onconephrology

A recent study published looked at using a "mastermind" chat using WhatsApp for onconephrology discussion. This group was created using Whatsapp in 2019. Since then close to 100 members are part of an ongoing online discussion. This study evaluated the 2 years of chat content via a survey, keywords and a full qualitative thematic analysis.

1. The keywords showed the figure below- The bigger the font, the most commonly discussed topic. 

2. In terms of thematic analysis, the 3 common themes that emerged were: collaboration, case discussions and knowledge sharing.

3. In terms of the survey, the key figure is below.  It is interesting that after uptodate.com, the chat was used by many for knowledge discussion and topic question answering. This is fascinating and could be because many of the topic experts and uptodate.com chapter writers were on this chat. 

Use of mastermind chats like this should grow in medicine. This allows for small subspecialty fields to have like minded individuals e-meet and discuss tough clinical challenges, share important knowledge and eventually collaboration for research. A recent paper on CDK4/6 inhibitors causing ATN was a result of collaboration led by this chat. 

Check out this amazing tweetorial by Prakash G on this.

Our manuscript Utility of WhatsApp® for onconeph education is out @CKJsocial @kdjhaveri @Sebi_Lapman , authored by 2 phenomenal students Simoni Khashi and Nitya Wanchoo, Quality analysis done by Kayla Kinuf @HofstraU @HofstraKidney @UCKidney @uofcincy @UCincyMedicine Tweetorial pic.twitter.com/ll46aCv7x2

— Prakash Gudsoorkar MD, FASN, FNKF (@prakashneph) December 16, 2021

American Society of Onconephrology

We have come a long way in the last 13 years. The origins  of this field can be traced back to 2005 when the first book on this topic was released by Eric Cohen et al. The field of oncology has continued to rapidly evolve since then, and the advent of tyrosine kinase inhibitors, chimeric antigen receptor T-cell (CAR-T) therapy, and immunotherapy has further necessitated the development of this new subspecialty. Onconephrology has since become its own rapidly-growing subspecialty. As many of you know my passion for this field has been evident on my blog for the last decade. With the help of the amazing founding members team, this organization was created this fall of 2021.

The website is at https://www.ason-online.org/ and twitter( @onconephsociety)

The mission is to promote research, clinical activities, and education related to onconephrology. 

More specifically, the primary objectives of this society shall be to further the investigation of onco-nephrology and reach a better understanding of the basic mechanisms involved as follows:

By informal group discussion of material that is of cross disciplinary interest as it pertains to care of patients with kidney disease and cancer.

By exchange of ideas pertaining to clinical experiences and experimental research

By consideration of problems encountered in onco-nephrology research. 

By the promotion of good fellowship and mutual trust among members of this organization.

By fostering education and identifying gaps in knowledge as it pertains to onconephrology.

Membership will be soon available. Let's welcome the beginning of the next phase of this field in nephrology.

​

Topic Discussion: CDK4/6 inhibitors and the Kidney

Selective estrogen receptor inhibitors and aromatase inhibitors are the mainstay of therapy for hormonal receptor-positive (HR+) breast cancer; however, most metastatic HR+, human epidermal growth factor receptor 2-negative (HER2-) progress and acquire resistance to endocrine therapies. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6 inhibitors) comprise a new class of drugs that overcome this resistance.  Three CDK4/6 inhibitors—palbociclib, ribociclib, and abemaciclib—have been approved for HER2-negative metastatic breast cancers, usually in combination with hormone therapy. 

Interestingly, the renal community has seen elevated serum creatinine associated with these agents. Several early trials of palbociclib and ribociclib did not describe the incidence of AKI, whereas clinical trials of abemaciclib have reported that up to 25% of patients experienced a rise in creatinine. In vitro studies of abemaciclib have shown that the drug and its major metabolites inhibit renal transporters like organic cation transporter-2, multidrug and toxin extrusion-1 (MATE-1), and MATE2-K, potentially leading to a reversible rise in creatinine without actually changing GFR. Cases have been described that show this pseudo-AKI. 

More recently, biopsy proven cases of acute tubular injury also have been noted- 6 cases with tubular and interstitial damage.

Finally, a search of the FAERs database revealed that, in addition to AKI, metabolic disturbances like hypokalemia, hyponatremia, and hypocalcemia may occur while on CDK4/6 inhibitors. Hyponatremia has been reported with ribociclib and with abemaciclib and grade 2 hypokalemia was reported in 20.8% of patients taking abemaciclib. 

In summary, the common renal associations with CDK4/6 inhibitors are

Pseudo AKI, ATI, hyponatremia, hypokalemia and hypocalcemia

In the NEWS: Immunotherapy and the Kidney( new data in 2021)- AKI and electrolytes

Immune checkpoint inhibitors (ICI) are a novel class of immunotherapy drugs that have vastly improved cancer care for patients. Data on AKI has been evolving. 

In a multicenter international study just published in JITC by Gupta et al involving 30 sites across 10 countries, researchers collected data on 429 patients with ICI-AKI and 429 control patients who did not develop ICI-AKI. Armed with the largest ICI-AKI database to date, the team of researchers was able to identify predictors, recovery potential and survival outcomes of those patients with ICI-AKI.

One of the most important findings from the two-year study reveals that among patients who take ICI again – even after an episode of ICI-AKI – only 16.5 percent developed recurrent ICI-AKI, which shows that most patients can still take these life-saving medications safely.

Additional findings show that in renal-recovery occurs in approximately two-thirds of patients with ICI-AKI. Early treatment with corticosteroid is associated with a higher likelihood of renal recovery. Lower baseline kidney function, proton pump inhibitor use and extrarenal immune-related adverse events are independent risk factors for developing ICI-AKI.

A related paper recently published in the journal Kidney International by Wanchoo et al looking at the scope of electrolyte disorders that are seen with ICI. Hyponatremia, hypokalemia and hypercalcemia were the most common findings. SIADH is the most common cause of hyponatremia and adrenal disorders led the way in the cause of hypercalcemia. 

Concept Map: Methotrexate Renal Toxicity

 

Picture created using biorender.com
Pathology pic obtained from google: Arkana lab collection. 

Concept Map- Causes of Renal Amyloidosis

 

Created using biorender.com 

Immune checkpoint inhibitors and the Kidney infographic

 

Here is a comprehensive infographic by Tejas Desai on 4 studies from around the world with ICI and the Kidney. 

Hypophosphatemia with anti-cancer agents

 

Here is a schematic of what we know for now in 2021 in relation to anti cancer agents leading to low phosphorus. This was made using biorender.com and inspired by the article Adhikari et al. 

In the News: Immune checkpoint inhibitors in the renal transplant patient

 

Use of immunotherapy in the renal transplant patient is challenging. Initial case reports had shown over and over acute rejections. In 2017, we had tried a novel way to prevent rejection in a single case report published in NEJM( using mini steroid pulse and mTOR over CNI use). Since then, we have used this approach successfully in several patients to allow for good tumor response and prevent rejection. But one case, two cases, three cases cannot tell the whole story.  More data is needed. A recent meta-analysis done on use of immunotherapy and transplant patients showed of 44 patients,  18 were reported to have acute rejection. Median time from immune checkpoint inhibitors to acute rejection diagnosis was 24 (interquartile range, 10–60) days. Reported types of acute allograft rejection were cellular rejection (33%), mixed cellular and antibody-mediated rejection (17%), and unspecified type (50%). Fifteen (83%) had allograft failure and 8 (44%) died. Three patients had a partial remission (17%), 1 patient achieved cancer response (6%), and 5 patients had stable disease (28%).

Other studies similar to this have showed similar rejection rates of 40%. No studies have tested the clinical efficacy of the use of these agents in renal transplant patients.

In a recent study published in Kidney International, we collected 69 cases from 23 institutions from US, Canada and Europe. This is the largest study to look at both transplant outcomes and efficacy of these agents in renal transplants patients.

Acute rejection rate 42% (29 out of 69), median ICI to rejection=24 days. Rejection is severe: cellular rejection and mixed cellular and antibody-mediated rejection are both common. Once rejection happened, 65% lost allograft.

What are the risk factors of rejection? Being on 3-agents immunosuppression and mTOR inhibitor use were associated with LOWER risk of rejection. This is an interesting finding. This is to tell us the obvious- the less the immunosuppression- the risk for rejection increases but the mTOR finding is interesting( caution- still low Ns). Take a look at this paper as well.
We looked at rejection rate and cancer objective response rate in skin squamous cell carcinoma (cSCC) and melanoma, two most common cancer types in our cohort. In cSCC, rejection rate 37.5%, ORR 36.4% and ICI may be associated with longer overall survival. In melanoma: rejection rate 54.5% (# of immunosuppression agent-dependent), ORR 40%. OS did not differ but limited by small # of patients and short follow-up.

An important figure that is hidden in the supplemental content is below: This tell us the majority of the changes done by centers when immunotherapy was initiated, see the % who increased steroids, converted CNI to mTOR inhibitors, dc CNI , dc MMF. etc.  Interesting changes which were made are not at all standardized. 

Although our study is to our knowledge the largest multicenter cohort of patients with advanced solid malignancies with kidney transplant who received ICI to date, there are several limitations Firstly it is retrospective and small-sample nature of our cohort limited our ability to adjust for a number of confounders in multivariable analysis for the risk of graft rejection. Also less than half of acute rejection were biopsy proven, which limits the accuracy of the diagnosis of rejection. The comparison of outcomes using these historical cohorts suffers from the lack of power due to the small number of cases, but provides a pragmatic approach to address the risk of rejection and objective response rate. Lastly, immunosuppression modification was the providers’ choice at each institution and not standardized.

So what now? This tells us that immunotherapy is a feasible option for kidney transplant pts but with very high risk of rejection.

mTOR inhibitor plus steroid mini-pulse may be effective in preventing rejection?
Or should we continue the immunosuppressive meds “as is” or at least 2 of them and then give the immunotherapy as efficacy was amazing in cSCC and prevent the rejection as well.
What this study also told us is that- stopping the immunosuppression when planning to give immunotherapy doesn’t really help in cancer outcomes or renal transplant outcomes? So should we be even stopping them??

A collaborative effort led by Naoka Murakami from around the world.