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

In the News: A new virus- Pegivirus induced CNS disease in organ transplants

A letter in NEJM describes a potential new neurological disease, pegivirus-associated encephalomyelitis (PAEM), linked to the common virus Pegivirus hominis (HPgV-1).  Four immunosuppressed patients presented with progressive optic neuropathy and myelopathy, including spastic paraparesis or tetraparesis and sensory disturbances. 

Two patients died within two years of symptom onset, while the others remained severely disabled.  MRI scans revealed a distinctive pattern of bilateral, symmetrical lesions in the anterior visual pathway and spinal cord's corticospinal tracts and posterior columns.  

HPgV-1 was detected in the patients' cerebrospinal fluid, serum, and brain tissue, but not in controls, suggesting a causative role.  Viral loads were highest in the optic nerve and spinal cord, and genomic sequencing revealed compartmentalization within the CNS, further supporting this link.  

The authors propose that PAEM, characterized by these specific clinical, radiological, and virological findings, may be underdiagnosed and that characteristic MRI findings should prompt HPgV-1 testing.

The appendix includes in-depth methods, results, discussion, and individual patient case reports.  It elaborates on the clinical presentation, MRI and CSF findings, HPgV-1 RNA detection and quantification, and full-genome sequencing analysis supporting viral compartmentalization within the CNS. Two of the 4 patients were renal transplant recipients. 

One of them was a  57-year-old kidney transplant recipient due to pANCA-associated vasculitis, presented with progressive hypoesthesia and weakness in his legs, followed by vision loss, nausea, vomiting, and cognitive difficulties. He was on CNI, MMF and steroids and had received cyclophosphamide in the past.  He developed bladder and bowel dysfunction and lost the ability to walk. MRI showed abnormalities in the optic nerves, chiasm, pyramids, and spinal cord. HPgV-1 RNA was detected in both serum and CSF.  Despite immunosuppression reduction and treatment with ribavirin, his condition didn't improve, and he died 17 months after symptom onset.  Autopsy revealed myelin loss, glial cell abnormalities, and T-cell and macrophage infiltration in affected brain regions. Viral loads were highest in the optic nerve and cervical spinal cord.

Another patient was a 62-year-old kidney transplant recipient due to polycystic kidney disease, experienced progressive paresthesia and leg weakness, leading to spastic tetraparesis.  She was on mTORi, Steroids and belatacept.  She later experienced vision loss. Spinal MRI revealed lesions in the cervical and upper thoracic spinal cord.  HPgV-1 RNA was detected in both serum and CSF.  Belatacept was discontinued, and she was maintained on methylprednisolone and later azathioprine.  Her condition was complicated by aspiration pneumonia, infections, and renal graft failure requiring ICU care.  While her neurological symptoms partially improved, allowing for ventilator weaning and improved arm strength, she remained paralyzed in her legs and required dialysis.  Follow-up revealed no HPgV-1 RNA in serum but persistent presence in CSF.

This new virus will require us to be more vigilant in the transplant world and perhaps even in the world of immunosuppression. 

Consult Rounds: BK in non renal solid organ transplantation

What is the incidence of BK viremia, and BK Nephropathy in non renal solid organ transplants?

Not much that I could find in the literature.

In this retrospective study from 2021, the authors investigated the clinical characteristics, pathological findings, and outcomes of BK viremia and nephropathy in non-renal solid organ transplant patients (NRSOT) who sought nephrology consultation over a five-year period. Among liver, heart, and lung transplant recipients referred to Nephrology, 14% were diagnosed with BK viremia, with a median peak serum BK viral load of 35,500 copies/ml (ranging from 250 to 21,100,000 copies/ml). Notably, BK viremia resolved in six out of seventeen patients (35%), but four out of five biopsied patients exhibited BK virus (BKV) nephropathy. Furthermore, eleven out of the seventeen patients with BK viremia progressed to advanced stages (stage 4 or 5) of chronic kidney disease. Additionally, four patients experienced rejection of their solid organ transplant within the first year following the detection of BK viremia after reducing immunosuppressive treatments. This may be a sign of just net immunosuppression.

Another study back in 2019 had looked at literature systematically on report of BK disease in native kidneys. In their review at that time, in heart transplant recipients, 13 cases of BKV nephropathy had been reported, with most occurring in males (10 out of 13), and the mean age being 36.6 years. In lung transplant patients, six cases of BKV nephropathy were identified, with a mean diagnosis age of 47.3 years. Only one case of BKV nephropathy was reported in a liver transplant recipient, and one in a pancreas transplant recipient. More have been reported since their report. The average time from transplant to BKV nephropathy diagnosis in the solid organ transplant population was 2.88 years. For patients who had undergone hematopoietic cell transplantation (HSCT), 19 cases of BKV nephropathy were found, with a mean diagnosis age of 30.6 years. In cases with demographic information, 58% were males, and half of these patients required renal replacement therapy, with a mortality rate of 63.2%. Ten cases of BKV nephropathy were reported in the context of hematologic malignancies, with an average time from malignancy diagnosis to BKV nephropathy diagnosis of 3.06 years. Ten cases of BKV nephropathy were reported in HIV-infected patients, all in males, with a mean age of 34.5 years. Three of these patients required renal replacement therapy, and mortality at the time of publication was 30%. Additionally, individual cases of BKV nephropathy were described in various other clinical settings, such as rheumatoid arthritis, Hyper IgM immunodeficiency syndrome, pulmonary tuberculosis, diabetes mellitus, prostate cancer, and an immunocompromised patient with an unclear medical history. This is fascinating to note that this entity has been ignored in the recent non renal transplant literature. 

In a meta-analysis evaluating the frequency and risk factors for BK viruria and viremia in NRSOT patients, Viswesh et al found a relatively high rate of viruria (8%-52%) but infrequent progression to viremia (3%-7%) and BKV nephropathy (1 biopsy-proven case in an heart transplant recipient). Among those NRSOT patients who did have progression to viremia and BKV nephropathy, heart transplants patients represented the majority of cases. This finding might be due to the proposed “double-hit” hypothesis, which suggests that the cumulative insult of immunosuppression and renal hypoperfusion secondary to cardiac allograft dysfunction causes clinical progression to BKV nephropathy.  

Should implementing a systematic BK screening program could effectively identify and manage this issue in the NRSOT population and or HCT patients?

In the News: Is it prime for Xenotransplantation

A seminal paper in Lancet published in 2023 focuses on the immune response after pig-to-human kidney xenotransplantation. The study uses a comprehensive approach to characterize this response in detail. 

Two pig kidney xenografts transplanted into deceased human recipients were thoroughly analyzed using various methods including morphological evaluation, immunophenotyping, gene expression profiling, digital spatial profiling, and cell deconvolution. The findings indicate early signs of antibody-mediated rejection, with evidence of microvascular inflammation, immune deposits, endothelial cell activation, and positive xeno-reactive crossmatches. The inflammation primarily consists of innate immune cells like CD68+, CD15+, and NKp46+ cells. Gene expression analysis reveals increased activation of various immune-related pathways, such as monocyte and macrophage activation, natural killer cell response, endothelial activation, complement activation, and T-cell development. 

The injury associated with antibody-mediated rejection is concentrated in the glomeruli of the xenografts, with transcripts related to monocytes, macrophages, neutrophils, and natural killer cells being significantly enriched. This rejection pattern is distinct from control autografts and ischemia-reperfusion models. The study suggests that despite initial positive outcomes, antibody-mediated rejection might still be occurring in pig-to-human kidney xenografts. The findings highlight potential therapeutic targets to address the humoral aspect of rejection and improve the success of xenotransplantation.

Interestingly, in JAMA surgery, a case report is published at the same time. The paper presents a case involving a male individual in his 50s who was declared brain dead and had acute kidney injury on top of a history of chronic kidney disease (CKD) and hypertension. After all other organ donation options were exhausted, the individual received bilateral native nephrectomy and cessation of dialysis. Crossmatch-compatible xenotransplantation was performed using 10-gene-edited pig kidneys (UKidney). The pig kidneys were modified with 10 gene changes, including knockdowns, knockouts, and human transgene insertions. The recipient was treated with a complement inhibitor (anti-C5; eculizumab) prior to xenotransplantation, followed by standard induction therapy and maintenance immunosuppression. The pig kidneys were transplanted en bloc with their vasculature anastomosed to the recipient's arteries and veins, and the ureters connected to the recipient's bladder. The pig kidneys exhibited rapid function, producing significant amounts of urine within minutes of reperfusion, and urine concentration improved over time. Serum creatinine levels dropped significantly after xenotransplantation, and creatinine clearance improved as well.

Biopsies of the xenografts showed normal histology without evidence of thrombotic microangiopathy. The authors discuss that while this case series demonstrates the success of pig-to-human xenotransplantation in providing kidney function to a deceased individual with CKD, more research with living human recipients is needed to determine the long-term function of xenograft kidneys and their potential use as a solution for the organ shortage crisis. Although single case, it highlights the potential of xenotransplantation as a viable solution for addressing the shortage of organs, which results in preventable deaths annually.

Concept Map: Infections and Renal Transplant

 

Based on a recent article in CJASN by Agrawal et al.

Figure made using biorender.com 

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. 

Topic Discussion: Gut Microbiota and UTIs

 

A Gut Microbiota – Urinary Tract Infection Connection

It is presumed that gut bacteria are the source for urinary tract infection, but is there any proof? If so, could changing the gut microbiota impact urinary tract infection?

Lee et al. evaluated this premise in a cohort of 168 kidney transplant recipients and profiled the gut microbiota serially using 16S rRNA deep sequencing. They reported that having higher gut abundance of E. coli was a risk factor for development of E. coli. They further performed strain analysis on matched fecal-urine specimens and found that the E. coli in the urine most closely resemble the E. coli in the gut from the same patients, supporting a gut origin of UTIs .

A follow up analysis identified that the gut abundances of two commensal bacteria, Faecalibacterium and Romboutsia, are associated with a decreased risk for UTIs. 

The data suggest the possibility that manipulation of the gut microbiota could alter the balance of commensal bacteria and pathogenic bacteria and could decrease the risk of UTIs, especially in patients with recurrent UTIs. Indeed, there is some recent evidence in case reports. In a case series by Tariq et al., patients with recurrent UTIs and recurrent C. difficile infections underwent fecal microbial transplantation for recurrent C. difficile infections and had a significant decrease in the number of UTIs after fecal microbial transplantation.

Whether gut microbial-based therapies can break the cycle of recurrent UTIs is still not known. Nevertheless, these therapies could be a novel approach to treating this common problem.

Image credit: http://www.sci-news.com/biology/gut-microbiota-manipulate-our-minds-05956.html

In the NEWS: The New Kidney Health Order

Few weeks ago, there was an executive order signed to advance kidney health in the US. This is an historic event for the field of Nephrology and for kidney patients. The above image is a visual abstract that summarizes the changes that might be coming in 2020. This image is courtesy of Dr Tejas Desai @nephondemand

The goal of this order is to increase home dialysis options, increase organ transplantation and promote kidney health and keep patients "away from dialysis".  In addition, several incentives have been built in to allow for improved compensation for physicians and what looks like better options for patients. What does this mean for Nephrology?- Time will tell but this is a huge improvement in terms of patient care and patient choices. Hope this also sparks some more interest in the field of nephrology where we are still struggling for trainees.

Topic Discussion: Lenalidomide and the Transplanted Kidney

Lenalidomide has multiple immunomodulatory effects that provide antitumor properties and has been used in treatment of myeloma and AL amyloidosis. Recently, several cases have been reported of acute allograft rejection in patients who got this agent with a renal transplant.

Activation of the immune system by lenalidomide has been shown to result in immune-mediated complications. In a retrospective analysis, Montefusco et al discovered a 4-fold increased risk for the development of autoimmune disease following the administration of lenalidomide for the treatment of multiple myeloma, most of which occurred in the first 3 to 5 weeks after initiating therapy.

Meyers et al had reported the first case of rejection in a patient after heart-kidney transplantation with stable immunosuppression following lenalidomide administration. Since then two additional cases are reported in the renal transplant population both in the recent years.

The two cases are listed below

The AJKD case report

Transplantation Proceedings case report

Why does this happen? The authors of most articles postulate that lenalidomide might activate T cells by directly inducing tyrosine phosphorylation of CD28, an essential T-cell−signaling protein in the costimulatory pathway. Direct activation of this pathway allows for T-cell activation in the presence of CTLA4 immunoglobulin blockade, increased secretion of interferon γ and IL-2, and stimulation of cytotoxic CD8-positive and CD4-positive helper cells.

In addition to CTLA-4 antagonist and PD1 and PDL1 inhibitors that activate the immune system and cause transplant rejection, we will have to add Lenalidomide to the list as well.

Immune check point inhibitors and renal transplant: the saga continues with more twists and turns

Immune check point inhibitors have been used sparingly in the organ transplant world.
A review last time we did on this topic in Journal of Onconephrology listed a list of cases that led to rejection in majority of the cases when PD-1 inhibitors( nivolumab or pembrolizumab) was used alone or in combination with CTLA-4 inhibitors. 

Last year, a case from our institution(Barnett et al.) showed that if pre emptive steroids and mTOR inhibitors were used, rejection could be potentially prevented in a single case report. To date, to my knowledge, this has not been repeated. Nevertheless, new cases have come to light showing more rejection but a few showing no rejection despite PD-1 inhibitor use.

The table below is an updated list since our last publication in JON and NEJM(appendix)

Transplant type	ICI therapy	Time	Rejection(yes/no)	Graft loss(yes/no	Reference
DDRT	Ipilimumab	None	No	No	Lipson et al
DDRT	Ipilimumab	None	No	No	Lipson et al
DDRT	Ipilimumab +pembrolizumab	5 weeks	Cellular and antibody rejection	Yes	Alhamad et al
DDRT	Pembrolizumab	8 weeks	Cellular rejection	Yes	Lipson et al
DDRT	Ipilimumab +  nivolumab	5 weeks	Cellular rejection	Yes	Spain et al
DDRT	Nivolumab	6 weeks	Cellular rejection	Yes	Bolis et al
DDRT	Pembrolizumab	6 weeks	Cellular rejection	Yes	Kwatra et al
DDRT	Nivolumab	3 weeks	Cellular rejection	Yes	Deltombe et al
DDRT	Ipilimumab + nivolumab	1 week	Cellular rejection	Yes	Miller et al
LRRT	Pembrolizumab	None	No	No	Saadat et al
DDRT	Pembrolizumab + chemo	None	No	No	Wu et al

The last four cases shed some new light. Miller et al and Deltombe et al showed two cases that had converted to everolimus but still had rejection. No pre treatment of steroids were used. Saadat et al and Wu et al, no immunosuppressive treatments were made and PD-1 inhibitors were used and no rejection happened but cancers did progress. Saadat et al did use high levels of sirolimus during the treatment of the PD-1 inhibitor. The last case is fascinating as no pre- treatment was used and the patient had a DDRT and despite getting cisplatin, bevacizumab and PD-1 inhibitor, the creatinine remained stable. Could VEGF inhibition be protective here? Why did this patient not reject? Perhaps The Barnett et al case and Saadat et al didn’t reject due to being LRRT and having accommodation and tolerance but Wu case is intriguing.

A twitter poll I did on what folks are doing around showed the following when using PD-1 inhibitors in the renal transplant world.

Are you using Pd-1 inhibitors in renal Transplant patients ?

— Kenar Jhaveri (@kdjhaveri) January 1, 2018

What are your thoughts?