Friday, December 29, 2017

The ELITE & the Rest in Kidney Transplantation

Image result for cocktail party
The ELITE-Symphony study enshrined standard triple therapy immunosuppression of tacrolimus, mycophenolic acid and prednisolone, for renal transplant recipients. We get familiar with these agents relatively quickly in our renal training, but what about the other less common agents that are used?  Why do we not use them as first line, when should we consider them and what side effects do we need to be aware of?
Sirolimus and everolimus are mTOR inhibitors (see previous RFN post), and prevent cell cycle progression and lymphocyte proliferation.  Their anti-proliferative effects mean they have a role in conditions such as tuberous sclerosis, psoriasis and certain cancers.  The antiproliferative and antiangiogenic effects pose issues post-surgery however with poor wound healing and lymphocele formation meaning they should not be used for around 6 months post-transplant.  Other side effects include pneumonitis, hyperlipidaemia, bone marrow suppression, thrombotic microangiopathy and proteinuria due to FSGS-type lesions. Alongside this relatively long list of side effects, the main concern with sirolimus is related to mortality. A meta-analysis of 21 studies with a total of 5876 patients showed sirolimus was  associated with increased mortality post-transplant, mainly from cardiovascular and infectious complications (adjusted hazard ratio 1.43, 95% CI 1.21-1.71). So why do some patients end up on sirolimus?  The same meta-analysis showed that sirolimus is associated with a 40% reduced risk of malignancy, particularly in non-melanoma skin cancers. The most common reasons for switching to mTORi are malignancy, often recurrent skin cancers, and for calcineurin-inhibitor (CNI) induced injury (although if eGFR<40mls/min or overt proteinuria outcomes are likely to be poor or no better with a switch). Moreover, as seen in ELITE-Symphony and other, acute rejection rates and patient dropouts are consistently higher with mTORi compared to CNIs.
Image result for belatacept mechanismAnother agent we may be hearing more about in the future is belatacept: a co-stimulation pathway blocker. It is attractive as it is designed to replace the CNI in the treatment regime. It binds to CD80 and CD86 on antigen-presenting cells, thereby blocking CD28 mediated activation of T Cells. It is administered as an IV infusion every 4-6 weeks alongside steroid and an anti-metabolite.
The BENEFIT and BENEFIT-EXT (extended criteria donors) trials compared high and low intensity belatacept regimes with cyclosporine in non-sensitised recipients undergoing DBD or living donor renal transplants. Over 7 years of follow-up, they found improved patient and graft survival with belatacept in BENEFIT and better measured GFR and reduced formation of DSA with belatacept in both studies. There was an increased incidence of acute rejection in BENEFIT although this obviously didn’t translate into inferior outcomes. There were also initial concerns regarding a small increase in cases of PTLD in EBV seronegative recipients although longer term data was reassuring that the overall risk of this was very low.
A potential benefit of belatacept is it’s a directly observed therapy, so compliance will be known. Although it is expensive, if patients experience improved graft outcomes then any longer term savings need to be considered. However what about patients who are highly sensitised? Many patients we want to avoid CNIs in are sensitised but here is a dearth of data in using belatacept in this circumstance. Moreover, the studies compared belatacept to cyclosporine, not tacrolimus, the current standard of care. Currently belatacept is not available for new patients due to supply issues, another issue likely preventing its more widespread use.  
Post by Ailish Nimmo

Sunday, December 24, 2017

Adenovirus and graft versus host disease in the kidney

A young man with a myelodysplastic syndrome status post allogeneic bone marrow transplant was recently found to have graft-versus-host disease (GVHD) of the skin and presumed liver involvement which was treated with tacrolimus and methotrexate. The increased immunosuppression was complicated by an upper respiratory tract infection which was treated with empiric cefepime; also, at that time,  a nasopharyngeal swab culture tested positive for rhinovirus.

The patient was discharged on amoxicillin-clavulanate to complete a 14-day course. A few days later, the patient presented to the hospital with dysuria and hematuria. Kidney function was within normal limits (creatinine 0.6-0.8 mg/dL) on admission and he was diagnosed with rhinovirus infection again. Additionally,  he was found with a concomitant adenovirus infection, confirmed with culture and DNA PCR amplification test (2,250,000 copies/ml). Also, the patient developed acute kidney injury (AKI) with a rise in creatinine up to 1.32 mg/dL. He had 5.6 grams of proteinuria on 24 hour urine collection and he was presumed to have adenovirus related hemorrhagic cystitis.

A renal biopsy was performed for further management of the acute kidney injury, revealing signs of both GVHD and adenovirus infection. In order to treat the patient’s GVHD of the native kidney he was given methylprednisolone and was continued on tacrolimus. Furthermore, for the hemorrhagic cystitis due to adenovirus infection, he was given intravesicular and intravenous cidofovir, probenecid, in addition to hyperbaric oxygen. The patient’s kidney function improved, however, he had recurrent AKI due to obstructive nephropathy due blood clots, for which he underwent bilateral stent placement. At the time of discharge, the patient was hemodynamically stable and kidney function was almost at his baseline.

According to the National Institute of Health (NIH) consensus criteria, Acute GVHD usually happens within the first 100 days after transplant, then it becomes chronic.  Classification is based mostly on clinical findings, rather than period of time. Acute GVHD is characterized by maculopapular rash, nausea and vomiting, diarrhea, ileus or hepatitis;  persistent, recurrent, or late-onset GVHD have symptoms of acute GVHD but it presents after 100 days, without features of chronic GVHD. Overlap GVHD happens when the patient has both symptoms of acute and chronic GVHD. It has been reported that patients with overlap syndrome have increased morbidity and mortality. GVHD rarely affects the kidney and usually presents after decreasing immunosuppressive therapy. In the chronic form it usually causes nephrotic syndrome such as membranous glomerulonephropathy and minimal change disease; less commonly it can cause focal segmental glomerulosclerosis, IgA nephropathy, and membranoproliferative glomerulonephritis.

First line therapy includes corticosteroids either topical or intravenous, depending on the stage. When the GVHD is grade I limited to the skin, it is treated with topical corticosteroids and possible adjustments of the patient's methotrexate and tacrolimus . Grade II GVHD or higher is treated with high-dose systemic corticosteroids- usually 2 mg/kg/day of intravenous methylprednisolone or oral steroids. Finally, extensive GVHD is treated with high-dose systemic corticosteroids, and occasionally with cyclosporine with trough levels of 200-450 ng/ml. Tacrolimus has been used in some case reports.

Adenovirus may cause an upper respiratory tract infection. It can cause a tubulointerstitial nephritis and hemorrhagic cystitis which affects the kidney as well, usually seen after a renal transplant. Diagnosis can be made by viral culture, viral antigen assay and PCR. Renal biopsy is needed for definitive diagnosis of renal involvement. On light microscopy, we can see necrotizing granulomas with interstitial nephritis and electron microscope shows icosahedral virions that form large paracrystalline aggregates with the nuclei of infected cells. Current treatment is with cidofovir with probenecid to decrease its nephrotoxic effects. Concurrently, if the patient is on immunosuppressive therapy, it should be decreased to promote immune recovery. Hyperbaric oxygen has been shown to treat radiation and cyclophosphamide induced hemorrhagic cystitis, and according to several small case reports, it has been used to treat adenovirus-induced hemorrhagic cystitis.

In conclusion, this is a unique case not commonly encountered in which a patient suffered from adenovirus infection and GVHD, concomitantly. Renal biopsy is generally required for diagnosis and when both diseases are present, there is a challenge on how to manage immunosuppression.

Cassiopia Lippold, MD
Second year Nephrology Fellow
University of Maryland Medical Center

Friday, December 15, 2017

Another Great Masquerader: Amyloidosis

A middle-aged man with a history of microcytic anemia, well-controlled diabetes mellitus (DM)/hypertension (for 15 years), and a 16 month history of diarrhea with a 30-pound weight loss, and a creatinine of 1.9 mg/dL.

Laboratory tests showed a urine protein to creatinine ratio of 0.35 mg/g, hemoglobin of 9.3 g/dL, white blood cell count of 13.5 x 10^9/L, and a platelet count of 662 x 10^9/L. A workup for chronic diarrhea revealed an elevated erythrocyte sedimentation rate and C-reactive protein of 85 mm/hr and 18 mg/dL, respectively. Serologies for systemic lupus erythematosus, mixed connected tissue diseases, tuberculosis, hepatitides, and monocolonal gammoapthies were also unrevealing. Computed tomography of the abdomen, EGD, and colonoscopy were unrevealing – biopsy specimens of both the small and large bowel did not show evidence of inflammation. His urine sediment did not have red blood cells (RBCs) or RBC casts.

Despite his long-standing DM and hypertension, a kidney biopsy was performed – which revealed AA amyloidosis (see immunohistochemistry staining for amyloid A protein and an electron microscopy images below)

Endoscopic biopsies were subsequently stained for amyloid A protein – which was also positive.

Serum amyloid A (SAA) is part of a family of apolipoproteins associated and an acute phase reactant whose production is upregulated by the liver typically in the setting of infection or inflammation, which leads to increased expression of inflammatory cytokines like interleukin (IL)-1, IL6, and TNF-alpha. Increased SAA levels ultimately lead to the formation of amyloid fibrils that are immune to proteolysis.

The differential diagnosis of AA amyloidosis is broad – including autoimmune disorders, inflammatory arthritis, inflammatory bowel disease, lymphoma, familial Mediterranean fever, IgG4-related disease, Castleman disease, and chronic infection. A study of the natural history and outcome in systemic AA amyloidosis of a few hundred patients found that the underlying disorder was inflammatory arthritis in 60%, chronic sepsis in 15%, and periodic fever syndromes in 9%. The underlying disorder was unknown in 6% of cases.

Like most other secondary diseases processes, treatment for AA amyloidosis is treatment of the underlying disease. Other therapies should enhance clearance of amyloid deposits, decrease or interrupt fibril assembly, and decrease fibril deposition. For example, two agents that have been used with some success are a monoclonal antibody to IL-6 (tocilizumab) and the newer agent eprodisate, which directly interferes with amyloid fibril formation and deposition. SAA levels may predict disease progression and prognosis. These therapies would be potential options in this patient who did not have a proven underlying disease process.

To conclude, the presentation of amyloidosis can be nonspecific and the differential is widespread. It is important to remember that kidney biopsy can change management in a significant percentage of cases – even in a case like this, where the urinalysis was misleading and masked underlying amyloidosis.

*This is a fictionalized case based on a true account, details have been modified/changed

Samira Farouk, MD
Chief Fellow, Division of Nephrology
Icahn School of Medicine at Mt. Sinai

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The Top 10 will be posted over at NephJC

Thursday, December 14, 2017

The Heart-Kidney Connection: An Update in Nephro-Cardiology 2018

Northwell health in Long Island New York will host a one-day symposium aimed at providing updates on the Nephro-Cardiology on Saturday March 10th

go to this link for more information and to register. Fellow registration is free

Kenar Jhaveri

Below is the itinerary

7:30am Registration, Breakfast and Exhibits

8am Contrast Nephropathy? Does it Exist-The Latest Update and Prevention
Paul M. Palevsky, MD

9am Cardio-Renal Syndrome
Jai Radhakrishnan, MD, MS, MRCP

9:30am TAVR and the Kidney
a. Basics of Transcatheter Aortic Valve Replacement: A Primer
Barry Kaplan, MD

b. The Renal Effects of Transcatheter Aortic Valve Replacemen
Kenar D. Jhaveri, MD

10:30am Break

10:45am Left Ventricular Assist Devices
a. Basics of Left Ventricular Assist Devices
David Majure, MD

b. Left Ventricular Assist Devices and the Kidney
Daniel W. Ross, MD

11:30am Novel Agents Used in Hyperkalemia - What Cardiologists and Nephrologists Need to Know
Steven Fishbane, MD

12:15pm Interventional Therapies for Refractive Hypertension
Avneet Singh, MD

12:40pm Lunch 1:30pm Novel Anticoagulants and the Kidney
Nupur N. Uppal, MD

2pm Cardiac Workup of the Kidney Transplant Patient
Alexander Lee, MD

2:30pm Cardiac Surgery and the Kidney
Mitchell H. Rosner, MD

3:30pm Panel Discussion

4pm Program Conclusion

Tuesday, December 12, 2017

December Renal Path Web Episode available!

The final episode for this year's season of nephrology web episodes from Wash U Nephrology is available for viewing now.  The series has been going for two years strong, and we want to thank all the support from viewers, trainees, faculty, social media gurus, etc. that have helped launch this project!

December 2017 video link below: