Recurrence of Kappa monoclonal gammopathy after kidney transplantation

Monoclonal gammopathies generally arise from the development of an abnormal clone of B-cell lineage. The monoclonal protein can be intact immunoglogulin (often associated with free light chain), free light chain (FLC) in isolation, or more rarely immunoglobulin heavy chain, either in isolation or with associated free light chain. Monoclonal light chains have the ability to self-aggregate and form tissue deposits either in the form of beta-pleated fibrils (amyloid) or not (non-amyloid deposits).

Monoclonal gammopathies may lead to kidney injury through a variety of mechanisms, depending on the biochemical properties of the light chain and/or immunoglobulin. These include: cast nephropathy (usually kappa); monoclonal immunoglobulin deposition disease; crystal-storing tubulopathy; amyloidosis (usually lambda), cryoglobulinemia or MPGN (membranoproliferative glomerulonephritis).

Monoclonal gammopathies can frequently recur after transplant (Sethi et al. CJASN 2010). In a cohort of transplant recipients in our center, Dr Batal had reported 8 cases of IgG/Kappa MPGN, of which 3 failed post-transplant while 2 were still functioning; 3 were lost on follow up (Batal et al. AJKD 2014).

Recently, a 65 year-old Female with CKD secondary to MPGN/IgG Kappa monoclonal gammopathy underwent a living-unrelated kidney transplant. Creatinine came down to nadir of 1.2mg/dl three days after transplant and then started to rise up to 2.5mg/dl. An emergent kidney biopsy was performed which revealed aggressive MPGN (view picture above). Immunofluorescence staining was negative for IgG, kappa or lambda. However, when the biopsy sample was treated with pronase and restained, suddenly diffuse Kappa staining was uncovered, confirming recurrence of her primary disease. Pronase digestion has a denaturing effect on cell membranes, which may unveil sequestered antigenic sites. This was previously shown to be useful in other forms of monoclonal gammopathies such as in crystal-storing tubulopathy. Electron microscopy may also help in identifying the deposits and triggering additional tests to elucidate the composition of those. Unfortunately, prognosis of early recurrence is not good and requires aggressive treatment against the possible source of light chain (abnormal plasma cells) and removal of light chains from the circulation through plasmapheresis.

To learn more about glomerular disease recurrence after transplantation, refer to Kidney Transplant iBook (Chapter 4/Section 8); Ponticelli et al. CJASN 2010; Ponticelli et al. CJASN 2011; and MPGN review on Sethi, Fervenza. NEJM 2012.

Point of Care Evidence-Based Nephrology Diagnosis

The use of evidence-based diagnosis is what we are taught that we should all do but in practice, this is quite difficult. EBM diagnoses rely on likelihood ratios but it is impossible to remember the diagnostic accuracy of the thousands of tests out there.

This is why I developed a simple tool to help with the scientific diagnosis of common nephrological problems, as well as diseases spanning most specialties. It is a database of more than 700 likelihood ratios of tests (history, physical exam, radiology, etc.). The likelihood ratios are completely free for all to access and are available on my website and on an app I developed for the iphone/ipad called DxLogic. Android users are not left out as the website is mobile-friendly.

The following examples will demonstrate how you to can use this resource to approach some common clinical nephrology situations in a probabilistic and rational manner. The screenshots found below are from the iOS application.

Example #1

You are consulted for a 50yr old man admitted with pneumonia who has developed AKI in hospital. He was started on ceftriaxone 10 days ago and, after examining the patient and a chart review, you wonder about acute interstitial nephritis secondary to antibiotics. You remember being told that urinary EOS are a great test for this disease. But does this test actually increase or decrease the possibility of this diagnosis? From the screenshot below, we see that the presence of EOS in the urine actually has no diagnostic value for AIN. You save the lab time and money by not ordering the test.

Example #2

A 30 year old woman presents to your clinic with symptoms and signs consistent with nephrotic syndrome. She also has a questionable malar rash and a family history of lupus.  You wonder if she could have lupus nephropathy. Using the resource we find that her probability of having lupus nephropathy before any tests are ordered is 14%,

You order an ANA titer and this comes back negative. Plugging this into that app we find that her probability of having lupus nephropathy on renal biopsy is now 3% - a low, but not an insignificant percentage. 

I hope this article has made you aware of the important role that likelihood ratios can play in nephrological practice. Please give my app/website a try and feel free to contact me with any comments or suggestions.

Contact information:

Michael Garfinkle

University of Calgary

Email – mgarfinkle@gmail.com

Twitter –  @joyofmed 

Renal Effects of Anti-Cancer Medications

With the proliferation of new therapies for cancer including novel targeted therapies, it is difficult to keep up with the potential renal problems related to these medications. Thankfully, Nature Reviews Nephrology have published a comprehensive review of the nephrotoxic effects of targeted anticancer therapies that could serve as a reference for practicing nephrologists. As is pointed out in the review, this is a rapidly evolving field and novel toxicities are being recognized with real world use that may not have been seen in the initial trials..

Of particular interest was the fact that many of these agents cause severe electrolyte abnormalities. For example, approximately 17% of individuals receiving cetuximab (an EGFR inhibitor used in the treatment of some lung cancers) develop hypomagnesemia. It turns out that TRPM6, a DCT  magnesium channel, it regulated by EGF which is highly expressed in that area of the nephron and cetuximab therapy leads to inhibition of Mg reabsorption and subsequent hypomagnesemia (along with hypocalcemia and hypokalemia).

The figure below shows a list of the commonest adverse effects of chemotherapeutic agents. Click on the picture for a larger image:

EVOLVEing past Cinacalcet

One of the regular criticisms of nephrology is the lack of good quality randomized controlled trials. This is particularly the case in the world of renal bone disease where we target surrogate endpoints without necessarily knowing for certain what the effect this has on the most important outcome - patient survival. The EVOLVE trial was once such trial which examined the role of cinacalcet in preventing all-cause and cardiovascular mortality. The results of this trial were somewhat ambiguous in that the overall results were negative but this could have been affected by the slightly older age of the treatment group (after adjustment for age, there was a benefit to cinacalcet). There was, however, a wonderful rebuttal to this particular argument in a letter to the editor published later in the NEJM by Giovanni Tripepi.

Overall, the number needed to treat to prevent a single death was 500 and this is balanced by a 62% drop-out rate in the treatment group. There was also a lower rate of parathyroidectomy in the treatment group.

Last month NDT published and ERA-EDTA position statement on the use of calcimimetics in patients on dialysis. Based on a meta-analysis (which was largely derived from the EVOLVE trial), they made the definitive statement that cinacalcet should not be used in patients on dialysis to reduce cardiovascular or all-cause mortality. Further, they pointed out that although the original trials showed that PTH could be successfully lowered using these drugs and that this could reduce the rate of parathyroidectomies, there is no evidence that this has any benefits either beyond the prevention of surgery. They called for a randomized trial of parathyroidectomy vs. cinacalcet for the treatment of intractable hyperparathyroidism with hard endpoints. I second that call.

Osteoporosis treatment in patients with renal failure: the gray zone...

Chronic kidney disease (CKD) patients develop significant changes in bone mineral density (BMD) and bone structure, which together with an increased risk for falls, put them at high risk for fracture. This can be due, in part, to renal osteodystrophy, since bone loss and reduced bone quality may be present in both low- (osteomalacia and adynamic bone disease) and high-turnover bone disease (osteitis fibrosa and mixed uremic osteodystrophy). In addition, some patients may have underlying traditional risk factors for bone loss, such as early menopause or smoking. The heterogeneity of bone loss in patients with CKD complicates its management, requiring frequently a combination of interventions. Performing a bone biopsy is the gold-standard to characterize potential etiologies though not frequently available in most centers. 


 One of the major challenges of treatment of osteoporosis in patients with eGFR below 30 mL/minute is the limited available data. Bisphosphonates are usually not advocated in this population since most agents have renal clearance and patients were frequently excluded from clinical trials. Post-hoc analyses of studies in postmenopausal women with grades 4 and 5 CKD and a definite diagnosis of osteoporosis revealed efficacy and short-term safety of bisphosphonates, denosumab, and raloxifene in addition to calcium and vitamin D supplementation. Bisphosphonates demonstrated increase in BMD, and reduction in vertebral fracture incidence regardless of degree of renal dysfunction. To date, anti-osteoporotic agents have not been recommended in CKD stage 5D due to lack of data on security and on its beneficial impact against fracture. Though some small studies have reported an amelioration of BMD with these drugs in hemodialysis patients. 

Monitoring: 

Patients with severe renal impairment are at higher risk for hypercalcemia due to calcium and vitamin D supplements, or for hypocalcemia if taking denosumab therapy. Therefore, serum calcium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D should be monitored at least every four months. Furthermore, renal function should be routinely measured in patients taking bisphosphonates. Markers of bone turnover, including but not limited to C terminal telopeptide (CTX), N terminal telopeptide (NTX), and pyridinolines (PYR) are metabolized and/or excreted renally, and will accumulate in renal dysfunction. Therefore, they should not be used to monitor response to therapy in patients with eGFR below 30 mL/minute. Despite neither predicting fracture risk nor the type of renal osteodysthrophy, bone densitometry of the hip and spine may be performed to monitor for changes in BMD. In complex patients, a bone biopsy should be considered prior to initiating osteoporosis treatment. 

Recommendations: 

• For patients with low BMD (T-score below 2.5) associated with fragility fracture and grades 4 or 5 CKD, pharmacologic therapy might be considered after excluding all other CKD-related low BMD diagnoses. 

• Adjusted dose of oral bisphophonates are typically recommended based on clinical experience and existing data. 

• Intravenous (IV) bisphosphonates should be used as a last resort only in patients who cannot tolerate previous therapies and are at high risk for multiple fractures. 

• Nephrotoxicity is a significant potential problem with IV bisphosphonates (Zoledronic acid). It is dependent on both dose and infusion rates. 

 • The patterns of nephrotoxicity from IV bisphosphonates include acute tubular necrosis and collapsing focal segmental glomerulosclerosis. 

 • Strict adherence to guidelines for monitoring renal function prior to each dose and temporarily withholding therapy in the setting of renal insufficiency, may help prevent nephrotoxicity from these agents. Denosumab can be an interesting alternative since it is not renally excreted. Further studies are required in patients with CKD. 

• Medications that increase bone formation, such as teriparatide and anti-sclerostin monoclonal antibodies (romosozumab and blosozumab) seem to be promising alternatives for treating osteoporosis in CKD patients with low-turnover bone disease.

Sandra El Hajj, PharmD

Steven Gabardi, PharmD, BCPS, FCCP

Fellype Barreto, MD, PhD

Leonardo Riella, MD, PhD

Additional References: 

1.        Miller PD,Roux C, Boonen S, et al. Safety and efficacy of risedronate in patients withage-related reduced renal function as estimated by the Cockcroft and Gaultmethod: a pooled analysis of nine clinical trials. J Bone Miner Res 2005;20:2105

2.         Jamal SA,Bauer DC, Ensrud KE, et al. Alendronate treatment in women with normal toseverely impaired renal function: an analysis of the fracture interventiontrial. J Bone Miner Res 2007; 22:503

3.   Ishani A,Blackwell T, Jamal SA, et al. The effect of raloxifene treatment inpostmenopausal women with CKD. J Am Soc Nephrol 2008; 19:1430.

4.       Jamal SA, Ljunggren O, Stehman-Breen C, et al.Effects of denosumab on fracture and bone mineral density by level of kidneyfunction. J Bone Miner Res 2011;26(8):182

Remote ischemic preconditioning (RIPC)— Preparing your kidneys for surgery.

Prevention of perioperative AKI, mostly from ATN by ischemic insult, has been a major challenge in nephrology. Recent study (Zarbock et al. JAMA) showed a simple, non-invasive method—remote ischemic preconditioning (RIPC), could be a promising strategy.

This multicenter, double-blind study in Germany randomized 240 patients undergoing on-pump cardiac surgery, who had high risk for AKI (based on Cleveland Clinic Foundation score). Exclusion criteria included eGFR below 30 ml/min or transplant recipient. Intervention consisted of: 3 cycles of 5-minute inflation of a blood pressure cuff to 200 mmHg (or 50 mmHg higher than the systolic pressure) to one upper arm, followed by 5-minute reperfusion with the cuff deflated.

Primary endpoint was the incidence of AKI within 72-hour post-op (KDIGO criteria). They found significantly fewer patients in RIPC group developed AKI (37.5% vs 52.5%; p=0.02; RR, 71% 95% CI, 54-95%). Use of renal replacement therapy was also lower (5.8% vs 15.8%; p=0.01). Of note, the authors examined urine biomarkers: tissue inhibitor of metaloproteinases 2 (TIMP-2) x insulin-like growth factor-binding protein 7 (IGFBP7), as well as urine neutrophil gelatinase-associated lipocalin (NGAL) and high-mobility group box (HMGB). TIMP-2 and IGFBP were measured by Nephrocheck® (see previous blog entry for details). Biproduct of TIMP2 x IGFBP7 and HMGB increased right after RIPC, suggestive of cell cycle arrest as an epithelial defensive mechanism against ischemic insult, however, in 4-24 hours post-op, TIMP2 x IGFBP7 and NGAL were lower in RIPC group compared to control (schematic figure above from eSupplement), indicating less kidney damage.

 RIPC has been studied in kidney transplant field as well. The REPAIR trial recruited 406 live donor-recipient pairs and looked into 12-month post-transplant eGFR with or without early or late RIPC for both donors and recipients. The result was not significant, but as Zarbock et al. pointed out in their article, it could be due to differences in study protocols, confounding comorbidities, or surgical technique. Further studies to explain the mechanism of protection is warranted and it might be no exaggeration to say that RIPC would be a standard pre-op protocol for cardiac surgery in the near future. Are your kidneys ready for surgery?

Naoka Murakami

ASN Fellow's Survey

The American Society of Nephrology (ASN), in collaboration with a research team from George Washington University (GWU), is conducting its 2^nd annual survey of fellows training in nephrology. The goal of this important survey is to better understand developments in the marketplace for nephrologists.

The survey gathers data on the types of positions, practice settings, and geographic locations where the next generation of nephrologists will be working. Responses will help determine whether there is an imbalance in different practice settings or regions. By administering the survey on an annual basis, the research team hopes to understand trends in nephrology fellows' plans and job market experiences over time. This is a great opportunity for nephrology fellows to share their experiences with the nephrology community.

Survey Results will be presented at ASN Kidney Week 2015, November 3–8 in San Diego, CA, and GWU and ASN will publish a final report by the end of the year. A report from last year’s survey, Findings from the 2014 Survey of Nephrology Fellows, is available at https://www.asn-online.org/education/training/workforce/.

ASN Fellow Members should have received an email with information on how to participate in the survey directly from ASN. If you haven’t received it or have any questions about the survey, please contact ASN Content and Media Analyst Kurtis Pivert at kpivert@asn-online.org.

We urge all fellows to complete this important survey.

Edward Salsberg, MPA

Leah Masselink, PhD

Leo Quigley, MPH

George Washington University

Washington, DC