MGRS and MGUS- the 1/3-2/3 rule of pathology in the kidney?

When someone has MGUS, what is the true incidence of kidney disease? – this has not been answered. An old study from AJKD in 2003 did help us guide the breakdown of kidney diseases when someone has MGUS.  In other words, if someone has MGUS, and there is some form of renal disease- AKI, proteinuria, hematuria and you biopsy them- what percent of the time you will find renal disease associated with proteinuria, what percent of the time you would find diseases other than paraproteinemic disease?

In summary, the AJKD paper looked at a single center experience of their paraprotein related kidney diseases biopsy bank.  Patients who underwent renal biopsy and had monoclonal gammopathy on serum and/or urine electrophoresis and/or had a renal biopsy diagnosis related to paraprotein (cryoglobulinemic glomerulonephritis(cryo) monoclonal immunoglobulin deposition disease [MIDD], light chain cast nephropathy [CN], or light chain amyloidosis [AL]) were identified.  One hundred twenty-one patients met the inclusion criteria and were classified as having renal disease related or unrelated to monoclonal gammopathy. Among 66 cases of renal disease related to monoclonal gammopathy, diagnoses were cryo (30.3%), MIDD (28.8%), CN (19.7%), AL (19.7%), and CN plus MIDD (1.5%).

Among 55 patients with monoclonal gammopathy and unrelated renal disease (63.2% of all patients with monoclonal gammopathy), various lesions were found, including diabetic nephropathy (18.1%), focal segmental glomerulosclerosis (18.1%), arterionephrosclerosis (12.7%), membranous glomerulonephritis (9.0%), minimal change disease (7.3%), various immune complex diseases, interstitial nephritis, or nonspecific changes. MPGN was also included in this group. We know now that MPGN is likely related to MGUS and not a non paraprotein disease.

But what about patient’s with MGUS and true MGRS- what I calculated from the paper was around 22( either had cyro, CN, AL or MIDD) patients and if we remove MPGN from the current 55 patients stated above, would be 52 patients.  This makes it a 1/3-2/3 rule.  So if there is MGUS or smoldering MM and some form of renal disease on clinical presentation , there is 1/3 chance that their disease would be paraprotein related in the kidney if you did a kidney biopsy. But majority of the time, it would be a non paraprotein mediated disease.

While this paper looks at it at a single center, it gives some insight into the incidence of true MGRS when there are renal clinical presentations. 

Clinical Case and Discussion 90

Which has a better prognosis?

C3GN, idiopathic	1 (16%)
C3GN secondary to paraproteinemias	5 (83%)

Which has a better prognosis?

— Kenar Jhaveri (@kdjhaveri) November 29, 2017

One study from the Mayo Clinic found 31% of patients with C3GN had a paraprotenemia. Bone marrow biopsy revealed a diagnosis of monoclonal gammopathy of undetermined significance (MGUS) in 90% of these patients, whereas 10% were diagnosed with low-grade chronic lymphocytic leukemia (CLL). No outcome data was reported. Another study of patients with DDD from the same institution found 71.4% of the patients. All had MGUS at the time of diagnosis, but one patient progressed to MM at 120 months of follow-up. These results are similar to those from the University of Utah, which found 83% of the patients with C3G over the age of 49, had an monoclonal gammopathy. In this cohort, 40% had multiple myeloma (MM) or smoldering MM, 40% had monoclonal gammopathy of renal significance (MGRS), and 10% had polyclonal plasmacytosis. The data was mixed regarding outcomes in that small study.

Chavet et al recently in Blood 2017 reported the outcomes of 50 patients with C3G and monoclonal gammopathy treated after treatment. The patients were divided into groups based on the treatment received: clone-directed therapy (alkylator or bortezomib [or rituximab for CLL]), immunosuppressive therapy (corticosteroids, cyclophosphamide, rituximab, mycophenolate, and azathioprine), or RAS inhibition. In this study clone-directed therapy produced superior renal survival than immunosuppressive and RAS inhibition therapy. No differences in patient survival were noted.  The differences in hematological response helped explain why renal response was superior in patients treated with clone-directed therapy. Only 5% of patients treated with immunosuppressive or RAS inhibition therapy achieved a very good partial response (VGPR) or better vs 31% of patients treated with clone-directed therapy. In fact, 95% of the patients treated with immunosuppressive or RAS inhibition therapy had no hematological response. The authors were also able to show renal function was only preserved in patients who achieved a VGPR or better, similar to other MGRS-associated kidney diseases.

While idiopathic C3GN and C3GN associated with MGUS have not been directly compared, based on the large study by Chavet et al, we can expect the outcomes to be better when there was an MGUS associated with the C3GN and the clone was treated. If you have a secondary cause, fix it and the kidney improves!

Topic Discussion: What is the incidence of MGRS?

There is a new entity that is now being defined as MGRS ( when MGUS affects the kidney). The incidence of MGUS rises with age and there is lifetime 1% risk of transforming to myeloma or other cancers such as amyloidosis.

What is the incidence of MGRS? So what percentage of MGUS patients develop renal disease? Turns out, no published work has this answer.  An abstract presented at American society of Hematology (ASH) in 2013 might have the closest answer.

The study looked at a large database of lab values and 15 year follow up analyzed.   425 confirmed MGUS patients with no progression to Myeloma were evaluated.  297 patients had MGUS and normal renal function at baseline.  Over median of 852 days , 21/297 developed renal Impairment.  15/21 had monoclonal free light chain production.  Time to renal impairment was shorter with the higher free light chain ratio at baseline. Patients with involved Free light chain >100mg/dl were at the highest risk of renal failure.   So based on this one study, there is about 7% risk of MGRS from MGUS.  Seems high but we really need to wait published data on this topic. If it is truly 7%, screening with UA and protein/crt ratio with a complete metabolic panel might be indicated in patients with rising FLC ratios. 

Topic Discussion: MGUS and kidney transplantation

MGUS is defined as having a monoclonal protein in a small but abnormal concentration( <3g/dl). But the bone marrow doesn’t meet criteria for plasma cell percentage that qualifies for myeloma.  The incidence of MGUS is around 3.2% especially in the age >50 and the incidence rises as you age. Given the number of renal transplants are increasing especially in the age >50, it is evident that this entity comes up now frequently at transplant selection meetings.  What do we do? Is it a risk factor? Should we be worried?

MGRS( monoclonal gammopathy of renal significance) is a term now used to describe entities that have renal damage from MGUS. A recent KI paper sheds more light on the pathology of such cases. High rates of recurrence and the recurrence is early and more severe than in the native kidney. ( 40-60%) if MGUS had presented as MGRS( or some folks might want to call is MGKS).  Risk is especially high when there is a circulating Monoclonal immunoglobulins still around.  Recurrence is early and much more severe than the native disease.

Soltero et al. looked at transplant candidates with MGUS between 2000 and 2007 in a single center study.  MGUS that received a KT were compared with MGUS that were not transplanted.( similar age and CV risks) . Of 1215 KT candidates, 34 were found to have MGUS  (11%). The gammopathy was monoclonal in 76% of the cases. Nine patients with MGUS were transplanted. Following transplantation, the MGUS group had a lower survival than the non-transplanted group. (p = 0.0008).  Follow-up of 18.7 ±  15.4 months, seven patients (78%) died. Causes of death were cerebral abscess, lung cancer, sepsis, melanoma, bacterial meningitis, myocardial infarction. They had requested UNOS database from 1987-2003 and only found two reported cases of MGUS to UNOS.  Hence data might not be possible to be obtained from UNOS as not many centers are asking this information.

There are cases of LCDD, MPGN and proliferative GN with monoclonal deposits recurring after transplant. Most of the cases had untreated monoclonal clones prior to transplantation. They would now be classified as MGRS cases.

Is MGUS a risk factor for development of MM post transplantation?  A study from Mayo Clinic had indentified patients who had MGUS either before or after transplant. Of the 3518 patients who underwent transplantation, MGUS was found in 42 patients( 23 pre and 19 post).  They were followed for 8 years.  17% of pre transplant MGUS patients developed malignancies such as smoldering myeloma and other hematologic cancers.  None of the patients who developed MGUS post transplant progressed to MM.
Another more recent study by the Mayo group looked at newly diagnosed MM cases post transplantation. 7 cases were identified and 4 of them had MGUS pre transplant and two of them had clonal plasma cells in bone marrow. They concluded that MGUS prior to transplant was a risk factor for MM post transplant.

Garcia et al showed recently that MGUS following transplantation is a different phenomenon. It was  >100 times more frequent in transplant patients than in general population. Of their small subset of 11 patients with post transplant MGUS, only one developed PTLD.  In contrast to MGUS  in general population, progression to plasma cell dyscrasias was absent and it’s incidence is unknown A longitudinal study in 55 patients demonstrated that most of the MG reflected transient B-cell monoclonal proliferations, probably due to an immunodeficiency. Usually associated with intense immunosuppression and M protein is usually small and multiple bands.

In summary, MGRS may not be a contraindication to kidney transplantation as risk of dying from their clone is low.  No data to suggest that small B-cell clones are truly curable but there might be a high rate of recurrence in certain types. While LCDD and amyloidosis might have a slower recurrence rate, proliferative GN with monoclonal deposits might be must faster. MGUS might be a risk factor for development of active hematologic disease post kidney transplant.  The decision to transplant might depend on considering the underlying MGRS characteristics, initial therapeutic response, extrarenal manifestations, and the patient’s status. Risk of graft loss, its link with the B-cell clone and the potential need for reintroduction of chemotherapy should be explained to the recipient and the donor.

The field is still unsure on the question asked?