Although kidney disease is a common complication of malignant hematologic cancers, most kidney diseases are associated with nonmalignant blood dyscrasias, such as monoclonal gammopathy (MG). Monoclonal gammopathy of uncertain significance (MGUS) is the most usual form. It is more frequent at older ages, affecting about 3% of the population over 50 years of age. It is defined as a clonal proliferative disorder of B cells or plasma cells, producing a monoclonal immunoglobulin with a monoclonal peak below 30g/L, infiltration of anomalous plasma cells into the bone marrow less than 10% and absence of clinical evidence of myeloma, lymphoma or amyloidosis. A lesion is considered to be nonmalignant or premalignant if it does not damage any target organ. The monoclonal immunoglobulins are mainly of the classes IgG, IgA or IgM.

The term monoclonal gammopathy of renal significance (MGRS) was proposed by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. It describes those disorders of MGUS with renal involvement associated with a monoclonal protein. The IKMG later redefined MGRS as a clonal proliferative disorder of B cells or plasma cells that produces a monoclonal immunoglobulin with nephrotoxic effects and that does not fulfill the hematologic criteria to start the treatment of a specific malignant cancer.1 This monoclonal protein may be light chain, heavy chain or an intact immunoglobulin.

The reason for defining this new entity arose from the need to differentiate patients with MG but with no lesion in any other organ from patients at risk of developing kidney disease, as these latter have a high degree of morbidity and mortality due to the severity of their kidney (and sometimes systemic) lesions induced by the monoclonal protein. Early recognition and characterization of the kidney lesion is crucial in order to start treatment and detain the secretion of the paraprotein, thereby avoiding progression to end-stage renal disease and improving both kidney and patient survival.

Monoclonal gammopathy is considered a nonmalignant hematologic disease and does not require any specific hematologic treatment. Its effects on the kidney are sometimes deleterious, as reflected in a retrospective study that included 19 patients with light-chain deposition kidney disease, of whom just 12 had MGUS. After a follow-up of five years kidney and patient survival were 37% and 70%, respectively.2 Steiner et al. showed that patients with MGRS had a greater risk of progression to multiple myeloma (MM) than those with MGUS, with a mean progression time of 18.8 years.3

Monoclonal gammopathy of renal significance can present with a wide variety of clinical symptoms. The toxicity of the monoclonal protein is not just limited to the kidney; it can also cause neuropathy, dermopathy, eye disorders and other extrarenal conditions. The kidney is the organ most affected in dysproteinemias, as several physiological factors come together to increase the potential risk of damage. After the lung, the kidney is the organ exposed to the greatest cardiac output. The kidney is also immersed in a medium where the pH and the electrolyte concentrations can alter the physical and chemical characteristics of the monoclonal protein, making it more toxic.

Renal involvement is generally manifested by varying degrees of proteinuria, which can reach the nephrotic range, or it may also be associated with microhematuria and hypertension. A high percentage of patients have kidney failure at the time of diagnosis, which can progress to end-stage renal disease.4 Proteinuria with albuminuria is the most common finding if there is glomerular involvement. However, if there is tubulointerstitial involvement, as occurs in Fanconi syndrome, it is necessary to assess proximal tubular dysfunction, noting in these cases the presence of glycosuria, uricosuria, phosphaturia and proximal renal tubular acidosis.

Extrarenal manifestations are not uncommon. In light-chain amyloidosis, in addition to renal damage, there can also be cardiac, hepatic or neurologic involvement. In cryoglobulinemic glomerulonephritis joint and skin involvement is common. MGRS can also indirectly cause lesions to the vascular endothelium via deregulation of the alternative complement pathway or the release of endothelial growth factors. In these cases the disease can present with cutaneous lesions, thrombotic microangiopathy and the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, MG, and skin changes).

The most frequent alterations as a consequence of tubular dysfunction are: hypouricemia, hypophosphatemia, normoglycemic glycosuria, aminoaciduria, proximal tubular acidosis, and tubular proteinuria (without albuminuria). Progressive kidney failure is also seen. Among the main tubular disease entities associated with MGRS are the following:

• 1.

  Light chain-associated Fanconi Syndrome presents the characteristic alterations of tubular dysfunction, as well as tubular proteinuria and slow evolution to end-stage kidney failure. Renal biopsy shows atrophy and dedifferentiation of proximal tubular cells (PTC) with intracytoplasmic inclusions. On immunofluorescence, light chains are deposited in PTC. In 90.9% of cases these are kappa FLC.19

• 2.

  Proximal tubulopathy without crystals slowly evolves to end-stage kidney failure with the presence of tubular proteinuria. On light microscopy and immunofluorescence we observe similarities with Fanconi syndrome, but on immunofluorescence both kappa and lambda light chains may be seen.

• 3.

  Crystal-storing histiocytosis presents crystal deposits formed by light chains in the PTC that may also appear in the lysosomes of the histiocytes in the bone marrow. It presents the characteristic alterations of tubular dysfunction with slow impairment of renal function. On light microscopy, histiocytes with crystalline inclusions in the renal interstitium (pseudo-Gacher cells) are visualized with atrophy and dedifferentiation of PTC in the vicinity of perirenal fat. Immunofluorescence shows mainly kappa FLC inclusions in the PTC.

• 4.

  Cast nephropathy is associated with MM in 90% of cases and is less frequent in MG, which requires a high tumor load.

The most common clinical manifestations are proteinuria, microhematuria, nephritic or nephrotic syndrome, hypertension and kidney failure, generally related to the main associated pathologies listed below:

• 1.

  Immunoglobulin light chain-related amyloidosis is produced by the secretion of kappa or lambda FLC by the B cell clone. Involvement of a heavy chain is extremely rare. The fibrils in light chain amyloidosis are derived from the variable region of the lambda FLC in 75% of cases. This type of amyloidosis is associated with elevated proteinuria and nephrotic syndrome, and kidney failure is usually present at diagnosis in 70–80% of cases.20 On light microscopy, glomeruli show massive amyloid deposits (eosinophilic, pale and acellular material), but other renal compartments such as arterioles, arteries and the tubulo-interstitial compartment may also show these deposits. On immunofluorescence, lambda light chain staining is characteristic, and on electron microscopy amyloid is identified as unbranched fibrils with a diameter of 8–10nm. The definitive diagnosis is made by Congo red staining that detects apple green birefringence under polarized light in amyloid deposits.

• 2.

  Fibrillary glomerulonephritis is rarely a primary glomerular disease. Fifty percent of cases present proteinuria in the nephrotic range, with or without kidney failure, hypertension or microhematuria. Fibrillary deposits have a larger diameter than amyloid deposits and are Congo red negative. Light microscopy shows a pattern of membranoproliferative glomerulonephritis (MPGN) and mesangial proliferation with fibrils deposited in the mesangium and/or glomerular basement membranes. Immunofluorescence highlights polyclonal glomerular IgG and FLC deposits are more frequent than monoclonal deposits. Electron microscopy shows randomly aligned fibrils.12

• 3.

  Immunotactoid glomerulonephritis presents clinically with nephrotic syndrome, with infrequent extrarenal involvement and microtubular immunoglobulin deposits organized at the glomerular level that on electron microscopy measure more than 30nm in diameter and are negative for Congo red. On light microscopy, an MPGN or membranous pattern is observed on immunofluorescence staining for monoclonal IgG and complement components.

• 4.

  Cryoglobulinemic glomerulonephritis usually presents with nephritic syndrome and kidney failure that progress in flare-ups, with frequent extrarenal, cutaneous, articular and neurologic involvement. There are three types of cryoglobulinemia. Type I is associated with a monoclonal immunoglobulin generally of the IgG or IgM class, with more frequent renal manifestations when associated with IgG20 and is associated with lymphoproliferative disorders. Types II and III are mixed cryoglobulinemias, frequently associated with infections and autoimmune disorders, respectively, that present with immunocomplexes formed by monoclonal and polyclonal immunoglobulin in Type II and immunocomplexes formed by polyclonal immunoglobulins in Type III. In mixed cryoglobulinemias, the elevation of rheumatoid factor and serum complement anomalies are more frequent than in Type I. On light microscopy, an MPGN pattern is seen with immunofluorescence staining for IgG, IgM and complement components. Electron microscopy shows subendothelial and intracapillary organized fibrillary or microtubular deposits.

• 5.

  Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication in MG, although when it occurs it is usually associated with extrarenal manifestations with hepatic and cardiac involvement, with renal manifestation of proteinuria in the nephrotic range and kidney failure. MIDD is associated with the deposit of light chain, heavy chain or both light and heavy chain. It is most frequently associated with kappa light chain and when associated with heavy chain, this is usually lambda. Deposits are nonorganized and Congo red staining is negative. Light microscopy shows nodular sclerosing lesions and thickening of tubular basement membranes; a membranoproliferative pattern can also be observed. On immunofluorescence, monoclonal light and heavy chains in glomerular and tubular basement membranes are stained linearly and diffusely. On electron microscopy, dense punctiform deposits are seen in the glomerular and tubular basement membranes.21 Joly et al. retrospectively analyzed a cohort of 255 patients with histological diagnosis of MIDD associated with MG and MM in 64% and 35%, respectively. Approximately 35% of cases had extrarenal involvement, mainly cardiac and hepatic. Of the 169 patients who received treatment (58% with Rituximab), hematologic and renal remission was achieved in 67% and 36%, respectively. All the patients who had a renal response also had a hematologic response, with the absence of severe interstitial fibrosis and a hematologic response being predictive factors of renal response.22

• 6.

  Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) manifests with proteinuria, microhematuria, hypertension and kidney failure with C3 hypocomplementemia. It is an MPGN mediated by immune complexes in the mesangial and subendothelial areas. A membranoproliferative pattern is observed on light microscopy, with immunofluorescence staining for a single light- or heavy-chain isotype, most commonly IgG3. On electron microscopy, granular nonorganized deposits are seen in the mesangial, subendothelial and intramembranous areas.21

• 7.

  C3 glomerulopathy includes two subtypes, C3 glomerulonephritis and dense deposit disease, which can be differentiated under electron microscopy. Both manifest with proteinuria, microhematuria with or without kidney failure and C3 hypocomplementemia. Monoclonal protein is not deposited directly into renal structures, but may interfere with the regulatory proteins of the alternative complement pathway, such as factor H or act as a nephritic factor, resulting in dysregulation of the alternative complement pathway, through abnormal control of its activation, degradation or deposition.23 On light microscopy, several mesangial proliferation, membranoproliferative and endocapillary proliferation patterns can be observed. Immunofluorescence shows intense C3 deposits in the mesangium and capillaries, with absence or scarcity of other reactants. The two subtypes are differentiated on electron microscopy. While C3 glomerulonephritis presents nonorganized dense deposits in the mesangial, intramembranous and subendothelial areas, in dense deposit disease the deposits are only in the mesangial and intramembranous areas.12

The most accepted classification of MGRS-associated lesions is based on the distinction according to the organization of deposits on electron microscopy, whether they are organized (fibrils, microtubules, crystals) or nonorganized24 (Table 1).

The goal of treating patients with MGRS is to stop the natural progression of the kidney disease. The time from diagnosis to treatment is of vital importance as prolonging this time increases the likelihood of irreversible renal and systemic complications due to progression to tubulointerstitial fibrosis with development of end-stage kidney failure. Multiple studies show that a rapid decrease in serum FLC allows a high rate of renal recovery.4 The nephrologist has a central role in early diagnosis, since in most cases patients present with kidney failure without a known diagnosis of MG, with the findings on renal biopsy preceding the hematologic diagnosis. Thus, treatment from early stages has a great impact on the prognosis of renal and patient survival.11

It is important to emphasize that kidney transplantation in patients with MGRS without previous treatment may present a significant risk of renal allograft loss due to disease recurrence, since the mechanism of the lesion remains in full activity.25 For this reason, treatment should also be considered in those patients who are candidates to receive a kidney transplant, since in this case complete remission of the hematologic disease may prevent subsequent recurrence in the renal transplant.26

In 2013 the IKMG published a consensus document that includes treatment strategies for MGRS based on the underlying clone and the severity of the disease20,27,28 (Table 2).

The last ten years have seen a revolution in the treatment of MM, with the identification of CD38 and the signaling lymphocytic activation molecule family (SLAMF).29–31 These have enabled the introduction of various molecules whose mechanisms are based on proteasome inhibition, blockade of histone deacetylase (HDAC) and immunomodulation via the monoclonal antibodies daratumumab and elotuzumab, approved by the Food and Drug Agency (FDA) in 2015.30 The HDCA drugs panobinostat and rocilinostat (ACY-1215) are under experimentation. Daratumumab is a monoclonal antibody directed against CD38+ cells. Its use has been approved in combination in cases of refractory and/or recurrent disease, and also as first-line therapy in patients not eligible for transplant of hematopoietic progenitor cells. Elotuzumab is a monoclonal antibody directed against SLAMF7 and is used in combination with lenalidomide and dexamethasone in patients already treated with one or three drugs. Denosumab is another monoclonal antibody approved by the FDA to treat MM-associated bone loss.30,32,33 The era of immunotherapy for MM was opened up by the approval of these two drugs in 2015, with current clinical trials studying other promising molecules for the treatment of MM. When these can be incorporated there will be other new alternative therapies for MM (Fig. 8).

Fig. 8.

Treatment algorithm for MGRS. SCT (stem cell transplantation), immunomodulator (thalidomide, lenalidomide, pomalidomide), proteasome inhibitor (bortezomib, carfilzomib, ixazomib), monoclonal antibodies (daratumumab, elotuzumab).

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Follow-up of MGRS patients should be close both during treatment and afterwards. It must include clinical and laboratory controls, involving multidisciplinary assessment by hematologists and nephrologists to evaluate the treatment response, as well as any possible treatment-associated complications. The disease is often refractory or recurrent, requiring various lines of treatment (Fig. 9).

Fig. 9.

Follow-up algorithm for patients with MGRS.

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Monoclonal gammopathy of renal significance is a newly diagnosed entity that encompasses a broad spectrum of kidney diseases associated with MG. In an elevated number of cases, the presence of kidney failure and/or alterations in urinary sediment precede the hematologic diagnosis. In many cases, renal histological lesions condition the search for MG or other blood dyscrasia as the underlying cause of kidney failure.

Although MG does not initially require treatment from the tumor standpoint, when there is associated renal disease, treatment should be considered obligatory and early, with the appropriate therapeutic regimen based on the underlying clone and renal function.

The present study was supported in part by grants from the Instituto de Salud Carlos III co-funded by the Fondo Europeo de Desarrollo Regional – FEDER (RD16/0009/0006; grant ICI14/00016 and grant PI17/02043) from the Spanish Ministry of Economy and Competitiveness. These institutions had no part in the design of the study and collection, analysis, and interpretation of data or in writing the manuscript.

All the authors contributed to the manuscript. J.A.-T., MD, M.-E., V.L., M.L., G.M.-R., P.R.-E., D.H., wrote the manuscript, contributed to discussion and reviewed/edited the manuscript. All authors have read and approved the final version.

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

The authors declare no conflicts of interest.