Initial symptoms may be vague including loss of appetite and weight, bone pain, or symptoms related to renal failure. Laboratory workup may reveal abnormal kidney function or worsening chronic kidney disease (CKD), hypercalcemia and anemia. About 75% of patients present with anemia. Patients with light chain cast nephropathy have acute kidney injury (AKI) or worsening CKD and proteinuria. The proteinuria is predominantly monoclonal immunoglobulin known as Bence Jones protein (FLC in the urine). Patients with AL and MIDD can have systemic symptoms that include purpura, gastrointestinal bleeding, the involvement of the heart resulting in arrhythmias, or symptoms related to heart failure. The cardiac involvement is more common in AL. Typically hypertension is seen in patients with cast nephropathy and MIDD due to renal failure. Patients with AL can have hypotension due to the involvement of the autonomic nervous system and or cardiac system.[21][22][23] Fanconi syndrome can present with glucosuria in the absence of diabetes along with electrolyte derangements (including hyponatremia, hypokalemia, hypophosphatemia, type II or proximal renal tubular acidosis) due to the defective proximal tubule reabsorption. 

Diagnosing renal failure in a patient with plasma cell dyscrasias should be done carefully as the prognosis is very grim without treatment. CKD-EPI using cystatin C not only predicts the overall survival, but it can also diagnose more patients with renal failure in MM. Creatinine of more than 2 mg/dL is one of the criteria to diagnose renal failure secondary to MM along with hemoglobin of less than 10 g/dL, the serum calcium level of more than 12 mg/dL. Urine dipstick can be misleading as it detects only albumin and not the paraproteins. The urine needs to be tested with sulfosalicylic acid to detect abnormal myeloma proteins. Quantification of the 24-hour urine protein and creatinine would be abnormal due to the presence of paraproteins. Paraproteins should be suspected when the ratio of urine microalbumin over urine creatinine is low and the ratio of urine protein over urine creatinine is high. Serum-free light chains (SFLC), serum protein electrophoresis (SPEP), serum immunofixation (SIFE), urine electrophoresis (UPEP) and urine immunofixation (UIFE) are performed. SPEP lacks sensitivity as it cannot differentiate between monoclonal and polyclonal light chains, whereas SIFE has limited use in monitoring the progression or treatment response of myeloma light chains.[24]

Cast nephropathy typically presents with proteinuria in the absence of albuminuria, as the glomerular basement membrane (GBM) remains intact. Whereas, MIDD and light chain amyloid presents with proteinuria and albuminuria due to the involvement of the GBM.

The SFLC assay quantitates the concentration of circulating kappa and lambda (unbound) free light chains (FLCs). The normal serum-free kappa to lambda ratio is 0.26 to 1.65 in patients without kidney impairment. Patients with kidney impairment have high SFLC, and it can be as high as 3.1 in patients with severe kidney impairment. Elevated FLCs along with an abnormal kappa to lambda ratio indicates a monoclonal plasma cell disorder. The SFLC assay is more sensitive than the urine protein electrophoresis for detecting FLCs. It helps in diagnosing the new cases and also the relapse of the disease. Light chain cast nephropathy should be strongly suspected in any patient presenting with unexplained kidney injury over fewer than 6 months and an elevated FLC level of greater than or equal to 1500 mg/L.

Though kidney biopsy is the diagnostic test to confirm the association between a monoclonal protein and kidney disease, it can be deferred in the following situations:

• A presumptive diagnosis of the light chain cast nephropathy can be made, when MM presents with AKI or subacute kidney injury with an SFLC concentration greater than or equal to 1500 mg/L, the predominance of monoclonal light chains in the urine by urine protein electrophoresis and immunofixation.
• A presumptive diagnosis of renal amyloidosis can be made in patients with albuminuria or nephrotic syndrome with an established diagnosis of immunoglobulin light chain AL based on biopsies of non-kidney tissues.
• A presumptive diagnosis of light chain proximal tubulopathy can be made in patients with multiple myeloma or monoclonal gammopathy when they present with symptoms consistent with Fanconi syndrome (aminoaciduria, glycosuria in non-diabetics, hypophosphatemia, hypokalemia, hypouricemia, proteinuria).

Initial treatment should be focused on assessing the degree of renal impairment and correcting the hemodynamics, volume status, and electrolyte disturbances. The formation of casts and paraprotein concentration needs to be minimized as early as possible. Most of the patients have some degree of renal injury which recovers with the treatment of myeloma. 

Nephrotoxic agents including non-steroidal anti-inflammatory agents, renin-angiotensin inhibitors, intravenous contrast, and hypotension need to be avoided. Patients need to be adequately hydrated. Loop diuretics should be avoided, as they can precipitate the cast formation. Depending on the severity of renal impairment and the symptoms, hemodialysis is needed to correct acid-base balance, electrolyte disturbances, volume overload symptoms, and uremic symptoms.[1][25][26] Along with extended dialysis sessions, the use of the dialysis cartridge that can help in removing the light chains effectively has shown to improve the renal recovery.[27][28]

The concentration of the paraproteins can be decreased by the use of chemotherapy and plasma exchange or plasmapheresis. The molecular weight of the FLC is about 25-50 kDa. Evidence favoring the use of plasmapheresis is limited in cast nephropathy, due to a large volume of distribution of light chains resulting in a rapid rebound of light chains after the treatment.[29][30]. Each session removes < 10% of extracellular FLC. There is a clear indication of hyperviscosity syndrome due to IgM, IgA and IgG3 myeloma. It does not have any effect on the overall survival or need for hemodialysis. Leung et al have shown the efficacy of plasma exchange (PE) in biopsy-proven myeloma cast nephropathy and concluded that PE for FLC removal had a role in only biopsy-proven MCN who had a 50% reduction in sFLC levels from baseline.[30]

About 80% of the patients could have a recovery of renal function by 3 weeks if there is a reduction in the SFLC by at least 60%. This can be achieved by early diagnosis and prompt initiation of treatment. During treatment, labs need to be monitored carefully for any evidence of tumor lysis syndrome which is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. The most common treatment regimen of MM involves cyclophosphamide, bortezomib (velcade) and dexamethasone (CyBorD) or lenalidomide (revlimid), dexamethasone (Rd), revlimid, velcade, dexamethasone (RVD), velcade, thalidomide, dexamethasone (VTD). The most commonly used agent is bortezomib, and it has a rapid onset of action. It is not renally dosed, however, the dosing of lenalidomide needs to be adjusted based on the creatinine clearance.

Use of bisphosphonates to reduce the risk of skeletal events and hypercalcemia. The most commonly used agents are palmidronate and zoledronic acid. Caution, in the setting of renal failure. Palmidronic acid can cause focal segmental glomerulosclerosis (FSGS). In the setting of reduced GFR, denosumab is preferred over bisphosphonates.

The risk of contrast-induced nephropathy (CIN) in patients with plasma cell dyscrasia and chronic renal insufficiency can be assessed by beta-2-microglobulin levels. Levels less than 2.8 mg/L have a 100% negative predictive value.[31] The guideline recommends that the risk of CIN increases when the estimated glomerular filtration rate (eGFR) < 45 ml/min per 1.73 m2. A kidney transplant can be considered if the myeloma is in remission for at least 3 to 5 years. It can be associated with the recurrence of myeloma due to the use of immunosuppressive agents and Ig-mediated graft rejection. 

Intense pre-renal state depending upon the degree of hypercalcemia. 

Amyloidosis

Monoclonal gammopathy of renal significance (MGRS)

Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes (POEMS)

The prognosis depends mainly on the extent of kidney injury. Patients who have kidney dysfunction could have an average survival of about 20 months. Response to chemotherapy is the main predictor of survival outcomes. Patients who respond to chemotherapy have an average survival of 3 years.

kidney injury 

Tumor lysis syndrome 

Hypercalcemia

Hyperviscosity syndrome

Dialysis

Skeletal events including Fractures

Cord compression

Peripheral neuropathy

Hematology/ Oncology

Nephrology

• Kidney failure is a common complication of multiple myeloma. When initially diagnosed, about 20% to 40% of patients with multiple myeloma will have some amount of kidney failure. 
• It can affect different parts of the kidney, including the glomerulus, tubules, and the interstitium. 
• Serum free light chains (SFLC), serum electrophoresis, urine electrophoresis and immunofixation should be performed.
• Initial treatment should be focused on assessing the degree of renal impairment, correcting the hemodynamics, volume status and electrolyte disturbances. 
• The most commonly used chemotherapeutic agent is bortezomib, and it has a rapid onset of action.

Multiple Myeloma affects many organ systems and is best managed by an interprofessional team. Kidney involvement has been well documented in patients with plasma cell disorders. The light chains produced are filtered through the glomerulus and are endocytosed by the megalin receptors. Few of these light chains are resistant to degradation and tend to accumulate causing damage to the proximal tubules. It can also cause Fanconi syndrome by the formation of crystalline inclusions in the proximal tubules. It is important to get the nephrologist involved early in the course of the disorder as renal failure is a complication of multiple myeloma. Initial treatment should be focused on assessing the degree of renal impairment, correcting the hemodynamics, volume status and electrolyte disturbances.  The hematologist should be consulted on the overall management of the disorder. the prognosis for patients with renal involvement in multiple myeloma depends on the severity of renal dysfunction and other comorbidities. For those whose renal function is irreversibly damaged, dialysis is necessary. However, at this stage, life expectancy is significantly reduced. (Level II)