Monoclonal gammopathy and kidney disease

Rana, Ritika (2023). Monoclonal gammopathy and kidney disease. University of Birmingham. Ph.D.

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Abstract

Kidney disease associated with monoclonal gammopathy is increasingly recognized as a complex group of conditions associated with significant morbidity. Advances in treatments to suppress clonal disorders over the last two decades have resulted in significant improvement in survival in patients with multiple myeloma (MM) and subsequent changes to its natural history, including the impact on kidney disease. The work in this thesis evaluates the prevalence of kidney diseases at diagnosis of monoclonal gammopathy and how kidney function changes during the course of the disease. At presentation patients with monoclonal gammopathy may have renal impairment (RI) related to the monoclonal gammopathy, but also this generally elderly population have a high prevalence of RI, caused by unrelated pathogenesis such as hypertension and/or diabetes. I have characterized three main disease groups 1) MM 2) Monoclonal gammopathy of renal significance (MGRS) and 3) Monoclonal gammopathy of undetermined significance (MGUS).

The diagnostic pathway in MM is often delayed but simple measures can be effective in improving the time to diagnosis. An audit of 56 patients with newly diagnosed multiple myeloma (NDMM) and acute kidney injury (AKI) showed delays in diagnosis that indicated a need for direct communication of high free light chain (FLC) results to the haematology team, and this was shown to halve the time to anti-myeloma therapy in the next 19 patients.

Kidney disease in MM is common, 39% of the 4158 patients had an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 at presentation. Novel and intensive therapies have dramatically improved survival in myeloma, however, the impact on renal outcomes is not well defined. At 12 months, 62% (1450/2334) of the NDMM patients have unchanged kidney function and overall renal outcomes are reassuring. In the 38% showing a >25% change in eGFR from baseline; this comprised 22% (502/2334) patients who had an improvement and 16% (382/2334) who had a decline in eGFR at 12 months. Improved renal function was more likely if patients were <70 years old, male, had an average eGFR <60 ml per minute per 1.73m2, a higher baseline FLC level >1000 mg/L, and/or a FLC response of >90% whilst M-protein response did not correlate with renal improvement. Despite improved survival with new therapies patients with an eGFR ≥30 ml/min still survive longer compared to those with eGFR <30 ml/min.

Albuminuria is a powerful adverse determinant of outcomes in kidney disease but there are limited data on patients with MM. Patients who at 12 months had an improvement in eGFR or a decline in eGFR compared to baseline, were matched with those who had no change in eGFR. The two groups comprised (i) improvement matched with no change (184 pairs) and (ii) decline matched with no change (123 pairs). These groups were matched for age, sex, baseline difference between the involved and the uninvolved FLC (dFLC) and 12-month dFLC response.

At presentation 305 patients (58%) had albuminuria (albumin creatinine ratio (ACR) >3 mg/mmol). In 15 patients (3%) this approximated to ≥1 gram/24 hours (ACR ≥70 mg/mmol). Albuminuria at baseline was not independently associated with a lower eGFR category at 12 months. At 12 months, 162 patients (30%) had albuminuria.

Patients with unexplained RI, atypical clinical course, risk factors for MGRS or those on the renal transplant waiting list with unknown primary renal disease should be evaluated for MGRS. Clone specific chemotherapy is required to target the underlying clone, and this may improve graft survival; however, this can be challenging as many patients are elderly with age related comorbidities and may have complications associated with increasing immunosuppression. Albuminuria in myeloma is not associated with a decline in kidney function at 12 months; however, it is of critical importance in MGUS cohorts to identify undiagnosed MGRS lesions.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):