Ann Ibd. Pg. Med 2012. Vol.10, No.2 28-33
RENAL STATUS OF MULTIPLE MYELOMA PATIENTS IN IBADAN, NIGERIA
F.A Fasola1, K.I.I Eteng1, W.A Shokunbi1, J.O Akinyemi2 and B.L Salako3
1. Departments of Haematology, University College Hospital, Ibadan
2. Departments of Epidemiology and Medical Statistics, University College Hospital, Ibadan
3. Departments of Medicine, University College Hospital, Ibadan
Correspondence
Dr. F.A. Fasola
Department of Haematology,
University College Hospital,
Ibadan, Nigeria
E-mail: folukefasola@yahoo.com
ABSTRACT
Introduction: The spectrum of clinical manifestation in multiple
myeloma (MM) ranges from asymptomatic disease to severely
debilitative state. Unexplained renal disease is an indication for the
investigation of patients for MM. This study is a retrospective
analysis of the renal profile of patients with multiple myeloma in
relation to management strategy in our institution.
Methods: Medical records of 64 patients with multiple myeloma
seen between 2000 and 2008 were retrospectively reviewed at an
850–bed tertiary hospital in South-Western Nigeria. The MahnWhitney test was used to compare laboratory features between
patient with renal failure and those without renal failure. Subjects
with serum creatinine >2mg/dL were regarded to have renal failure.
Overall survival was calculated from diagnosis to death or lost to
follow-up
Results: A total of forty three patients were eligible. The renal status
was categorized into three according to serum creatinine level; those
with normal serum creatinine level (0.5-1.5mg/dl) were 26 (60.5%),
serum creatinine level (>1.6-1.9mg/dl), and creatinine level >2mg/
dl were 3(7%) and 14(32.5%) respectively. Hyperuricaemia was
observed in 6(42.9%) of MM patients with renal failure compared
with 7(26.9%) of patient without renal failure (p<0.05). Twenty–
one percent of those with renal failure had hypercalceamia. Thirty–
six percent of the renal failure patients had haemodialysis. The
average survival for all patients with renal failure was 18 months
after diagnosis.
Conclusion: The outcome in patients with renal failure remained
poor with early mortality despite supportive management.
Hyperuricaemia and dehydration, given the hot climate might have
worked in concert with other factors to worsen the renal status in
these patients.
Keywords: renal, creatinine, myeloma, dehydration
INTRODUCTION
Multiple Myeloma (MM) is a malignant clonal
proliferation of plasma cells, which are terminally
differentiated B–cell. It is invariably accompanied by
production of monoclonal (M) protein. The diagnosis
is hinged on bone marrow plasmacytosis >10% or
histological confirmation of plasmacytoma, a
monoclonal protein in the serum and/or urine (except
in non-secretory myeloma) and bone disease. Spectrum
of clinical manifestation ranges from asymptomatic
disease to severely debilitative state. The tumor, its
product and the host response to it result in a number
of clinical features including organ dysfunction. Clinical
features are heterogeneous and include renal failure,
increased susceptibility to infection, anaemia,
hypercalcaemia, occasionally neurological symptoms,
vascular manifestation of hyperviscosity and clotting
abnormality. The incidence of myeloma increases with
advancing age. It is commonest among blacks 1, it
accounts for 0.5% of all malignancies and 5.7% of
haematological disorders in our hospital2.
Kidney involvement is seen in up to 50% of cases 3,
and can be identified at presentation or during the
course of the disease. Unexplained renal disease is an
indication for the investigation of multiple myeloma.
The pathology is heterogeneous with a variety of
Annals of Ibadan Postgraduate Medicine. Vol. 10 No. 2 December, 2012
28
pathogenetic mechanisms3, many factors contribute to
this renal lesion, most frequent being deposition of
monoclonal immunoglobulins or fragments with cast
nephropathy3,4. Tubular damage associated with the
excretion of light chains is almost always present4. Renal
status of MM patients is an important prognostic
determinant, and this forms the basis for subdivision
of Durie-Salmon staging into A and B. Thus the
approach to management is often modified by the
patient’s renal status.
This aim of this study was to assess the renal profile
of patients with multiple myeloma in relation to current
management strategies in our institution.
MATERIALS AND METHOD
Medical records were retrospectively reviewed for all
patients diagnosed as multiple myeloma in the
Haematology department of a tertiary hospital in
South-Western Nigeria between 2000 and 2008.
Multiple myeloma was defined by at least 2 of the
following-bone marrow with clonal plasma cells of at
least 10% or histologic confir mation of a
plasmacytoma; a monoclonal protein in the serum or
urine (unless the patient has a nonsecretory myeloma);
and end-organdamage evidenced by renal insufficiency,
hypercalcemia, anemia, or lytic bone lesions
(International Myeloma Working Group, 2003,
Rajkumar & Kyle, 2005).
Forty three patients who met the diagnostic criteria
and had complete data with regard to availability of
serum creatinine, urea and electrolytes were included
in the study. The presenting features and significant
co-morbidity were recorded. All patients included in
this study had bone marrow plasmacytosis greater than
30%. Clinical staging was determined according to the
Parameter
Durie -Salmon system. Drug regimen, supportive care
and outcome were recorded.
Renal status was categorized into normal, renal
insufficiency and renal failure using results of serum
creatinine. Normal renal status was defined by the
hospital laboratory reference value of serum creatinine
level between 0.5 and 1.5mg/dl. Renal insufficiency
was defined as a serum creatinine level of 1.6–1.9 mg/
dl while renal failure was defined as serum creatinine
>2 mg/dl. In all the patients, diagnosis of renal disease
was made at the time of investigating patient for MM.
In line with the International Prognostic Index (IPI)
hypoalbuminaemia was defined as serum albumin
<3.5mg/l
A corrected calcium concentration = Serum calcium
concentration + 0.02 (40 – serum albumin
concentration) was calculated for each patient.
Statistical Analysis
The Kruskal Walliis test was used to compare the
biochemical parameters of MM patients with renal
failure and those without. The survival time was
calculated as number of months from diagnosis to
death or date of last follow-up. Survival rates were
estimated using the Kaplan – Meier method while the
long rank test was used to compare the survival rate
between the two categories of MM patients (with and
without renal failure). P-values less than 0.05 were
considered statistically significant.
RESULTS
A total of forty-three patients consisting of 26(60.5%)
males and 17(39.5%) females were studied. Their age
ranged from 36 to 85 years with a median of 65 years.
The urea level at presentation ranged from 10 to 390
Mean (SD)
p-value
Normal Renal
Status
9.06 (2.26)
10.16 (0.95)
Renal
insufficiency
11.10 (2.75)
11.53 (1.09)
Renal failure
9.16 (2.10)
10.16 (2.15)
0.482
0.136
5.07 (3.29)
9.18 (8.28)
5.95 (6.06)
0.675
PCV (%)
25.64 (6.32)
17.5 (6.36)
21.08 (7.50)
0.088
WBC(/mm3)
5027.78 (1924.39)
6300
5322.22(2976.48)
0.757
ESR(hr-1)
Platelet(/mm3)
92.11 (36.41)
215788.9 (124176.8)
5.93 (2.24)
1.32 (0.95)
34.58 (18.11)
107.46 (40.35)
1597333.3
(108657.2)
5.90 (1.59)
1.23 (1.01)
137.92 (85.43)
0.355
0.301
Globulin(g/l)
Albumin(g/l)
Urea(mg/dl)
118.33 (22.55)
120000
(113137.08)
8.70 (3.18)
2.00
98.00 (33.29)
Total protein(g/l)
Corrected calcium
(mg/dl)
Uric acid(mg/dl)
0.224
0.227
0.000*
Table 1: Laboratory features of MM Patients according to renal status
Annals of Ibadan Postgraduate Medicine. Vol. 10 No. 2 December, 2012
29
Characteristic
Osteolytic lesions
Renal failure,
N=14
n(%)
11(78.6)
Without renal failure
N=26
n(%)
20(76.9)
Hypercalcaemia
5 (35.7)
3 (11.5)
Hyperuricaemia
6 (42.9)
7(26.9)
Bence Jones Protein 5(35.7)
9(34.6)
Hypoalbuminaemia
16(61.5)
11(78.6)
N = number of patients
Table 2: characteristics of MM patients with renal
failure and without renal failure
mg/dl with a median value of 49mg/dl while
creatinine had a range of 0.3 to 19.7 with a median of
1.5. Renal failure was observed in 14 patients (32.6%),
3 (7.0%) had renal insufficiency while 26(60.5%) had
normal renal status.
protein and globulin, corrected serum calcium, uric
acid, white blood cell count, erythrocyte sedimentation
rate (ESR) tend to be higher in patients with renal
insufficiency while the packed cell volume(PCV) and
platelet were lower. According to Durie-Salmon
staging, 13(92.8%) were stage 111. Figure 1 shows the
frequency of renal failure among the patients. Younger
patients were more likely than older adult to have renal
failure. Bence Jones Protein was positive in the urine
of 5(35.7%) patients with renal failure. Of the patients
with renal failure, 4(28.6%) had Ig (immunoglobulin)
G myeloma while 2(14.2%) had IgA and non–
secretory myeloma respectively. The number of
patients with radiological evidence of osteolytic lesion
and other complications of the disease are as shown
in Table 2. All patients received supportive treatment
with hydration and blood transfusion as needed. The
patients with abnormal blood urea level were not given
biphosphonate. The chemotherapeutic regimen
Treatments
Responders (%)
non responders(%)
Number of Patients (%)
M+P
2 (33.3)
2 (25)
4
VAD
1 (16.7)
3(37.5)
4
VAD/M+P
3 (50)
1(12.5)
4
No treatment
0 (0)
2 (25)
2
Total
6 (100)
8 (100)
14
Table 3: Treatment response of patients with renal failure
Table 1 shows the mean laboratory features of the
MM patients with renal failure and those without. Urea
was significantly elevated in patients with renal failure
(p<0.05). Mean serum creatinine for patients with renal
failure was 7.41mg/dl. The values for total serum
administered were melphalan and prednisolone (M +
P), Vincristine, Adriamycin and Dexamethasone (VAD)
and a hybrid of VAD/M+P. The hybrid combination
was received by patients who did not have an initial
favourable response to VAD. The response of patients
Figure 1: Distribution of MM patients with according to age group and renal status
Annals of Ibadan Postgraduate Medicine. Vol. 10 No. 2 December, 2012
30
Figure 2: Survival curve for MM patients not in renal failure versus those in renal failure
to chemotherapeutic regimen is as shown in Table 3.
The patients who did not receive chemotherapy died
before commencement of either cytotoxic or
haemodialysis. Renal function test of 6 (35.2%) patients
were corrected with administration of cytotoxic drugs,
allopurinol and hydration. The remaining patients had
varying degrees of partial recovery. Of the 14 patients
with renal failure, 5(35.7%) had haemodialysis. Three
(3) of the 5 patients who had haemodialysis died within
3 months of diagnosis and treatment.
The average survival time for all patients irrespective
of renal status was 56 months after diagnosis. The
survival curve for patients with renal failure compared
to normal is shown in Figure 2. Patients with renal
failure were more likely to have shorter survival rates.
The cumulative survival at 3 and 15 months for patients
with normal renal status was, 86.4%and 62.9%,
respectively while it was 73.3% and 57% respectively
for patients with renal failure (p>0.05).
DISCUSSION
Renal disease is one of the major complications of
MM particularly in the advanced stage with prognostic
significance. Different criteria have been used to define
renal insufficiency in patients. The incidence of renal
insufficiency in our patients is comparable to published
data using serum creatinine of 1.3mg/dl as cut off,
but slightly higher proportion of patients are observed
to have renal failure5-7. Some studies with similar or
higher percentage of renal insufficiency attributed it
to advanced disease6,8. The different criteria used to
define renal failure and presence of other co-morbidity
may be responsible for the different figures obtained.
The spectrum of renal lesion observed in MM is quite
wide and varied ranging from acute to chronic and
tubular to lesion in the nephron4. More than one type
of renal disease may be present in a single patient with
several factors working together to provoke this
complication. Acute renal failure accounts for 50% of
it, Often this may be precipitated by dehydration,
hypercalcaemia, infection, non steroidal antiinflammatory drugs and radiological contrast4.
The frequency of hypercalcemia was similar to findings
in some other studies 8,9. The presence of hypocalcaemia often associated with renal failure may be
responsible for an almost similar average value for
calcium level in both circumstances. Chronic renal
disease should be considered in patients with
hypocalcaemia with the possibility of the initial cause
being unrelated to multiple myeloma .The biochemical
abnormality of multiple myeloma might had worsen
the renal status. Reversibility of renal failure obtained
in 35.2% of renal failure patients in this study is lower
than 50% documented for other studies8,9. Correction
of hypercalcemia has been linked to reversibility in
those studies. The severity of renal damage may be
responsible for the lower number of patients with
reversible renal failure in the current study.
Annals of Ibadan Postgraduate Medicine. Vol. 10 No. 2 December, 2012
31
There are studies that demonstrated that recovery of
renal function was also associated with the severity of
renal failure and degree of proteinuria6,8,10. The higher
white cell count in patients with renal failure may
suggest the presence of infection. Dehydration
occasioned by hot weather that is peculiar to the tropics
might have contributed to the degree of renal failure
in these patients.
The high tumour burden (stage III) observed in 93%
of our patients with renal failure may suggest the
presence of cast nephropathy. Cast nephropathy has
been identified to be an important underlying factor
in patients with high tumour burden11. In some renal
biopsy studies of patients with myeloma and renal
disease, 40 - 63% had cast nephropathy, 19 - 26% had
light-chaindeposition disease, 7 - 30% had amyloidosis,
and <1% had cryoglobulinemic renal disease 12,13.
Though renal biopsy results were not available for our
set of patients, the presence of Bence Jones protein
and amyloid deposition could not be completely ruled
out considering the insensitivity of the heat method
of BJP detection used in diagnosis. The role of cast
nephropathy has been reported particularly when the
creatinine is >7mg/dl11, however, it might be difficult
to ascertain its degree of contribution in this study.
These patients could benefit from plasmapharesis 14,15.
The lower haematocrit observed in patients with renal
failure has also been linked with cast nephropathy4.
There is no doubt that the precipitating factor for renal
failure in the patients is multifactorial, however, the
incidence of hyperuricaemia is higher in the patients
with renal failure compared to those without renal
failure (43% vs. 27%) but the mean uric acid level
showed that there was no difference, but when both
groups were compared with renal insufficiency group
hyperuricemia was significantly evident in the
insufficiency group. Although the reason for this is not
clear, it may be due to the fact that subjects in the renal
failure group often present acutely requiring hydration
and sometimes emergency dialysis which obviously
would have affected their serum uric acid levels since
blood sample might have been collected during
resuscitation. High tumour burden is an established
cause of hyperuricaemia. It is well known that
rehydration, correction of hyperuricaemia and
hypercalcaemia or discontinuation of nephrotoxic
drugs often improve renal function. The higher
percentage of patients with renal dysfunction in the
younger age group was unexpected and contrary to
the observation in other studies. Advancing age with
median age of 58 years in developed countries has
been associated with renal dysfunction5,16. The younger
patients in this study had higher incidence of
hyperuricaemia and therefore more severe disease.
Haemodialysis provide a survival benefit for patients
with end stage renal failure with 25% becoming
independent of dialysis17,18. The average time for those
patients who had haemodialysis could not be
determined due to insufficient follow up information.
The patients with renal failure had poorer survival than
those with normal renal function. The average time
for those who recover renal function on cytotoxic drug
and supportive treatment was 4 weeks. Co-morbidity
may be responsible for early demise (<3 months) in
some MM patients with renal failure. Thus
individualized treatment is a veritable option to
improve outcome. Newer approaches to management
include allogeneic bone marrow transplantation and
kidney transplant 8. This may be particularly more
important in the younger age group having renal failure.
However, this modality of management maybe
considered farfetched in a financially constrained
economy.
The patients’ response to chemotherapy were not
encouraging though melphalan and prednisolone at
conventional dose was observed to be more effective
in our patients than VAD, this was probably the reason
for switching from VAD to M+P. This is contrary to
previous documentation about VAD being more
effective in patients with renal failure than the alkylating
agents. Although a meta-analysis of 6633 patients
found no difference between MP and various multiple
combination chemotherapy regimen and survival19,20.
The poor outcome with early mortality seen in this
and other reports9,18 could be improved upon with
the use of plasmapharesis and bortezomib based
regimen particularly in patients with poor response to
routine supportive therapy21. There is a need to evolve
treatment strategies that would produce better
outcome.
CONCLUSION
This study confirms the findings in previous reports
that, the factors contributing to renal failure in the
myeloma patients are multifactorial. We suggest high
index of suspicion among clinicians to aid early referral.
Newer treatment strategies should be employed in
those with renal failure.
REFERENCES
1. Benjamin M, Reddy S, Brawley OW. Myeloma
and race: a review of literature. Cancer Metastasis
Rev 2000; 221, 87-93,
2. Fasola FA, Shokunbi WA, Salimonu LS,
Paraproteinemia in Nigerian patients with multiple
myeloma Proceeding of the XVII meeting
Internation Society of Haematology (European
and African division) Graz (Austria) 2003.
Annals of Ibadan Postgraduate Medicine. Vol. 10 No. 2 December, 2012
32
3. Haubitz M, Peest D, Editorial review: Myeloma–
new approaches to combined nephrologicalhaematological management. Nephrology Dialysis
Transplantation 2006;21(3); 582-590,.
4. Korbet SM, Schwartz MM, Multiple Myeloma J
Am Soc Nephrol 2006.;17: 2533-2545,
5. Knudsen LM, Hippe E, Hjorth M, Holmberg
E, Westin J: Renal function in newly diagnosed
multiple myeloma: A demographic study of 1353
patients. The Nordic Myeloma Study Group. Eur
J Haematol 1994;53 (4): 207–212,
6. Knudsen LM, Hjorth M, Hippe E: Renal failure
in multiple myeloma: Reversibility and impact on
the prognosis. Nordic Myeloma Study Group. Eur
J Haematol 2000; 65: 175–181
7. Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy
MQ, Dispenzieri A, Review of 1027 patients with
newly diagnosed multiple myeloma. Mayo Clin
Proc 2003;78 : 21–33,
8. Bladé J, Fernández-Llama P; Bosch f; Montolíu
F, M. Lens X; Montoto S; Renal Failure in Multiple
Myeloma: Presenting Features and Predictors of
Outcome in 94 Patients From a Single Institution,
Arch Intern Med. 1998;158:1889-1893
9. Alexanian R, Barlogie B, Dixon D. Renal failure
in multiple myeloma: pathogenesis and prognostic
implications. Arch Intern Med. 1990; 150:16931695.
10. Bernstein SP, Humes HD. Reversible renal
insufficiency in multiple myeloma. Arch Intern
Med. 1982;142: 2083-2086
11. Winearls G, Acute myeloma kidney .Kidney
Int.1995;48:1347-1361
12. Ganeval D, Rabian C, Guerin V, Pertuiset P,
Landias P, Jungers P: Treatment of multiple
myeloma with renal involvement. Adv Nephrol
1992;21: 347–370,
13. Montseny JJ, Kleinknecht D, Meyrier A, Vanhille
P, Simon P, Pruna A, Eladari D: Long-term
outcome according to renal histological lesions in
118 patients with monoclonal gammopathies.
Nephrol Dial Transplant 13: 1438–1445, 1998
14. El-Achkar TM, Sharfuddin AA, Dominguez J:
Approach to acute renal failure with multiple
myeloma: Role of plasmapheresis. Ther Apher
Dial 9 : 417–422, 2005
15. Gupta D, Bachegowda L, Phadke G, Boren S,
Johnson D, Misra M Role of plasmapharesis in
the management of myeloma kidney : A systemic
review .Haemodial Int 2010;14(4) :355 -363 ,
16. Ludwig H, Durie BG, Bolejack V, Turesson I,
Kyle RA, Blade J, Myeloma in patients younger
than 50 years presents with more favourable
features and shows better survival :an analysis of
10549 patients from the International Myeloma
Working Group. Blood , 2008;111 (8) :4039-47
17. Johnson WJ, Kyle RA, Pineda AA, O Brien PC,
Holley KE. Treatment of Renal Failure associated
with multiple myeloma. Plasmapheresis,
Hemodialysis, and Chemotherapy.Arch Intern
Med 1990; April;150(4):863-9
18. Hutchison CA. Bradwell AR, Cook M, Basnayake
K, Basu S, Harding S, Hattersley J, Evans ND,
Mike J. Chappel MJ, Sampson P, Foggensteiner
L, Adu D, and Cockwell P Treatment of Acute
Renal Failure Secondary to Multiple Myeloma with
Chemotherapy and Extended High Cut-Off
Hemodialysis. Clin J Am Soc Nephrol 2009; 4(4)
745-754,
19. Myeloma Trialist’ Collaborative Group.
Combination chemotherapy versus melphalan plu
prednisolone as treatment for multiple myeloma:
an overview of 6633 patients from 27 randomised
trials .J Clin Oncol, 1998;16 ;3832-3842,
20. Blade J. Fernandes-Llama P, Bosch F et al Renal
failure in multiple myeloma Arch Intern Med
1998;158;1889-1893 ,
21. Dimopoulos MA, Roussou M, Gavriatopoulou
M, Zagouri F, Migkou M, Matsouka C,.
Reversibility of Renal Impairment in Patients with
Multiple myeloma treated with Bortezomib-based
Regimens: identification of predictive factors. Clin
lymphoma myeloma 2009; Aug; 9(4):302-6.
Annals of Ibadan Postgraduate Medicine. Vol. 10 No. 2 December, 2012
View publication stats
33