Dimethyl sulphoxide does not contribute to renal failure in patients undergoing stem cell transplant for multiple myeloma and primary amyloidosis

Dear Editor,

Renal failure, whether acute or chronic, occurs in almost 20% of patients with multiple myeloma and primary amyloidosis¹. It is due to the deposition of immunoglobulin in renal tubules, infections, and toxicity of drugs such as aminoglycosides, amphotericin B and dimethyl sulphoxide (DMSO), the cryopreservant for stem cells². A few transplant centres wash their products to decrease DMSO toxicity, but the disadvantages of this washing are quite important, ranging from loss of cells during the washing process to risk of contamination. Since our human cell therapy laboratory does not wash stem cell products, we decided to review the main complications of DMSO involving the kidneys.

We reviewed the medical records of patients diagnosed with multiple myeloma and primary amyloidosis from 2001 until the end of 2005. Patients were classified into three categories: (i) patients with multiple myeloma with IgG, (ii) patients with multiple myeloma with non-IgG, and (iii) patients with primary amyloidosis. We collected data on age at first stem cell transplant, gender, number of transplants, type of disease, the type and dose of conditioning chemotherapy, the main antibiotics (vancomycin, and amphotericin B) that were administered in the 2 weeks prior to and 2 weeks after the transplant and might have caused renal failure, and the volume and number of CD34 stem cells infused. The quantity of DMSO used was calculated from the volume and number of CD34 stem cells, since all the stem cells in bags are preserved in 10% solution. The effect on renal function was assessed through data on creatinine level and creatinine clearance (CCr) 14 days before the transplant, the day of the transplant, and 3 and 28 days after the transplant.

Renal function was divided into five categories according to the CCr: normal function (≥90 mL/min), mild renal failure (60 to 89 mL/min), moderate renal failure (30 to 59 mL/min), severe renal failure (15 to 29 mL/min), and very severe renal failure (<15 mL/min). Significant acute renal failure was determined in two ways: as an increase of creatinine of 0.5 mg/dL over a period of 3 days and as CCr categories at 3 days post-transfusion. Significant chronic renal failure was also determined in two ways: as an increase of 0.5 mg/dL of creatinine over 1 month and as CCr categories at 1 month post-transfusion. The relationships of renal failure with gender and disease were assessed using χ² and Fisher’s exact tests, as appropriate. The relationships between baseline renal failure and both acute and chronic renal failure were assessed using McNemar’s test to adjust for the dependence of these variables.

Six hundred and forty-five patients were included in the study: 380 males (59%) and 265 females (41%). One hundred and forty-five patients did not have electronic documentation about the use of potential nephrotoxic medications. Of the 500 patients with electronic documentation of potential nephrotoxic medications, 384 (76.8%) had received vancomycin, 7 (1.4%) had been given an aminoglycoside and 8 (1.6%) had been prescribed amphotericin B. The dose of melphalan ranged from 0 mg/m² up to 200 mg/m²; however 525 (82%) received the usual dose of 100 mg/m²/day.

At baseline, renal failure (creatinine >1.4 mg/dL for males and 1.2 mg/dL for females) was seen in 117 (18%) patients; of these 67 (57%) were males and 50 (43%) females (p=0.68). Of the 645 patients included in this study, 32 (5%) did not have baseline creatinine measured (2 weeks prior to transplant), 35 (5%) did not have creatinine measured at 3 days, and 47 (7%) did not have creatinine measured at 1 month. The median creatinine at 14 days prior to transplant (baseline) was 1.0 (range, 0.6–9.8) mg/dL.

Of the 493 patients with normal values at baseline and for whom creatinine measurements were available at day 3 post-operatively, 485 (98.4%) patients maintained their normal creatinine values at day 3 and eight patients (1.6%) developed acute renal failure within 3 days of their transplant. Of the 117 patients who already had renal failure at baseline, 104 (88.9%) improved while the other 13 patients (11.1%) remained in renal failure (p<0.0001).

Of the 488 patients with normal values at baseline and for whom creatinine measurements were available at 1 month, 466 (95.5%) maintained their normal values after 1 month, while 22 (4.5%) had developed chronic renal failure. One month data were available for 110 of the 117 patients with renal failure at baseline: renal status improved from baseline in 98 (89.1%) patients while 12 (10.9%) remained in chronic renal failure (p<0.0001).

Baseline CCr was measured 2 weeks prior to transplantation: 417 (68%) patients had a normal CCr, 52 (8%) patients had mild renal failure (CCr between 60 and 69 mL/min), 122 (20%) had moderate renal failure, 13 (2%) had severe renal failure, and 9 (1%) patients had very severe renal failure. The median CCr at baseline was 83.96 mL/min (range, 5.34 to 291.67 mL/min). Of the 414 (67.9%) patients with a normal baseline CCr and day 3 CCr values available, 393 (94.9%) remained with normal CCr values until 3 days post-transplant. Among the nine patients with very severe baseline renal damage according to CCr values, renal function improved slightly in four (44.4%) patients by 3 days post-transplant. The complete distribution of baseline and acute renal function as measured by CCr was only moderately changed after 3 days (p=0.06). Even after 1 month, 381 (92.7%) of patients with a normal baseline CCr for whom 1-month CCr values were available still had normal CCr levels. Of those presenting with very severe renal failure as measured by CCr, six (66.7%) had improved slightly. According to CCr values, there was a significant change in renal function from baseline to 1 month post-transplant (p<0.0001) with more patients having an improvement in function than a decline.

Another important factor that might cause renal failure is the administration of a large dose of DMSO (a large dose being defined by more than 1 mg/Kg of body weight). We compared those patients who received a usual dose (<1mg/Kg body weight) with those who received a larger dose. There was no statistical difference between the two groups (p=1).

We concluded that the renal damage due to DMSO is minimal. The large volume of stem cells and hydration following the transplant helps to decrease the side effects of DMSO, which might lower the Cr levels by dilution to some extent too. It should also be noted acute deterioration of renal function necessitating hemodialysis did not occure.

Since the improvement of renal function was most marked in the first 3 days and since more chronic than acute renal damage was observed, we suggest that DMSO is not really involved in renal damage, which is more likely to be caused by progression of the original disease, complications or side effects of medications such as antibiotics and chemotherapeutic regimens.