SDMA seems to increase before

SDMA seems to increase before the urine SG is reduced and way before changes in urea and creatinine. As the the SDMA is elevated, early renal disease is highly likley although reduced renal perfusion from dehydration is also possible. Is there polyuria? 

Lymphoma and Symmetric

Lymphoma and Symmetric Dimethylarginine Concentration in Dogs: A Preliminary Study

Anthony Abrams‐Ogg1, Bronwyn Rutland2, Phillippe Levis2, Vicky Sabine3, Allison Majeed3, Dorothee Bienzle4, Alex Zur Linden3, Danielle Richardson5, Anthony Mutsaers6, Paul Woods3

1University of Guelph, Guelph, ON, Canada, 2VCA Canada 404 Veterinary Emergency and Referral Hospital, Newmarket, ON, Canada, 3Department of Clinical Studies, Ontario Veterinary College, Guelph, ON, Canada, 4Department of Pathobiology, University of Guelph, Guelph, ON, Canada, 5Animal Cancer Centre, Ontario Veterinary College, Guelph, ON, Canada, 6Department of Biomedical Sciences, Ontario Veterinary College, Guelph, ON, Canada

Symmetric dimethylarginine (SDMA) is a product of arginine metabolism that is cleared by the kidney. It is considered a more sensitive and specific biomarker than serum creatinine for the diagnosis and staging of chronic kidney disease in dogs. It is possible that serum SDMA levels may be increased in animals with malignancies because of increased protein metabolism. We observed that some dogs with untreated lymphoma appeared to have disproportionately increased serum SDMA levels compared to other biomarkers of kidney function, and that SDMA levels normalized when the dogs achieved remission. A previous study in humans reported that asymmetric dimethylarginine, but not SDMA levels, may be increased with hematologic malignancies, including non‐Hodgkin’s lymphoma (Szuba et al. Leuk Lymphoma 2008;49:2316–2020). A preliminary study in dogs reported that SDMA levels may be increased in tumor‐bearing dogs with normal creatinine levels, which was attributed to kidney disease or neoplastic infiltration (Yerramilli et al. J Vet Intern Med 2017;31:251), but changes in SDMA levels after treatment were not reported. Therefore, the purpose of this study was to retrospectively and prospectively investigate the effect of lymphoma on SDMA levels in dogs. Cases were retrospectively identified in autumn 2016. Prospective case enrollment began December 1, 2016.

Inclusion criteria were: (1) cytologic ± histologic diagnosis of lymphoma by a pathologist; (2) measurement of serum SDMA level at any stage of disease; (3) routine abdominal ultrasound examination for cases prospectively studied, to identify evidence of renal lymphoma; (4) informed owner consent. Dogs with indolent lymphomas were not included. All treated cases initially received the 25‐week Madison Wisconsin CHOP combination chemotherapy protocol using prednisone, vincristine, cyclophosphamide and doxorubicin. Complete remission (CR) was defined as resolution of lymphadenopathy ± previous imaging abnormalities attributed to lymphoma. Clinicians assessing remission status were not aware of SDMA levels. Cases include: (1) Dogs with a diagnosis of lymphoma and measurement of SDMA but no further assessment or treatment; (2) Dogs currently receiving CHOP in CR or partial remission (PR); (3) Dogs currently in CR after completing CHOP; (4) Dogs in relapse receiving rescue therapy; and (5) Dogs euthanized after relapse. Groups 2–5 include dogs with or without pre‐treatment measurement of SDMA. Creatinine was measured on a cobas® analyzer (Roche Diagnostics). Samples for SDMA measurement were submitted to IDEXX Laboratories, Inc., Markham, Ontario, Canada. Data were summarized with descriptive statistics. Differences between means were analyzed by t‐tests and paired t‐tests. Differences between medians were analyzed by Wilcoxon rank‐sum and signed‐rank tests. Correlations were examined by Spearman Rank method.

Fifty‐two dogs are included to date with mean, median and age range of 8, 7 and 3–13 years, respectively. Fifty dogs had WHO Stage III‐V multicentric nodal lymphoma, one dog had primary mediastinal lymphoma, and one dog had primary bilateral renal lymphoma with sternal lymphadenopathy. No dog had clinical or clinicopathologic signs of pre‐existing chronic kidney disease when diagnosed with lymphoma. Results for serum SDMA and creatinine levels are shown in Table 1.

Comparing all dogs with untreated lymphoma and all dogs with CR ranging from 1 week to > 2 years, differences between mean and median SDMA levels and mean and median SDMA:Creatinine were significant (P < 0.001), while differences between mean and median creatinine levels were not significant. Overall correlation between SDMA and creatinine was moderate (rho = 0.29, P = 0.04). In the one case where SDMA was measured twice prior to treatment, SDMA increased from 18 to 22 ug/dL over 37 days, while creatinine remained stable at 76–78 µmol/L (SDMA:Creatinine increased from 0.24 to 0.28).

Fourteen dogs had serial SDMA and creatinine measurements beginning before treatment and then after achieving CR. Eleven of these 14 dogs (79%) had elevated SDMA before treatment, of which 3 of these 11 dogs (which included the dog with primary renal lymphoma) also had elevated creatinine. All 11 dogs with increased SDMA at diagnosis had normal SDMA levels in CR, and differences in the means and medians from baseline were significant (P < 0.05). Ten of the 11 dogs also had normal creatinine levels when in CR. For the 2 dogs that did not have primary renal lymphoma but had increased pre‐treatment creatinine levels, in one dog normalization of SDMA from 15 to 10 ug/dL may have been due to correction of pre‐renal azotemia, as creatinine decreased from 149 to 109 umol/L, and SDMA:Creatinine decreased from 0.10 to 0.09. However, in the other dog, the decrease in SDMA from 90 ug/dL to 12 ug/dL was disproportionately large compared to the decrease in creatinine from 227 mmol/L to 166 mmol/L, with SDMA:Creatinine decreasing from 0.47 to 0.07.

Five dogs had lymphoma in relapse. Results in these dogs were similar to those with untreated lymphoma, while results for dogs in PR were in between those of dogs with untreated lymphoma/lymphoma in relapse, and dogs in CR.

No relationships between SDMA level and signalment were identified. Nineteen (38%) dogs had immunophenotyping. Differences in SDMA levels between dogs with B‐cell and T‐cell lymphomas were not significant.

Twenty‐nine (56%) dogs had abdominal ultrasound examinations performed as part of staging. For the dog with primary bilateral renal lymphoma, at diagnosis, SDMA was 15 ug/dL, creatinine was 149 umol/L and SDMA:Creatinine was 0.10. In CR 4 months later, SDMA was 12 ug/dL, creatinine was 109 umol/L, and SDMA:Creatinine was 0.11. The dog relapsed 1 month later with mediastinal involvement, and SDMA was 21 ug/dL, creatinine was 105 umol/L, and SDMA:Creatinine was 0.20. Abdominal ultrasound examination was not repeated. Only one of the 27 dogs with multicentric nodal lymphoma that had abdominal ultrasound examinations had evidence of renal infiltration. Ultrasound examination of this dog was performed again 6 weeks and 6 months later, and on both examinations the lesion had resolved. At diagnosis SDMA was 22 ug/dL, creatinine was 92 umol/L, and SDMA:Creatinine was 0.24, and in CR SDMA was 8 ug/dL, creatinine was 105 umol/L, and SDMA:creatinine was 0.08. The dog with the highest SDMA level (90 ug/dL), had no evidence of renal lymphoma and had normal kidney architecture on ultrasound examination. No dog examined by ultrasound had ultrasonographic evidence of chronic kidney disease at diagnosis.

Serum lactate dehydrogenase (LDH) activity was analyzed retrospectively in 29 available samples as a marker of lymphoma metabolic activity. There was no correlation between LDH activity and SDMA levels. Markers of spontaneous tumor lysis were analyzed to investigate acute kidney injury secondary to tumor lysis as a potential cause of increased SDMA. All dogs had normokalemia at all stages. Two dogs with untreated lymphoma had hyperphosphatemia and 5 dogs had mild hypocalcemia, while no dogs in CR had hyperphosphatemia and 2 had mild hypocalcemia; these differences were not significant. Uric acid was prospectively measured in 8 dogs. Prior to treatment uric acid levels were: mean = 17 mmol/L, median = 16 mmol/L, range = 9 – 28 mmol/L. When these dogs achieved CR, results were mean = 12 mmol/L, median = 12 mmol/L, range = 12 – 14 mmol/L. These results were significantly different (P = 0.02). Uric acid levels were moderately correlated with SDMA levels (rho = 0.26, P = 0.04, N = 59). Although uric acid is eliminated by the kidney, uric acid levels were not significantly correlated with creatinine levels (rho = −0.08, P = 0.57) which may indicate that uric acidemia was caused more by increased release by lymphoma than by decreased renal excretion.

We conclude that some dogs with lymphoma and large tumor burden may have increased SDMA levels which may normalize if dogs achieve CR, and that SDMA should not be interpreted in these dogs as evidence of age‐related chronic kidney disease. SDMA might have potential as a biomarker of treatment response in some dogs, although the data are insufficient to make firm conclusions in this regard. The data may be underpowered to detect relationships of SDMA to immunophenotype or other characteristics of the patients or malignancy. The pathophysiology of increased SDMA in dogs with lymphoma is unknown. If the assumption is correct that SDMA production is not increased by lymphoma, potential mechanisms include 1) reversible acute kidney injury, and 2) reversible decrease in SDMA excretion without compromise to other aspects of kidney function, with either of these mechanisms being secondary to renal infiltration below the threshold of routine sonographic detection, or kidney injury resulting from spontaneous tumor lysis.