Acute Kidney Injury With TDF and NSAID Co-administration
Acute Kidney Injury With TDF and NSAID Co-administration
In this retrospective study, we found an unexpectedly high incidence of AKI (14.6%) shortly after initiation of diclofenac therapy in HIV-positive patients on cART. Cases of AKI occurred exclusively in TDF-treated patients, although all had stable renal function under this regimen for several months or (in > 80% of cases) even years. All cases of AKI were accompanied by new onset of at least two parameters indicating proximal tubular damage, such as normoglycaemic-glucosuria and hypophosphataemia. TFV-associated nephrotoxicity was demonstrated by renal biopsy in four cases of AKI. In contrast, diclofenac did not affect renal function in patients with TDF-sparing cART. In addition to the patients with AKI, another 9.0% of all diclofenac-treated patients developed new-onset laboratory parameters suggesting proximal renal tubolopathy, while having a preserved eGFR, and all but one of these patients were on TDF-containing cART.
As the main clinical presentation of TFV-associated nephrotoxicity is proximal tubular dysfunction with or without renal failure, our findings may be explained by a renal DDI between TFV and NSAIDs increasing the nephrotoxic potential of TFV. However, the observed increase in individual markers of tubulopathy may also be attributable to other concomitant diseases, for example hypophosphataemia caused by chronic diarrhoea, kachexia, vitamin D deficiency or malabsorption. In addition, NSAIDs such as diclofenac can independently induce two different forms of AKI; the most common form is caused by a reduction of renal blood flow mediated by reduced prostaglandin synthesis, and the other, very rare form is caused by interstitial nephritis. However, haemodynamically mediated AKI is not associated with proximal tubular dysfunction, as found in our patients. Interstitial nephritis can indeed cause tubulopathy, but its clinical and laboratory presentation is distinct from that of proximal tubular dysfunction. Patients typically present with haematuria and pyuria, white cell casts or eosinophilia and possibly symptoms of allergic reaction. None of these were found in our patients with AKI. Thus, other types of renal disease cannot fully account for the high incidence of AKI found in the TDF-treated patients. The occurrence of AKI was significantly associated with prior hypophosphataemia, which could be TFV-related, as tubular dysfunction may precede a decline in eGFR, resembling subclinical nephrotoxicity. In addition, laboratory findings suggestive of a TFV-related tubular injury without AKI were also found in 11.5% of TDF-treated patients shortly after diclofenac therapy, arguing in favour of TFV-associated nephrotoxicity as the common pathological mechanism. Finally, renal biopsies confirmed TFV toxicity in four cases.
In addition to AKI related to drug-specific effects of TFV and/or NSAIDs, it was shown in previous studies that TDF, indinavir and atazanavir were associated with the development of acute and chronic renal failure. Yet, in our study no patient had been on indinavir therapy and the numbers of patients receiving atazanavir were comparable between groups (Table 1). Although therapy with other known nephrotoxic agents, such as trimephoprim-sulfamethoxazole, was not more frequent in the TDF group, this does not rule out additive nephrotoxic effects. Only two patients experiencing AKI after initiation of diclofenac treatment had been on trimephoprim-sulfamethoxazole therapy, and diagnosis of renal TFV toxicity was confirmed by renal biopsy in one of them. Moreover, no patient with AKI had been on angiotensin conversion enzyme inhibitor or angiotensin-1 receptor blocker therapy, which is known to increase the nephrotoxic potential of diclofenac. It therefore appears unlikely that the numbers of patients with AKI after diclofenac prescription were attributable to other nephrotoxic drug effects than that of TDF.
AKI under cART has also been associated with prior CKD, AIDS, lower CD4 cell count, HCV coinfection and liver disease in HIV-infected out-patients and also with malignancies and traditional risk factors, such as older age, African descent, hypertension and diabetes, in hospitalized patients. However, these risk factors did not differ between HIV-infected patients with and without AKI. In addition, traditional risk factors for AKI such as CKD were even more frequent in patients on TDF-sparing cART.
Withdrawal of the causative agent is the main therapeutic option and may avoid irreversible damage. After discontinuation of diclofenac and/or TDF, renal function did not fully recover in one-third of patients, which is consistent with previous findings on TFV-associated nephrotoxicity. Recovery of renal function was dependent on the severity of AKI in our study, underlining that early detection and withdrawal of the causative agent can avoid irreversible damage.
Our study has several limitations, mostly resulting from its retrospective design. First, NSAIDs such as diclofenac are freely available over-the-counter drugs and it is very likely that more patients in our cohort had taken NSAIDs than was reported, resulting in an overestimation of the frequency of AKI. Patients who received a prescription for diclofenac were probably those with higher doses and a longer duration of treatment compared with those who had taken NSAIDs occasionally, but precise data on indication, dose, frequency and duration were unavailable in this relatively small study. A control group of patients treated with TDF but not taking NSAIDs may have been more appropriate, but as NSAIDs are available without prescription such a control group could not be identified reliably retrospectively.
Secondly, we did not assess all parameters according to the gold standard to assess for proximal tubular dysfunction, such as aminoaziduria, metabolic acidosis with normal anion gap or the fractional excretion of phosphate and uric acid in all patients, as these are not routinely tested.
Especially in view of the limited number of patients treated with TDF-sparing cART, our findings need to be confirmed in larger studies allowing multivariate analysis of associated risk factors. Moreover, the impact of other NSAIDs should also be studied in order to assess whether the observed effect is limited to diclofenac.
In summary, we found evidence that co-administration of diclofenac and TDF seems to be a possible contributor to TFV-associated nephrotoxicity. DDI via MRP4 could well be the reason for this finding. We believe that NSAIDs should be used with caution in patients on TDF-containing cART, especially in those with pre-existing hypophosphataemia. Although deterioration of renal function was only mild and transient in the majority of patients, the clinical relevance should not be underestimated: acute renal failure is a strong predictor of morbidity and mortality not just in the general population, but also in the HIV-infected population in the cART era. This increased risk persists even after renal recovery. Together with antibiotics, NSAIDs are among the most commonly prescribed drugs with nephrotoxic properties in HIV-infected patients. With an aging HIV-infected population, it can be assumed that the use of NSAIDs will increase over time. Recently developed tenofovir alafenamide (GS-7340) is not a substrate of renal organic anion transporters (OATs) and thus is unlikely to accumulate in proximal tubular cells. Future studies will have to determine whether this might also be associated with less renal toxicity.
Discussion
In this retrospective study, we found an unexpectedly high incidence of AKI (14.6%) shortly after initiation of diclofenac therapy in HIV-positive patients on cART. Cases of AKI occurred exclusively in TDF-treated patients, although all had stable renal function under this regimen for several months or (in > 80% of cases) even years. All cases of AKI were accompanied by new onset of at least two parameters indicating proximal tubular damage, such as normoglycaemic-glucosuria and hypophosphataemia. TFV-associated nephrotoxicity was demonstrated by renal biopsy in four cases of AKI. In contrast, diclofenac did not affect renal function in patients with TDF-sparing cART. In addition to the patients with AKI, another 9.0% of all diclofenac-treated patients developed new-onset laboratory parameters suggesting proximal renal tubolopathy, while having a preserved eGFR, and all but one of these patients were on TDF-containing cART.
As the main clinical presentation of TFV-associated nephrotoxicity is proximal tubular dysfunction with or without renal failure, our findings may be explained by a renal DDI between TFV and NSAIDs increasing the nephrotoxic potential of TFV. However, the observed increase in individual markers of tubulopathy may also be attributable to other concomitant diseases, for example hypophosphataemia caused by chronic diarrhoea, kachexia, vitamin D deficiency or malabsorption. In addition, NSAIDs such as diclofenac can independently induce two different forms of AKI; the most common form is caused by a reduction of renal blood flow mediated by reduced prostaglandin synthesis, and the other, very rare form is caused by interstitial nephritis. However, haemodynamically mediated AKI is not associated with proximal tubular dysfunction, as found in our patients. Interstitial nephritis can indeed cause tubulopathy, but its clinical and laboratory presentation is distinct from that of proximal tubular dysfunction. Patients typically present with haematuria and pyuria, white cell casts or eosinophilia and possibly symptoms of allergic reaction. None of these were found in our patients with AKI. Thus, other types of renal disease cannot fully account for the high incidence of AKI found in the TDF-treated patients. The occurrence of AKI was significantly associated with prior hypophosphataemia, which could be TFV-related, as tubular dysfunction may precede a decline in eGFR, resembling subclinical nephrotoxicity. In addition, laboratory findings suggestive of a TFV-related tubular injury without AKI were also found in 11.5% of TDF-treated patients shortly after diclofenac therapy, arguing in favour of TFV-associated nephrotoxicity as the common pathological mechanism. Finally, renal biopsies confirmed TFV toxicity in four cases.
In addition to AKI related to drug-specific effects of TFV and/or NSAIDs, it was shown in previous studies that TDF, indinavir and atazanavir were associated with the development of acute and chronic renal failure. Yet, in our study no patient had been on indinavir therapy and the numbers of patients receiving atazanavir were comparable between groups (Table 1). Although therapy with other known nephrotoxic agents, such as trimephoprim-sulfamethoxazole, was not more frequent in the TDF group, this does not rule out additive nephrotoxic effects. Only two patients experiencing AKI after initiation of diclofenac treatment had been on trimephoprim-sulfamethoxazole therapy, and diagnosis of renal TFV toxicity was confirmed by renal biopsy in one of them. Moreover, no patient with AKI had been on angiotensin conversion enzyme inhibitor or angiotensin-1 receptor blocker therapy, which is known to increase the nephrotoxic potential of diclofenac. It therefore appears unlikely that the numbers of patients with AKI after diclofenac prescription were attributable to other nephrotoxic drug effects than that of TDF.
AKI under cART has also been associated with prior CKD, AIDS, lower CD4 cell count, HCV coinfection and liver disease in HIV-infected out-patients and also with malignancies and traditional risk factors, such as older age, African descent, hypertension and diabetes, in hospitalized patients. However, these risk factors did not differ between HIV-infected patients with and without AKI. In addition, traditional risk factors for AKI such as CKD were even more frequent in patients on TDF-sparing cART.
Withdrawal of the causative agent is the main therapeutic option and may avoid irreversible damage. After discontinuation of diclofenac and/or TDF, renal function did not fully recover in one-third of patients, which is consistent with previous findings on TFV-associated nephrotoxicity. Recovery of renal function was dependent on the severity of AKI in our study, underlining that early detection and withdrawal of the causative agent can avoid irreversible damage.
Our study has several limitations, mostly resulting from its retrospective design. First, NSAIDs such as diclofenac are freely available over-the-counter drugs and it is very likely that more patients in our cohort had taken NSAIDs than was reported, resulting in an overestimation of the frequency of AKI. Patients who received a prescription for diclofenac were probably those with higher doses and a longer duration of treatment compared with those who had taken NSAIDs occasionally, but precise data on indication, dose, frequency and duration were unavailable in this relatively small study. A control group of patients treated with TDF but not taking NSAIDs may have been more appropriate, but as NSAIDs are available without prescription such a control group could not be identified reliably retrospectively.
Secondly, we did not assess all parameters according to the gold standard to assess for proximal tubular dysfunction, such as aminoaziduria, metabolic acidosis with normal anion gap or the fractional excretion of phosphate and uric acid in all patients, as these are not routinely tested.
Especially in view of the limited number of patients treated with TDF-sparing cART, our findings need to be confirmed in larger studies allowing multivariate analysis of associated risk factors. Moreover, the impact of other NSAIDs should also be studied in order to assess whether the observed effect is limited to diclofenac.
In summary, we found evidence that co-administration of diclofenac and TDF seems to be a possible contributor to TFV-associated nephrotoxicity. DDI via MRP4 could well be the reason for this finding. We believe that NSAIDs should be used with caution in patients on TDF-containing cART, especially in those with pre-existing hypophosphataemia. Although deterioration of renal function was only mild and transient in the majority of patients, the clinical relevance should not be underestimated: acute renal failure is a strong predictor of morbidity and mortality not just in the general population, but also in the HIV-infected population in the cART era. This increased risk persists even after renal recovery. Together with antibiotics, NSAIDs are among the most commonly prescribed drugs with nephrotoxic properties in HIV-infected patients. With an aging HIV-infected population, it can be assumed that the use of NSAIDs will increase over time. Recently developed tenofovir alafenamide (GS-7340) is not a substrate of renal organic anion transporters (OATs) and thus is unlikely to accumulate in proximal tubular cells. Future studies will have to determine whether this might also be associated with less renal toxicity.
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