Tenofovir Induced Acute Kidney Injury and Severe Anemia: A Case Series of Four Patients

Introduction

Tenofovir Disoproxil Fumarate (TDF) is the first nucleotide reverse transcriptase inhibitor to be approved for the treatment of Human Immunodeficiency Virus (HIV) infection. TDF is one of the most prescribed antiretroviral drug around the World. In Cameroon, it is recommended as first line agent therapy in association with Lamuvidine and Efavirenz. TDF is generally considered safe [1-3]. Renal toxicity is the most severe adverse effect but it is uncommon with an incidence < 1% [2]. TDF nephrotoxicity is due to tubular lesion and usually manifest as proximal dysfunction, including Fanconi syndrome, isolated hypophosphatemia and decreased bone mineral density or distal dysfunction with nephrogenic diabetes insipidus. Anemia is also rarely described with TDF used and association between TDF nephrotoxicity and anemia is unusual. We reported 4 cases of atypical TDF nephrotoxicity associated with severe anemia and both resolved after discontinuation of TDF in the nephrology clinic of the General Hospital of Douala.

Cases series

We registered 4 cases (3 females) of atypical TDF induced AKI from 2014 to 2017. Baseline characteristics of patients are presented in table 1. Age varies between 32 to 67 years old. HIV was known for less than 2 years in 2 patients. Two patients were nonobservant to ARV treatment. Severe immunodepression (CD4< 200 cells/mm3) at ARV initiation was common and use of Metformin was noted in one patient. Malnutrition was not observed. ARV protocol was the same for the 4 patients: 3TC + TDF+ EFV (Lamuvidine + Tenofovir + Efavirenz). Nephrotoxicity appear during the first 3 months of TDF introduction in 3 patients. Uremic syndrome was the main complaint in 3 patients. Severe anemia with multiple transfusions was noted for the other one. Anuria or oliguria were not observed and one patient had hyposthenuric polyuria. Glycosuria with normal blood sugar, high serum phosphate and AKI stage 3 KDIGO were found in the four patients. One patient had hypocalcemia. Severe normochromic normocytic anemia was also usual and each patient received at least 4 units of blood. Hyponatremia was also common as well as massive proteinuria (> 2g/g). One patient had a concomitant Escherichia coli urinary tract infection. Normal kidney size was observed in the forth. No patient had formal indication of dialysis and none benefit of it. Medical treatment of AKI was done and TDF was discontinued. The evolution was marked by improvement in GFR with completed recovery in 1 patient and partial recovery in the 3 others (figure 1). Hemoglobin level also improved and all the patient were free of blood transfusion after 6 months (figure 2). Although serum phosphate decrease in the 4 patients, high serum phosphate persist in two patients with partial recovery.

                                                                    Table 1: Baseline characteristics of patients

Serum calcium corrected to albumin level

Figure 1: evolution of GFR after discontinuation of Tenofovir

Figure 2: evolution of hemoglobin after discontinuation of Tenofovir

Discussion

AKI secondary to proximal tubular dysfunction is a well know complication of TDF used. It usually manifest as a complete or partial Fanconi syndrome which manifest as glycosuria with normal blood sugar, renal tubular acidosis, low serum phosphate, hypokalemia; hypouricemia, aminoaciduria and tubular proteinuria. TDF nephrotoxicity result from mitochondrial toxicity secondary to high intracellular TDF concentration. Indeed, drugs (eg probenecid) which inhibited the uptake of TDF at the basal membrane by OAT1 (organic acid transport 1) may prevent TDF nephrotoxicity by keeping proximal intracellular level of TDF low. By the contrary, drug (eg metformine or ritonavir) that inhibit the transport of TDF at the apical membrane by MRP2 or 4 (multidrug resistant protein 2 or 4) could increase the risk of TDF toxicity. Decrease in GFR also increase the risk of TDF nephrotoxicity by increase plasma level of TDF and then proximal tubular cell uptake of TDF through OAT1. Other situation associated with increased risk of TDF toxicity included older age, low body weight, low CD4 count, ABCC2 gene polymorphism (encoding for MRP2 transporter,) used of other nephrotoxic drug such as aminoglycoside, HCV coinfection [2,4-8]. The four cases have low CD4 count at TDF initiation, and one patient a concomitant used of Metformin. The delay between the TDF introduction and AKI may vary from weeks to years (1month-8 years) [5,7,9,10]. In our series, AKI appears during the year following TDF initiation.

The four cases we reported had an atypical AKI presentation with biological feature of chronic kidney disease (normochromic normocytic anemia and high serum phosphate). These features associated with uremic syndrome suggest chronic kidney disease and chronic hemodialysis initiation was planned in all of them. However; careful review of their files reveals normal creatinine prior to TDF initiation and normal kidney size. TDF was then discontinued and serum creatinine unexpectedly dropped. High serum phosphate is unusual in TDF induced nephropathies since it induced proximal tubulopathy with urinary loss of phosphate. However, it have been noted by some authors and it considered to be due to decrease GFR [11]. This hypotheses seem to be true since high serum phosphate persist in patient with partial recovery. Severe anemia in our series may also be due to decrease GFR since hemoglobin level increase with GFR rise. Anemia has been described with TDF used, but it rarely less than 8 g/dl [9]. A cohort study on anemia among HIV infected patients on HARRT in Ethiopia found that TDF- based HAART increased the risk of anemia [12]. Fatouma and al also described two cases of TDF induced AKI with severe anemia in Kenya [13]. Hemolytic anemia could be another explanation of the atypical presentation of our cases since hypocalcemia and high serum phosphate is usually found in AKI associated with hemolytic anemia. Unfortunately; LDH and haptoglobin were not done.

One patient had a polyuric polydipsic syndrome with hypotonic polyuria which started 2 months after TDF initiation. It was probably due to a diabetes insipidus, a well know TDF nephrotoxicity features. Association between Fanconi syndrome, AKI and distal tubular injury had been reported in TDF induced nephropathies [8]. TDF was incriminated in the four patients since all the signs disappear after TDF withdrawal. Lamuvidine and Efavirenz was still used in the substituted protocol as well as cotrimoxazol.

TDF was reintroduced after 5 months in case 1 and after 2 weeks, the creatinine started to increase and glycosuria reappear. Creatinine normalized and glycosuria disappear after withdrawal of TDF. He had been followed now for 48 months with normal creatinine and no proteinuria.

Concerning outcome, kidney function generally improved in the month following TDF withdrawal. However, AKI does not always revert completely. In a study of 24 patients who stopped TDF because of AKI, only 42% recovered their initial kidney function [14]. Patients with better kidney function improvement after stopping TDF had faster GFR decline, were more frequently prescribed a proteinase inhibitor and had been treated with TDF for a shorter period [14]. Our cases obeyed to this picture: patients that developed AKI within the first 3 months of TDF initiation had a better improve in GFR (1 complete recovery and 2 partial recovery with GFR > 35ml/min/1.75 m2 within 6 months). In contrast; the patient that developed AKI after 6 months of TDF had the lowest kidney function improvement with a GFR < 30ml/min/1.75 m2 after 6 months).

Conclusion

TDF induced AKI nephrotoxicity can present with severe anemia and high serum phosphate. As the used of TDF-based HARRT is widely spread in our setting, clinician should be aware of the complexity of TDF induced AKI nephrotoxicity and careful evaluate all patient on TDF with decrease GFR since TDF induced AKI can present with pathognomonic sign of end stage kidney disease.

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