MO177RENAL PROXIMAL TUBULAR DISORDER AND RENAL FUNCTION LOSS IN HIV-INFECTED PATIENTS TREATED WITH TENOFOVIR DISOPROXIL FUMARATE

Background and Aims Tenofovir disoproxil fumarate (TDF), as the most common antiviral drug, can cause both proximal tubular transportation dysfunctions and eGFR decline. The relationship between them is not clear due to lack of clinical data from large cohorts, especially in the Chinese population. In this study, we summarized the characteristics of proximal tubular injuries and eGFR decline in the cohort of HIV-infected patients treated with TDF, and explore the the impact of tenofovir on tubular transporters in vitro. Method We enrolled HIV-infected patients treated with TDF, who were regularly followed up in our hospital from Sep 1, 2001 to August 31, 2019. Their baseline and follow-up clinical data were collected. Proximal tubular dysfunction was defined as meeting two or more of the following criteria: hypophosphatemia, hypouricemia, low carbon dioxide binding capacity, positive urine glucose with normal plasma glucose level, and positive urine protein. Rapid deterioration of renal function was defined as the annual decline rate of eGFR exceeding 5ml/min/1.73m2. We also used human renal proximal tubular epithelial cell line (HK2) to further investigate the impact of tenofovir on transporters including SGLT2, NaPi-IIa, and URAT1 through immunofluorescence. Results A total of 375 HIV-infected patients receiving TDF were enrolled, mainly males (90.1%), with a median follow-up duration of 34(17, 58) months. The most common clinical manifestations were proteinuria (20.3%) and hypophosphatemia (12.3%). The prevalence of proximal tubular injury was 6.7%, which was significantly associated with low body weight, but was not associated with age, TDF course, baseline viral load, or baseline CD4+ T lymphocyte count. Their eGFR levels at the end of the follow-up were significantly lower than the baseline levels (104.6±15.2 vs. 110.6±14.2 ml/min/1.73m2, P<0.001). The average annual decline rate of eGFR was 5.0± 22.7 ml/min/1.73m2, and 23.6% of our patients had an annual decline rate of eGFR exceeding 5 ml/min/1.73m2. Rapid deterioration of renal function (≥ 5 ml/min/1.73m2 per year) was significantly associated with female but not related to proximal tubular dysfunction in multivariate logistic regression analysis. In vitro, the survival rate of HK2 cells was more than 95% when treated with tenofovir with a concentration of 1μmol/L for 48h. The expression levels of transporters (SGLT2, URAT1, and NaPi-IIa) were declined under the condition. Conclusion Among the HIV-infected Chinese patients treated with TDF, 6.7% had proximal tubular dysfunction and 23.6% showed accelerated annual decline rate of eGFR (≥ 5 ml/min/1.73m2 per year).

Transient generalized proximal tubular dysfunction in an infant with a urinary tract infection: the effect of maternal infliximab therapy?

Objectives Urinary tract infections (UTIs) are common in childhood. Distal tubular dysfunction during a UTI is relatively common, but proximal tubular involvement is a unique feature in humans. Case presentation We present the first case of transient generalized proximal tubular dysfunction (renal Fanconi syndrome) in an infant with an UTI. During pregnancy, his mother was treated for Crohn’s disease with infliximab (last dose at 28 weeks of gestation). He presented at the age of six weeks with a reduced intake, and was found to have amino-aciduria, glucosuria, and urinary loss of potassium, bicarbonate and low-molecular-weight proteins. Within a few weeks after antibiotic treatment for the UTI, no proximal tubular disorder remained and the boy is doing well. Conclusions We hypothesize that the inflammatory response caused by the UTI was more profoundly present due to the maternal infliximab therapy, and thereby included not only the distal but also the proximal tubules.

The growing pains of ifosfamide

Ifosfamide is a commonly used chemotherapeutic known to have numerous adverse kidney manifestations. In this issue of Clinical Kidney Journal, Ensergueix et al. report a multicentric observational retrospective French study on 34 adult patients with tubular dysfunction and /or kidney dysfunction following ifosfamide treatment. Of these patients, 18% had isolated proximal tubular dysfunction, 14% had isolated acute kidney injury (AKI), 18% had isolated chronic kidney disease (CKD) and 50% had a combination of proximal tubular dysfunction and AKI. Concomitant treatment with cisplatin was identified as a risk factor for the development of AKI, and cisplatin and age were associated with estimated glomerular filtration rate at last follow-up. Interestingly, the cumulative dose of ifosfamide was not associated with renal outcomes. This report highlights the need for additional studies on the prevalence, spectrum and management of ifosfamide-associated nephrotoxicity and clearly demonstrates that patients who received ifosfamide should be followed long term to detect proximal tubular dysfunction and CKD early.

Rickets with hypophosphatemia, hypokalemia and normal anion gap metabolic acidosis: not always an easy diagnosis

Rickets other than those associated with advanced kidney disease, isolated distal renal tubular acidosis (dRTA) and hypophosphatasia (defective tissue non-specific alkaline phosphatase) are associated with hypophosphatemia due to abnormal proximal tubular reabsorption of phosphate. dRTA, however, at times is associated with completely reversible proximal tubular dysfunction. On the other hand, severe hypophosphatemia of different aetiologies may also interfere with both distal tubular acid excretion and proximal tubular functions giving rise to transient secondary renal tubular acidosis (distal and/or proximal). Hypophosphatemia and non-anion gap metabolic acidosis thus pose a diagnostic challenge occasionally. A definitive diagnosis and an appropriate management of the primary defect results in complete reversal of the secondary abnormality. A child with vitamin D resistant rickets was thoroughly evaluated and found to have primary dRTA with secondary proximal tubular dysfunction in the form of phosphaturia and low molecular weight proteinuria. The child was treated only with oral potassium citrate. A complete clinical, biochemical and radiological improvement was noticed in follow-up.

The renal tubular acidoses

Renal tubular acidosis (RTA) arises when the kidneys either fail to excrete sufficient acid, or are unable to conserve bicarbonate, with both circumstances leading to metabolic acidosis of varying severity with altered serum potassium. Proximal and distal types of RTA can be differentiated according to which nephron segment is malfunctioning. Proximal RTA: aetiology and diagnosis—the condition may be (1) secondary to generalized proximal tubular dysfunction (part of the renal Fanconi’s syndrome), or rarely (2) due to an inherited mutation of a single transporter (NBC1) located at the basolateral surface of the proximal tubular epithelium. The combination of normal anion gap acidosis with other features of proximal tubular dysfunction such as renal phosphate wasting (and hypophosphataemia), renal glycosuria, hypouricaemia (due to uricosuria), aminoaciduria, microalbuminuria, and other low molecular weight proteinuria suggests the diagnosis. Management—this requires large quantities of oral alkali with (in most cases) potassium supplements to prevent severe hypokalaemia. Distal RTA: aetiology/diagnosis—two main classes are differentiated by whether (1) the acid-handling cells in the collecting ducts are themselves functioning inadequately, in which case there is associated hypokalaemia (this is ‘classic’ distal RTA); or (2) the main abnormality is of the salt-handling principal cells in the same nephron segment, in which case hyperkalaemia occurs and the acidosis is a secondary phenomenon—this is hyperkalaemic distal RTA. The combination of normal anion gap acidosis with a urine pH higher than 5.5 suggests classic distal RTA. Management—(1) classic distal RTA—1 to 3 mg/kg per day of oral alkali; (2) hyperkalaemic distal RTA—treatment is with sodium bicarbonate, but fludrocortisone and/or potassium-lowering measures may also be necessary. Precipitating drugs should be stopped.