Salt-losing syndrome as a mimicker of the Nephroprotective effect of Gliflozins in Proteinuric nephropathies

Abstract

Gliflozins are oral antidiabetic drugs associated with a direct nephroprotective effect. Their administration reduces glomerular hyperfiltration and proteinuria by activating the tubule-glomerular feedback through an increased sodium delivery to the macula densa. We hypothesized a similar mechanism for nephroprotection in a patient with limited proteinuria, despite long-lasting glomerular damage secondary to suspected focal segmental glomerulosclerosis in a solitary kidney who also had salt-losing nephropathy.

Introduction

Gliflozins were first approved to improve glycemic control in diabetic patients. Their inhibition of sodium-glucose co-transporter 2 (SGLT2) in the proximal tubule of the nephron [1] delivers more sodium and glucose downstream and into the urine. Further research revealed that gliflozins exert important nephroprotective effects by reducing proteinuria and progression of renal disease even in the absence of diabetes [2]. This kidney-protective action is thought to be caused by the activation of the tubule-glomerular feedback mechanism, which reduces glomerular hyperfiltration by constricting the afferent while dilating the efferent arteriole. This response is induced by an increased sodium delivery to the macula densa [2]. We hypothesize that a similar kidney protective process might happen during a proteinuric nephropathy when it coexists with proximal tubular damage that makes more sodium arrive at the macula densa. In this case, proteinuria and progression of the kidney disease might be slowed down by activating the tubule-glomerular feedback in a way that is similar to what occurs with the administration of SGLT2 inhibitors [3].

Case presentation

We report the case of a male patient with a solitary right kidney after left kidney nephrectomy at 4 years of age because of congenital cystic dysplasia. At the age of two months, surgery was performed to correct right ureteral stenosis. At the age of 19, he was examined by a nephrologist for chronic kidney disease (CKD), Kidney Disease Improving Global Outcomes (KDIGO) stage 3A, which was characterized by increased serum creatinine to 1.89 mg%. The estimated glomerular filtration rate (eGFR, adjusted to body surface area) was 53.0 ml/min/1.73 m², according to the 2009 CKD-epidemiology collaboration (EPI) equation. Urine spot albumin and protein to creatinine ratios (ACR and PCR) were both increased to 745 mg/g and 1090 mg/g, respectively. No treatment was ongoing, as a low dose of ramipril (2.5 mg/day) had reduced eGFR by more than 30%. The patient was normotensive (average blood pressure 110/80 mm Hg) and euglycemic (glycosylated hemoglobin HbA1C 5.5%). Autoimmunity assessment was negative, erythrocyte sedimentation rate (ESR) was 8 mm/hour (upper limit corrected for age 9.5 mm/hour), urine specific gravity was 1010, urine pH 5.0, serum bicarbonate 25, potassium 4.0, and sodium 142 mEq/L. Glycosuria was absent, urinary β2-microglobulin was increased to 461 μg/24 h, 24-h urine sodium was high (281 mEq), and measured fractional excretion of sodium (FENa) was 3.38% in the face of an ‘expected’ FENa (according to the formula Expected FENa = 62.8/GFR [4]) of 1.18%. Plasma renin activity (PRA) was low at 2.3 ng/ml/h (normal value > 2.9 ng/ml/h, Angiotensin I RIA KIT, Beckman Coulter, Brea, California, USA). Renal ultrasonography showed a right kidney longitudinal dimension of 130 mm, a dilated renal pelvis (20 mm), a renal resistance index within normal range (0.67), and the absence of right renal artery stenosis (peak systolic velocity 80 cm/sec).

Discussion

The patient showed these features: he carried a solitary kidney since birth and developed secondary focal segmental glomerulosclerosis (FSGS). FSGS was a condition induced by a reduced overall kidney mass and a consequent maladaptive response to compensatory glomerular hyperfiltration in the remnant kidney [5]. In this case, there was no severe hyperfiltration since proteinuria was stable at about 1 g/24 h, even without targeted therapy because of intolerance to ACE inhibitors. This clinical course was unusual, as proteinuria is expected to be in the nephrotic range in secondary FSGS [6]. Another distinctive feature was that, despite chronic renal failure, the patient was normotensive, and administration of only 2.5 mg/day of ramipril had provoked an extremely severe drop of eGFR by more than 30%. These findings prompted us to search for a salt-losing nephropathy as a consequence of the right ureteral stenosis that was removed surgically when he was two months old. This hypothesis was confirmed by finding a rise in ‘measured’ FENa, much greater than the ‘expected’ [4]. We also looked for the site of the sodium reabsorption defect and located it in the proximal tubule because of the increased urinary β2-microglobulin and a preserved urine acidification ability. The coexistence of a reduced PRA (measured without any treatment) suggested that the patient showed the same clinical-laboratory frame of nephroprotection afforded by gliflozins. In fact, these drugs reduce proteinuria and glomerular hyperfiltration through the activation of the tubulo-glomerular feedback (which implies inhibition of PRA), induced by the increase in sodium delivery to the macula densa. In turn, this mechanism is triggered by the gliflozins’ inhibitory effect on the sodium-glucose co-transporter located in the proximal convoluted tubule [7]). Salt-losing nephropathy caused by ureteral obstruction is usually caused by a distal tubular transport defect, which is associated with decreased urine concentration and acidification mechanisms. However, most studies have focused on sodium transport defects during acute ureteral obstruction. In chronic obstruction, hydronephrosis can increase intrarenal pressure and extend it to the proximal tubule, resulting in a sodium transport defect at this site. Our patient’s concentration mechanism was impaired, as evidenced by isosthenuria, while acidification and potassium handling were unaffected. This proximal tubule defect in this case was minor, as glucose and bicarbonate resorption remained normal, but it appeared significant enough to cause a mild salt-losing nephropathy. On the other hand, we excluded a transport defect in the Henle loop because it would have resulted in a greater increase in sodium loss due to the loop’s high quantitative reabsorption provided by a single mechanism [8]. These findings support our conclusion that the natriuresis was caused by an unreported defect in proximal tubular transport. This condition, in turn, protected the kidney by reducing hyperfiltration through activation of tubule-glomerular feedback, allowing blood pressure to remain normal despite the presence of FSGS.

Conclusions

In a condition capable of causing pathological glomerular proteinuria and a salt-losing nephropathy (where the sodium reabsorption defect is located in the proximal tubule), the administration of gliflozins is probably not indicated, as the related nephroprotective mechanism is already spontaneously activated. Finally, it should be noted that the sodium reabsorption defect induced by furosemide, does not have a nephroprotective effect, since this drug desensitizes the macula densa to sodium increase in the distal tubule and, therefore, the tubule-glomerular feedback is not activated [8, 9].

Study approval statement

Ethics approval was not required for the writing of this case report. The author declare that this study has been carried out in accordance with the Declaration of Helsinki.

Consent to publish statement

The authors declare that they have obtained written informed consent, from the patient reported in this article, for publication of the information about him that appears within this case report.

Conflict of interests

Authors declare that they have not received any form of support of financial involvement (in form of employment, consultancies, honoraria, ownership interests, research funding, expert testimony, royalties, or any other form of support) in the previous three years, that can lead to any possible conflict of interest.

Funding

This study was not supported by any sponsor or funder.

Data availability

The data that support the findings of this article are available after anonymization on request from the corresponding author. The data are not publicly available due to their containing information that could compromise the patient’s privacy.