Reference values of renal tubular function tests are dependent on age and kidney function

Background: Gitelman syndrome (GS) is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. GS is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of GS, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a GS phenotype, the genotype is unknown. Methods: We identified mitochondrial DNA (mtDNA) variants in three families with GS-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced In NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. Results: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF) and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV reduced maximal mitochondrial respiratory capacity in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. Conclusion: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a GS-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained GS-like tubulopathies.

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“…Thiazide tests were performed in three families as described in the Supplementary Material, according to previously described protocols 20 , 21 …”

Section: Methodsmentioning

confidence: 99%

“…Thiazide tests were performed in three families according to previously described protocols (20,21).…”

Section: Clinical Datamentioning

confidence: 99%

Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA

Viering

Schlingmann

Hureaux

et al. 2022

JASN

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“…All patients were mechanically ventilated. The median time from initiation of norepinephrine to inclusion was 18 [12][13][14][15][16][17][18][19][20][21][22][23][24] h. The fluid balance was positive before inclusion with a median of 54 [38-93] mL/kg since ICU admission. No patients died during the study (Table 2).…”

Section: Study Populationmentioning

confidence: 99%

“…A washout period was also possible on the urine sample, since it was collected on the last hour collection. The time to assess a change in renal tubular function is not known for this clinical setting either, but response to renal tubular function tests is often observed within hours in nephrology studies [22]. Second, patients were included after the initial resuscitation of septic shock, i.e., after the crucial period for the onset and severity of AKI.…”

Section: Primary Endpointmentioning

confidence: 99%

High mean arterial pressure target to improve sepsis-associated acute kidney injury in patients with prior hypertension: a feasibility study

Dewitte

Labat

Duvignaud³

et al. 2021

Ann. Intensive Care

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Background The optimal mean arterial pressure (MAP) in cases of septic shock is still a matter of debate in patients with prior hypertension. An MAP between 75 and 85 mmHg can improve glomerular filtration rate (GFR) but its effect on tubular function is unknown. We assessed the effects of high MAP level on glomerular and tubular renal function in two intensive care units of a teaching hospital. Inclusion criteria were patients with a history of chronic hypertension and developing AKI in the first 24 h of septic shock. Data were collected during two 6 h periods of MAP regimen administered consecutively after haemodynamic stabilisation in an order depending on the patient's admission unit: a high-target period (80–85 mmHg) and a low-target period (65–70 mmHg). The primary endpoint was the creatinine clearance (CrCl) calculated from urine and serum samples at the end of each MAP period by the UV/P formula. Results 26 patients were included. Higher urine output (+0.2 (95%:0, 0.4) mL/kg/h; P = 0.04), urine sodium (+6 (95% CI 0.2, 13) mmol/L; P = 0.04) and lower serum creatinine (− 10 (95% CI − 17, − 3) µmol/L; P = 0.03) were observed during the high-MAP period as compared to the low-MAP period, resulting in a higher CrCl (+25 (95% CI 11, 39) mL/mn; P = 0.002). The urine creatinine, urine–plasma creatinine ratio, urine osmolality, fractional excretion of sodium and urea showed no significant variation. The KDIGO stage at inclusion only interacted with serum creatinine variation and low level of sodium excretion at inclusion did not interact with these results. Conclusions In the early stage of sepsis-associated AKI, a high-MAP target in patients with a history of hypertension was associated with a higher CrCl, but did not affect the kidneys' ability to concentrate urine, which may reflect no effect on tubular function.

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Reference values of renal tubular function tests are dependent on age and kidney function

Cited by 2 publications

References 9 publications

Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA

Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA

High mean arterial pressure target to improve sepsis-associated acute kidney injury in patients with prior hypertension: a feasibility study

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