An unusual cause of severe kidney tubular dysfunction: Questions

Background: : Drug-induced Acute Kidney Injury (AKI) develops in 10-15% of patients who receive nephrotoxic medications. Urinary biomarkers of renal tubular dysfunction may detect nephrotoxicity early and predict AKI. Methods:: We prospectively studied patients who received aminoglycosides, vancomycin, amphotericin, or calcineurin inhibitors, and collected their serial urine while on therapy. Patients who developed drug-induced AKI (fulfilling KDIGO criteria) were matched with non-AKI controls in a 1:2 ratio. Their urine samples were batch-analyzed at time-intervals leading up to AKI onset; the latter benchmarked against the final day of nephrotoxic therapy in non- AKI controls. Biomarkers examined include clusterin, beta-2-microglobulin, KIM1, MCP1, cystatin-C, trefoil-factor- 3, NGAL, interleukin-18, GST-Pi, calbindin, and osteopontin; biomarkers were normalized with corresponding urine creatinine. Results:: Nine of 84 (11%) patients developed drug-induced AKI. Biomarkers from 7 AKI cases with pre-AKI samples were compared with those from 14 non-AKI controls. Corresponding mean ages were 55(±17) and 52(±16) years; baseline eGFR were 99(±21) and 101(±24) mL/min/1.73m2 (all p=NS). Most biomarker levels peaked before the onset of AKI. Median levels of 5 biomarkers were significantly higher in AKI cases than controls at 1-3 days before AKI onset (all µg/mmol): clusterin [58(8-411) versus 7(3-17)], beta-2-microglobulin [1632(913-3823) versus 253(61-791)], KIM1 [0.16(0.13-0.76) versus 0.07(0.05-0.15)], MCP1 [0.40(0.16-1.90) versus 0.07(0.04-0.17)], and cystatin-C [33(27-2990) versus 11(7-19)], all p<0.05; their AUROC for AKI prediction were >0.80 (confidence intervals >0.50), with average accuracy highest for clusterin (86%), followed by beta-2-microglobulin, cystatin-C, MCP1, and KIM1 (57%) after cross-validation. Conclusion: : Serial surveillance of these biomarkers could improve the lead time for nephrotoxicity detection by days.

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Acute kidney injury, metabolic acidosis, and hypercalcemia with proximal tubular dysfunction—a diagnostic challenge: Answers

Pediatric Nephrology ◽

10.1007/s00467-021-05033-8 ◽

2021 ◽

Author(s):

Adem Yasin Köksoy

Keyword(s):

Acute Kidney Injury ◽

Metabolic Acidosis ◽

Kidney Injury ◽

Tubular Dysfunction ◽

Diagnostic Challenge ◽

Proximal Tubular Dysfunction ◽

Proximal Tubular

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Functional tests to guide management in an adult with loss of function of type-1 angiotensin II receptor

Pediatric Nephrology ◽

10.1007/s00467-021-05018-7 ◽

2021 ◽

Author(s):

Daan H. H. M. Viering ◽

Anneke P. Bech ◽

Jeroen H. F. de Baaij ◽

Eric J. Steenbergen ◽

A. H. Jan Danser ◽

...

Keyword(s):

Angiotensin Ii ◽

Collecting Duct ◽

Perinatal Period ◽

Tubular Dysfunction ◽

Loss Of Function ◽

Angiotensin Ii Receptor ◽

Salt Wasting ◽

Truncating Mutation ◽

Urinary Potassium

AbstractBackgroundGenetic loss of function ofAGT(angiotensinogen),REN(renin),ACE(angiotensin-converting enzyme), orAGTR1(type-1 angiotensin II receptor) leads to renal tubular dysgenesis (RTD). This syndrome is almost invariably lethal. Most surviving patients reach stage 5 chronic kidney disease at a young age.MethodsHere, we report a 28-year-old male with a homozygous truncating mutation inAGTR1(p.Arg216*), who survived the perinatal period with a mildly impaired kidney function. In contrast to classic RTD, kidney biopsy showed proximal tubules that were mostly normal. During the subsequent three decades, we observed evidence of both tubular dysfunction (hyperkalemia, metabolic acidosis, salt-wasting and a urinary concentrating defect) and glomerular dysfunction (reduced glomerular filtration rate, currently ~30 mL/min/1.73 m2, accompanied by proteinuria). To investigate the recurrent and severe hyperkalemia, we performed a patient-tailored functional test and showed that high doses of fludrocortisone induced renal potassium excretion by 155%. Furthermore, fludrocortisone lowered renal sodium excretion by 39%, which would have a mitigating effect on salt-wasting. In addition, urinary pH decreased in response to fludrocortisone. Opposite effects on urinary potassium and pH occurred with administration of amiloride, further supporting the notion that a collecting duct is present and able to react to fludrocortisone.ConclusionsThis report provides living proof that even truncating loss-of-function mutations inAGTR1are compatible with life and relatively good GFR and provides evidence for the prescription of fludrocortisone to treat hyperkalemia and salt-wasting in such patients.

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High sucrose diet induces morphological, structural and functional impairments in the renal tubules of Drosophila melanogaster: A model for studying type-2 diabetes mediated renal tubular dysfunction

Insect Biochemistry and Molecular Biology ◽

10.1016/j.ibmb.2020.103441 ◽

2020 ◽

Vol 125 ◽

pp. 103441

Author(s):

Lavi Rani ◽

Sanjay Saini ◽

Neha Shukla ◽

Debapratim Kar Chowdhuri ◽

Naveen Kumar Gautam

Keyword(s):

Type 2 Diabetes ◽

Tubular Dysfunction ◽

Renal Tubular Dysfunction ◽

Renal Tubules ◽

Functional Impairments ◽

Sucrose Diet ◽

High Sucrose Diet ◽

Renal Tubular ◽

High Sucrose

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Renal Sodium Handling in Relation to Environmental and Genetic Factors in Untreated Chinese

American Journal of Hypertension ◽

10.1093/ajh/hpaa160 ◽

2020 ◽

Author(s):

Yuan-Yuan Kang ◽

Yi-Bang Cheng ◽

Qian-Hui Guo ◽

Chang-Sheng Sheng ◽

Qi-Fang Huang ◽

...

Keyword(s):

Blood Pressure ◽

Multiple Testing ◽

Genetic Factors ◽

Blood Pressure Monitoring ◽

Lithium Concentration ◽

Tubular Dysfunction ◽

Renal Tubular Dysfunction ◽

Renal Sodium Handling ◽

Renal Tubular ◽

Sodium Handling

Abstract Background We investigated proximal and distal renal tubular sodium handling, as assessed by fractional excretion of lithium (FELi) and fractional distal reabsorption rate of sodium (FDRNa), in relation to environmental and genetic factors in untreated patients. Methods Our study participants were suspected hypertensive patients being off antihypertensive medication for ≥2 weeks and referred for 24-hour ambulatory blood pressure monitoring. We collected serum and 24-hour urine for measurement of sodium, creatinine and lithium concentration, and calculated FELi and FDRNa. We genotyped 19 SNPs associated with renal sodium handling or blood pressure using the ABI SNapShot method. Results The 1409 participants (664 men, 47.1%) had a mean (±SD) age of 51.0±10.5 years. After adjustment for host factors, both FELi and FDRNa were significantly (P≤0.01) associated with season and humidity, explaining ~1.3% and ~3.5% of the variance, respectively. FELi was highest in autumn and lowest in summer and intermediate in spring and winter (P=0.007). FDRNa was also highest in autumn but lowest in winter and intermediate in spring and summer (P<0.001). Neither FELi nor FDRNa was associated with outdoor temperature or atmospheric pressure (P≥0.13). After adjustment for host and environmental factors and Bonferroni multiple testing, among the 19 studied genetic variants, only rs12513375 was significantly associated with FELi and FDRNa (P≤0.004) and explained about 1.7% of the variance. Conclusions Renal sodium handling as measured by endogenous lithium clearance was sensitive to major environmental and genetic factors. Our finding is towards the use of these indexes for the definition of renal tubular dysfunction.

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