Apparent full recovery from acute kidney injury (AKI) can be deceptive in humans, who suffer a significant risk of progression to chronic kidney disease (CKD). Practitioners might not monitor for this complication and have no tools to prevent it. Understanding the pathophysiologic mechanism of AKI-to-CKD progression is of the utmost importance in terms of risk stratification, detection, and prevention.
Two of many mechanisms that contribute to progression are (1) the disintegration of the renal vasculature leading to chronic under-perfusion, and (2) phosphate-induced impairment of autophagy. We study these mechanisms using animal models with genetic ad pharmacologic manipulations, and human observations in a post-AKI study using biomarkers and functional MRI.
A patient with stage 3 chronic kidney disease (CKD) is ten times more likely to die than to progress to higher stages of CKD. The number one killer of patients with CKD is cardiovascular disease, but the conventional Framingham risk factors are poor predictors in cases of uremic cardiomyopathy
Uremic cardiomyopathy is a metabolic disease caused by the uremic milieu, which encompasses a myriad of factors including excess FGF23 and phosphate, and deficiency in aKlotho.
Our laboratory uses animal interventional and human observational studies to test therapeutic regimens to alleviate uremic cardiomyopathy, and stem cell-derived cardiomyocyte cellular studies to unravel the molecular mechanisms of how this triad of disturbances affect cardiac cell function.
Uric acid nephrolithiasis is part of the spectrum of disorders integral to the metabolic syndrome. The sine qua non of uric-acid stone formation is excessively acidic urine pH; low pH promotes protonation of urate to the sparingly soluble uric acid, resulting in precipitation and lithogenesis. Obesity is associated with a different gut microbiota and uric acid stone formers yet have more specific microbiota.
Our working hypothesis is that the origin of aciduria starts in the gut lumen where the microbiota-host interaction contributes to uric acid nephrolithiasis by provision of enriched organic fatty acids, compounded by hepatic steatosis resulting in delivery of more acid to the kidney. The impaired ability of the kidney to buffer the acid eventually cumulates in unduly acidic urine pH. The underlying pathobiology stems from hepatic and renal steatosis and lipotoxicity. The combination of this microbiota-hepatic-renal defect generates and amplifies the aciduria which is the prerequisite in uric acid lithogenesis.
The pathogenesis of aciduria in uric acid nephrolithiasis is driven by excessive acid delivery to the kidney and impaired ability of the kidney to buffer the acid jointly cumulating in excessively low urine pH. The underlying pathobiology stems from hepatic and renal steatosis and lipotoxicity. The liver is unable to metabolize fatty acids and in fact adds fatty acids to the circulation. The kidney is handicapped in making its major urinary buffer of H+, ammonia. The combination of this hepatic-renal defect generates and amplifies the aciduria which is the prerequisite in uric acid lithogenesis. Both of the hepatic and renal lesions involve the PPARγ pathways as they are partially alleviated by activators of PPARγ in both animals and humans.
Urinary citrate has dual functions as a urinary alkali and to chelate calcium as a soluble calcium-citrate complex to prevent precipitation as oxalate and phosphate salts. Hypocitraturia is a common cause of kidney stones.
There are several related projects in our group centered on mechanisms of hypocitraturia. In addition to the known causes of hypocitraturia - acid loading and potassium deficiency - there are “idiopathic” cases, probably due to subtle defects in urinary acidification causing intracellular acidosis. We try to elucidate the mechanism of this condition.
Another important pathogenic factor for calcium phosphate stone is alkalinuria, so maintaining normal pH is critical. Our laboratory is working out ways to increase urine citrate without raising urine pH to devise a therapy of calcium phosphate stones.
Finally, in chronic kidney disease (CKD), low serum bicarbonate is a relatively insensitive parameter for acid loading. Serum bicarbonate is the defended parameter whereas hypocitraturia is the defense mechanism, which is a much more sensitive read-out for acid-base disturbances. We are working out conditions where urine citrate can be used as a biomarker of acid-base disturbance in human CKD.
Full-blown distal renal tubular acidosis (dRTA) is a clear cause of relentless kidney stone formation, nephrocalcinosis, and loss of kidney function, while a forme fruste of the condition is incomplete dRTA. Using typical clinical parameters, subjects with dRTA are indistinguishable from people who normally form calcium stones.
We have found that there are genetic variants of the B1 subunit of the V-ATPase and the anion exchanger AE-1, which results in incomplete dRTA in an autosomal dominant fashion.
We explore the molecular mechanisms of mutant B1 and AE1 alleles and their relationship to human incomplete dRTA using protein biochemistry and human metabolic studies.