Incomplete Distal Renal Tubular Acidosis and Kidney Stones.

Renal tubular acidosis (RTA) is comprised of a diverse group of congenital or acquired diseases with the common denominator of defective renal acid excretion with protean manifestation, but in adults, recurrent kidney stones and nephrocalcinosis are mainly found in presentation. Calcium phosphate (CaP) stones and nephrocalcinosis are frequently encountered in distal hypokalemic RTA type I. Alkaline urinary pH, hypocitraturia, and, less frequently, hypercalciuria are the tripartite lithogenic factors in distal RTA (dRTA) predisposing to CaP stone formation; the latter 2 are also commonly encountered in other causes of urolithiasis. Although the full blown syndrome is easily diagnosed by conventional clinical criteria, an attenuated forme fruste called incomplete dRTA typically evades clinical testing and is only uncovered by provocative acid-loading challenges. Stone formers (SFs) that cannot acidify urine of pH < 5.3 during acid loading are considered to have incomplete dRTA. However, urinary acidification capacity is not a dichotomous but rather a continuous trait, so incomplete dRTA is not a distinct entity but may be one end of a spectrum. Recent findings suggest that incomplete dRTA can be attributed to heterozygous carriers of hypofunctional V-ATPase. The value of incomplete dRTA diagnosis by provocative testing and genotyping candidate genes is a valuable research tool, but it remains unclear at the moment whether they alter clinical practice and needs further clarification. No randomized controlled trials have been performed in SFs with dRTA or CaP stones, and until such data are available, treatment of CaP stones are centered on reversing the biochemical abnormalities encountered in the metabolic workup. SFs with type I dRTA should receive alkali therapy, preferentially in the form of K-citrate delivered judiciously to treat the chronic acid retention that drives both stone formation and bone disease

Steady-state Function of the Ubiquitous Mammalian Na/H Exchanger (NHE1) in Relation to Dimer Coupling Models with 2Na/2H Stoichiometry

We describe the steady-state function of the ubiquitous mammalian Na/H exchanger (NHE)1 isoform in voltage-clamped Chinese hamster ovary cells, as well as other cells, using oscillating pH-sensitive microelectrodes to quantify proton fluxes via extracellular pH gradients. Giant excised patches could not be used as gigaseal formation disrupts NHE activity within the patch. We first analyzed forward transport at an extracellular pH of 8.2 with no cytoplasmic Na (i.e., nearly zero-trans). The extracellular Na concentration dependence is sigmoidal at a cytoplasmic pH of 6.8 with a Hill coefficient of 1.8. In contrast, at a cytoplasmic pH of 6.0, the Hill coefficient is <1, and Na dependence often appears biphasic. Results are similar for mouse skin fibroblasts and for an opossum kidney cell line that expresses the NHE3 isoform, whereas NHE1−/− skin fibroblasts generate no proton fluxes in equivalent experiments. As proton flux is decreased by increasing cytoplasmic pH, the half-maximal concentration (K1/2) of extracellular Na decreases less than expected for simple consecutive ion exchange models. The K1/2 for cytoplasmic protons decreases with increasing extracellular Na, opposite to predictions of consecutive exchange models. For reverse transport, which is robust at a cytoplasmic pH of 7.6, the K1/2 for extracellular protons decreases only a factor of 0.4 when maximal activity is decreased fivefold by reducing cytoplasmic Na. With 140 mM of extracellular Na and no cytoplasmic Na, the K1/2 for cytoplasmic protons is 50 nM (pH 7.3; Hill coefficient, 1.5), and activity decreases only 25% with extracellular acidification from 8.5 to 7.2. Most data can be reconstructed with two very different coupled dimer models. In one model, monomers operate independently at low cytoplasmic pH but couple to translocate two ions in “parallel” at alkaline pH. In the second “serial” model, each monomer transports two ions, and translocation by one monomer allosterically promotes translocation by the paired monomer in opposite direction. We conclude that a large fraction of mammalian Na/H activity may occur with a 2Na/2H stoichiometry

Renal cortical mitochondrial aconitase is regulated in hypo- and hypercitraturia

Renal cortical mitochondrial aconitase is regulated in hypo- and hypercitraturia.BackgroundChronic metabolic acidosis and K+ deficiency increase, while alkali feeding decreases proximal tubule citrate absorption and metabolism. The present studies examined the regulation of mitochondrial aconitase (m-aconitase), the first step in mitochondrial citrate metabolism, in these conditions.MethodsRats were fed appropriate diets, and m-aconitase activity and protein abundance measured.ResultsIn chronic metabolic acidosis and chronic K+ deficiency, renal cortical m-aconitase activity was increased 17% and 43%, respectively. This was associated with respective 90% and 221% increases in renal cortical m-aconitase protein abundance. With chronic alkali feeding, there was a 12% decrease in renal cortical m-aconitase activity, associated with a 35% decrease in m-aconitase protein abundance. Hepatic m-aconitase activity was not regulated in a similar manner. There was no regulation of citrate synthase, the enzyme responsible for mitochondrial citrate synthesis.ConclusionsThese studies demonstrate tissue specific chronic regulation of renal cortical m-aconitase activity and protein abundance, which likely contributes to the hypocitraturia and hypercitraturia seen in these conditions. As m-aconitase is the only step in citrate transport and metabolism found to be regulated in alkali feeding, its regulation likely plays a significant role in mediating the hypercitraturia seen in this condition

Long-term combined treatment with thiazide and potassium citrate in nephrolithiasis does not lead to hypokalemia or hypochloremic metabolic alkalosis

Long-term combined treatment with thiazide and potassium citrate in nephrolithiasis does not lead to hypokalemia or hypochloremic metabolic alkalosis.BackgroundPotassium citrate is commonly used in combination with a thiazide diuretic in the medical management of recurrent hypercalciuric nephrolithiasis. However, concerns have been raised that administration of this nonchloride potassium alkali with a kaliuretic and natriuretic agent such as thiazide may not be efficacious in correcting or preventing hypokalemia, and may produce hypochloremic metabolic alkalosis. This retrospective analysis was conducted to determine if these two potential complications are encountered in patients on long-term potassium citrate and thiazide therapy.MethodsData were collected on 95 patients who had been on combination therapy for at least 4 months from the stone clinics of the University of Texas Southwestern Medical Center, Duke University Medical Center, and Ochsner Clinic.ResultsMean serum potassium concentration remained within normal limits without a significant decrease during combined therapy. Serum chloride was significantly lower from pretreatment but by only 1 mEq/L and remained within normal limits throughout treatment. There was a small increase in serum bicarbonate concentration compared to the baseline level of less than 1 mEq/L at 8 to 12 and 18 to 24 months, but not at other treatment periods.ConclusionCo-administration of potassium citrate did not induce hypokalemia or hypochloremic metabolic alkalosis in our thiazide-treated patient population

Metabolic syndrome and the risk of calcium stones

Sakhaee et al in this issue have investigated whether the risk of the common calcium nephrolithiasis is associated with the metabolic syndrome (MS). This question is interesting since it deals with a more general problem on whether calcium nephrolithiasis is a ‘systemic disorder' and entails a cardiovascular ris

Relative effect of urinary calcium and oxalate on saturation of calcium oxalate Rapid Communication

Relative effect of urinary calcium and oxalate on saturation of calcium oxalate.BackgroundThe study compared the effect of urinary calcium with that of oxalate on urinary saturation [relative saturation ratio (RSR)] of calcium oxalate.MethodsA retrospective data analysis was conducted on urinary stone risk analysis from 667 patients with predominantly calcium oxalate stones. Urinary RSR of calcium oxalate was individually calculated using Equil 2. A “theoretical” curve of the relationship between urinary RSR of calcium oxalate and concentration of calcium or oxalate was obtained at two stability constants for calcium oxalate complex, while varying calcium or oxalate and using group mean values for urinary constituents.ResultsAt the stability constant of 7.07 × 103, the increase in RSR of calcium oxalate was less marked with calcium than with oxalate. However, at the stability constant of 2.746 × 103 from the Equil 2 that is considered the “gold standard,” calcium and oxalate were equally effective in increasing RSR of calcium oxalate. The above theoretical curves (relating RSR with calcium or oxalate) were closely approximated by the actual curves constructed with data from individual urine samples. Urinary saturation of calcium oxalate was equally dependent on urinary concentrations of calcium and oxalate (r = 0.75 unadjusted and 0.57 adjusted for variables, and P < 0.0001 for calcium; r = 0.73 unadjusted and 0.60 adjusted, P <0.0001 for oxalate).ConclusionAmong calcium oxalate stone-formers, urinary calcium is equally effective as urinary oxalate in increasing RSR of calcium oxalate

Sepsis-Associated Acute Kidney Disease and Long-term Kidney Outcomes

Rationale & Objective: Sepsis-associated acute kidney injury often leads to acute kidney disease (AKD), predisposing patients to long-term complications such as chronic kidney disease (CKD), kidney failure with replacement therapy (KFRT), or mortality. Risk stratification of patients with AKD represents an opportunity to assist with prognostication of long-term kidney complications. Study Design: Single-center retrospective cohort. Setting & Participants: 6,290 critically ill patients admitted to the intensive care unit with severe sepsis or septic shock. Patients were separated into cohorts based on incident acute kidney injury or not, and survivors identified who were alive and free of KFRT up to 90 days. Predictors: AKD stage (0A, 0C, or ≥1) using the last serum creatinine concentration available by discharge or up to 90 days postdischarge. Outcome: Time to development of incident CKD, progression of CKD, KFRT, or death. Analytical Approach: Multivariable Cox proportional hazards models. Results: Patients surviving kidney injury associated with sepsis often fail to return to baseline kidney function by discharge: 577/1,231 (46.9%) with stage 0C or 1 or greater AKD. AKD stage was significantly associated with the composite primary outcome. Stages 0C AKD and 1 or greater AKD were significantly and progressively associated with the primary outcome when compared with stage 0A AKD (adjusted HR [aHR], 1.74; 95% CI, 1.32-2.29, and aHR, 3.25; 95% CI, 2.52-4.20, respectively). Additionally, stage 1 or greater AKD conferred higher risk above stage 0C AKD (aHR, 1.87; 95% CI, 1.44-2.43). CKD incidence or progression and KFRT, more so than mortality, occurred with greater frequency in higher stages of AKD. Limitations: Retrospective design, single center, exclusion of patients with KFRT within 90 days of discharge, potential ascertainment bias, and inability to subclassify above AKD stage 1. Conclusions: Risk stratification using recommended AKD stages at hospital discharge or shortly thereafter associates with the development of long-term kidney outcomes following sepsis-associated acute kidney injury

Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet

Vascular calcification is common in chronic kidney disease, where cardiovascular mortality remains the leading cause of death. Patients with kidney disease are often prescribed vitamin D receptor agonists (VDRAs) that confer a survival benefit, but the underlying mechanisms remain unclear. Here we tested two VDRAs in a mouse chronic kidney disease model where dietary phosphate loading induced aortic medial calcification. Mice were given intraperitoneal calcitriol or paricalcitol three times per week for 3 weeks. These treatments were associated with half of the aortic calcification compared to no therapy, and there was no difference between the two agents. In the setting of a high-phosphate diet, serum parathyroid hormone and calcium levels were not significantly altered by treatment. VDRA therapy was associated with increased serum and urine klotho levels, increased phosphaturia, correction of hyperphosphatemia, and lowering of serum fibroblast growth factor-23. There was no effect on elastin remodeling or inflammation; however, the expression of the anticalcification factor, osteopontin, in aortic medial cells was increased. Paricalcitol upregulated osteopontin secretion from mouse vascular smooth muscle cells in culture. Thus, klotho and osteopontin were upregulated by VDRA therapy in chronic kidney disease, independent of changes in serum parathyroid hormone and calcium

Serum Renin and Major Adverse Kidney Events in Critically Ill Patients: A Multicenter Prospective Study

BACKGROUND: Preliminary studies have suggested that the renin-angiotensin system is activated in critical illness and associated with mortality and kidney outcomes. We sought to assess in a larger, multicenter study the relationship between serum renin and Major Adverse Kidney Events (MAKE) in intensive care unit (ICU) patients. METHODS: Prospective, multicenter study at two institutions of patients with and without acute kidney injury (AKI). Blood samples were collected for renin measurement a median of 2 days into the index ICU admission and 5-7 days later. The primary outcome was MAKE at hospital discharge, a composite of mortality, kidney replacement therapy, or reduced estimated glomerular filtration rate to ≤ 75% of baseline. RESULTS: Patients in the highest renin tertile were more severely ill overall, including more AKI, vasopressor-dependence, and severity of illness. MAKE were significantly greater in the highest renin tertile compared to the first and second tertiles. In multivariable logistic regression, this initial measurement of renin remained significantly associated with both MAKE as well as the individual component of mortality. The association of renin with MAKE in survivors was not statistically significant. Renin measurements at the second time point were also higher in patients with MAKE. The trajectory of the renin measurements between time 1 and 2 was distinct when comparing death versus survival, but not when comparing MAKE versus those without. CONCLUSIONS: In a broad cohort of critically ill patients, serum renin measured early in the ICU admission is associated with MAKE at discharge, particularly mortality