Anton C. Schoolwerth

Chronic kidney disease: issues and establishing programs and clinics for improved patient outcomes

The spectrum of chronic kidney disease (CKD) extends from the point at which there is slight kidney damage, but normal function, to the point at which patients require either a renal transplant or renal replacement therapy to survive. Epidemiological studies suggest there are approximately 20,000,000 patients with various stages of CKD. These patients have many comorbidities, including cardiovascular disease, hypertension, diabetes, anemia, nutritional and metabolic derangements, and fluid overload. Unfortunately, evidence shows that current CKD care in the United States is suboptimal, and late referral to a nephrologist is often the rule and not the exception. Roles of primary care physicians (PCPs) and nephrologists in the care of patients with CKD remain undefined. Several studies have suggested that care provided by multidisciplinary nephrology teams can improve patient outcomes. Currently, there are published evidence-based clinical practice guidelines for anemia management, nutritional therapy, and vascular access placement, with other CKD guidelines under development. The intent of this review includes providing compelling evidence for earlier screening, identification, and management of patients with CKD; showing that current CKD care is suboptimal; encouraging the development of multidisciplinary teams that provide collaborative care to patients with CKD, suggesting roles for PCPs and nephrologists in the care of these patients; describing CKD initiatives from national organizations; and providing a comprehensive checklist that can guide the development of CKD clinics and programs.

Acute Aluminum Toxicity Associated with Oral Citrate and Aluminum-Containing Antacids

The authors report the development of a rapidly progressive encephalopathy marked by confusion, myoclonus, seizures, coma, and death in a group of women with renal failure who received an oral solution of citrate and aluminum hydroxide gel concurrently. Two patients were documented as having marked hyperaluminemia far exceeding blood aluminum levels encountered in the chronic state of aluminum intoxication. We ascribe the toxicity to enhanced gastrointestinal absorption of aluminum when complexed with citrate.

Part 1. Uric acid and losartan.

Purpose of reviewTo characterize the mechanism and clinical impact of the angiotensin-receptor blocker losartan on both renal uric acid handling and thereby serum uric acid. Recent findingsLosartan effect on serum uric acid has been demonstrated at various stages of renal failure including most recently observations obtained in end-stage renal disease patients. Other angiotensin-receptor blockers do not alter renal handling of uric acid. The uricosuria, which accompanies losartan administration, has not been associated with adverse renal consequences, in part, because of the increase in urinary pH that follows its administration. SummaryHyperuricemia is closely linked to both hypertension and cardiovascular disease. The development of hyperuricemia and its persistence are clearly renal processes. Likewise, the correction of hyperuricemia is often accomplished by increasing its renal excretion. A number of medications, by way of varying mechanisms, can alter renal urate handling and thereby influence serum uric acid values. Most recently, the angiotensin-receptor blocker losartan has been shown to reduce serum uric acid. The mechanism of this process relates to losartan alone and does not involve the E-3174 metabolite of this compound. This probenecid-like effect of losartan occurs shortly after drug administration, and is both transient and dose-dependent. This property of losartan, touted by some as a meaningful pharmacological distinction among the angiotensin-receptor blockers, remains to be proved, since, to date, the hypothesis that a reduction in serum uric acid alters the natural history of cardiovascular disease has not been formally tested.

The Role of the Renin-Angiotensin System in Cholesterol and Puromycin Mediated Renal Injury

BackgroundPuromycin aminonucleoside (PAN) nephropathy is a widely studied model of glomerular sclerosis (GS) in the rat, and cholesterol feeding exacerbates the injury induced by PAN. The importance of the interaction of angiotensin II (Ang II) with the AT2 receptor is unclear. We investigated the role of the renin-angiotensin system, particularly with regard to AT1 and AT2 receptor dynamics, in PAN and cholesterol-mediated GS. MethodsSprague-Dawley rats were given a 4% cholesterol diet (group II), subcutaneous PAN (group III), or a 4% cholesterol diet and PAN (group IV) and compared with a control group given PAN vehicle (group I). After 16 weeks, kidneys were harvested and tissue Ang II concentration, angiotensin-converting enzyme (ACE) activity, and ACE, AT1, and AT2 mRNA levels were determined. ResultsCompared with control rats, proteinuria was significantly higher in groups II to IV. Kidney ACE activity and ACE mRNA levels in groups III and IV were 2- and 3-fold higher than in groups I and II, respectively. Kidney Ang II concentration also was increased in the experimental groups. Whereas kidney AT1 mRNA was significantly lower in groups III and IV, kidney AT2 mRNA was significantly increased in groups II to IV. ConclusionIn these experimental models of GS, there is significant activation of the tissue-based renin-angiotensin system. Puromycin with and without cholesterol decreased the AT1 receptor mRNA and increased the AT2 receptor mRNA. Up-regulation of AT2 receptors may be important in ameliorating the proliferative effects of Ang II, which presumably occur through the AT1 receptor.

Acute Glomerulonephritis in a Patient With Rocky Mountain Spotted Fever

It is generally assumed that acute tubular necrosis is the etiology of renal failure that can occur during the course of Rocky Mountain spotted fever (RMSF). However, histologic examination of kidneys has been mainly limited to autopsy cases of fulminant infections. Acute glomerulonephritis due to glomerular immune complex deposition has not been reported in RMSF. We describe a case of acute oliguric renal failure that developed more than 2 weeks following the onset of RMSF. Renal biopsy showed acute glomerulonephritis with inflammatory cell infiltration and subendothelial immune deposits. Thus, acute glomerulonephritis should be in the differential diagnosis of acute renal failure that occurs in RMSF.

The Presence of HCO3- Does Not Inhibit Alpha-Adrenergic Increases in Proximal Tubular Intracellular pH

Hormonal stimulation of Na+/H+ exchange increased intracellular pH (pHi) in a dose-dependent manner in proximal tubules suspended in Krebs-Henseleit buffer (KHB) supplemented with 25 mM HCO3- and CO2 (KHB + HCO3). The maximum increase in pHi was approximately 45% of the response observed with segments suspended in bicarbonate-free buffer (KHB-HCO3) and the time required to achieve maximum pHi alterations was significantly increased (p less than 0.05) in the presence of KHB + HCO3 when compared to responses obtained in KHB - HCO3. Dose-response curves for agonist-induced pHi increases were shifted to the right by a factor of 10 for segments suspended in KHB + HCO3. Increases in pHi induced by agonists in KHB + HCO3 were effectively blocked by pretreatment with 10 microM ethylisopropyl amiloride but not with the Cl-/HCO3- inhibitor, DIDS (0.1 mM, 30 min). We conclude that stimulation of alpha-adrenergic receptors on proximal nephrons increased pHi due to activation Na+/H+ exchange and can be detected in the presence of HCO3- although the time course and maximum level of change differ significantly from those observed in a HCO3(-)-free buffer.

Regulation of Rat Kidney Mitochondrial Metabolism in Acute Acidosis

Proximal tubular ammoniagenesis is amplified under conditions of acute and chronic metabolic acidosis. Current hypotheses postulate that alterations in intracellular pH (pHi) or in the pH gradient across the inner mitochondrial membrane (delta pHm) influence mitochondrial glutamine metabolism. Enhanced glutamine transport across the inner mitochondrial membrane might constitute a key regulatory factor in acidosis. To examine changes in delta pHm, a technique was used to determine pHi and intramitochondrial pH (pHm) simultaneously. Regulation of the enzyme alpha ketoglutarate dehydrogenase (alpha KGDH) was assessed by evaluating enzyme activity at varied levels of medium pH, Ca++, and adenosine diphosphate (ADP). The results indicate that pHi decreased with an acid external pH. A fall in pHi correlated to increase activity of alpha KGDH associated with increased affinity for the substrate, alpha KG. Increments in either buffer Ca++ or ADP concentration increased enzyme affinity for alpha KG at pH 7.6 but not at pH 6.8. These results, compatible with previous reports, indicate that pH, Ca++, and ADP are effectors of the enzyme alpha KGDH. Alterations in pH across the inner mitochondrial membrane might augment flux through alpha KG by accelerating glutamine metabolism. Increased alpha KG oxidation over the range of 10 to 500 mumol/L Ca++ concentration is compatable with data for Ca++ regulation reported for the solubilized enzyme. These studies provide evidence that the above factors, through enhancing alpha KGDH activity, participate in regulation of ammoniagenesis during states of acidosis.

Effects of Acid-Base Alterations and Protein Depletion on Hepatic Nitrogen Metabolism

An alteration in acid-base balance has wide-ranging effects on many systems in the body. It has long been recognized that acid-base regulation is linked to nitrogen metabolism. Ammonium (NH4 +), which is a constituent of normal urine, is excreted in greater quantities in metabolic acidosis. Earlier work showed that the rise in NH4 + excretion in acidosis coincided with a decrease in the rate of urea excretion. When it was realized that the enzyme urease was lacking in mammalian tissues, it was concluded that urea is not a direct source of urinary NH4 +. The discovery that the extraction of glutamine by the kidney contributed significantly to urinary NH4 + focused attention on the renal metabolism of glutamine. It is now well established that the extraction of glutamine by the kidney and the renal mitochondrial deamidation of glutamine are accelerated in chronic metabolic acidosis.