Glomerular filtration rate and blood pressure monitoring in awake baboons

Minimally invasive techniques were used to collect urine with an external catheter together with automated intermittent monitoring of arterial blood pressure in awake male baboons. Using endogenous creatinine, 24-hour creatinine clearances were measured for 2 to 3 consecutive days in four intact and in four uninephrectomized baboons. Despite large differences in urinary volume and sodium excretion, reproducibility of 24-hour creatinine clearances was within 15% in 15 of 19 studies obtained from 6 of 8 animals. Arterial blood pressure was monitored intermittently at 30 to 60 minute intervals over 24 hours with a Dinamap monitor and recorder. Mean blood pressure averaged 71 +/- 4.4 to 89 +/- 5.5 mm Hg in different animals. Blood pressure tended to be lower at night than during the day. In separate studies using 15 to 60 minute urine collection periods, inulin clearance was compared in awake and in anesthetized animals with endogenous or exogenous creatinine clearance measured simultaneously. The clearance of creatinine systematically exceeded the clearance of inulin, even in intact animals with a normal serum creatinine. The creatinine-to-inulin clearance ratio averaged 1.16 +/- 0.03 at a serum concentration of 0.7 to 0.8 mg/dl; 1.27 +/- 0.03 at a serum creatinine of 1.0 to 1.1 mg/dl and 1.56 +/- 0.04 at a serum creatinine greater than 10 mg/dl. All values exceed unity significantly (p less than 0.001). Thus, renal function, including inulin clearance, can be measured in awake baboons. Duplicate or triplicate 24-hour urine collections are needed to assess the reliability of creatinine excretion. However, creatinine clearance overestimates glomerular filtration rate, as it does in humans.     

Measurement of urinary clusterin as an index of nephrotoxicity.

Measurements of tissue immunoassayable clusterin, a protein associated with programmed cell death and tissue reorganization, were performed in rats treated with nephrotoxic doses of gentamicin sulfate. Adult Lewis rats were treated with 100 mg/kg/day of gentamicin sulfate for 12 days. Urine, serum, and tissue levels of clusterin protein were measured, as were urinary N-acetyl beta-glucosaminidase (NAG) and serum creatinine levels. Induction of renal injury by gentamicin was detectable within 4 days by increased levels of urinary N-acetyl beta-glucosaminidase (from 280 +/- 66 (mean +/- SD) to 910 +/- 210 nmol/mg creatinine), and within 9 days of initiating gentamicin treatment by increased serum creatinine (from 0.5 +/- 0.1 to 1.2 +/- 0.4 mg/dl). Paralleling these changes, renal, urinary, and serum levels of clusterin increased 10-, 116-, and 3-fold (P less than 0.05). Treatment with gentamicin sulfate did not increase clusterin levels in the seminal vesicle, ventral prostate, testis, or epididymis. The measurement of urinary or serum clusterin may play a role in the early detection of renal injury.     

Glomerular function in spontaneously diabetic rats.

This study was undertaken to determine whether hyperfiltration exists at the single nephron level and whether albumin excretion is increased early in the course of diabetes in Biobreeding rats. Diabetic rats were studied at 8-12 weeks after the onset of diabetes. Control animals were age-matched, diabetes-resistant rats. Urinary and tubular fluid albumin concentrations were measured by polyacrylamide gel electrophoresis. Clearance and micropuncture techniques were used to determine whole kidney and single nephron glomerular filtration rate, renal blood flow, and glomerular capillary pressure. The urinary albumin excretion rate (1.3 +/- 0.1 mg/24 hr) and the tubular fluid albumin concentration (4.7 +/- 0.7 mg/dl) in the diabetic group were significantly elevated when compared with urinary albumin excretion (0.9 +/- 0.1 mg/24 hr) and tubular fluid albumin concentration (2.5 +/- 0.5 mg/dl) in the control group. There were no significant differences in glomerular hemodynamics (whole kidney or single nephron glomerular filtration rate or glomerular capillary pressure) between diabetic and control rats. The kidney weight and kidney weight to body weight ratio were significantly higher in diabetic rats when compared with control rats. Early diabetes in Biobreeding rats is characterized by mild albuminuria and increased kidney size, but not glomerular hyperfiltration.     

DPP4 inhibition improves functional outcome after renal ischemia-reperfusion injury

Dipeptidyl peptidase 4 (DPP4) is an exopeptidase which modulates the function of its substrates, among which are insulin-releasing incretins. DPP4 inhibitors are currently used to improve glucose tolerance in type 2 diabetes patients. Inhibition of DPP4 exhibits protective effects on ischemia-reperfusion injury (IRI) of the heart and lung. As DPP4 and its substrates are also expressed in the kidney, we studied the effect of the DPP4 inhibitor vildagliptin on the outcome of IRI-induced acute kidney injury in rats in a model of 30-min unilateral renal ischemia, followed by contralateral nephrectomy. Saline, 1, or 10 mg/kg vildagliptin (VG1/VG10) was administered intravenously 15 min before the surgery. Animals were euthanized after 2, 12, amd 48 h of reperfusion. DPP4 inhibition resulted in a significant dose-dependent decrease in serum creatinine (1.31 ± 0.32 and 0.70 ± 0.19 mg/dl for VG1 and VG10, respectively, vs. 1.91 ± 0.28 mg/dl for controls at 12 h; P < 0.01). Tubular morphology (PAS-PCNA) revealed significantly reduced tubular necrosis at 12 h (62.1 ± 18.0 and 77.5 ± 22.0% in VG10 and saline, respectively). VG did not affect regeneration but decreased apoptosis, as shown by twofold decreased Bax/Bcl-2 mRNA expression and a threefold decrease in apoptotic bodies on terminal deoxynucleotidyl transferase dUTP nick-end labeling-stained sections. VG treatment significantly reduced serum malondialdehyde twofold in both VG1- and VG10-treated ischemic and sham-operated animals compared with controls and also resulted in a significant decrease in mRNA expression of the proinflammatory marker CXCL10 at 2 h of reperfusion. Through a mechanism yet to be fully understood, VG treatment results in a functional protection of the kidney against IRI. This protection was associated with antiapoptotic, immunological, and antioxidative changes.     

Effect of chronic renal failure,dialysis and transplantation on motor nerve conduction velocity in children.

Ulnar and peroneal motor nerve conduction volocities (MNCVs) were measured in 47 children in a dialysis-transplantation program. Mean peroneal MNCV was significantly decreased from normal in children with mild renal failure (serum creatinine concentration, 1.5 to 2.9 mg/dl), whereas ulnar MNCV was significantly decreased only when the serum creatinine value was at least 9 mg/dl. Both ulnar and peroneal MNCVs remained unchanged during long-term hemodialysis or peritoneal dialysis; however, after individual dialyses ulnar MNCV increased. After renal transplantation ulnar MNCV returned to normal within a year and peroneal MNCV within 3 years. Before dialysis was required and during long-term dialysis most plasma magnesium values were elevated; ionized calcium activity was decreased in about 50% of determinations. After transplantation and the concentration of divalent cations rapidly returned to normal. These children differed from adults studied in that (a) there was no correlation between severity of renal failure and MNCV, (b) long-term dialysis did not improve MNCV and (c) peroneal velocities did not recover for 3 years after transplantation.     

Evaluation of Intestinal Phosphate Binding to Improve the Safety Profile of Oral Sodium Phosphate Bowel Cleansing

Prior to colonoscopy, bowel cleansing is performed for which frequently oral sodium phosphate (OSP) is used. OSP results in significant hyperphosphatemia and cases of acute kidney injury (AKI) referred to as acute phosphate nephropathy (APN; characterized by nephrocalcinosis) are reported after OSP use, which led to a US-FDA warning. To improve the safety profile of OSP, it was evaluated whether the side-effects of OSP could be prevented with intestinal phosphate binders. Hereto a Wistar rat model of APN was developed. OSP administration (2 times 1.2 g phosphate by gavage) with a 12h time interval induced bowel cleansing (severe diarrhea) and significant hyperphosphatemia (21.79 ± 5.07 mg/dl 6h after the second OSP dose versus 8.44 ± 0.97 mg/dl at baseline). Concomitantly, serum PTH levels increased fivefold and FGF-23 levels showed a threefold increase, while serum calcium levels significantly decreased from 11.29 ± 0.53 mg/dl at baseline to 8.68 ± 0.79 mg/dl after OSP. OSP administration induced weaker NaPi-2a staining along the apical proximal tubular membrane. APN was induced: serum creatinine increased (1.5 times baseline) and nephrocalcinosis developed (increased renal calcium and phosphate content and calcium phosphate deposits on Von Kossa stained kidney sections). Intestinal phosphate binding (lanthanum carbonate or aluminum hydroxide) was not able to attenuate the OSP induced side-effects. In conclusion, a clinically relevant rat model of APN was developed. Animals showed increased serum phosphate levels similar to those reported in humans and developed APN. No evidence was found for an improved safety profile of OSP by using intestinal phosphate binders.     

Role of the kidney in the metabolism of apolipoprotein A-IV: influence of the type of proteinuria

Increased plasma concentrations of apolipoprotein A-IV (apoA-IV) in chronic renal disease suggest a metabolic role of the kidney for this antiatherogenic protein. Therefore, we investigated patients with various forms of proteinuria and found increased serum concentrations of apoA-IV in 124 nephrotic patients compared with 274 controls (mean 21.9 +/- 9.6 vs. 14.4 +/- 4.0 mg/dl; P < 0.001). Decreasing creatinine clearance showed a strong association with increasing apoA-IV levels. However, serum albumin levels significantly modulated apoA-IV levels in patients with low creatinine clearance, resulting in lower levels of apoA-IV in patients with low compared with high albumin levels (21.4 +/- 8.6 vs. 29.2 +/- 8.4 mg/dl; P = 0.0007). Furthermore, we investigated urinary apoA-IV levels in an additional 66 patients with a wide variety of proteinuria and 30 controls. Especially patients with a tubular type of proteinuria had significantly higher amounts of apoA-IV in urine than those with a pure glomerular type of proteinuria and controls (median 45, 14, and 0.6 ng/mg creatinine, respectively). We confirmed these results in affected members of a family with Dent's disease, who are characterized by an inherited protein reabsorption defect of the proximal tubular system. In summary, our data demonstrate that the increase of apoA-IV caused by renal impairment is significantly modulated by low levels of serum albumin as a measure for the severity of the nephrotic syndrome. From this investigation of apoA-IV in urine as well as earlier immunohistochemical studies, we conclude that apoA-IV is filtered through the normal glomerulus and is subsequently reabsorbed mainly by proximal tubular cells.     

Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system

The klotho gene encodes a novel type I membrane protein of beta-glycosidase family and is expressed principally in distal tubule cells of the kidney and choroid plexus in the brain. These mutants displayed abnormal calcium and phosphorus homeostasis together with increased serum 1,25-(OH)2D. In kl-/- mice at the age of 3 wk, elevated levels of serum calcium (10.9 +/- 0.31 mg/dl vs. 10.0 +/- 0.048 mg/dl in wild-type mice), phosphorus (14.7 +/- 1.1 mg/dl vs. 9.7 +/- 1.5 mg/dl in wild type) and most notably, 1,25-(OH)2D (403 +/- 99.7 mg/dl vs. 88.0 +/- 34.0 mg/dl in wild type) were observed.Reduction of serum 1,25-(OH)2D concentrations by dietary restriction resulted in alleviation of most of the phenotypes, suggesting that they are downstream events resulting from elevated 1,25-(OH)2D. We searched for the signals that lead to up-regulation of vitamin D activating enzymes. We examined the response of 1alpha-hydroxylase gene expression to calcium regulating hormones, such as PTH, calcitonin, and 1,25-(OH)2D3. These pathways were intact in klotho null mutant mice, suggesting the existence of alternate regulatory circuits. We also found that the administration of 1,25-(OH)2D3 induced the expression of klotho in the kidney. These observations suggest that klotho may participate in a negative regulatory circuit of the vitamin D endocrine system, through the regulation of 1alpha-hydroxylase gene expression.     

Alteration of vascular thromboxane in rats with subtotal renal ablation

To assess the roles of vascular prostaglandins in the hypertension of chronic renal failure, the release of prostacyclin and thromboxane (TX) from aorta was evaluated in male Sprague-Dawley rats, the renal mass of which was reduced by removing one kidney and two-thirds of the contralateral kidney ("5/6 nephrectomy"). Five-sixths nephrectomy was followed by significant rises in serum creatinine to 0.55 +/- 0.03 mg/dl and urea nitrogen to 42.9 +/- 3.8 mg/dl, with a concomitant rise in mean blood pressure from 121.6 +/- 1.6 mmHg to 155.3 +/- 8.4 mmHg. In 5/6 nephrectomized rats, the release of TX A2 from aorta, as measured by its stable metabolite TX B2, increased by 60% (p less than 0.01) and prostacyclin, as measured by its stable metabolite 6-keto-prostaglandin, F1 alpha (6-keto-PG F1 alpha) increased by 51% (p less than 0.05). The amounts of both TX B2 and 6-keto-PG F1 alpha released from aorta were closely related to the height of mean blood pressure. These results suggest that the enhanced vasoconstrictor TX production in the vascular walls may be relevant to hypertension in rats with subtotal renal ablation. The adaptive increase in prostacyclin production in the vascular walls may compensate for the elevation of blood pressure due to chronic renal failure in this animal model.     

Serum cholesterol and triglyceride measurements in Canadian physicians.

In a study of serum cholesterol and triglyceride concentrations in male physicians, blood was drawn after fasting from 2071 registrants at 17 Canadian medical meetings from 1968 to 1973. Eight regional medical laboratories participated in the study. About two thirds of the samples were analysed in one of two laboratories to diminish method variations. When chylomicronemia, hyperglycemia or extremely high triglyceride values were detected, suggesting nonfasting, the data were discarded. The mean serum cholesterol value for the total study population was 233.9 plus or minus 1.22 mg/dl and the mean serum triglyceride value, 150.5 plus or minus 2.48 mg/dl. The mean values and the prevalence of elevated values (cholesterol larger than or equal to 250 mg/dl; triglyceride larger than or equal to 150 mg/dl) were related to age. Of the total study population 34.7% had elevated cholesterol values and 36.2% had elevated triglyceride values; only the cholesterol value was elevated in 17.5%, only the triglyceride value in 19.6% and both values were elevated in 16.8%. Although this was not a random sampling of Canadian physicians or of Canadian men, our findings of elevated serum lipid values were similar to those in French Canadian civic workers, American executives and Scandinavians, and somewhat higher than those in the Albany, New York and Framingham populations, but distinctly higher than those reported by a recent Nutrition Canada survey.     

Clinical and pathological features of six cases of sarcoidosis presenting with renal failure

Six patients with biopsy-proven renal sarcoidosis presented with renal failure of unknown origin; in none was the diagnosis of sarcoidosis initially considered. The serum creatinine concentration at the time of presentation ranged from 265 to 1380 μmol/l (3.0 to 15.6 mg/dl), with a mean of 787 μmol/l (8.9 mg/dl). Although only two patients were hypercalcemic at the time of presentation, the 24-hour urinary excretion of calcium was increased in three of the four patients in whom it was measured, and renal calculi were present in one case. Renal biopsy revealed interstitial nephritis and tubular atrophy in all cases, as well as nephrocalcinosis in three cases and noncaseating granulomas negative for acid-fast bacilli in four cases. In each patient steroid therapy led to a rapid improvement in renal function (mean post-treatment serum creatinine level 274 μmol/l [3.1 mg/dl]). The follow-up period ranged from 8 months to 8 years (mean 3.0 years). In three patients renal function remained stable with low-dose steroid therapy. In two cases recurrent hypercalcemia and deteriorating renal function accompanied steroid withdrawal but resolved with its reinstitution. In one additional case reversible deterioration in renal function accompanied tapering of the steroid dose; however, there was no hypercalcemia.This report emphasizes the importance of considering sarcoidosis in the differential diagnosis of acute renal failure of unknown origin. Long-term follow-up of such patients is essential, as relapse is common.     

Cytokine elevation and transaminitis after laparoscopic donor nephrectomy

Acute kidney injury frequently occurs in the critically ill and often progresses into multiorgan dysfunction syndrome, resulting in high mortality. We previously showed that nephrectomized mice had increased interleukin (IL)-6 and tumor necrosis factor (TNF)-α that directly contributed to systemic inflammation and hepatic injury. In this study, we examined whether patients undergoing laparoscopic donor nephrectomy have increased postoperative cytokine levels with injury to the liver and whether the remaining kidney sustains injury. Serial serum and urine samples were collected from 32 patients undergoing laparoscopic donor nephrectomy and 17 patients undergoing nonrenal laparoscopic surgery. Serum IL-6, IL-18, TNF-α and monocyte chemotactic protein-1 (MCP-1) (markers of systemic inflammation) and urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), MCP-1, and IL-18 (markers of acute kidney injury) were quantified by enzyme-linked immunosorbent assay. We also analyzed serum creatinine, aspartate transaminase (AST), and alanine transaminase to assess liver injury. Patients who underwent donor nephrectomy not only demonstrated increased serum creatinine but also had significant increases in serum IL-6, MCP-1, and AST. Serum TNF-α also trended upward in donor nephrectomy patients. Finally, the donor nephrectomy group showed increased urinary NGAL but not KIM-1 at 24 h. Taken together, our findings of increased serum IL-6, MCP-1, and AST after donor nephrectomy suggest that an acute reduction of kidney function induces systemic inflammation and may have distant effects on the liver. Further studies are needed to correlate increased urinary NGAL after donor nephrectomy both as a potential marker for renal tubular stress and/or hypertrophy in the contralateral kidney.     

Allantoxanamide: A potent new uricase inhibitor in vivo

Allantoxanamide (2,4-dihydroxy-6-carboxamide-1,3,5-triazine) was studied as a uricase inhibitor in the rat. Uricase activity $\text{in vitro}$ was inhibited 50% by allantoxanamide at 9 × 10- M concentration. A single 250 mg/kg i.p. dose in the rat gave rise to a serum uric acid level of 14 mg/dl 6 hr after dosing; serum uric acid was still elevated (10 mg/dl) after 24 hr. At this dose level, deposition of uric acid in kidney tubules was observed. Studies with [8-¹⁴ C] uric acid indicated that the effect of allantoxanamide on serum uric acid was due to inhibition of uricase. The allantoxanamide-treated rat may serve as a useful animal model for the study of problems related to purine biosynthesis, drug-induced hyperuricemia and hyperuricosuria, and associated nephropathy.     

Hydration status affects urea transport across rat urothelia

Although mammalian urinary tract epithelium (urothelium) is generally considered impermeable to water and solutes, recent data suggest that urine constituents may be reabsorbed during urinary tract transit and storage. To study water and solute transport across the urothelium in an in vivo rat model, we instilled urine (obtained during various rat hydration conditions) into isolated in situ rat bladders and, after a 1-h dwell, retrieved the urine and measured the differences in urine volume and concentration and total quantity of urine urea nitrogen and creatinine between instilled and retrieved urine in rat groups differing by hydration status. Although urine volume did not change >1.9% in any group, concentration (and quantity) of urine urea nitrogen in retrieved urine fell significantly (indicating reabsorption of urea across bladder urothelia), by a mean of 18% (489 mg/dl, from an instilled 2,658 mg/dl) in rats receiving ad libitum water and by a mean of 39% (2,544 mg/dl, from an instilled 6,204 mg/dl) in water-deprived rats, but did not change (an increase of 15 mg/dl, P = not significant, from an instilled 300 mg/dl) in a water-loaded rat group. Two separate factors affected urea nitrogen reabsorption rates, a urinary factor related to hydration status, likely the concentration of urea nitrogen in the instilled urine, and a bladder factor(s), also dependent on the animal's state of hydration. Urine creatinine was also absorbed during the bladder dwell, and hydration group effects on the concentration and quantity of creatinine reabsorbed were qualitatively similar to the hydration group effect on urea transport. These findings support the notion(s) that urinary constituents may undergo transport across urinary tract epithelia, that such transport may be physiologically regulated, and that urine is modified during transit and storage through the urinary tract.     

Effect of pre-treatment with St John's Wort on nephrotoxicity of cisplatin in rats

An herbal health care supplement, St John's Wort (SJW, Hypericum perforatum) has become widely used in the treatment of depression, and is known to interact with therapeutic drugs. Here we report a preventive effect of SJW on cisplatin nephrotoxicity in rats. Rats were given SJW (400 mg/kg/day, p.o.) for 10 consecutive days, and were injected with cisplatin (5 mg/kg, i.v.) on the day after the final SJW treatment. Cisplatin treatment increased the serum creatinine level, which is an index of nephrotoxicity, to 1.51+/-0.22 mg/dl (mean+/-SE) from 0.28+/-0.05 mg/dl (control) on day 5 after the cisplatin injection. This increase fell significantly to 0.86+/-0.13 mg/dl by pre-treatment with SJW. Cisplatin-induced histological abnormality of the kidney was blocked by pre-treatment with SJW. When SJW was administered for 10 days, the amounts of renal metallothionein (MT) and hepatic multidrug resistance protein 2 (Mrp2) were increased to 164.8+/-13.0% and 220.8+/-39.3% (mean+/-SE) of controls, respectively. GSH levels in the kidney and liver were not changed. Total and free cisplatin concentration in serum was not influenced by SJW treatment. In conclusion, the results suggest that pre-treatment with SJW may diminish cisplatin nephrotoxicity.     

Role of dietary phosphorus in the progression of renal failure

Dietary phosphorus is thought to be a factor that impairs the residual renal function in patients with chronic renal failure. To determine the effect of dietary phosphorus on the prognosis of chronic renal failure, low-phosphorus milk was prepared from normal cow's milk using boehmite, a synthetic phosphate-ion absorbent. Regular diet, normal cow's milk, and low-phosphorus milk were then given to 5/6-nephrectomized rats and the serum levels of inorganic phosphorus, calcium, creatinine, and blood urine nitrogen in the rats in each group were compared. The serum levels of inorganic phosphorus and calcium were not different among the groups, despite a significant difference in phosphorus intakes. On the other hand, serum levels of creatinine (Cr) and blood urine nitrogen (BUN) in the rats fed low-phosphorus milk were significantly lower (Cr, 0.54+/-0.054mg/dl; BUN, 29.2+/-3.90mg/dl) than those in the rats fed a regular diet (Cr, 0.64+/-0.057mg/dl; BUN, 37.4+/-3.55mg/dl) or normal milk (Cr, 0.61+/-0.040mg/dl; BUN, 34.5+/-3.59mg/dl). No beneficial effect of protein restriction was observed when residual renal functions in rats fed a regular diet and those fed normal milk were compared. The results suggest that dietary phosphorus plays a major role in the progression of renal failure.     

Exertional heat stroke: the runner's nemesis.

Heat stroke in distance runners is increasing in frequency. A case is reported of a 41-year-old man who collapsed during a 10-km "fun run" held when the temperature was 31.6 degrees C and the humidity 80%. Acute renal failure (serum creatinine level 1530 mumol/l [17.3 mg/dl]), rhabdomyolysis, disseminated intravascular coagulation and hepatic damage complicated the clinical picture. Repeated peritoneal dialysis and one cycle of hemodialysis because of a very high serum level of uric acid (1.23 mmol/l [20.7 mg/dl]) were required. Although the illness was prolonged, recovery was almost complete, and 4 months after the man''s collapse the serum creatinine level had fallen to 133 mumol/l (1.5 mg/dl).     

Distinct effects on long-term function of injured and contralateral kidneys following unilateral renal ischemia-reperfusion

Salt-sensitive hypertension and chronic kidney disease (CKD) following recovery from acute kidney injury (AKI) may occur secondary to incomplete repair, or by activation of circulating factors stimulated by injury. We created two types of renal injury induced by unilateral ischemia-reperfusion (I/R); in a direct/ipsilateral AKI group, rats were subjected to unilateral I/R and the untouched contralateral kidney was removed by unilateral nephrectomy after 5 wk to isolate effects on the injured kidney. In the remote/contralateral AKI group, the injured kidney was removed after 5 wk to isolate effects on the untouched kidney. When these animals were subsequently challenged with elevated dietary sodium for an additional 4 wk (0.4 to 4%), both remote/contralateral and direct/ipsilateral AKI rats manifested a significant increase in blood pressure relative to sham-operated controls. Similarly, in acute studies, both ipsilateral and contralateral kidneys had impaired pressure natriuresis and hemodynamic responses. Reductions in vascular density were observed following direct/ipsilateral injury, but were not observed in the remote/contralateral kidney. However, both remote/contralateral and direct/ipsilateral kidneys contained interstitial cells, some of which were identified as activated (low CD62L/CD4+) T lymphocytes. In contrast, only the direct/ipsilateral AKI group demonstrated significant CKD following exposure to elevated salt. This was characterized by a significant reduction in creatinine clearance, an increase in albuminuria, and a dramatic expansion of interstitial inflammation. Taken together, these data suggest that the salt-sensitive features of AKI on hypertension and CKD are segregable such that effects on hemodynamics and hypertension occur independent of direct renal damage. However, prior direct injury to the kidney is required to elicit the full manifestation of CKD induced by elevated sodium intake.     

Humoral hypercalcemia caused by a rat Leydig-cell tumor is associated with suppressed parathyroid hormone secretion and increased urinary cAMP excretion

We studied the effect of a transplantable Leydig-cell tumor (Rice H-500) on serum calcium, parathyroid hormone (PTH), and urinary cAMP in intact Fischer-344 rats. The tumor caused rapid and severe hypercalcemia (control = 10.5 +/- 0.1 mg/dl [mean +/- S.E.] vs. 14.6 +/- 0.9 at day 12 post tumor inoculation) without evidence of metastasis. Progressive renal impairment and death generally occurred within 15 days of tumor inoculation. Serum PTH declined from control values before hypercalcemia occurred and was significantly reduced in tumor-bearing hypercalcemic rats (mean = 60 +/- 8% of control values). Urinary cAMP excretion was increased in tumor-bearing rats (mean at day 12 post inoculation = 12.2 +/- 1.4 nmol/dl creatinine clearance vs. control = 6.2 +/- 0.2) and correlated positively with serum calcium. The Rice H-500 Leydig-cell tumor appears to secrete a humoral factor capable of causing hypercalcemia. This factor may also increase urinary cAMP excretion in a manner analogous to PTH, but it is not detected by PTH radioimmunoassay.     

Hypothyroidism and Reversible Kidney Dysfunction: An Essential Relationship to Recognize

ObjectiveTo report 3 cases of reversible hypothyroidism-induced kidney dysfunction and review the interaction between these commonly encountered, yet seemingly disparate, conditions.MethodsWe describe the clinical course and laboratory and physical findings of 3 patients who presented with kidney dysfunction that improved after initiating thyroid hormone replacement therapy. We also review similar cases in the literature and discuss the pathophysiologic mechanisms.ResultsA 68-year-old male presented with classical signs and symptoms of hypothyroidism, including fatigue, confusion, and gait imbalance. Physical exam showed bradycardia, thyromegaly, slow mentation, and cracked, thin skin; he was found to have decreased kidney function. Second, a 42-year-old previously healthy female presented with bilateral hand swelling and elevated serum creatinine with an otherwise unremarkable physical exam. The third patient was a 72-year-old male with advanced heart failure on amiodarone and stage 3 chronic kidney disease who presented with fatigue, acute kidney injury, and lower extremity edema. In all cases, serum creatinine and thyroid-stimulating hormone (TSH) were elevated at presentation (1.4-3.0 mg/dL and 94.1-184 mIU/L respectively), and free thyroxine (T4) was low (undetectable-0.4 ng/dL). The initiation or increased dose of levothyroxine normalized serum creatinine to baseline within 2 to 10 months.ConclusionHypothyroidism and kidney dysfunction are both commonly encountered clinical entities, but the interplay between the thyroid gland and kidneys may be infrequently recalled, causing the reversible relationship between these 2 disorders to be missed. (Endocr Pract. 2014;20:490-499)