Characterization of tubular functional capacity in humans using para-aminohippurate and famotidine.

BACKGROUND: Renal drug excretion by glomerular filtration and active tubular secretion may be altered by factors such as acute and chronic renal disease, nephrotoxins, and drug interactions. Thus, accurate and reproducible methods for quantitation of glomerular filtration rate (GFR) and tubular functional capacity are critical. METHODS: We utilized a four-step sequential infusion method to characterize anionic [para-aminohippurate (PAH)] and cationic (famotidine) tubular functional capacity in healthy volunteers. Filtration and secretion rates were quantitated from renal clearance and iothalamate-derived GFR determinations. RESULTS: Concentration-dependent renal clearance of PAH was observed at plasma concentrations> 100 mg/L; renal clearances were 442 +/- 131 (mean +/- SD), 423 +/- 94, 233 +/- 45, and 152 +/- 18 mL/min/1.73 m2 at plasma concentrations of 18 +/- 2, 92 +/- 5, 291 +/- 47 and 789 +/- 28 mg/L, respectively. The apparent affinity (Km) and maximum secretory capacity (TmPAH) were 141 +/- 70 mg/L and 71 +/- 16 mg/min/1.73 m2, respectively. The unbound renal clearance and tubular secretory clearance of famotidine were 384 +/- 70 and 329 +/- 78 mL/min/1.73 m2, respectively, and were not significantly correlated with the unbound plasma concentrations, which ranged from 126 to 2659 ng/mL. The rate of tubular secretion was linear at unbound plasma concentrations up to 2659 ng/mL. CONCLUSIONS: These data indicate that a sequential infusion method using PAH may be used to characterize the anionic secretory component of proximal tubular function. The tubular clearance of famotidine may be a suitable index of the cationic secretory capacity of the proximal tubule in humans. Saturation of the cationic secretory pathway was not observed, and further investigation into parallel pathways of cationic secretion, such as p-glycoprotein, may be warranted.

Comparison of iothalamate clearance methods for measuring GFR.

STUDY OBJECTIVE: To evaluate the bias and precision of three methods of measuring glomerular filtration rate (GFR) relative to a standard method. DESIGN: Prospective, outpatient study. SETTING: University-affiliated general clinical research center. PATIENTS: Twenty-six patients with various degrees of renal function (GFR range 25-151 ml/min/1.73 m2). INTERVENTIONS: Each patient received iothalamate twice during the study visit, first as a bolus injection and then as a priming dose followed by a constant-rate infusion for 2.5 hours. MEASUREMENTS AND MAIN RESULTS: Plasma (ClpIVB) and renal clearances (ClrIVB) after bolus injection and plasma clearance during constant-rate infusion (ClpINF) were compared with standard renal clearance during constant-rate infusion (ClrINF). All three measures were highly correlated with ClrINF (r>0.90, p<0.001). The mean ClrIVB was not significantly different from ClrINF (106.3+/-30.4 vs 104.2+/-28.5 ml/min/1.73 m2) and provided a precise (8.8%, 95% CI 6.5-11.1%) and unbiased measure of GFR. Both ClpIVB and ClpINF were positively biased; values exceeded ClrINF by 11.8+/-11.1 (p=0.0001) and 10.5+/-12.5 ml/min/1.73 m2 (p=0.0003), respectively. Use of a nonrenal correction factor of 9.8 and 10.5 ml/min/1.73 m2 for infusion and bolus plasma clearance values, respectively, eliminated bias and improved the precision of these methods. CONCLUSIONS: Iothalamate renal clearance after bolus injection is a simple, accurate, and precise measurement of GFR and may be a useful alternative to the standard infusion method in clinical investigations. The corrected plasma clearance provides a simple index of GFR for clinical practice.

Impact of acute renal failure on mortality in end-stage liver disease with or without transplantation.

BACKGROUND: Acute renal failure (ARF) is traditionally considered a poor prognostic factor in end-stage liver disease and is associated with a mortality approaching 90%. While the increased use of orthotopic liver transplantation (OLTX) has changed the outcome for patients with end-stage liver disease (ESLD), it is not clear whether this has affected the outcome of patients with ESLD and ARF. METHODS: We prospectively followed the course of ARF in 177 patients with ESLD being evaluated for OLTX. Of these patients 111 received OLTX. In-hospital mortality was compared to that of 316 ESLD patients without ARF, of these 196 received OLTX. Variables include severity of illness as assessed by APACHE II, co-morbid conditions, oliguria, need for renal replacement therapy, and etiologies of ESLD and ARF. These variables were evaluated with respect to the outcome in-hospital mortality by multiple regression analysis for patients with ARF. RESULTS: Mortality was significantly higher in oliguric versus non-oliguric patients and in patients who required renal replacement therapy. Mortality correlated strongly with the number of co-morbid conditions, especially sepsis, encephalopathy, respiratory failure, and DIC. For OLTX recipients who developed ARF, no significant difference in survival occurred whether the ARF was pre-OLTX or post-OLTX. CONCLUSION: ARF was associated with an increased mortality consistent with the known adverse prognostic effect of ARF in ESLD. However, the effect of ARF on mortality was remarkably reduced in patients who received a functioning OLTX. Since expected mortality generated from APACHE II scores was higher in the ARF groups, it is not clear that there is an additional effect of ARF beyond the physiologic derangements captured by APACHE II. ARF per se should not necessarily be a contraindication to liver transplant.

Disposition of foscarnet during peritoneal dialysis.

OBJECTIVE: To report the disposition of foscarnet in a patient undergoing peritoneal dialysis. CASE SUMMARY: A 34-year-old man with AIDS received foscarnet for the treatment of esophageal cytomegalovirus. We characterized the clearance of foscarnet in this patient during continuous cyclic peritoneal dialysis (CCPD) and continuous ambulatory peritoneal dialysis (CAPD). DISCUSSION: The foscarnet half-lives during CCPD and CAPD were 41.4 and 45.8 hours, respectively. These values are significantly greater than the half-life of 4.5 hours observed in patients with normal renal function and about half that reported in anuric patients undergoing hemodialysis during the interdialytic period. The CCPD and CAPD clearances of foscarnet were 5.8 and 4.5 mL/min, respectively; the CAPD clearances of creatinine and urea nitrogen were 4.1 and 6.0 mL/min, respectively. The patient's estimated total body clearance values of foscarnet during CCPD and CAPD were 9.8 and 8.8 mL/min, respectively. Thus, CCPD and CAPD augmented the patient's residual clearance of foscarnet by 145% and 105%, respectively. CONCLUSIONS: Since incremental increases in residual clearance of 30% or more generally will result in clinically significant changes in a drug's serum concentration, foscarnet dosage needs to be individualized for patients receiving peritoneal dialysis.

Evaluation of platelet hyperfunction in hemodialysis patients receiving recombinant human erythropoietin.

There are data suggesting that recombinant human erythropoietin (rHuEPO) may induce thromboses in hemodialysis patients, possibly due to alterations in platelet function. In an earlier study, we found evidence of platelet hyperfunction in several patients 4 to 8 weeks following the start of rHuEPO therapy, which was begun shortly after hemodialysis was initiated. Studies were performed to examine the effects of rHuEPO on whole blood platelet aggregation and adenosine triphosphate (ATP) release independent of changes in hematocrit or the uremic state. Eight hemodialysis patients without and four with a history of vascular access clotting had platelet aggregation tests performed at baseline while receiving rHuEPO, off rHuEPO for 2 weeks, and 4 to 6 weeks after restarting the drug. While the plasma EPO level decreased significantly after the 2-week period off rHuEPO (P < 0.0001), the hematocrit did not change at any of the three time periods. Whole blood platelet aggregation in response to adenosine diphosphate (ADP), collagen, and ristocetin was not significantly altered on or off rHuEPO in either patient group. Platelet hyperfunction, determined by aggregation or ATP release either spontaneously or in response to low-dose ADP or ristocetin, was not seen in any patient. These data suggest that the increase in access clotting is not the result of platelet hyperfunction induced directly by rHuEPO.

Desmopressin (d-DAVP) effects on platelet rheology and von Willebrand factor activities in uremia.

Bleeding times, von Willebrand activities, and platelet retentions were examined before and following d-DAVP in 13 uremic patients. Shortening of the bleeding time from 16.6 +/- 2.2 (SEM) to 6.8 +/- 0.7 min was seen in six patients. However, bleeding times remained greater than or equal to 20 min in the remaining seven individuals. The only baseline parameter that correlated with response to d-DAVP was the amount of blood loss (mg/min) during the bleeding time test. Responders had normal blood loss values averaging 6.2 +/- 1.5 mg/min. By contrast, these values were elevated in 6/7 of the non-responders and averaged 28.4 +/- 5.9 mg/min (P = 0.01). Von Willebrand activities increased following d-DAVP in the responders but not in the non-responders. Platelet retention was uniformly low in all patients and improved from 21.0 +/- 7.0% to 75.0 +/- 7.9% (P = less than 0.001) following d-DAVP in responders but not non-responders. To further define the retention abnormality in uremia, the two-stage platelet retention assay was performed prior to d-DAVP. Most of the patients (9/12) had both first- and second-phase abnormalities. Therefore, the retention defect in uremia appears to be more complex than that seen in von Willebrand's disease (2nd phase abnormality only). Nevertheless, d-DAVP seems to improve platelet rheology in uremic individuals whose von Willebrand activities increase with d-DAVP.

Sustained remission of membranous glomerulonephritis after cyclophosphamide and prednisone.

OBJECTIVE: To determine the effect of cyclophosphamide and prednisone on progressive renal failure and on nephrotic features in patients with membranous glomerulonephritis. DESIGN: Prospective, nonrandomized time series. SETTING: Outpatient clinic at a university medical center. PATIENTS: Eleven consecutive patients with biopsy-proven membranous glomerulonephritis and rising plasma creatinine levels over at least 6 months. INTERVENTION: Cyclophosphamide and prednisone in ten patients and cyclophosphamide alone in one patient. MEASUREMENTS AND MAIN RESULTS: In ten patients treated with both agents, the median plasma creatinine rose 53 mumol/L (0.6 mg/dL) over the months before treatment from 141 to 194 mumol/L (1.6 to 2.2 mg/dL) (95% CI, 27 to 141 mumol/L; P = 0.002). After combined therapy for 6 months, the median plasma creatinine fell to 133 mumol/L (1.5 mg/dL) for a median decline of 62 mumol/L (0.7 mg/dL) (CI, 44 to 150 mumol/L; P = 0.006). Pretreatment plasma creatinine levels, which ranged from 159 to 371 mumol/L (1.8 to 4.2 mg/dL), decreased in the ten patients by 6 months and remained stable in seven of the eight patients followed 24 to 54 months after therapy was completed. The median urine protein excretion decreased by 9.6 g/d with 12 months of therapy in the ten patients from 11.9 to 2.3 g/d (CI, 6.0 to 15.1 g/d; P less than 0.001). The median plasma albumin rose by 14 g/L from 24 to 38 g/L (CI, 11 to 19 g/L; P less than 0.001). The median plasma cholesterol fell by 3.26 mumol/L (140 mg/dL) from 10.45 to 6.52 mumol/L (405 to 252 mg/dL) (CI, 1.42 to 7.16 mumol/L; P = 0.01). One patient who had a relapse 30 months after completing therapy responded to re-treatment with renal function and nephrotic variables returning toward normal. The eleventh patient received cyclophosphamide alone and had a course similar to that of the combined therapy group. CONCLUSION: Cyclophosphamide plus prednisone can promote prolonged remissions in membranous glomerulonephritis even when renal function is already declining.

Ibuprofen-associated lipoid nephrosis without interstitial nephritis.

A report of ibuprofen-associated lipoid nephrosis without interstitial nephritis is presented. Previous reported cases had incomplete biopsy descriptions or concurrent interstitial disease. The patient responded to withdrawal of ibuprofen.

Long-term follow-up of aggressively treated idiopathic rapidly progressive glomerulonephritis.

PURPOSE: We wanted to examine the long-term effects of aggressively treating idiopathic rapidly progressive glomerulonephritis (RPGN), with a particular focus on clinically characterizing the patient population, assessing the short- and long-term effects of therapy on renal function, and determining complications of the therapy. PATIENTS AND METHODS: Twenty-three consecutive patients with RPGN were treated and followed from one to 11 years. On renal biopsy, 13 had immune complexes, eight had no immune complexes, and two had antiglomerular basement membrane deposits. All had greater than 25 percent crescents and 19 of 23 had greater than 50 percent crescents. Every patient responded on a short-term basis to either large-dose pulse methylprednisolone or plasma exchange, with reduction of the mean plasma creatinine level from 6.5 +/- 2.0 mg/dl to 2.9 +/- 1.0 mg/dl (p less than 0.001). Each patient received oral prednisone and all but one received cyclophosphamide. RESULTS: Three died of non-renal causes. Fifty percent of the remaining 20 patients maintained stable renal function for at least two years. Four of nine patients followed-up for longer than two years had a relapse, but all responded again to therapy. No characteristic clinical symptoms predicting relapse were found, although nearly all had hematuria and proteinuria. Complications of therapy were frequent and may have contributed to death in two patients. CONCLUSION: Thus, long remissions are seen in most patients with RPGN treated aggressively.

The effect of serum potassium on theophylline-induced seizures.

Generalized seizures may be associated with therapeutic or intentional theophylline overdose. Toxic levels of theophylline are also associated with a fall in potassium which could potentiate theophylline-induced seizures. To evaluate the role of serum potassium concentration in theophylline-induced seizures we investigated the seizure threshold in normokalemic and hyperkalemic rats during theophylline infusion to toxic levels. Hyperkalemic rats were prepared with intraperitoneal amiloride and potassium chloride and had a mean +/- SEM initial potassium of 5.29 +/- 0.15 mEq/L. Control animals received either amiloride or potassium and had initial serum potassium concentrations of 4.00 +/- 0.08 and 3.93 +/- 0.16 mEq/L, respectively. Potassium levels after 30 minutes of theophylline infusion were 4.11 +/- 0.18 mEq/L in the hyperkalemic rats and 3.47 +/- 0.06 and 3.51 +/- 0.12 mEq/L in the control animals. There were no significant differences in the serum theophylline concentrations at time of seizure, nor was there a correlation between serum potassium concentration and theophylline concentration at time of seizure. Since the preservation of normokalemia does not influence the onset of seizures in theophylline toxicity, this suggests that the potassium level has little effect on seizure activity in this model.

Rupture of ovarian cyst: massive hemoperitoneum in continuous ambulatory peritoneal dialysis patients: diagnosis and treatment.

Two women on continuous ambulatory peritoneal dialysis (CAPD) developed recurrent episodes of hemoperitoneum while in the reproductive age group. Initially, both were thought to have mechanical problems with the peritoneal catheter system. A laparotomy was performed in the first patient, and a bleeding ovarian cyst was identified. The second patient had ovarian cysts documented by ultrasound. Thus, abdominal pain and bloody dialysate should not just be ascribed to catheter-related problems. The second patient's midcycle bleeding was suppressed with birth control pills.

A rat model for hyperkalemia.

It is often necessary to have a small animal model for hyperkalemia for use in electrolyte and acid base experiments. In reviewing the literature, we found a paucity of such animal models, especially for acute hyperkalemia. We have had difficulty in inducing acute hyperkalemia in rats using potassium chloride alone either intravenously or intraperitoneally and felt the need for an easily reproducible small animal model for hyperkalemia. We gave experimental animals a combination of intraperitoneal amiloride 3 mg/kg and potassium chloride 2 meq/kg in two divided doses while control animals received only the potassium chloride. Initial serum potassiums were similar but at 2 hr, the experimental group had significantly higher serum potassium levels which were sustained throughout the 8 hr of the experiment. Arterial blood gas revealed no significant difference in blood pH values at all time points during the experiment. We conclude that the combination of amiloride and potassium chloride is useful to produce acute hyperkalemia in rats and that this hyperkalemia is sustained beyond 6 hr. This model is convenient for use in metabolic experiments requiring the use of acutely hyperkalemic rats.

Genital edema in patients on continuous ambulatory peritoneal dialysis. Report of 3 cases and review of the literature.

Severe genital edema is a well-described complication of continuous ambulatory peritoneal dialysis (CAPD). Leakage of dialysate fluid from defects in the peritoneum may occur from clinically detectable and undetectable inguinal hernias, defects at the catheter insertion site, or other defects in the peritoneal membrane. We describe 3 patients (who underwent five surgical procedures), illustrating the complexity of the problem. In 2 patients, unsuccessful surgical repairs (1 catheter replacement, 1 hernia repair) were performed based on misleading radiologic findings using intraperitoneal contrast without computerized tomography (CT) scanning. The use of CT scanning with intraperitoneal contrast led to the correct diagnosis and prompt surgical correction in both patients so studied. One patient had leakage from a clinically undetectable inguinal hernia, and the other had a peritoneal defect at the Tenckhoff insertion site which was only demonstrated following a period of upright posture with a 3-liter exchange. Our experience and a review of the literature convinces us that a CT scan of the abdomen utilizing radiocontrast material added to the dialysate accurately identifies the site of leakage in CAPD patients who develop genital edema. Thus, the CT scan can help avoid unnecessary surgery and prolonged hospitalization in CAPD patients who develop genital edema.

Autosomal dominant polycystic kidney disease: presentation, complications, and prognosis.

Fifty-three symptomatic adults with autosomal dominant polycystic kidney disease were studied retrospectively for a mean follow-up of 12 years (range 10 months to 33 years). Diagnosis was confirmed by either x-ray, ultrasound, laparotomy, or autopsy. Commonest presenting clinical findings were flank pain (30%), hypertension (21%), symptomatic urinary tract infection (UTI) (19%), gross hematuria (19%), and palpable masses (15%). A total of nine patients (17%) progressed to end-stage renal disease. Change in renal function measured using the reciprocal of plasma creatinine plotted against time was linear for each individual patient with a maximum functional decline of 0.7 mg/dL/yr (slope = -0.07). Past the age of sixty renal failure was uncommon. Easily controlled hypertension developed in 64% attended by mild retinopathy. UTIs were common (53%), often recurrent (61%), precipitated by instrumentation in 6 of 14 patients (43%), leading to death in two (33%). Renal calculi were extremely common (34%) and had no defined metabolic cause. The presence of hematuria (64%), gross or microscopic, bore no relationship to the decline in renal function. Pregnancy was normal in these patients with no increase in fetal or maternal morbidity or mortality. We conclude the following: Renal functional deterioration is linear, less than previously reported, and bears no relationship to hematuria. Hypertension is common, easily treated, and causes minor end-organ damage. Renal calculi are frequent. Urinary tract instrumentation often induces infection with considerable morbidity and mortality and must be avoided. Pregnancy is not contraindicated if renal function is normal. The prognosis for survival in this disease is better than previously reported.

Relationship of phosphate-dependent glutaminase activity to ammonia excretion in potassium deficiency and acidosis.

Ammonia production and excretion are elevated in potassium depletion alkalosis, although normally they are reduced in alkalosis and elevated in acidosis. Studies were conducted with or without acute acid loading in normokalemic rats or rats made chronically hypokalemic with deoxycorticosterone acetate and a potassium-deficient diet to examine the role of phosphate-dependent glutaminase (PDG) in regulating ammonia excretion. Renal cortical PDG rose fourfold, and urinary ammonia excretion (UAE) doubled in potassium depletion compared to potassium-repleted controls. Following acid challenge PDG and urinary ammonia increased four- to sevenfold in both normokalemic and hypokalemic animals, but the rise in UAE did not correspond to the increase in PDG. Thus, PDG levels in acidotic normokalemic rats were one half those seen in potassium-depleted rats, but UAE in the acidotic rats was six times greater. These results could not be explained solely by changes in blood pH. The poor correlation between PDG and UAE also could not be explained by limited substrate availability, since blood glutamine levels were unaffected by potassium depletion. The disparity between UAE and PDG in potassium depletion was studied further during 9 days of potassium repletion of depleted rats. UAE was again increased by depletion but, after only 3 days of potassium repletion, UAE fell to levels found in normokalemic rats. The renal PDG activity, however, remained three times normal. Indeed, PDG remained significantly elevated even after 9 days of potassium replacement. Other enzymes involved in renal ammoniagenesis, including delta glutamyl transferase, glutamine transferase and omega deamidase, were assayed, and alterations in their activities could not account for the changes in UAE.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of streptokinase to treat renal artery thromboembolism.

The effects of streptokinase are difficult to determine. Furthermore, it has toxic side effects, and renal function may not recover from its use. However, because of favorable experiences with this drug in the early treatment of venous thromboembolism and following myocardial infarction, as well as the favorable findings with early perfusion in the dog model, the use of local streptokinase may be justified if the infusion is begun early, preferably within four to six hours.

Plasmapheresis as sole therapy in a patient with essential mixed cryoglobulinemia.

An 82-year-old woman with essential mixed cryoglobulinemia type II (IgM K IgG) presented with moderate renal failure and nephritic syndrome. Mesangiocapillary glomerulonephritis with mesangial and subendothelial granular deposits containing IgG, IgM, and C3 in conjunction with small-vessel vasculitis was seen on renal biopsy. Renal symptomatology preceded by a period of 10 months the development of leg ulcers and purpura. The onset of the skin lesions was accompanied by an acute decline of renal function and an increase in liver alkaline phosphatase. Plasmapheresis with a 50% plasma exchange each week over 12 weeks led to improvement in renal function, healing of leg ulcerations, disappearance of purpura, and a return to the baseline of alkaline phosphatase in association with the disappearance of circulating cryoglobulins.

Fenoprofen nephropathy: lipoid nephrosis and interstitial nephritis. A possible T-lymphocyte disorder.

Five patients are presented, each of whom had an acute idiosyncratic reaction to fenoprofen calcium (Nalfon) characterized by acute renal failure and marked proteinuria. Renal pathology was similar in all patients. Light microscopy revealed marked lymphocytic inflammatory infiltrates and normal glomeruli. Immunofluorescent staining was minimal or absent. Electron microscopy showed fusion of podocytes in otherwise normal glomeruli. Two patients were studied using T-cell and B-cell specific fluorescent staining, which revealed that the interstitial infiltrates were composed exclusively of T-lymphocytes. This finding is considered in relation to prior experimental and theoretic work. It is suggested that the various clinical and pathologic findings in fenoprofen nephropathy are all manifestations of a disordered cell-mediated immunity.