Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease.

It is known that several of the most severe complications of autosomal-dominant polycystic kidney disease, such as intracranial aneurysms, cluster in families. There have been no studies reported to date, however, that have attempted to correlate severely affected pedigrees with a particular genotype. Until recently, in fact, mutation detection for most of the PKD1 gene was virtually impossible because of the presence of several highly homologous loci also located on chromosome 16. In this report we describe a cluster of 4 bp in exon 15 that are unique to PKD1. Forward and reverse PKD1-specific primers were designed in this location to amplify regions of the gene from exons 11-21 by use of long-range PCR. The two templates described were used to analyze 35 pedigrees selected for study because they included individuals with either intracranial aneurysms and/or very-early-onset disease. We identified eight novel truncating mutations, two missense mutations not found in a panel of controls, and several informative polymorphisms. Many of the polymorphisms were also present in the homologous loci, supporting the idea that they may serve as a reservoir for genetic variability in the PKD1 gene. Surprisingly, we found that three independently ascertained pedigrees had an identical 2-bp deletion in exon 15. This raises the possibility that particular genotypes may be associated with more-severe disease.

Ventilation-perfusion scintigraphic evaluation of pulmonary clot burden after percutaneous thrombolysis of clotted hemodialysis access grafts.

The objective of this study is to determine, by using rigorous methods, if pulmonary perfusion defects were detectable by ventilation-perfusion scintigraphy after percutaneous thrombolysis of clotted hemodialysis access grafts. Thirteen patients were studied. Four patients underwent pharmacomechanical thrombolysis with urokinase and the remainder had mechanical thrombolysis alone. Pre- and postthrombolysis scintigraphic studies were performed on all patients. Perfusion defects were described as vascular (well-defined borders confined to segmental boundaries) or nonvascular. Vascular defects were graded by severity (0 to 3) and area (0 to 3) for each involved segment. Nonvascular defects were graded by severity (0 to 1) and area (0 to 1). Two experienced readers evaluated the scans blinded to each other's results and all other clinical data, including thrombolysis outcomes. Twelve patients did not have any significant worsening of their perfusion defect scores postthrombolysis. In only one patient did a study show a new nonvascular perfusion defect with a matching ventilation abnormality. The defect was believed to be caused by mucus plugging. The patient had no evidence of pulmonary embolism. Our study suggests emboli that resulted from the pharmacomechanical or mechanical thrombolysis procedure were either small, underwent lysis before impacting the lung, or were below the limit of detection of ventilation-perfusion scintigraphy.

Cerebral embolism after mechanical thrombolysis of a clotted hemodialysis access.

Clinically significant embolic complications after thrombolysis of clotted hemodialysis grafts are uncommon. Most of the concern has focused on the risks associated with pulmonary emboli. We report a case of a hemodialysis patient who developed a cerebral embolism after percutaneous graft thrombolysis who was found to have a patent foramen ovale and intermittent right-to-left shunt.

Role of physician assistants in dialysis units and nephrology.

We surveyed physician assistants who work in nephrology to report their experience level, primary employer, salary, job responsibilities, and job satisfaction. Additional data were obtained from the Nephrology Manpower Study. The 67 responding physician assistants of 97 surveyed have 10.8 +/- 6.5 years (mean +/- standard deviation) total experience (6.2 +/- 5.0 years in nephrology). Typically, nephrologists (56.1%) or hospitals (30.3%) employ them. The majority (74%) earn $49,999 to $75,000; 79.1% work in outpatient units, 52.4% in inpatient units, 52.4% in hospitals, 43.3% in outpatient offices, and 23.9% in transplant units. In outpatient units, they manage 111 +/- 111 patients, mostly in free-standing (71.1%), for-profit (69.7%), corporately owned (87.3%) units in urban (80%) or suburban (18%) areas. Most (>85%) manage all dialysis- and nondialysis-related problems, including health maintenance; 84.3% are contacted first by staff, and 78% see patients more often than physicians. Of nephrologists who responded to the Manpower Study, 8.9% work with physician assistants and 20.7% work with nurse practitioners. Nephrologists in academic practice or private nephrology groups are more likely to use physician assistants (P < 0.05) and nurse practitioners (P < 0.005) than those in solo practice or multispecialty groups. Nephrologists with physician assistants (33.8 +/- 19.5 v 41.7 +/- 16.8 h/wk) or nurse practitioners (35.8 +/- 18.1 v 42.7 +/- 16.9 h/wk) tended to spend less time in direct patient care than those without physician extenders (P < 0.001). Nephrologists with renal fellows, however, spent the least time of all in direct patient care (30.0 +/- 15.9 v 47.3 +/- 14.9 h/wk; P < 0.001). Physician assistants can perform nearly all the medical tasks in dialysis units. They may offer one approach to providing effective and complete care for patients if nephrology manpower becomes limited.

A randomized trial of three iron dextran infusion methods for anemia in EPO-treated dialysis patients.

Forty-three hemodialysis patients receiving recombinant erythropoietin (rHuEPO, epoietin alpha) were randomized to receive intravenous iron dextran as a total-dose infusion, 500-mg infusion to total dose, or 100-mg bolus to total dose, in each case during the dialysis procedure. The dose of iron dextran was calculated from the patient's existing hemoglobin to achieve a desired hemoglobin. Patients were eligible to receive intravenous iron dextran if they had a serum ferritin of < or = 100 ng/mL or a serum ferritin of 100 to 200 ng/mL, along with a transferrin saturation of < or = 19%. Patients were excluded if they had prior therapy with iron dextran, aluminum intoxication, or transfusion during the study. The time to the maximum hemoglobin, acute adverse reactions, and delayed adverse reactions were analyzed statistically, and no differences were seen in any of the three groups. Total-dose intravenous iron dextran infusion is safe, convenient, less expensive, and as efficacious as divided-dose infusions.

Phosphorus removal with a variable chloride, CO2 acidified dialysate using an unmodified single pass system.

A method of providing dialysate was developed that used CO2 gas, rather than acetic acid, as an acidifying agent, allowing for the delivery of a variable chloride concentration. The system can be used on a standard, unmodified dialysis machine. The aim of the study was to test the technical feasibility of the dialysate delivery system and to determine whether use of the dialysate, which is free of acetate and can increase serum chloride concentrations above those normally achieved during the early phases of dialysis, could influence mass phosphorus removal. Using a crossover design, the effects of a standard acetate containing dialysate were compared with the acetate free, variable chloride dialysate on serum phosphorus kinetics and mass phosphorus removal in six hemodialysis patients. Although, as predicted, the serum chloride levels were higher during the initial phases of dialysis and serum bicarbonate concentrations were equivalent at the end of treatment, it was not possible to measure any differences in serum phosphorus levels during any of the time points during or immediately after dialysis, nor was any difference in mass phosphorus removal observed. Despite the presence of considerable animal evidence that acetate metabolism causes the intracellular shift of phosphorus, our study did not show any benefit, in terms of mass phosphorus removal, of an acetate free dialysate solution.

Neurocognitive effects of aluminum.

The neurocognitive effects of aluminum (Al) were studied in 35 hemodialysis patients. Higher Al levels were associated with a decline in visual memory. As Al levels increased, patients with lower vocabulary scores (a measure of premorbid intelligence) showed a decline in attention/concentration, frontal lobe functions, and on several neurocognitive measures, while those with higher vocabulary scores revealed no Al-related decline. These results suggest that individuals with lower verbal intelligence may possess less well-developed compensatory strategies to overcome the neurocognitive effects associated with Al. These data also indicate that Al is neurotoxic and, therefore, potential sources of environmental Al should be identified and eliminated.

Effects of acetate dialysate on transforming growth factor beta 1, interleukin, and beta 2-microglobulin plasma levels.

To evaluate potential adverse effects of acetate use in hemodialysis (HD), we measured plasma interleukin (IL-1 alpha, IL-1 beta, IL-6), TNF alpha, TGF beta 1, and beta 2-microglobulin levels with ELISA assays in normal (N = 9), CRF (N = 6), CAPD (N = 7) and HD (N = 8) subjects and compared the effects of acetate (Ac) and acetate-free (Ac-free) dialysate. TGF beta 1 was the only cytokine consistently detected. Compared to normals (median 57, range 53 to 68 pg/ml, one undetected; N = 8), TGF beta 1 was higher in the CRF (75, 70 to 97 pg/ml, one undetected) and CAPD (75.5, 66 to 116 pg/ml, N = 6) groups (P less than 0.05), and was somewhat higher in the HD (68, 52 to 88 pg/ml) group (P less than 0.10). Acutely, TGF beta 1 pre-HD (70, 63 to 88 pg/ml) increased above normals post AcHD [79.5, 65 to 140 pg/ml uncorrected for ultrafiltration (UF)] and was higher after AcHD versus Ac-free HD both uncorrected (79.5, 65 to 140 pg/ml vs. 70, 52 to 86 pg/ml) and corrected for UF (68, 51 to 115 pg/ml vs. 57, 43 to 69 pg/ml; P less than 0.05). beta 2-microglobulin was not different after AcHD (81.2 +/- 8.0 mg/ml) versus Ac-free HD (72.5 +/- 6.9 mg/ml). Significantly lower serum inorganic phosphorus was also found four hours post-AcHD compared to four hours post-Ac-free HD (0.87 mmol +/- 0.10 SEM vs. 1.05 mmol +/- 0.07 SEM; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Dihydropteridine reductase activity: lack of association with serum aluminum levels and cognitive functioning in patients with end-stage renal disease.

Although increased levels of aluminum (Al) are present in patients with dialysis encephalopathy (DE), it is unclear if the association is causal. The enzyme dihydropteridine reductase (DHPR) plays a critical role in neurotransmitter formation and its activity. Elevated levels of Al are reported to decrease DHPR activity, which would alter neurotransmitter metabolism, thus producing DE. We examined the association between erythrocyte DHPR activity and Al levels, attention/psychomotor skills, and depression in a group of 21 patients with end-stage renal disease. DHPR activity was not related to Al level, mental status, psychomotor ability, or depression score. After administration of deferoxamine (an Al chelating agent), Al level increased significantly but DHPR activity remained the same. Our results suggest that the mechanism for the development for DE does not involve alterations of neurotransmitter metabolism caused by Al-mediated reductions in DHPR activity.

Altered expression of HLA antigens and CD16 Fc receptors on leukocytes of alcoholic subjects and uremic patients.

The possible influences of ethanol and its metabolic product acetate on the surface expression of HLA class I and class II antigens and CD16 Fc receptors were examined. Fluorescent-labeled monoclonal antibodies and flow cytometry were used to measure these antigens on leukocytes from reference controls, subjects admitted for alcohol detoxification, uremic patients undergoing hemodialysis using Cu-prophan dialyzers and fluids containing 4 to 37 mM acetate, and uremic patients that were not hemodialyzed. In comparison to the controls, the mean intensity of staining for class I antigens was not changed significantly on lymphocytes or monocytes from alcoholics but was depressed on cells from eight of 12 uremic patients. Interferon-gamma above 5 units/ml was detected in less than 15% of plasma samples from controls, uremic patients or alcoholics on admission but was detected in four of eight samples from alcoholics at discharge (2-4 days after admission). The intensity of staining for class II antigens was depressed by more than 50% on lymphocytes from alcoholics and uremic patients. The expression of HLA class I and class II antigens was depressed whether uremic patients were hemodialyzed or not. The percentage of lymphocytes expressing CD16 was depressed in three of seven alcoholics and five of seven hemodialyzed patients. In contrast, the percentage of monocytes expressing CD16 was increased in six of seven hemodialyzed patients and three of five uremic patients not undergoing hemodialysis suggesting activation of monocytes in these patients. Plasma levels of beta 2-microglobulin were elevated by 61% in alcoholics, 50-fold in hemodialyzed patients, and 26-fold in nonhemodialyzed uremic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Early effects of subtotal nephrectomy and food restriction on urinary calcium in the rat.

Urinary calcium excretion (UCa) is normal several weeks following subtotal nephrectomy (Nx) in the rat, despite factors such as magnified solute load per nephron which should promote hypercalciuria. To define the levels of UCa during the first few weeks after Nx and to determine if the development of compensatory mechanisms governing renal conservation of calcium are detectable, we measured UCa in Nx and sham Nx rats with matched food intake (10 g/day) from 10 days before through 20 days following Nx. In the sham Nx animals, UCa rose during the first 5 days following surgery from 27 +/- 8 to 66 +/- 5 microM/day and then plateaued for the remaining time. In Nx rats, UCa also rose during the first 5 postoperative days from 23 +/- 5 to 110 +/- 10 microM/day (Nx vs. sham Nx, p less than 0.05), but then fell over the next 3 days to levels observed simultaneously in sham Nx animals. The rise in UCa after Nx, but not after sham Nx, was associated with a doubling of urine flow rate and increased urinary titratable acid excretion. In parathyroidectomized rats, UCa also rose following Nx; however, maximum UCa was then sustained for at least 4 days. In an additional sham Nx group fed 20 g/day, no increase in UCa occurred following surgery. Thus, hypercalciuria is present following Nx in the rat, in part possibly attributable to increased acid excretion. The transient nature of calciuria reflects an adaptive phenomenon, most likely hyperparathyroidism. Diminished food intake following surgery independently contributes to hypercalciuria, regardless of the status of renal mass.

In vivo pretreatment with human chorionic gonadotropin fails to reverse the dysfunction of isolated Leydig cells from chronically uremic rats.

In order to further investigate the previously reported hypogonadal state of chronically uremic rats, we examined the effects of in vivo pretreatment with human chorionic gonadotropin (hCG) on in vivo and in vitro Leydig cell function, comparing paired intact rats with rats made chronically uremic by 5/6 nephrectomy. The in vitro testosterone (T) secretory responses to varying concentrations of hCG or dibutyryl cAMP and the number of gonadotropin receptors were determined following hemicastration. The rats were then treated with hCG for 3 days and the remaining testes were removed and studied as before. Compared with intact rats, the uremic rats had higher serum concentrations of urea nitrogen (P less than 0.001); serum T concentrations were lower in uremic rats before (P less than 0.001), but not after (P greater than 0.6) treatment. Treatment produced increases in serum T only in uremic rats (P less than 0.001). Serum LH was lower in uremic rats before treatment (P less than 0.001) and was reduced (P less than 0.001) to similar levels (P greater than 0.8) in both groups after treatment. Baseline in vitro T secretion was lower (P less than 0.001) from Leydig cells of uremic than intact rats both before and after treatment. Analysis of variance of dose-response curves showed pre- and post-treatment T secretory responses to hCG or dibutyryl cAMP in vitro to be less from Leydig cells of uremic rats (P less than 0.01). Before treatment, Leydig cell gonadotropin receptor number was lower in uremic than intact rats (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphate excretion in uremic rats: effects of parathyroidectomy and phosphate restriction.

As progressive renal failure develops, phosphate excretion per functioning nephron increases, thus preserving homeostasis. To test whether dietary phosphate supply might contribute to the regulation of renal phosphate excretion in the uremic setting, groups of male Sprague-Dawley rats that were either parathyroidectomized (PTX) or sham PTX (S-PTX) and either five-sixths nephrectomized (Nx) or sham Nx (S-Nx) were studied following a 4-wk dietary regimen consisting of 0.1 or 0.7% phosphate. For Nx rats fed the 0.7% phosphate diet the fractional excretion of phosphate (FEPi) was enhanced (47 +/- 6 vs. 21 +/- 3%) and the maximum tubular reabsorption of phosphate per milliliter GFR (TmPi/GFR) was suppressed (1.65 +/- 0.19 vs. 2.33 +/- 0.19 mumol/ml). FEPi was unchanged by PTX in these Nx animals (42 +/- 6 vs. 47 +/- 6%). TmPi/GFR remained suppressed in PTX, NX animals when compared with S-Nx, PTX controls (3.38 +/- 0.33 vs. 5.07 +/- 0.41 mumol/ml). For rats fed the 0.1% phosphate diet Nx did not affect TmPi/GFR in either S-PTX (5.40 +/- 0.43 vs. 4.97 +/- 0.34 mumol/ml) or PTX (7.03 +/- 0.23 vs. 6.98 +/- 0.21 mumol/ml) animals. For both S-Nx and Nx animals the effects of PTX and dietary phosphate restriction on TmPi/GFR were independent and additive. In all groups of animals, tubular reabsorption of phosphate per milliliter GFR (TRPi/GFR) dropped acutely with continued infusion of phosphate once TmPi/GFR was achieved. Thus, a resetting of TRPi/GFR occurs among Nx rats in response to both chronic dietary phosphate deprivation and acute intravenous phosphate loading.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of immune status of hemodialyzed adults: association with prior transfusions.

Peripheral blood leukocytes of 29 hemodialyzed adults, 19 transfused and 10 nontransfused, were studied using immunofluorescent staining with monoclonal antibodies and in vitro measurement of natural killer (NK) cell activity. When compared with control subjects, the absolute number of leukocytes in transfused hemodialyzed patients was significantly reduced (P less than 0.01), as were the absolute numbers of OKT11+ cells (P less than 0.01), and OKT4+ cells (P less than 0.0001). The percent representation of OKT11+ and OKT4+ cells was also significantly lower among transfused hemodialyzed patients (P less than 0.01 and 0.001, respectively), and this loss of OKT4+ cells resulted in a decrease in the ratio of OKT4+/OKT8+ cells (P less than 0.01). The absolute number of Leu-7+ cells was also decreased in the transfused group (P less than 0.05). A decrease in in vitro NK cell activity was present in both transfused and nontransfused hemodialyzed subjects. Whether these differences in peripheral blood lymphocytes were induced by the erythrocyte transfusions could not be determined; however, if they reflect changes in central lymphoid tissues, then these results may help explain the prolonged survival of renal allografts in transfused individuals.

A controlled study of the effect of indomethacin in uremic pericarditis.

To determine the impact of indomethacin on the course of uremic pericarditis we performed a prospective, double blind study in which 24 patients with endstage chronic renal failure and pericarditis randomly received indomethacin, 25 mg four times daily, (11 patients) or a placebo (13 patients) for a 3-week period. All patients received peritoneal or hemodialysis treatment concurrently with the study drug. In contrast to the placebo, indomethacin produced an immediate and sustained reduction of fever in all but one patient. On the other hand, indomethacin had no effect on the duration of chest pain (mean days +/- SE: placebo 1.4 +/- 0.6, indomethacin 5.5 +/- 3.3), duration of pericardial friction rub (placebo 10.3 +/- 1.7, indomethacin 16.0 +/- 3.8), or on the amount of pericardial effusion. Further, indomethacin did not diminish the need for invasive surgical procedures for relief of tamponade (three of 13 placebo patients, two of 11 indomethacin patients) or result in decreased mortality rate. Death (not due to pericarditis) occurred in two patients treated with indomethacin and one patient who received the placebo. In our patients pericarditis encompassed a wide spectrum ranging from a mild illness of several days duration to a painful and debilitating disease lasting weeks and requiring surgical intervention. Although the size of our population prohibits definitive conclusions, it would appear that, except for fever, the manifestations and natural history of this illness are unaffected by indomethacin.

Renal transplantation in a patient with multiple myeloma and light chain nephropathy.

A case of multiple myeloma in a 41-year-old white man that resulted in chronic renal failure is discussed. During the period of hemodialysis treatment, remission of the patient's myeloma was induced by chemotherapy. Thereafter a transplanted cadaver kidney functioned well for 3.5 years despite episodes of sepsis, administration of nephrotoxic chemotherapeutic agents, and recurrence of the myeloma with intermittent excretion of Bence Jones protein in the urine. The results of this fully documented case, as well as two other cases we have previously reported, support the strategy of offering cadaver renal transplantation to carefully selected individuals who require long-term dialysis and whose myeloma is in remission after chemotherapy.

Recurrent renal vein thrombosis consequent to membranous glomerulonephritis.

The diagnosis by inferior vena cavography of right renal vein thrombosis with extension into the vena cava was made in a 33 year old man with idiopathic membranous glomerulonephritis and multiple pulmonary emboli. After one year of continuous anticoagulant drug therapy with heparin and coumadin, venography showed absence of clots in the vena cava and therapy was discontinued. Proteinuria in excess of 4 g/24 hr continued. Six months later pulmonary emboli recurred and venography again demonstrated large clots in the vena cava and right renal vein. The potential for recurrence of renal vein thrombosis and pulmopnary embolism in the presence of active renal diseases is thus demonstrated.

Field trial of compact travel dialysis system.

To increase mobility for home hemodialysis patients, a portable, light weight hemodialysis system has been bench and field tested. The combination of a 21 L dialysate reservoir and small, high speed blood and dialysate pumps has permitted the entire system to be contained in a twenty two pound, 22 X 13 X 6 inch aluminum suitcase. Initial evaluation in hospitalized patients has shown the system to be safe and efficient. Acceptable clearances of creatinine and urea are maintained throughout a five hour dialysis by changing the bath at 120 and 210 minutes. Successful application of the system in travel by 3 patients, who perfomed a total of 12 dialyses in their hotel rooms while on vacation, indicates the broad potential of the new system.