Arnold M. Chonko

Circulating Factor Associated with Increased Glomerular Permeability to Albumin in Recurrent Focal Segmental Glomerulosclerosis

BACKGROUND Heavy proteinuria and progressive renal injury recur after transplantation in up to 40 percent of patients with renal failure caused by idiopathic focal segmental glomerulosclerosis. A circulating factor may be responsible for this recurrence. METHODS To determine whether patients with focal segmental glomerulosclerosis have a circulating factor capable of causing glomerular injury, we tested serum samples from 100 patients with the disorder in an in vitro assay of glomerular permeability to albumin. Of the 56 patients who had undergone renal transplantation, 33 had recurrences. Sixty-four patients, many of whom had undergone transplantation, were being treated with dialysis. Thirty-one patients with other renal diseases and nine normal subjects were also studied. RESULTS The 33 patients with recurrent focal segmental glomerulosclerosis after transplantation had a higher mean (+/-SE) value for permeability to albumin (0.47+/-0.06) than the normal subjects (0.06+/-0.07) or the patients who did not have recurrences (0.14+/-0.06). After plasmapheresis in six patients with recurrences, the permeability was reduced (from 0.79+/-0.06 to 0.10+/-0.05, P = 0.008), and proteinuria was significantly decreased. Patients with corticosteroid-sensitive nephrotic syndrome or with membranous nephropathy after transplantation had low levels of serum activity. The circulating factor bound to protein A and hydrophobic-interaction columns and had an apparent molecular mass of about 50 kd. CONCLUSIONS A circulating factor found in some patients with focal segmental glomerulosclerosis is associated with recurrent disease after renal transplantation and may be responsible for initiating the renal injury.

Renal involvement in tuberous sclerosis

Abstract Three patients are described with renal angiomyolipoma without accompaning central nervous system involvement. Each patient presented in a different manner; the first with signs and symptoms of renal insufficiency, the second with gross hematuria, and the third with flank pain. All patients had replacement of renal parenchyma by hamartomatous tumors composed of blood vessels, adipose tissue and smooth muscle cells. The first case is the fifth report of the development of renal failure in tuberous sclerosis. In the latter two cases, intravenous pyelograms suggested polycystic kidney disease but renal arteriography was diagnostic of diffuse angiomyolipomas. Malignant transformation of these tumors is rare, but hemorrhagic complications following renal biopsy is a major problem in these patients.

The role of renin and aldosterone in the salt retention of edema

Abstract The response of plasma renin and aldosterone to five days of excessive sodium intake was determined in patients with congestive heart failure, cirrhosis and nephrosis. In eight patients with congestive heart failure, four had elevated plasma renin and aldosterone levels, 11.4 ± 0.5 ng/ml/hour and 21.9 ± .8 ng/100 ml, respectively, after a 3.9 ± 0.5 kg weight gain and a cumulative sodium retention of 501 ± 78 meq, but four had a similar weight gain, 3.8 ± 1 kg, and sodium retention, 488 ± 108 meq, without elevated plasma renin and aldosterone levels. In patients with cirrhosis, six had persistent hypersecretion of renin, 8.4 ± 2.3 ng/ml/hour, and plasma aldosterone, 17.7 ± 2.2 ng/100 ml, after a 6.1 ± 0.8 kg weight gain and 881 ± 104 meq sodium retention, but five gained 5.4 ± 1.5 kg weight and retained 794 ± 211 meq sodium with normal suppression of renin and aldosterone. In 10 patients with the nephrotic syndrome, eight maintained elevated plasma renin and aldosterone levels during a 6.5 ± 0.8 kg weight gain and 874 ± 99 meq sodium but two retained similar amounts of sodium with suppression of plasma renin and aldosterone. In all studies, there was no correlation between the response of plasma renin and aldosterone to sodium intake and glomerular filtration rate, urinary sodium excretion, blood pressure or serum protein concentration. These studies indicate that edema associated with cardiac, renal or hepatic disease can occur without increased aldosterone secretion. We postulate that increased renin secretion is needed in some edematous patients to maintain arterial blood pressure, but the secondary increase in aldosterone which occurs is not the primary cause of the sodium retention.

Ambulatory Blood Pressure in Type I Diabetes Mellitus: Comparison to Presence of Incipient Nephropathy in Adolescents and Young Adults

AMBP measurements were obtained at 20-min intervals during the day and at 60-min intervals during the night in 38 adolescents and young adults (12–25 yr old) with type I diabetes, and in 36 healthy, nondiabetic control subjects of comparable age. The group of patients with elevated AER (>15 μg/min) had higher mean 24-h sBP, dBP, and BPB (defined as the prevalence of systolic readings >130 mm Hg or diastolic readings >85 mm Hg) compared with both the group of patients with type I diabetes and AER<15, and the control group. The normal diurnal variation in BP and BPB was observed in the control group and the group with type I diabetes and AER<15, whereas the nocturnal decrease observed in the group with type I diabetes and AER>15 was not statistically significant. Elevations in AMBP of the patient group with AER>15 were reflected in random BP measurements. Even though the mean random BP measurements of all groups were within the normal range for age, the mean random sBP and dBP of the type I diabetes patients with AER>15 was higher than both the control group and the group with type I diabetes and AER<15. The GFR, determined by the clearance of 99Tc-DTPA, was associated negatively with measures of AMBP and AER in the group with AER>15. The mean 24-h sAMBP, dAMBP, and BPB of the type I diabetes patients with AER<15 were elevated compared with the control group. The mean random sBP of the type I patients with AER<15 was not significantly different from the control group, whereas the mean random dBP of this group was significantly greater than the control group. Significant overlap in the BPs and BPBs occurred among the groups, but the mean 24-h sBP and BPBs were above the 90th percentile for control subjects in most type I diabetes patients with AER<15 and in ∼50% of type I diabetes patients with AER<15. The three groups separated across the age range (12–25 yr old) for the different measures of AMBP. We conclude that AMBP measurement is useful in detecting abnormalities in BP that are not apparent in random BP measurement in patients with onset of type I diabetes before puberty and no evidence of early diabetic nephropathy. These findings may be important in identifying individuals who either are susceptible to the development of diabetic nephropathy or have early renovascular dysfunction not apparent in AER>15. AMBP measurement may be useful in monitoring interventions designed to prevent or delay the development of diabetic nephropathy.

Recognition of Hypertension and Abnormal Blood Pressure Burden With Ambulatory Blood Pressure Recordings in Type I Diabetes Mellitus

Ambulatory blood pressure (AMBP) measurements were obtained at 20-min intervals for 24 h in 25 subjects with insulin-dependent (type I) diabetes mellitus and 21 control subjects. The diabetic patients had normal kidney function (glomerular filtration rate 112.1 ± 7.2 ml · min−1 · 1.73 m−2, renal plasma flow 459.0 ± 23.4 ml · min−1 · 1.73 m−2) and were normotensive according to standard sphygmomanometer examinations. Mean ± SE AMBP (systolic/diastolic in mmHg) measurements in diabetic patients (24 h, 131.7/77.2 ± 2.9/1.8; 0600–2200, 132.3/78.4 ± 2.9/3.4; 2200–0600, 125.1/75.7 ± 3.9/3.4) significantly exceeded control values during all times (24 h, 121.8/70.3 ± 2.9/1.9; 0600–2200, 120.7/71.8 ± 2.6/2.0; 2200–0600, 108.2/61.5 ± 6.6/2.7). Mean 24-h AMBP exceeded 135/85 mmHg in 49% of diabetic patients. The same threshold of 135/85 mmHg was used to determine the prevalence of abnormal measurements per time period (pressure burden). Pressure burden was increased twofold in diabetic patients compared with control subjects. Mean AMBP was significantly reduced at night in control subjects but not in diabetic patients. Changes in blood pressure were not related to kidney function in diabetic patients. AMBP recordings uncovered an increased prevalence of abnormal mean blood pressure, increased pressure burden, and a lack of diurnal variation of blood pressure in subjects with type I diabetes mellitus. These findings have important implications for early intervention strategies in diabetes mellitus because AMBP recordings correlate well with end-organ damage.

Effect of Angiotensin-Converting Enzyme Inhibition on Renal Function and Albuminuria in Normotensive Type I Diabetic Patients

Normotensive patients with insulin-dependent (type l) diabetes mellitus (n = 18) were given 25 mg captopril (b.i.d.) and placebo for 3 mo in a randomized double-blind crossover study. Patients had normal renal function, and none had retinopathy. Albuminuria was <20 μg/min in 12 patients and between 20 and 200 μg/min in the other 6. Patients were examined at the end of the placebo and captopril phases. Captopril caused little reduction in blood pressure obtainedby 24-h ambulatory monitoring (systolic 126.0 ± 2.7 to 123.9 ± 2.4 mmHg, P< 0.08; diastolic 74.2 ± 1.9 to 72.1 ± 1.9 mmHg, P < 0.09). Captopril lowered glomerular filtration rate from 99.5 ± 7.7 to 71.0 ± 5.5 ml · min−1 · 1.73 m−2(P < 0.01), whereas renal plasma flow (443.9 ± 15.2 ml.min−1. 1.73 m−2) remained unchanged. Filtration fraction was reduced from 22.4 ± 1.4 to 17.4 ± 1.4% (P < 0.01). Urinary albumin excretion was reduced from 59.1 ± 0.15 to 27.7 ± 13.9 μg/min (P < 0.1). Reduction was relatedto the extent of initial albuminuria (r = 0.997, P < 0.001), a relationship that remained significant after logarithmic transformation (r = 0.540, P < 0.02). Dextran clearance was used to determine glomerular capillary function. Angiotensin inhibition caused reduction in effective glomerular pore size and also reduced flow via the nondiscriminatory shunt. Angiotensin inhibition in normotensive patients with type I diabetes was well tolerated. Reduction in albuminuria is mediated by a combination of hemodynamic changes and alterations in glomerular capillary function.

Markers of masked iron deficiency and effectiveness of EPO therapy in chronic renal failure

Recombinant erythropoietin (rHuEPO) is well established in the management of anemia of chronic renal disease. However, a number of clinical issues, including the best laboratory indicators of an imminent marrow response to rHuEPO replacement, the ideal measurements to detect masked iron deficiency, and optimal methods of iron replacement, remain unanswered. To investigate these issues, studies were performed in anemic chronic hemodialysis patients. A number of standard hematologic measurements in addition to automated reticulocyte counts (Sysmex R-1000) and serum transferrin receptors (TfR) were obtained in these patients. A response to initiation of rHuEPO administration could be predicted if the serum TfR concentration was less than 6 mg/L (normal, 3.8 to 8.5 mg/L). In patients on rHuEPO, an imminent hemoglobin response to an increased rHuEPO dose could be predicted after 1 week based on a greater than 20% increase from baseline in the serum TfR or absolute reticulocyte count, with a sensitivity of 92%. In patients on rHuEPO replacement with serum ferritin levels greater than 30 microg/L, none of the panel of tests, including serum TfR, reliably detected masked iron deficiency. In a long-term study over 5 months in patients on a stable maintenance dose of EPO, a gradual decline in total body iron occurred, even in subjects with initial adequate iron stores, and despite taking 50 mg elemental iron daily as oral ferrous sulphate. The serum TfR is useful for predicting a hemoglobin response when initiating rHuEPO therapy, and combined with automated reticulocyte counting it is valuable for predicting a hemoglobin response when increasing the dose of rHuEPO. The serum TfR loses its specificity for detecting tissue iron deficiency in patients on maintenance rHuEPO therapy because of increased erythropoiesis, which itself raises serum TfR levels.

Effective Use of Streptokinase for Peritoneal Catheter Failure

The fibrinolytic enzyme streptokinase (streptase) was infused into the peritoneal catheter in 19 episodes of catheter failure in 16 patients. Intraabdominal bleeding prior to infusion was seen in seven of these episodes. Fibrin strands and clots were present in four additional successful cases. Streptokinase successfully relieved the obstruction in 13 episodes in 11 patients. The procedure failed in two cases of omental ingrowth and in another with catheter malposition. Streptokinase infusion also failed in two patients with Pseudomonas aeruginosa and one patient with Staphylococcus epidermidis peritonitis. Intraperitoneal streptokinase infusion is simple and free of side effects. Its use should be considered in peritoneal catheter failure, particularly in cases where bleeding or fibrin accumulation may play a role.

Percutaneous Transluminal Angioplasty in Transplant Renal Artery Stenosis: Experience and Review of the Literature

Percutaneous transluminal angioplasty (PTA) was performed in five instances of renal transplant artery stenosis (RTAS) in four patients. Hypertension was present in all cases and improved after angioplasty together with reduction in medicine requirements. Abnormal renal function in four instances also improved after PTA. This reflects the current literature in which 76 of 90 patients were successfully treated by PTA (follow-up to 24 months), with two cases of recurrent stenosis, no mortality, and only a single case of graft loss. Vascular surgical repair succeeded in 130 to 180 patients, but graft loss occurred in 20 cases and recurrent stenosis in 11. Mortality was reported in five cases. Our review of the literature and experience suggests that PTA may be preferred in the treatment of RTAS.

The effect of water loading on albumin excretion in Type I diabetes mellitus

An increased albumin excretion rate is recognized as an important early marker for incipient kidney disease in patients with diabetes mellitus. Many different techniques have been used, and a single void technique has been proposed as the simplest method for screening for increased albumin excretion. We evaluated a previous observation that single void samples during water diuresis yield increased albumin excretion rates. Timed day, night, and 24 hour albumin excretion rates (AER) were obtained in 35 patients with Type I diabetes mellitus. This was followed by examination of 8 consecutive half-hour specimens obtained during continued water diuresis. We compared 26 patients with low AER (less than 20 micrograms/min/24 hr sample) to 9 patients with high AER (greater than 20 and less than 200 micrograms/min/24 hr). Sampling began 60 min after the initiation of the waterload. At first, the AER in the low AER group was significantly higher than it was at night, but it decreased over 60 to 90 min of sampling to levels comparable with daytime AER. This was paralleled by a similar pattern in urine flow rate, sodium, and solute excretion. The AER in the high AER group did not increase with the water load and remained high throughout the study periods. The pattern of urine flow rate, sodium, and solute excretion was similar to that of the group with low AER. The study demonstrates that early sampling after water-induced diuresis leads to overestimation of AER in patients with low AER as compared to patients with high AER.(ABSTRACT TRUNCATED AT 250 WORDS)