Jeffrey G. Mulhern

Changing incidence of glomerular diseases in adults

Studies performed at large metropolitan medical centers have reported an increasing incidence of idiopathic focal segmental glomerulosclerosis (FSGS) in adults. To determine whether a similar trend occurs in small urban and rural communities and to determine the role of race in these observations, we reviewed the patient records of all adults who underwent renal biopsies at our institution over the 20-year period from 1974 to 1994. The patients were grouped for analysis in 5-year intervals, 1975 to 1979, 1980 to 1984, 1985 to 1989, and 1990 to 1994, for the following diagnoses: FSGS, membranous nephropathy (MN), minimal change nephropathy (MCN), membranoproliferative glomerulonephritis (MPGN), immunoglobulin A (IgA) nephropathy, chronic glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, and chronic interstitial nephritis. Patients with secondary causes for these lesions were excluded. The relative frequency of FSGS increased from 13.7% during 1975 to 1979 to 25% during 1990 to 1994 (P < 0.05). The relative frequency of MN decreased from 38.3% during 1975 to 1979 to 14.5% during 1990 to 1994 (P < 0.01). There were no changes in the frequencies of MCN, MPGN, IgA nephropathy, chronic glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, or chronic interstitial nephritis over the 20-year period. However, there was a significant increase in the percentage of blacks with FSGS, from 0% in 1975 to 1979 to 22.6% in 1990 to 1994, and an increased percentage of Hispanics with FSGS, from 0% in 1975 to 1979 to 21.3% in 1990 to 1994 (P < 0.05). The modest increase in whites with FSGS did not reach statistical significance. The incidence of MN in blacks and whites decreased over the 20-year period. In the last 5 years, 15 patients per year had FSGS compared with 7 patients per year with MN (P < 0.05). No changes in age or sex between groups or over time accounted for these results. We conclude that FSGS is now diagnosed twice as often as MN and is the most common idiopathic glomerular disease at our hospital. Reasons for this increase include the emergence of FSGS in both Hispanics and blacks, with a modest increase of FSGS in whites. The increase in FSGS in the three most common races in our community suggests that factors other than genetic, perhaps environmental, have a role in the pathogenesis of FSGS.

Trough serum vancomycin levels predict the relapse of gram-positive peritonitis in peritoneal dialysis patients.

We reviewed 31 episodes of gram-positive peritonitis that occurred in our peritoneal dialysis population between 1990 and 1993 in an attempt to identify the risk factor(s) for peritonitis relapse. All patients were treated with 4 weekly doses of intravenous vancomycin. Vancomycin doses no. 1 and 2 were based on body weight (15 mg/kg with a 1-g minimum); vancomycin doses no. 3 and 4 were adjusted in an attempt to maintain the trough serum vancomycin level at greater than 12 mg/L. Nine peritonitis episodes complicated by a relapse were identified. Peritonitis episodes preceding a relapse were similar to relapse-free episodes with respect to patient age, diabetes, peritoneal dialysis modality, duration of peritoneal dialysis treatment, residual urea clearance, peritoneal fluid cell count, causative organism, and weekly vancomycin dose. However, cumulative 4-week mean trough vancomycin levels were consistently lower during peritonitis episodes preceding a relapse (7.8 +/- 0.6 mg/L during relapse-prone episodes v 13.7 +/- 0.9 mg/L during relapse-free episodes; P = 0.0004). Furthermore, relapses developed during nine of 14 peritonitis episodes demonstrating a 4-week mean trough vancomycin level less than 12 mg/L compared with zero of 17 episodes with a 4-week trough level greater than 12 mg/L (P < 0.05). The detection of a low initial 7-day trough vancomycin level also was a useful marker for subsequent peritonitis relapse. In 13 peritonitis episodes associated with an initial trough level less than 9 mg/L, nine were complicated by a relapse.(ABSTRACT TRUNCATED AT 250 WORDS)

Outcome and complications of intraoperative hemodialysis during cardiopulmonary bypass with potassium-rich cardioplegia.

BACKGROUND Potassium-rich cardioplegia has advantages over other cardioplegic solutions in preserving the myocardium during cardiopulmonary bypass, but it is avoided in patients with renal failure because of hyperkalemia. METHODS We first determined the ability of intraoperative hemodialysis (IHD) to remove potassium during cardiopulmonary bypass with potassium-rich cardioplegia in 9 patients by measuring potassium levels in all dialysate and urine. We then studied 24 patients with renal failure, grouped with the 9 previous patients, to assess safety, rebound hyperkalemia, and patient outcome with this technique. RESULTS In the first phase, 9 patients were administered 128 +/- 11 mmol of potassium in potassium-rich cardioplegia, and IHD removed 157 +/- 23 mmol. Urinary potassium excretion was only 10 +/- 3 mmol. Potassium removal occurred at a rate of 1.25 mmol/min with 0-mEq/L (mmol/L) potassium dialysate and a rate of 0.75 mmol/min with 3.0-mEq/L (mmol/L) potassium dialysate. In all 33 patients, successful initiation of cardiac rhythm occurred after cardiopulmonary bypass, and 5 patients had cardiac arrhythmias possibly from hypokalemia. In the next 24 hours, 5 dialysis-dependent patients developed hyperkalemia (potassium > 5.2 mEq/L [mmol/L]) requiring hemodialysis. Postoperative hemodialysis was delayed 2 to 3 days in the other patients. The overall death rate was 24% at 30 days. CONCLUSION IHD effectively and safely removes potassium administered during potassium-rich cardioplegia during cardiopulmonary bypass in patients with renal failure and prevents postoperative hyperkalemia in the majority of patients. Overall mortality in patients with acute and chronic renal failure undergoing cardiac surgery is high irrespective of control of potassium balance in these patients.

Pancreatitis and duodenitis from sarcoidosis: successful therapy with mycophenolate mofetil.

Sarcoidosis is a chronic granulomatous inflammatory disease that may affect extrapulmonary organs including the kidneys and the gastrointestinal tract (1). The most common renal complication from sarcoidosis is hypercalciuria, which may induce nephrocalcinosis and/or nephrolithiasis (2). Chronic interstitial nephritis with noncaseating granulomas in the renal interstitium may cause mild to end-stage chronic renal failure (2). In addition, glomerular lesions have been reported, including membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, focal glomerulosclerosis, and rarely, crescentic gomerulonephritis (2). Therapy for glomerular diseases associated with sarcoidosis is anecdotal, and there are no data showing successful, longterm therapy for sarcoidosis associated with crescentic glomerulonephritis. The most common gastrointestinal manifestation of sarcoidosis is acute or chronic hepatitis, but disseminated gastrointestinal sarcoidosis, especially in the small intestine and pancreas, can cause considerable morbidity (1, 3–7). Glucocorticoids and/or surgery are often utilized as therapy, but the long-term outcome of patients with intestinal or pancreatic sarcoidosis has never been reported (8). We describe a patient with sarcoidosis who initially presented with idiopathic crescentic glomerulonephritis successfully treated with prednisone and cyclophosphamide. Subsequently, the patient developed pulmonary, pancreatic, and gastrointestinal sarcoidosis with a severe relapsing course despite therapy with glucocorticoids, cyclosporin, methotrexate or pentoxyphilline. The gastroin-

Transplantation and 2-year follow-up of kidneys procured from a cadaver donor with a history of lupus nephritis.

BACKGROUND Two patients underwent cadaver transplantation with kidneys from a donor with a history of World Health Organization Class IV/V lupus nephritis, and we report their clinical and pathological outcome. METHODS The donor had a diagnosis of lupus nephritis made by renal biopsy 5 years before donation. At the time of donation, a biopsy was performed on the donor and on one of the recipients at 2 months and 1 year after the transplant. RESULTS Both recipients underwent uneventful renal transplantation. On the first postoperative day, the donors final pathological results became available. Although the frozen section seemed to be quite benign, the permanent sections revealed World Health Organization Class II/V lupus nephritis, with full house immunofluorescence and multiple electron dense deposits. Biopsies were performed on recipient #2 at 8 weeks and 1 year after the transplant. These revealed marked diminution followed by complete resolution of all tubular reticular structures and deposits as well as immunofluorescent activity. Both recipients remain with normal renal function and urinalysis at 3 years after the transplant. CONCLUSION Although a history of clinically significant renal disease has been considered an absolute contraindication to kidney donation, with appropriate workup and caution, select patients may still be considered, which would increase the potential donor pool.

Association of post-renal transplant erythrocytosis and microalbuminuria: response to angiotensin-converting enzyme inhibition.

Angiotensin-converting enzyme (ACE) inhibitor therapy has recently been shown to be effective in the treatment of post-renal transplant erythrocytosis (PTE). In an attempt to assess the effect of drug treatment on serum erythropoietin level, glomerular filtration rate, and urinary protein excretion, we prospectively evaluated 8 consecutive cadaveric renal transplant recipients with PTE treated with ACE inhibitor therapy for 3 months. In response to ACE inhibition, the mean hematocrit (HCT) value decreased from 53.7 +/- 0.6% before treatment to 42.7 +/- 2.2% at the conclusion of the study (p = 0.03). However, 1 patient failed to respond to ACE inhibition (HCT > 50%), and 2 patients with PTE developed anemia (HCT < 35%) while maintained on drug treatment. Although the mean serum erythropoietin level decreased during ACE inhibition (from 22.8 +/- 8.4 to 9.4 +/- 5.3 mU/ml; p = 0.06), a consistent change in individual erythropoietin levels was not identified. At the conclusion of the study, the serum erythropoietin levels were undetectable in 4 patients, decreased in 1, unchanged in 2, and increased in the only patient with PTE who failed to respond to drug treatment. All patients tolerated the ACE inhibitor therapy without developing cough or hyperkalemia. In addition, serum creatinine levels, 125I-iothalamate clearances, and mean arterial blood pressures were unchanged throughout the study. Microalbuminuria (spot urinary albumin/creatinine ratio between 30 and 200 mg/g) developed in 5 patients with PTE and coincided with the onset of erythrocytosis (25.2 +/- 7 mg/g before PTE and 76.3 +/- 36.7 mg/g at the time of PTE detection).(ABSTRACT TRUNCATED AT 250 WORDS)

Functional immunoassay technology (FIT), a new approach for measuring physiological functions: application of FIT to measure glomerular filtration rate (GFR)

This is the first description of functional immunoassay technology (FIT), which as a diagnostic tool has broad application across the whole spectrum of physiological measurements. In this paper, FIT is used to measure the renal clearance of an ultra low-dose administration of a clinically available contrast reagent for the purpose of obtaining an accurate glomerular filtration rate (GFR) measurement. Biomarker-based GFR estimates offer convenience, but are not accurate and are often misleading. FIT overcomes previous analytic barriers associated with obtaining an accurate GFR measurement. We present the performance characteristics of this diagnostic test and demonstrate the method by directly comparing GFR values obtained by FIT to those obtained by an FDA approved nuclear test in 20 adults. Two subjects were healthy volunteers and the remaining 18 subjects had diagnosed chronic kidney disease, with 12 being kidney transplant recipients. Measured GFR values were calculated by the classic UV/P method and by the blood clearance method. GFR obtained by FIT and the nuclear test correlated closely over a wide range of GFR values (10.9-102.1 ml.min(-1).1.73 m(-2)). The study demonstrates that FIT-GFR provides an accurate and reproducible measurement. This nonradioactive, immunoassay-based approach offers many advantages, chiefly that most laboratories already have the equipment and trained personnel necessary to run an ELISA, and therefore this important diagnostic measurement can more readily be obtained. The FIT-GFR test can be used throughout the pharmaceutical development pipeline: preclinical and clinical trials.

Accurate Measurement of Glomerular Filtration Rate

Measurement of the glomerular filtration rate (GFR) in patients with chronic renal disease has recently assumed increasing importance. Responsibility for this evolutionary change can be directly traced to our understanding of the limitations of plasma creatinine and creatinine clearance as markers of GFR (1,2) and the need for accurate and precise quantitation of GFR as potential therapies for progressive renal disease are being evaluated (3). Traditional methods for measurement of GFR are accurate but cumbersome and inconvenient for patients. Newer methods are sometimes less accurate but offer advantages of reproducibility and are more readily implemented. In this review, we discuss the attributes and limitations of different methods and markers for the assessment of GFR with an emphasis on clearance using radioisotopic markers.