Lee A. Hebert

The Living Donor in Kidney Transplantation

Kidney transplantation using either kidneys from living or nonliving donors is now generally regarded as the primary therapy for most patients with end-stage kidney failure. In 1984, 32% of all kidney transplantations done in the United States involved living donors. Reasons justifying the use of kidneys from living donors are the higher success rate and the inadequate supply of cadaveric kidneys. In addition, with a living donor, it is easier to arrange for kidney transplantation before dialysis therapy needs to be started. An analysis of 2495 donor nephrectomies reported in the literature, and 5698 donor nephrectomies reported from the 12 largest centers that do kidney transplantation with living donors, indicates an approximate incidence of 1 donor death per 1600 nephrectomies. Although long-term follow-up in kidney donors has shown only that mild, nonprogressive proteinuria develops in about 33% and that the frequency of hypertension may increase, we advise that the kidney donor have a careful long-term follow-up and avoid a high protein intake because of its potential to lead to progressive glomerular damage.

Staphylococcus Infection-Associated Glomerulonephritis Mimicking IgA Nephropathy

The association of methicillin-resistant Staphylococcus aureus (MRSA) infection with glomerulonephritis (GN) has been well documented in Japan but not in North America. Recently, eight renal biopsies with IgA-predominant or -codominant GN from eight patients with underlying staphylococcal infection, but without endocarditis, were observed at a single institution in a 12-mo period. Renal biopsies were worked up by routinely used methodologies. Eight cases of primary IgA nephropathy were used as controls. Five patients had MRSA infection, one had methicillin-resistant S. epidermidis (MRSE) infection, and two had methicillin-sensitive S. aureus infection. Four patients became infected after surgery; two patients were diabetic and had infected leg ulcers. All patients developed acute renal failure, with active urine sediment and severe proteinuria. Most renal biopsies showed only mild glomerular hypercellularity. Two biopsies had prominent mesangial and intracapillary hypercellularity; one of them (the MRSE-associated case) had large glomerular hyalin thrombi. This patient also had a positive cryoglobulin test. Rare glomerular hyalin thrombi were noted in two other cases. Immunofluorescence showed IgA pre- or codominance in all biopsies. Electron microscopy revealed mesangial deposits in all cases. Five biopsies had rare glomerular capillary deposits as well. In the MRSE-associated GN, large subendothelial electron-dense deposits were present. These cases demonstrate that staphylococcal (especially MRSA) infection-associated GN occurs in the US as well, and a rising incidence is possible. It is important to differentiate a Staphylococcus infection-associated GN from primary IgA nephropathy to avoid erroneous treatment with immunosuppressive medications.

Typing of amyloidosis in renal biopsies: diagnostic pitfalls.

CONTEXT Amyloidosis represents a group of diseases with extracellular deposition of congophilic fibrils of similar morphology but differing chemical composition. The types commonly involving the kidney are AL (light chain amyloid) and AA (serum amyloid A). Familial amyloidosis can also affect the kidney, but we have not encountered such a case during the study period. Distinguishing between the AL and AA forms of amyloid is clinically important because of the different treatments and outcomes. The classification of amyloidosis is made by immunostaining with antibodies to kappa and lambda immunoglobulin light chains and for serum amyloid A protein. OBJECTIVE To draw attention to the nonspecific immunofluorescence staining patterns in renal biopsies with amyloidosis, causing potential diagnostic pitfalls. DESIGN Renal biopsies from 15 patients, including 13 cases of AL and 2 cases of AA amyloidosis, were studied. Immunofluorescence staining with routine antibody panel and immunoperoxidase staining for amyloid A were performed. RESULTS Of the 13 cases of AL amyloidosis, 2 cases showed little difference in staining intensity between kappa and lambda light chains (2+ and 3+, respectively) and 4 cases showed only moderate intensity (2+) of the predominant light chain. The 2 cases diagnosed as AA amyloidosis also exhibited staining for light chains. One case had strong (3+) signal for kappa and moderate (2+) for lambda light chain, while the other showed weaker staining. CONCLUSIONS Immunofluorescence staining for immunoglobin light chains on renal biopsy, as the first step to differentiate between AL and AA amyloidosis, may sometimes be inconclusive or even misleading. Applying amyloid A immunostain on a routine basis and detailed clinical history are essential to avoid misclassification.

IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression.

Recent breakthrough findings revealed that most patients with idiopathic (primary) membranous glomerulonephritis have IgG4 antibodies to the phospholipase A2 receptor (PLA2R). These IgG4 antibodies can be detected in the glomerular immune complexes and they colocalize with PLA2R. In secondary forms of membranous glomerulonephritis, such IgG4 antibodies are absent or less prevalent. There are no studies addressing the IgG subclass distribution across different stages of membranous glomerulonephritis. During a 25-month period, we identified 157 consecutive biopsies with membranous glomerulonephritis with adequate tissue for light, immunofluorescence and electron microscopy. Of the 157 membranous glomerulonephritis cases, 114 were primary membranous glomerulonephritis and 43 were secondary membranous glomerulonephritis. We compared the intensity of IgG subclass staining (on a semiquantitative scale of 0 to 3+) and the IgG subclass dominance between primary and secondary membranous glomerulonephritis and between the different stages of membranous glomerulonephritis. In primary membranous glomerulonephritis most (76% of cases) were IgG4 dominant. In contrast, in secondary membranous glomerulonephritis IgG1 was dominant in 60% of biopsies (P=0.0018). Interestingly, in early stage (stage 1) primary membranous glomerulonephritis, IgG1 was the dominant IgG subclass (64% of cases); in all later stages IgG4 dominated (P=0.0493). It appears that there is an inverse relationship between the intensity of glomerular capillary IgG4 and C1q staining. In secondary forms of membranous glomerulonephritis (heterogeneous group with low case numbers), we did not find such associations. Our data indicate that in early stage membranous glomerulonephritis, antibody response is different from later stages, with IgG1 dominant deposits. It is possible that early on, antigens other than PLA2R have an important role, Alternately, there may be an IgG subclass switch in the antibody response with IgG4 taking over later as the dominant immunoglobulin.

Serum C3 Levels Are Diagnostically More Sensitive and Specific for Systemic Lupus Erythematosus Activity Than Are Serum C4 Levels

To determine whether serum C3 or C4 is more likely to be normal during systemic lupus erythematosus (SLE) remission and abnormal during SLE relapse we studied twelve SLE patients who presented with severe nephritis. The patients were followed long term (12 to 77 months) through multiple relapses (N = 41) and remissions (N = 13) defined by protocol. A total of 471 serum samples were obtained at defined intervals during these relapses and remissions and were analyzed for C3 and C4 levels by two different methods: nephelometry (N) and radial immunodiffusion (R). During SLE remission (defined by protocol and without reference to serum complement levels), C3 measured by N-assay (C3N) and by R-assay (C3R) tended to be normal (specificity of 93% and 71%, respectively). By contrast, C4 measured by N-assay (C4N) and by R-assay (C4R) showed no such tendency (specificity of 50% for both C4N and C4R). During SLE relapse (defined by protocol and without reference to serum complement levels), C3N and C3R were more likely to be abnormal (sensitivity 95% and 85%, respectively) compared with C4N and C4R (sensitivity 56% and 54%, respectively, P less than 0.001 compared with corresponding values for the C3 assay). Analysis by receiver-operator characteristic (ROC) curves demonstrated that the reduced diagnostic sensitivity of C4 versus C3 is not explained by use of an inappropriate lower limits of normal (LLN) for C4.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral Cyclophosphamide for Lupus Glomerulonephritis: An Underused Therapeutic Option

BACKGROUND AND OBJECTIVES In our center, systemic lupus erythematosus nephritis is routinely treated with an oral cyclophosphamide (POCY) regimen. POCY is easy to administer and less expensive than intravenous cyclophosphamide (IVCY) as it is currently used in the United States; however, the use of POCY has declined in favor of IVCY. Our experience with POCY suggests that it is well tolerated and consistently associated with good long-term outcomes. Here we report this experience to build a case for maintaining POCY as a therapeutic option in lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This is a single-center, retrospective analysis of the outcome of 46 patients who had systemic lupus erythematosus with nephritis and were treated with POCY between 1995 and 2006. POCY was given for 2 to 4 mo at a dosage of 1.0 to 1.5 mg/kg ideal body weight. After completing POCY, the patients received either azathioprine or mycophenolate mofetil. RESULTS Median follow-up was 23.5 mo, and median duration of POCY was 4 mo (range 1 to 16 mo). Durable complete or partial remission of proteinuria was achieved in 32 (70%) patients, whereas 5 (11%) progressed to ESRD. Outcomes were comparable in black and white individuals. Adverse effects occurred in fewer than 10% of the cohort, and only four patients discontinued POCY. CONCLUSIONS These results suggest that sequential therapy of POCY followed by azathioprine or mycophenolate mofetil is comparable to IVCY regimens but that efficacy may not be affected by race.

Relationship between albuminuria and total proteinuria in systemic lupus erythematosus nephritis: diagnostic and therapeutic implications.

BACKGROUND AND OBJECTIVES Albuminuria is regarded a sensitive measure of progression of glomerular disease. This study was undertaken in patients who had systemic lupus erythematosus glomerulonephritis (n = 57) and were followed in the Ohio SLE Study to determine whether measuring albuminuria offered clinical advantages over that of total proteinuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Twenty-four-hour urine collections (n = 127) were obtained at baseline and annually for measurement of microalbumin, total protein, and creatinine. RESULTS There was a strong linear relationship between microalbumin-creatinine and protein-creatinine ratios over the entire range of protein-creatinine ratios; however, in the protein-creatinine ratio range 0.0 to 0.3, as the protein-creatinine ratio increased, the microalbumin-protein ratio increased much more than the protein-creatinine ratio. Also, the greater the protein-creatinine ratio, the greater was the evidence for nonselective proteinuria (protein-creatinine ratio--microalbumin-creatinine ratio). CONCLUSIONS For the diagnosis of proteinuria renal flare, measuring albuminuria offers no advantage over measuring total proteinuria because changes in protein-creatinine and microalbumin-creatinine ratios are highly correlated over the designated ranges for systemic lupus erythematosus glomerulonephritis proteinuric flares. In those with normal-range proteinuria, subsequent changes in microalbumin-protein ratio might be a better forecaster of renal flare than changes in protein-creatinine or microalbumin-creatinine ratio. High protein-creatinine ratios are associated with evidence of nonselective proteinuria, which may increase the nephrotoxicity of proteinuria. Thus, using high-threshold criteria for systemic lupus erythematosus flare (allowing greater proteinuria increase before flare is declared) may expose the kidney to greater nephrotoxicity than using the low-threshold criteria for systemic lupus erythematosus flare.

D-Dimer Level and the Risk for Thrombosis in Systemic Lupus Erythematosus

BACKGROUND AND OBJECTIVES Patients who have systemic lupus erythematosus (SLE) and manifest antiphospholipid antibodies (APA) are at increased risk for thrombosis; however, it is difficult to predict who will clot. This study tested the hypothesis that peak D-dimer level measured routinely during follow-up identifies whether a hypercoagulable state is developing and, therefore, the patient is at increased risk for thrombosis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS One hundred consecutive patients who had SLE with recurrent activity (71% renal SLE) and were evaluated for or enrolled in the Ohio SLE Study were studied. D-dimer testing was done annually and usually at SLE flare or other serious illness. When D-dimer was elevated, evaluation for thrombosis (large vessel, small vessel, or Libman-Sacks) was undertaken. Mean follow-up was 37.5 +/- 15 SD months. RESULTS Of those with peak D-dimer <0.5 microg/ml (n = 46), 0% thrombosed, 33% had APA. Of those with peak D-dimer 0.5 to 2.0 microg/ml (n = 19), 6% thrombosed, 44% had APA. Of those with peak D-dimer >2.0 microg/ml (n = 36), 42% thrombosed, 76% had APA. The most common causes of elevated D-dimer in the absence of demonstrable thrombosis were SLE flare and systemic infection. D-dimer levels were usually elevated for several months before thrombosis. CONCLUSIONS Patients with SLE and normal D-dimer levels are at low risk for thrombosis, irrespective of APA status. Those with persistent unexplained elevated D-dimer levels, particularly when >2.0 microg/ml, are at high risk for thrombosis.

Angiotensin as a Possible Intrarenal Hormone in Isolated Dog Kidneys

The distribution of renal blood flow was measured in isolated blood-perfused dog kidneys using radioactive labeled microspheres. The kidneys were perfused at a constant systolic pressure of 140 mm Hg. For the first 50 minutes of perfusion, flow to the outer zones of the renal cortex was 79±2% (SE) of the total renal blood flow, and inner cortical blood flow accounted for 21±2%. With continued perfusion, inner cortical blood flow increased progressively, reaching 34±3% by 150 minutes—a time when renin substrate was depleted in the perfusates. Infusions of the tetradecapeptide renin substrate (5–50 μg/min) reestablished the fractional distribution of renal blood flow observed in the initial 50 minutes of perfusion, i.e., inner cortical blood flow was reduced significantly from 36±2% to 23±4% (P < 0.05). In contrast, infusions of angiotensin II (1–10 μg/min) did not reduce the fractional distribution of renal blood flow to the inner cortex. These data provide evidence to support the hypothesis that angiotensin might be formed as an intrarenal hormone which participates in the regulation of deep cortical and medullary vascular resistances. Circulating angiotensin II does not appear to serve a similar function.

My Doctor Said I Should Drink a Lot! Recommendations for Fluid Intake in Patients with Chronic Kidney Disease

Patients with chronic kidney failure commonly are advised to maintain a generous fluid intake. The reason that physicians tend to recommend such an increased fluid intake is difficult to understand. A scientific basis does not exist. To the modern nephrologist, this element of the therapeutic armamentarium seems long to be outdated; however, it was once recommended by authorities (1) and is still being advocated by primary care physicians. “My wife forgot to ask whether it is really necessary to keep a fluid intake of 4.5 L daily. This was the advice of her primary care physician. Perhaps 3 L would be better for her BP and sufficient for her kidney.” The husband of the patient raised this question at the end of her consultation visit at our University Hospital Clinic. The patient was seen for a second opinion regarding the management of her chronic kidney disease (CKD) manifested by a serum creatinine of 3.0 mg/dl and non-nephrotic proteinuria. The husband, who is an oncologist, was mainly concerned because his wife was losing sleep at night because of her many nocturnal trips to the bathroom. If the oncologist and his wife were an isolated case, then we would not be writing this article. However, over the years, we have encountered numerous such examples in our nephrology consultative practice. We suggest further that the patients who have CKD and complain about the instruction to drink large amounts of fluid may represent only the “tip of the iceberg.” Likely, there are many more patients who have CKD and whom we nephrologists never hear about because they silently accept their watery fate. Without complaint, they follow the advice of their primary care physician, which is reinforced by the lay press (“drink at least 8 glasses of water a day”) and by well-meaning friends who …