Pathogenesis of focal glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is the histologic expression of diverse processes affecting the renal glomeruli and occurring in primary and secondary forms. A number of pathogenic factors have been identified in primary FSGS, and multiple etiologies have been defined as contributing factors for the development of secondary FSGS. There is a complex interplay between etiologic and pathogenic factors, progression factors and intervention in the phenotypic expression of FSGS. Key components include genetic predisposition, environmental influences and the impact on phenotype of pharmacologic intervention. The phenotypic spectrum for FSGS ranges from mild proteinuria and slow progression to a devastating clinical syndrome characterized by heavy proteinuria and rapid loss of renal function over a period of months. While the pathogenesis is unknown, much is known about factors which are involved in the development and progression of both primary and secondary FSGS. The ultimate goal of understanding pathogenesis is to provide specific nontoxic therapy for those patients who have a definable form of FSGS. While this goal is not yet in sight, many types of intervention, not addressed in the current chapter, can influence the course of various diseases presenting as FSGS. Until specific therapy can be fashioned, it is necessary for the clinician caring for these patients to appreciate the complex interaction of pathogenetic factors involved in the development and pregression of FSGS, as a rationale for providing intervention to prevent development of the disease and to slow its course.

ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. VAL-K Study Group.

BACKGROUND: Inhibition of the renin-angiotensin system is known to raise serum potassium [K(+)] levels in patients with renal insufficiency or diabetes. No study has evaluated the comparative effects of an angiotensin-converting enzyme (ACE) inhibitor versus an angiotensin receptor blocker (ARB) on the changes in serum [K(+)] in people with renal insufficiency. METHODS: The study was a multicenter, randomized, double crossover design, with each period lasting one month. A total of 35 people (21 males and 14 females, 19 African Americans and 16 Caucasian) participated, with the mean age being 56 +/- 2 years. Mean baseline serum [K(+)] was 4.4 +/- 0.1 mEq/L. The glomerular filtration rate (GFR) was 65 +/- 5 mL/min/1.73 m(2), and blood pressure was 150 +/- 2/88 +/- 1 mm Hg. The main outcome measure was the difference from baseline in the level of serum [K+], plasma aldosterone, and GFR following the initial and crossover periods. RESULTS: For the total group, serum [K(+)] changes were not significantly different between the lisinopril or valsartan treatments. The subgroup with GFR values of < or = 60 mL/min/1.73 m(2) who received lisinopril demonstrated significant increases in serum [K(+)] of 0.28 mEq/L above the mean baseline of 4.6 mEq/L (P = 0.04). This increase in serum [K(+)] was also accompanied by a decrease in plasma aldosterone (P = 0.003). Relative to the total group, the change in serum [K(+)] from baseline to post-treatment in the lisinopril group was higher among those with GFR values of < or = 60 mL/min/1.73 m(2). The lower GFR group taking valsartan, however, demonstrated a smaller rise in serum [K(+)], 0.12 mEq/L above baseline (P = 0.1), a 43% lower value when compared with the change in those who received lisinopril. This blunted rise in [K(+)] in people taking valsartan was not associated with a significant decrease in plasma aldosterone (P = 0.14). CONCLUSIONS: In the presence of renal insufficiency, the ARB valsartan did not raise serum [K(+)] to the same degree as the ACE inhibitor lisinopril. This differential effect on serum [K(+)] is related to a relatively smaller reduction in plasma aldosterone by the ARB and is not related to changes in GFR. This study provides evidence that increases in serum [K(+)] are less likely with ARB therapy compared with ACE inhibitor therapy in people with renal insufficiency.

Intravenous iron dextran treatment in predialysis patients with chronic renal failure.

Iron deficiency anemia is common in patients with chronic renal failure not undergoing hemodialysis. Current therapy consists of oral or intravenous (IV) iron dextran (IVID). The standard IV regimen is 100 to 200 mg/dose for a 1-g total dose. We hypothesized that 500 mg/wk of IVID for two doses would be less costly and equally effective as 200 mg/wk for five doses. We prospectively studied 22 patients with creatinine clearances less than 50 mL/min who were not undergoing dialysis and had anemia and evidence of iron deficiency (ferritin level <100 ng/mL or transferrin saturation [TSAT] <20%). Patients were randomized into two groups: group I (n = 8), 200 mg/wk of IVID for 5 weeks, and group II (n = 14), 500 mg/wk of IVID for 2 weeks. All patients tolerated IVID infusions without serious adverse reactions. Over the 6-month follow-up, both groups experienced an increase in hemoglobin levels from baseline. Ferritin levels in both groups increased (P < 0.005), peaked at 2 weeks, then declined thereafter. Over the 6-month follow-up, both groups experienced significant improvement, although the beneficial effects of group II declined at a significantly faster rate than group I (P = 0.003). There was no significant difference in change in ferritin levels between groups. TSAT peaked at 2 weeks in both groups (P < 0. 001). Group I experienced a significant increase in TSAT throughout the 6-month follow-up (P < 0.03), and group II achieved a significant increase in TSAT at 2 weeks, but not at 3 and 6 months. There was no significant difference in pretreatment to posttreatment change in TSAT. Treatment in group II was 35.2% more cost-effective than in group I ($965 versus $1,490, respectively). We conclude that IVID, 500 mg/wk, for 2 weeks is as effective and safe as 200 mg/wk for 5 weeks, but much less costly.

Treatment of glomerular diseases: ANCA-negative RPGN.

Classification of rapidly progressive glomerulonephritis (RPGN) has evolved over the last decade into a variety of categories, some are which are more amenable to treatment than others. The advent of testing for antineutrophilic cytoplasmic antibody (ANCA) has further defined RPGN and aided in the diagnosis and treatment of these diseases. Although RPGN has traditionally carried a poor prognosis, this has been markedly improved by early diagnosis and intervention with aggressive therapy. The current chapter provides an oversight of ANCA-negative RPGN, and delineates an approach to diagnosis and therapy of various subtypes of this entity. Although current therapeutic options still encompass broad-spectrum immunosuppressive modalities, the future holds great hope for specific directed interventions at discrete points in the pathogenic progress. This offers the possibility of abrogation of the immune response leading to RPGN with less toxic general side effects then with treatments currently used. The next millennium will be marked by improved prognosis for ANCA-negative glomerulonephritis compared with that observed with this devastating disease in past decades.

Improved urea reduction ratio and Kt/V in large hemodialysis patients using two dialyzers in parallel.

Delivered dose of hemodialysis (HD) in large patients with end-stage renal disease is often less than adequate. Fourteen chronic HD patients with weights greater than 80 kg participated in a prospective, cross-over study comparing urea reduction ratio (URR +/- SEM) and the fractional clearance index for urea (eKt/V(urea) +/- SEM) on a single polysulfone dialyzer for a control (HDC) period of 4 weeks versus clearances obtained with two dialyzers in parallel during an intervention (HDP) period of 4 weeks. Clearance of the surrogate middle molecule iohexol (C(Io)) was also measured. Health status was assessed with the SF-36. Blood and dialysate flow rates and duration of HD sessions were constant. URR increased from 0.67 +/- 0.006 during HDC to 0.72 +/- 0.006 with HDP (P < 0.0001). eKt/V(urea) increased from 1.16 +/- 0.021 to 1.34 +/- 0.021 (P < 0.0001). Increased URR and eKt/V(urea) occurred in all 14 during HDP (P < 0.05). C(Io) during HDP averaged 182 +/- 7.7 mL/min compared with 131 +/- 5.4 mL/min in HDC sessions (P < 0.00001). Health status improved in six of eight categories. Expense increased approximately $14.27 per dialysis with HDP. In 11 of 14 patients continued on two dialyzers in parallel for 1 year, monthly eKt/V averaged 1.46 +/- 0.066, and health status further improved in five of eight categories. In large patients, two dialyzers in parallel increased urea and iohexol clearance. Increased urea clearance was maintained for 1 year, and health status improved.

Chronic renal insufficiency: current understandings and their implications.

Chronic renal insufficiency (CRI) is underrecognized and undertreated even in sophisticated health care systems. This is particularly distressing in light of the growing number of effective interventions available to slow the progression of kidney disease and ameliorate many of its comorbid conditions. Progress, to a certain extent, is impeded by the lack of generally accepted definitions, clear diagnostic criteria, and practical screening tests. Available epidemiologic data suggest that 800,000 Americans have creatinine levels >/=2.0 mg/dL and over 6 million have levels >/=1.5 mg/dL. Population-based surveys show that age, male gender, and black race are predictors of kidney disease. For reasons that are not well understood, the incidence of kidney failure has nearly doubled over the last 15 years, indicating a parallel increase in CRI. This trend has significant economic implications. Other implications of CRI related to the use and availability of health care resources are appropriate referrals to nephrologists and early intervention to optimize care of patients with CRI. A multipronged approach to providing optimal care involves interventions that may delay the progression of renal dysfunction, proactive prevention of uremic complications, measures to forestall the progress of comorbid conditions, and timely preparation of patients for renal replacement therapy. Early recognition of CRI, expeditious referral for specialty care, and the utilization of a comprehensive program of care optimization will help meet the nation's goals as articulated in the National Institutes of Health's Healthy People 2010: Chronic Kidney Disease.

Use of iohexol to quantify hemodialysis delivered and residual renal function: technical note.

BACKGROUND: Classically, urea (molecular wt = 60) is used to determine the urea reduction ratio (URR) or clearance, based on volume of distribution (Kt/V). These methods are subject to many errors. The purpose of this study was to determine whether iohexol (Io; molecular wt = 821) could be used instead of urea and provide better information as well as middle molecule clearance data. METHODS: Ten hemodialysis (HD) patients were evaluated. All were dialyzed for three hours, and a single bolus of 100 ml of Io was injected immediately post-HD. For direct dialysis quantification (DDQ), the spent dialysate was collected in a drum, and urea and iodine (I) determined immediately prior to, at the end of, and 30 minutes post-HD. As routinely used, DDQ measures clearance directly rather than estimates the levels. RESULTS: Calculated Kt/V urea (1.21+/-0.05) significantly overestimated DDQ Kt/V urea (0.78+/-0.04, P < 0.001) whereas calculated and DDQ Kt/V Io were similar (1.44+/-0.10 vs. 1.36+/-0.05). The URR and iohexol reduction ratio (IoRR) were also different (0.63+/-0.02 vs. 0.69+/-0.02; P < 0.002) with a urea but not Io rebound (URR30 min 0.59+/-0.02, P < 0.05). Calculated urea clearance (C(urea)), 247+/-21 ml/min, significantly overestimated DDQ C(urea) (157+/-10 ml/min P < 0.001). Calculated CIo and DDQ CIo, however, were similar (109+/-8 vs. 104+/-7 ml/min). Total body clearance (TBC) in six anuric subjects was 2.5+/-0.3 ml/min, and in four oliguric subjects was 5.2+/-0.5 ml/min. In 10 additional patients, direct urine measurements demonstrated a non-renal clearance (NRC) of 2.97+/-0.18 ml/min, which was 4.0+/-0.3% of body wt. Use of this factor allowed an estimation of residual renal function (RRF) that accurately reflected measured RRF (1.32+/-0.53 vs. 1.42+/-0.55 ml/min) CONCLUSION: A single injection of Io can be used to determine Kt/V, RR, and RRF without rebound or the inconvenience of urine collection. It may also represent middle molecule clearance better than urea kinetics, and may serve as a superior method for determining HD delivered and dialysis adequacy.

The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.

BACKGROUND: In patients with end-stage renal disease, anemia develops as a result of erythropoietin deficiency, and recombinant human erythropoietin (epoetin) is prescribed to correct the anemia partially. We examined the risks and benefits of normalizing the hematocrit in patients with cardiac disease who were undergoing hemodialysis. METHODS: We studied 1233 patients with clinical evidence of congestive heart failure or ischemic heart disease who were undergoing hemodialysis: 618 patients were assigned to receive increasing doses of epoetin to achieve and maintain a hematocrit of 42 percent, and 615 were assigned to receive doses of epoetin sufficient to maintain a hematocrit of 30 percent throughout the study. The median duration of treatment was 14 months. The primary end point was the length of time to death or a first nonfatal myocardial infarction. RESULTS: After 29 months, there were 183 deaths and 19 first nonfatal myocardial infarctions among the patients in the normal-hematocrit group and 150 deaths and 14 nonfatal myocardial infarctions among those in the low-hematocrit group (risk ratio for the normal-hematocrit group as compared with the low-hematocrit group, 1.3; 95 percent confidence interval, 0.9 to 1.9). Although the difference in event-free survival between the two groups did not reach the prespecified statistical stopping boundary, the study was halted. The causes of death in the two groups were similar. The mortality rates decreased with increasing hematocrit values in both groups. The patients in the normal-hematocrit group had a decline in the adequacy of dialysis and received intravenous iron dextran more often than those in the low-hematocrit group. CONCLUSIONS: In patients with clinically evident congestive heart failure or ischemic heart disease who are receiving hemodialysis, administration of epoetin to raise their hematocrit to 42 percent is not recommended.

Nephrology nurse practitioners in a collaborative care model.

The use of nurse practitioners in the primary care setting is increasingly common. However, little information is available on their use in specialty care areas. This is especially true in nephrology, in which end-stage renal disease (ESRD) lends itself well to this type of practice. We describe our experience with a university-based collaborative care model for ESRD with nurse practitioners in nephrology. Our experience shows that nephrology nurse practitioners have a significant impact on extending the quality and quantity of patient care provided by the nephrologist. They facilitate a holistic patient-friendly approach, and, as an integral part of the collaborative model, there is an associated significant decrease in patient mortality relative to standard comparators. Nurse practitioners provide a large amount of care for ESRD patients in a relatively independent fashion but under the supervision and with the collaborative interaction of nephrologists. Patient satisfaction, approval, respect, and trust for the nurse practitioners are exceptional. The use of nephrology nurse practitioners provides the potential for augmenting patient care, satisfaction, and access to care. It provides an avenue for potential cost reduction in nephrology while maintaining quality of care. It further provides a partial solution to the anticipated shortage of nephrologists in the twenty-first century.

The role of the nephrologist in ESRD/Pre-ESRD care: a collaborative approach.

The number of patients with chronic renal failure and end-stage renal disease continues to increase. Nonetheless, there are increasing pressures to decrease the number of nephrologists. To provide highly specialized care for these complex patients, nephrologists must render less care for more patients, or allow less qualified providers to render care. Use of a highly specialized professional colleague, the properly trained nephrology nurse practitioner, allows the nephrologist to provide care for a great number of patients while maintaining quality using an integrated collaborative practice model. This article describes the successful use of nurse practitioners to extend the scope of nephrology care with this paradigm. This model allows the nephrologist to provide specialized care to more patients, maintain quality control, improve cost effectiveness of care rendered, and is enthusiastically embraced by the patients cared for by the team.

Disposition and bioavailability of ceftazidime after intraperitoneal administration in patients receiving continuous ambulatory peritoneal dialysis.

This study investigated the disposition and bioavailability of ceftazidime when it was given intraperitoneally. Seven patients were given 1 gm of ceftazidime intravenously, and 1 wk later, the same dose was given intraperitoneally. After both intravenous and intraperitoneal dosing, serum and peritoneal dialysate samples were obtained at set time intervals over a 24-h period. High-performance liquid chromatography was used to determine the ceftazidime concentrations in the serum and dialysate samples. Inspection of the concentration versus time data after intraperitoneal dosing demonstrated that serum ceftazidime concentrations reached therapeutic (> 8 micrograms/mL) levels within 30 min and remained in the therapeutic range for the entire 24-h period. Simulation of a variety of ceftazidime dosing regimens using the mean pharmacokinetic parameters from this population of patients suggests that a regimen of 1.5 gm administered intraperitoneally every 24 h produces trough serum drug concentrations (approximately 40 micrograms/mL) similar to those achieved with a standard regimen of 1.0 gm given intravenously every 24 h in patients undergoing continuous ambulatory peritoneal dialysis. It was concluded that the intraperitoneal dosing of ceftazidime in these patients is an equally effective and a more convenient alternative to its administration.

Rapidly progressive glomerulonephritis.

Rapidly progressive glomerulonephritis (RPGN) is a dramatic disease that carries a poor prognosis but responds to early intervention and aggressive therapy. This review provides a schema for expeditious diagnosis and therapy of various types of RPGN encompassing application of current serological and other diagnostic tools, and addresses issues related to selection of therapy, assessment of expectation of response, and prognosis. Current therapeutic modalities have improved the prognosis of this devastating disease, but emerging therapeutic options promise to improve our treatment of these diseases yet more in the future.

Goodpasture's epitope in development of experimental autoimmune glomerulonephritis in rats.

The Goodpasture's epitope (GP) has recently been localized to the last 36 AA of the non-collagenous (NCl) domain of the alpha 3 chain of type IV collagen [alpha 3(IV)]. Since alpha 3(IV) induces glomerulonephritis (GN) in rats and rabbits, the purpose of the present study was to determine if the GP epitope itself could induce GN. We immunized rats with synthetic peptides of GP epitope, 36-mer, alone or as protein conjugates. Rats immunized with bovine GBM served as positive controls. Peptide immunized rats developed high titer antibodies to peptides, but only unconjugated 36-mer induced antibody against human and bovine GBM, but not to rat GBM. Acidic residues and the full length 36-mer were important in production of GBM reactive antibodies. Positive controls developed antibody to GBM without reactivity against 36-mer, had IgG and fibrin on the basement membrane, GN and proteinuria. Kidney eluted antibody was reactive with rat, bovine, and human GBM but not 36-mer. GN rat lymphocytes underwent blast transformation to GBM but not peptide, and peptide immunized animals responded only to the respective peptides. None of the animals immunized with GP peptide epitope, despite the development of anti-peptide antibodies or anti-GBM antibodies, developed any in vivo fixation of antibody to the GBM, abnormal proteinuria, or GN. The present study shows that the GP epitope is sufficient to induce an immune response to the epitope, but it is not sufficient to induce GN. This demonstrates that other factors or epitopes are important in the pathogenicity of GBM induced GN in this model. These remain to be delineated.

Membranoproliferative glomerulonephritis with primary Sjögren's syndrome.

Glomerular involvement in primary Sjögren's syndrome is rare and only five cases of membranoproliferative glomerulonephritis have been reported. We present a case of a 31-year-old white woman with primary Sjögren's syndrome who developed nephrotic syndrome. Evaluation showed no evidence of an associated connective tissue disease. Kidney biopsy was consistent with type I membranoproliferative glomerulonephritis. The patient's nephrotic syndrome resolved spontaneously, a course that has not been reported previously in this setting.

Study of EHS type IV collagen lacking Goodpasture's epitope in glomerulonephritis in rats.

The Goodpasture's epitope has been mapped to the alpha 3 non-collagenous chain (NC1) of type (IV) collagen [alpha 3col(IV)]. We have developed a model of experimental autoimmune glomerulonephritis (EAG) in rats immunized once with collagenase solubilized GBM (csGBM). Engelbreth-Holm-Swarm (EHS) tumor contains abundant col(IV) with little or no alpha 3col(IV). To test the hypothesis that antigens related to Goodpasture epitope are required to produce EAG in our model, we immunized rats once with 40 micrograms csEHS. Positive controls immunized with csGBM developed typical EAG with GBM bound antibody, proteinuria, and glomerulonephritis. EHS rats developed circulating and bound antibody to mesangium and tubular basement membrane with minimal GBM deposits, but did not develop proteinuria or glomerulonephritis. Although circulating antibody in EHS rats bound to csGBM by ELISA, there was no binding in ELISA to M2 antigen containing the Goodpasture epitope while EAG rat's serum did bind. By Western blot with antisera to Goodpasture epitope, EHS antigen was less complex than GBM in the monomer/dimer regions and appeared to lack NC1 corresponding to alpha 3col(IV). Blotting with sera from EHS rats demonstrated reactivity to various components of GBM but not to alpha 3col(IV). EAG sera and renal eluates bound to alpha 3col(IV). EAG rats evidenced cell mediated immunity while EHS rats did not (stimulation index EHS 1.1, EAG rats 8.0).(ABSTRACT TRUNCATED AT 250 WORDS)

Renal TGF-beta regulation in spontaneously diabetic NOD mice with correlations in mesangial cells.

Diabetic nephropathy is characterized by excessive glomerular matrix accumulation, basement membrane thickening and sclerosis. Although it is clear that systemic metabolic disturbances precipitate such renal changes, the signals and pathways involved in this process are not fully elucidated. Recent evidence suggests that growth factors/cytokines are intimately involved in the pathogenesis of diabetic nephropathy. Because of its prosclerotic properties, transforming growth factor-beta (TGF-beta) is a prime candidate mediator of diabetic nephrosclerosis. We examined perfused kidney tissues isolated from spontaneously diabetic, non-obese diabetic mice (NOD) for TGF-beta content. By using murine isotype specific TGF-beta probes, we demonstrate that within 5 to 10 days of hyperglycuria renal TGF-beta 2 mRNA and protein content increases. By immunohistochemical analysis, de novo TGF-beta immunoreactivity was detected within both glomeruli and the interstitium. In order to determine the signals involved in promoting kidney TGF-beta content in vivo, TGF-beta regulation was examined in renal mesangial cells in vitro. Murine mesangial cells stimulated with glycosylated protein secrete bioactive TGF-beta and demonstrate a disproportionate increase in the steady state levels of TGF-beta 2 mRNA. These data suggest that a major early renal response in NOD mice to hyperglycemia or to glycosylated proteins is characterized by increases in TGF-beta.