Progressive Chronic Renal Insufficiency Research Articles

Abstract P173: Proteomic Assessment of Progressive Chronic Renal Insufficiency Risk and Mortality in a Heart Failure Community Study

Introduction: Over six million U.S. adults have heart failure (HF). Evaluation of kidney function is critical to the care of patients with HF but may not be fully captured by traditional measures, such as estimated glomerular filtration rate (eGFR) or the Meta-Analysis Global Group in Chronic HF (MAGGIC) risk score. Identifying patients at highest risk of progressive chronic renal insufficiency (PCRI) may improve risk stratification in HF, beyond these traditional measures. High-throughput proteomics has allowed for the development of PCRI risk scores based on novel kidney function biomarkers. However, the prognostic value of a proteomic-based PCRI risk score in HF has not been explored. Hypothesis: Proteomic-based PCRI risk scores will improve risk stratification in HF. Methods: Clinical data and plasma were collected from 1,389 patients in a HF community cohort from Southeastern Minnesota (2003-2012). Results from the aptamer-based technology SomaScan® were used to derive PCRI risk scores using the SomaSignal™ Kidney Prognosis test, a protein-based algorithm developed to predict risk of PCRI within four years. Cox proportional hazard models were used to estimate the association between quintiles of PCRI and mortality, after adjustment for the MAGGIC score. Results: PCRI risk scores were available for 1,349 patients who were on average 75±13 years of age, 48% female, and had a median eGFR of 57 mL/min/1.73m 2 . There was a positive association with mortality across PCRI risk quintiles, after adjustment for the MAGGIC score. (Figure). Overall, the highest quintile was associated over a two-fold higher risk of mortality compared with the lowest quintile (HR 2.3, 95% CI 1.8,2.8). The higher risk of mortality remained in analyses stratified by patients with (HR 1.5, 95% CI 1.1,2.1) and without (HR 2.2, 95% CI 1.4,3.5) an eGFR <60 mL/min/1.73 m 2 . Conclusions: In this community HF cohort, proteomic-based PCRI risk scores improve risk stratification, independent of traditional measures of kidney function.

Renal Involvement in Antiphospholipid Syndrome

Renal involvement can be a serious problem for patients with antiphospholipid syndrome (APS). However, this complication has been poorly recognized and studied. It can be present in patients who have either primary or systemic lupus erythematosus-associated APS. Clinical and laboratory features of renal involvement in APS include hypertension, hematuria, acute renal failure, and progressive chronic renal insufficiency with mild levels of proteinuria that can progress to nephrotic-range proteinuria. The main lesions are renal artery stenosis, venous renal thrombosis, and glomerular lesions (APS nephropathy) that may be acute (thrombotic microangiopathy) and/or chronic (arteriosclerosis, arterial fibrous intimal hyperplasia, tubular thyroidization, arteriolar occlusions, and focal cortical atrophy). APS can also cause end-stage renal disease and allograft vascular thrombosis. This article reviews the range of renal abnormalities associated with APS, and their diagnosis and treatment options.

Cystatin C: a potentially useful marker for identifying individuals with spina bifida and early renal insufficiency

Background Individuals with spina bifida (SB) are at risk for deterioration of their upper urinary tracts due to neurogenic bladder and subsequent progressive chronic renal insufficiency (CRI). Serum creatinine (SCr) is the most widely used marker to assess renal function and to estimate glomerular filtration rate (GFR), although it has significant limitations. SCr is dependent on age, height, gender and muscle mass and has been shown to be an unreliable marker of renal function in SB. Cystatin C (CyC) is a cysteine proteinase inhibitor of low molecular weight, produced at a constant rate by all nucleated cells, freely filtered at the glomerulus, and not secreted or reabsorbed at the renal tubule. CyC is independent of age, height, and gender and is believed to be independent of muscle mass. Over the past several years, serum CyC has been shown to be a better marker of renal function and GFR than SCr (using the Schwartz formula) in children. One study by Pham-Huy in 2003 showed that CyC was much better correlated with GFR than SCr in children with SB.

Pharmacological and clinical trial data on a novel phosphate-binding polymer (sevelamer hydrochloride), a medicine for hyperphosphatemia in hemodialysis patients

Hyperphosphatemia is one of the major complications of hemodialysis patients and plays a key role in the pathogenesis of cardiovascular calcification and secondary hyperparathyroidism. Dietary phosphate restriction and removal of phosphate by dialysis are insufficient to control hyperphosphatemia. Therefore, almost all patients undergoing hemodialysis should take oral phosphate binders. Sevelamer hydrochloride (sevelamer) is a novel phosphate-binding polymer that contains neither aluminum nor calcium, and it is not absorbed from the gastrointestinal tract. In rat models with progressive chronic renal insufficiency, in addition to lowering effects on serum levels of phosphorus, calcium x phosphorus product, and parathyroid hormone, dietary treatment of sevelamer can prevent parathyroid hyperplasia, vascular calcification, high turnover bone lesion, and renal functional deterioration. In clinical studies with hemodialysis patients, sevelamer lowers serum phosphorus and calcium x phosphorus product without any incidence of hypercalcemia. Switching calcium-containing phosphate binders to sevelamer can decrease the percentage of hypoparathyroidism and hyperparathyroidism by negative calcium balance and increased dosage of vitamin D, respectively. Sevelamer also decreases serum low-density lipoprotein cholesterol levels by its bile acid-binding capacity. A long-term clinical study has demonstrated that the progression of coronary and aortic calcification in hemodialysis patients is attenuated by sevelamer. Thus, sevelamer offers the promise of impacting cardiac calcification and thereby reducing morbidity and mortality of hemodialysis patients.

Sevelamer hydrochloride (Renagel), a non-calcaemic phosphate binder, arrests parathyroid gland hyperplasia in rats with progressive chronic renal insufficiency.

It has been demonstrated that dietary phosphate restriction suppresses parathyroid hormone (PTH) secretion and parathyroid cell proliferation in experimental animals with chronic renal insufficiency (CRI) independently of serum calcium and 1,25(OH)(2)D3 levels. This study was conducted to examine whether sevelamer hydrochloride (Renagel); hereafter referred to as sevelamer), a non-calcaemic phosphate binder could inhibit the parathyroid gland (PTG) hyperplasia in rats with progressive CRI. Male Sprague-Dawley rats were injected twice with low doses of adriamycin (ADR). Two weeks after the last injection of ADR, rats were fed a diet containing 1 or 3% sevelamer for 84 days. Time course changes of serum levels of calcium, phosphorus, and PTH were measured. At the end of study, serum 1,25(OH)(2)D3 levels were measured and the maximal two-dimension area of the PTG in paraffin section was calculated using an imaging analyser. Dietary sevelamer treatment inhibited the elevations of serum phosphorus, calciumxphosphorus product, and PTH levels that occurred as the study progressed. Sevelamer also suppressed maximal PTG area and there existed positive strong correlation between maximal PTG area and serum PTH levels at the end of the study. Serum phosphorus levels positively correlated well with serum PTH levels and maximal PTG area. In contrast, serum calcium or 1,25(OH)(2)D3 levels did not show any correlation with serum PTH levels and maximal PTG area. Sevelamer treatment arrested hyperphosphataemia and PTG hyperplasia accompanied by the elevation of serum PTH levels. The correlation analysis suggests that reduced serum phosphorus levels contributed to the suppression of PTG hyperplasia and resulted in the reduction of PTH levels in this animal model after the sevelamer treatment. The management of phosphorus control started from early stage of CRI could prevent PTG hyperplasia and facilitate later management of secondary hyperparathyroidism.

Sodium balance in renal failure.

Sodium balance in patients with renal failure varies with the severity and clinical manifestations of renal disease. Progressive chronic renal insufficiency is typified by an adaptive increase in the sodium excretion rate per nephron as the total glomerular filtration rate declines. This increase is caused, at least in part, by the effect of atrial natriuretic peptide and other natriuretic peptides, whose release is augmented in the setting of volume expansion and renal failure. However, exogenous administration of natriuretic peptides in clinical chronic and acute renal disease does not consistently increase renal sodium excretion. As the glomerular filtration rate progressively declines towards end-stage renal disease, total renal sodium excretion eventually decreases, and extracellular volume expansion, hypertension, and edema develop. Sodium removal, induced by high dose diuretics or via convective ultrafiltration during dialysis, is necessary to decrease the extracellular volume to normal.

IgA nephropathy: Long-term prognosis for pediatric patients

Objective: The determination of the ultimate prognosis for patients with IgA nephropathy diagnosed in childhood requires long-term follow-up of identified patients. The purpose of this study was to obtain such follow-up for patients from two centers where the disease has been diagnosed for more than 20 years. Methods: Clinical data at the apparent onset of symptoms and renal histologic data were obtained for 103 patients in whom IgA nephropathy was diagnosed before age 18 years. Clinical status at last follow-up was obtained from office records or from direct contact with the patient. Predicted kidney survival was determined by the Kaplan-Meier method. Follow-up of more than 10 years from the time of biopsy was available for 40 of the patients. Results: Fourteen of the patients have progressed to end-stage renal disease; three others have progressive chronic renal insufficiency as defined by an estimated creatinine clearance of less than 50 ml/min per 1.73 m 2. Severity of the renal histologic findings and the degree of proteinuria at the time of biopsy were associated with poor outcome. For all patients, predicted kidney survival from the time of apparent onset was 94% at 5 years, 87% at 10 years, 82% at 15 years, and 70% at 20 years. Age at clinical onset and gender were not associated with poor outcome, but black race and severity of renal histologic findings were. Conclusion: With follow-up into adulthood, the outcome for pediatric patients with IgA nephropathy appears to be as serious as that reported in adult patients. Follow-up of a pediatric patient with persistent clinical findings should be maintained after the patient's care is transferred to a physician caring for adults. (J P EDIATR 1995;127:913-9)

Cyclosporine-induced pericardial effusion after cardiac transplantation

In the last 5 years, there has been a significant proliferation in the number of centers in which orthotopic cardiac transplantation is performed. This has been attributed to better surgical management, patient selection criteria and the introduction of cyclosporine as the immunosuppressant of choice. 1 Initially, it was hoped that cyclosporine would prevent the problems of sudden, catastrophic rejection, development of a Cushingoid appearance and other complications of high-dose steroid therapy. It was also hoped that by monitoring drug levels and titrating the dose, the incidence and severity of rejection would decrease, the length of hospitalization in the immediate postoperative period would decrease and both short-term and long-term survival would increase. 2 It soon became apparent, however, that long-term cyclosporine immun osuppression is associated with severe systemic hypertension and progressive chronic renal insufficiency. 3 Both complications of cyclosporine therapy may lead to the necessity of decreasing the dose of cyclosporine, a readjustment of immunosuppressive protocols to low-dose triple drug therapy (azathioprine, prednisone and cyclosporine) and even the necessity of withdrawing cyclosporine. 4 Less frequently, we have observed significant pericardial effusions in patients who have received cardiac allografts. We will discuss our observations of pericardial disease in the orthotopic cardiac recipient maintained on cyclosporine.

Polycythemia in Renal Transplant Patients

<h3>To the Editor.</h3> —Erythrocytosis is a well-recognized complication of successful renal transplantation.¹The clinical importance of polycythemia in this setting is largely related to an increased incidence of thromboembolic phenomena.²This report describes a superior sagittal sinus thrombosis, a previously undescribed manifestation of posttransplant erythrocytosis <h3>Report of a Case.</h3> —A 36-year-old man had insulin-dependent diabetes mellitus of 22 years' duration. At age 35, he had undergone a cadaveric renal transplant because of progressive chronic renal insufficiency. The patient had an uneventful postoperative course and was discharged one month after grafting with a BUN level of 32 mg/dL, a serum creatinine level of 1.2 mg/dL, and a hematocrit reading of 29%. During the ensuing months, the patient was asymptomatic. However, his hematocrit reading rose progressively to 59%. He maintained normal renal function with no evidence of rejection. Thirteen months after his kidney transplant, he experienced a grand mal seizure