Predicting decline of kidney function in lupus nephritis using urine biomarkers.

OBJECTIVE: To evaluate candidate biomarkers to predict future renal function decline (RFD) in children and adults with lupus nephritis (LN). METHODS: At the time of enrollment into prospective observational LN cohort studies liver-type fatty acid binding protein (LFABP), albumin, monocyte chemoattractant protein-1 (MCP-1), uromodulin, transferrin, and hepcidin were measured in urine samples of two cohorts of patients with LN, one followed at a pediatric (cohort-1; n = 28) and one at an adult institution (cohort-2; n = 69). The primary outcome was RFD, defined in cohort-1 as a decrease in estimated glomerular filtration rate (eGFR) of ≥20% and in cohort-2 as a sustained increase of ≥25% in serum creatinine concentration (SCr), both from baseline. RESULTS: All patients (n = 97) had normal eGFR or SCr at the time of urine collection at baseline. RFD occurred in 29% (8/28) of patients in cohort-1 during a mean follow-up of 6.1 months, and in 30% (21/69) of those in cohort-2 during a mean follow-up of 60 months. Individually, in cohort-1, levels of MCP-1, transferrin, LFABP, and albumin were higher in the RFD group than those who maintained renal function, with statistical significance for LFABP and albumin. In cohort-2 the RFD group also had higher levels of urine MCP-1 and albumin than others. The combination of LFABP, MCP-1, albumin, and transferrin had good predictive accuracy for RFD in both cohorts (area under the ROC curve = 0.77-0.82). CONCLUSION: The combinatorial urine biomarker LFABP, MCP-1, albumin, and transferrin shows promise as a predictor of renal functional decline in LN, and warrants further investigation.

Effect of carbohydrate intake on kidney function and structure in SHR/N-cp rats. A new model of NIDDM.

The SHR/N corpulent (cp) rat is a genetically obese rat that develops hyperglycemia, hyperinsulinemia, and proteinuria. This study was designed to evaluate the effects of high carbohydrate (CHO) intake on renal function and structure in this animal model and to determine whether the renal effects are related to the type of CHO ingested. Two groups of 5-wk-old obese male SHR/N-cp rats and lean male littermates were fed diets containing 54% CHO in the form of sucrose or starch. After 12 wk, renal function parameters, including creatinine clearance, urinary glucose excretion, and urinary protein excretion, were measured. Renal morphology was evaluated by semiquantitative light and electron microscopy. On either diet, obese rats had significantly higher urinary glucose and protein excretions than their lean littermates. Mean creatinine clearance (ml/min) in obese rats did not differ significantly from values observed in lean rats. When corrected for body weight, creatinine clearance (ml.min-1.kg-1) tended to be lower in obese than in lean rats, but the difference was significant (P less than .02) only for obese and lean sucrose-fed animals. Obese rats fed sucrose compared with their obese counterparts fed starch had higher body weight (+8%, P less than .05), glucose excretion (+63%, P less than .02), and protein excretion (+242%, P less than .005). In obese rats, protein excretion correlated with glucose excretion (r = .71, P less than .01). Glomerular lesions consisting of mesangial expansion and intercapillary nodules were found in obese but not in lean rats. Moreover, obese rats fed sucrose had a significantly greater number of involved glomeruli than obese rats fed starch.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of race on expression of acquired immunodeficiency syndrome-associated nephropathy.

The prevalence of renal disease associated with the acquired immunodeficiency syndrome (AIDS) is unknown, but appears to vary in different regions. Centers in New York, NY, and Miami, Fla, have reported patients with renal disease complicating AIDS. These populations have included large proportions of black patients and intravenous drug abusers. Reports from San Francisco, Calif, have suggested the prevalence of renal disease complicating AIDS is low, but the population was composed primarily of white patients, with a low proportion of drug abusers. The George Washington University Medical Center was the site of treatment for 31.4% of the patients with AIDS in Washington, DC. This population was split roughly evenly between black and white patients. A retrospective survey of patients with both AIDS and renal disease revealed approximately two thirds of the patients were black, reflecting the demographics of the population with AIDS; 11% of patients had intravenous drug abuse as a risk factor for the development of AIDS; and 74% had acute renal failure. Of these patients, approximately equal proportions were black and white. Twenty-six percent of the population had chronic renal failure, but the overwhelming proportion were black. There were no differences between proportions of patients in age, sex, race, or risk factors in patients with acute renal failure and chronic renal failure, but there was a significant difference in the proportions of black and white patients with chronic renal failure. The reason for these differences is unknown, but differences in host responses to viral proteins, physiologic adaptations, or socioeconomic factors in these populations may play an important role in mediating the expression of renal disease in individual patients.

Factors influencing erythrocyte sedimentation in patients with chronic renal failure.

Erythrocyte sedimentation was studied in stable patients with chronic renal failure free of complicating illnesses. The mean (+/- SD) Westergren erythrocyte sedimentation rate was 49 +/- 26 mm/hr in patients not receiving dialysis and 60 +/- 33 mm/hr in patients receiving hemodialysis. Both values are significantly higher than normal. Because anemia accelerates the Westergren determination, we restudied the patients with the zeta sedimentation ratio (ZSR), a method unaffected by hematocrit. In nine patients not receiving dialysis and 49 patients receiving hemodialysis, the ZSR was significantly higher than normal. The ZSR correlated positively with plasma fibrinogen concentration. Recombination experiments showed that the abnormal factor accelerating erythrocyte sedimentation was a constituent of plasma. Thus, erythrocyte sedimentation is accelerated in stable patients with chronic renal failure and a plasma factor, probably fibrinogen, is responsible. An elevated erythrocyte sedimentation rate in this population lacks diagnostic usefulness.

Metoclopramide-induced parkinsonism in hemodialysis patients. Report of two cases.

Metoclopramide hydrochloride is an antiemetic and gastric motility stimulant with a wide variety of extrapyramidal side effects, including parkinsonism. We describe two patients with end-stage renal disease secondary to diabetes mellitus treated with hemodialysis who developed extrapyramidal symptoms during treatment with metoclopramide. One patient with preexisting, well-controlled Parkinson's disease developed increasing rigidity and bradykinesia that became completely refractory to treatment with L-dopa and bromocriptine while taking metoclopramide for diabetic gastroparesis. A second patient with no history of Parkinson's disease developed a resting tremor and facial dyskinesia during treatment with metoclopramide. In both cases, discontinuation of metoclopramide therapy led to prompt improvement of symptoms.

Prevalence of viremia in human immunodeficiency virus-infected patients with renal disease.

BACKGROUND: The prevalence of viremia and its relationship to the pathogenesis of nephropathy in human immunodeficiency virus (HIV)-infected patients with renal disease is unknown. To assess the prevalence of plasma viremia in HIV-infected patients with chronic renal disease, we performed a cohort study in two urban university medical centers. METHODS: Samples of blood from 11 HIV-infected patients with renal failure who were treated with hemodialysis were analyzed concurrently with control samples from three non-HIV-positive patients receiving hemodialysis treatment. Samples from four HIV-infected patients with chronic renal insufficiency were evaluated concurrently. Thirty-three HIV-infected patients with serum creatinine levels of less than 132 mumol/L (1.5 mg/dL), and trace or absent dipstick proteinuria served as controls for the population with renal disease. The patients infected with HIV were staged by CD4 cell counts and the presence of opportunistic infections. Blood samples were analyzed for plasma HIV p24 antigenemia by antigen capture enzyme-linked immunosorbent assay. Blood samples were analyzed for the presence of viremia by infection of normal stimulated peripheral blood mononuclear cell cultures with plasma samples and detection of HIV p24 antigen in culture supernatants. RESULTS: Two of the 11 patients treated with hemodialysis had evidence of HIV p24 antigenemia, while seven of the 11 had evidence of plasma viremia. The proportion of hemodialysis patients with detectable antigenemia and viremia was similar to that in patients with chronic renal insufficiency. A significantly greater proportion of HIV-infected patients with renal disease had plasma viremia and antigenemia, compared with HIV-infected patients without renal disease. In logistic regression analysis, race, CD4 cell count (either on a continuous scale or dichotomized at 0.2 x 10(9)/L), and treatment with zidovudine were not significantly associated with the presence of plasma viremia, but patient age and the presence of renal disease were factors independently associated with viremia. CONCLUSIONS: The similar proportions of HIV-infected patients with viremia in groups of patients with chronic renal insufficiency and with renal disease treated with hemodialysis suggest that dialysis treatment does not increase the prevalence of plasma viremia in HIV-infected patients with renal disease. The similar proportions of HIV-infected hemodialyzed patients and patients with chronic renal insufficiency with plasma viremia, and the greater prevalence of viremia in patients with renal disease compared with HIV-infected patients without clinical renal disease suggest that plasma viremia and renal dysfunction are related. Whether this represents a cause and effect relationship is unknown. The greater prevalence of viremia in HIV-infected patients with renal disease has implications for the pathogenesis of HIV-related renal diseases and for caregivers in clinical settings and dialysis units.

Sleep apnea syndrome in chronic renal disease.

PURPOSE: We performed this study in order to expand on an earlier report indicating a high prevalence of the sleep apnea syndrome in male patients with end-stage renal disease treated with hemodialysis and to determine whether patients with chronic renal insufficiency (prior to the initiation of therapy for end-stage renal disease) and female patients with end-stage renal disease treated with hemodialysis were affected. PATIENTS AND METHODS: Polysomnography was performed in 26 male and female patients with chronic renal insufficiency and end-stage renal disease treated with hemodialysis who were not receiving testosterone. They included 22 whose histories were suggestive of sleep apnea ("symptomatic") and four whose histories were not ("asymptomatic"). RESULTS: Sixteen of the symptomatic (73 percent) and none of the asymptomatic patients were found to have clinically significant sleep apnea syndrome (p less than 0.02). Both female patients and patients with chronic renal insufficiency had sleep apnea. In nine of these 16 cases, the disorder was primarily of the obstructive type. CONCLUSION: These preliminary data raise the possibility of an association of chronic renal disease and the sleep apnea syndrome, and suggest that some of the daytime sleepiness and disturbed nocturnal sleep in such patients may be related to sleep apnea. They also indicate that questioning patients with chronic renal disease and symptoms suggestive of a sleep disorder is useful in determining who are at high risk for the sleep apnea syndrome. Further study is required to establish a causal relationship between chronic renal disease and the sleep apnea syndrome, and to determine the prevalence of the latter in patients with end-stage renal disease.

Psychiatric illness in patients with end-stage renal disease.

PURPOSE: We sought to determine the prevalence of psychiatric illness in hospitalized patients with end-stage renal disease. We also examined the association between end-stage renal disease treatment modality and risk of hospitalization with a diagnosis of a mental disorder, and compared rates of hospitalization with a diagnosis of psychiatric illness in renal failure patients to patients with other chronic medical illnesses. SUBJECTS AND METHODS: We performed a cohort study of all Medicare-enrolled dialysis patients in 1993. Risk of hospitalization with a diagnosis of a mental disorder among renal failure patients was compared with Medicare patients with diabetes mellitus, ischemic heart disease, cerebrovascular disease, and peptic ulcer disease. RESULTS: Almost 9% of all dialysis patients were hospitalized with a mental disorder. Men, African-Americans, and younger patients were more likely to be hospitalized with a mental disorder. The adjusted risk of hospitalization for peritoneal dialysis patients was lower compared with hemodialysis patients for any mental disorder, depression, and alcohol and drug use. Hospitalization with mental disorders was 1.5 to 3.0 times higher for renal failure patients compared with other chronically ill patients. CONCLUSIONS: Hospitalization with a psychiatric illness is common among the US end-stage renal disease population. Depression, dementia and drug-related disorders were especially common. The coexistence of psychiatric illness in patients with renal failure who require specialized medical regimens represents a challenge to nephrologists in diagnosis and treatment. Disparities between hospitalization rates of psychiatric illnesses among end-stage renal disease patients compared with other chronically ill populations warrant further research.

Correlation of in vitro CD4+ T helper cell function with clinical graft status in immunosuppressed kidney transplant recipients.

We recently identified three distinct T helper pathways which contribute to interleukin-2 (IL-2) production by human peripheral blood lymphocytes following stimulation with HLA alloantigens. In two of these pathways, CD4+ T helper cells respond to alloantigen using either self antigen-presenting cells (sAPC)* or allogeneic antigen-presenting cells (aAPC). A third pathway involves CD8+ T helper cells using aAPC. Previous in vitro studies have shown that the T helper pathway dependent on CD4+ T helper cells and sAPC (CD4-sAPC) is the most susceptible to suppression by cyclosporine. In the present study, we measured alloantigen-stimulated IL-2 production by PBL from 42 kidney transplant recipients to characterize the strength of the three T helper-APC pathways. In 58% of patients, a loss of the CD4-sAPC pathway was identified and was correlated with cyclosporine treatment. However, several patients not receiving cyclosporine also exhibited a similar loss of T helper cell function, suggesting that cyclosporine is not the only factor involved. Of 27 patients exhibiting depressed CD4-sAPC function, none had evidence of ongoing/recent graft rejection. In contrast, of 11 patients with no defects in the three pathways of in vitro T helper cell function, 6 had evidence of chronic graft rejection. Of considerable interest are the data obtained from a separate group of 4 patients who had episodes of acute rejection during the study. In each case, at the time of the rejection episode, all exhibited an intact CD4-sAPC pathway. However, samples tested prior to the rejection episode or after successful treatment of the rejection episode showed a depressed CD4-sAPC pathway. These results suggest that depression of the CD4-sAPC pathway represents adequate immunosuppression for graft retention and that patients not exhibiting such suppression are at increased risk for both acute and chronic graft rejection. These data may have relevance for diagnosis and/or prediction of graft rejection and may provide an in vitro method of monitoring the functional degree of immunosuppression in transplant recipients.

Compliance in hemodialysis patients: multidimensional measures in search of a gold standard.

The gold standard to assess the compliance of hemodialysis (HD) patients has not been established. Compliance parameters should be easily measured and verified, reproducible, clearly interpretable, and accurate. They should have meaning for the patient, clear pathophysiological significance unrelated to other factors, and be related to important outcomes. There is poor correlation of subjective and objective measures and poor correlation of laboratory compliance measures. Different factors have been associated with differential compliance in different patient populations, depending on the measures assessed. Recently, behavioral measures of compliance with dialysis prescription, such as shortening or skipping HD treatments, have been developed. New data confirm that many compliance measures, including both laboratory and behavioral compliance indices, are associated with patient outcomes. It is the duty of the nephrologist and staff to make the importance of compliance understandable to patients. It is important for the health care team to understand patients' expectations and attitudes about their illness and their beliefs about the efficacy and importance of the treatment, as well as patients' demographic, medical, psychological, familial, and socioeconomic status, before realistically evaluating compliance. Such knowledge and approaches may be critical in achieving mutually agreed on compliance goals. We suggest that although assessment of indirect indices is useful, behavioral compliance measures that quantify shortening and skipping behaviors generally should be used in HD patients. Hopefully, analyses of results that control for multiple potentially confounding factors and effective interventions to improve compliance will be developed in the near future.

Depression and marital dissatisfaction in patients with end-stage renal disease and in their spouses.

Little research has been performed assessing patients with end-stage renal disease (ESRD) as parts of marital dyads or within family structures. Recent findings suggest patient interactions within such systems are associated with patient outcomes. To evaluate the relationship between level of patient depression and spouse psychosocial status, 55 couples in which one partner was undergoing chronic hemodialysis therapy for ESRD were interviewed. Two variables that alone and in interaction with one another were expected to relate to the spouse's level of depression and marital satisfaction were investigated: patient depression level and spouse's perceived social support. Depression was assessed using the Beck Depression Inventory (BDI). Spouses' levels of depressive affect correlated directly with patient BDI scores. A significant two-way interaction for spousal depression (patient depression and spousal support) supported viewing spouses' adjustment as a function of the interaction between spouse and patient factors. Additionally, a main effect of perceived spousal social support on spousal marital satisfaction indicated that spouses reporting high levels of social support had the least marital strain. The severity of the patient's illness did not correlate with any of the predictor variables or measures of spousal adjustment, but spouses reported significantly lower functional status for patients than did nephrologists. Spouse and patient levels of depression are related, although causal relationships cannot be determined by these studies. Moreover, spouse perception of marital satisfaction is related to depression scores. These findings suggest the patient with ESRD functions in a psychosocial dyad. Spouse psychosocial status could impact on the level of patient depression, and the spouse might be amenable to interventions that could improve patient outcome.

Quality of life and psychosocial relationships in patients with chronic renal insufficiency.

The goal of the present study was to assess the psychological functioning level and the relationship between psychosocial variables and psychological functioning and social support buffering effects among a population of outpatients with chronic renal insufficiency (CRI). The Beck Depression Inventory, Illness Effects Questionnaire, Multidimensional Scale of Social Support, and Satisfaction With Life Scale were administered to 50 patients with CRI. The patients' nephrologist provided a Karnofsky scale rating to assess physical functioning. Sample scores were also compared for descriptive purposes to a previously reported sample of patients with more advanced disease and chronic renal failure (CRF), and a population of patients who had just started hemodialysis therapy for end-stage renal disease (ESRD). Patients with CRI are minimally depressed and perceive few negative illness effects. Satisfaction with life and cognitive depression scores were similar among the patients with CRI, CRF, and ESRD. Within the CRI sample, perception of illness, depression, and quality of life were significantly intercorrelated, indicating an emerging pattern of negative psychological reactions among some patients. Level of perceived social support was not correlated with other study variables. The mean level of perceived social support was lower among patients with CRI than in patients with ESRD. We conclude that even though most adjustment variables are in normal ranges, higher negative perception of illness is associated with higher depression scores and lower quality of life, even at this early stage of CRI. Additionally, social support may play an important role for those individuals beginning to experience a decline in renal functioning.

Trends in erythropoietin therapy in the U.S. dialysis population: 1995 to 1998.

Anemia is an important cause of morbidity, and may be associated with increased mortality in patients with end-stage renal disease (ESRD) receiving dialysis. Therapy with recombinant human erythropoietin (rHuEPO) has revolutionized the care of ESRD patients, but this is a costly medication and concerns have been expressed about whether the outcome, as measured by achieved hematocrit (Hct), could be improved. The number and proportion of ESRD patients receiving rHuEPO increased steadily from 1995 to 1998, as did the dose of rHuEPO per patient. The amount of intravenous iron administered to patients increased markedly over the study period. The patients' mean hematocrit also rose, but proportionally less over the study period. The increase in both the amounts of payments per patient for rHuEPO, and the number of patients receiving rHuEPO over this time has resulted in a marked increase in the total costs to Medicare for this therapy. We suggest that a combination of payment regulations, provider financial opportunities and disincentives, and patient resistance to the effects of rHuEPO, as a result of both iron deficiency and inflammation, largely explain the findings.

Treatment of human immunodeficiency virus (HIV)-associated nephropathy.

Patients with human immunodeficiency virus (HIV) nephropathy (HIVN) face improved outlooks both before and after starting renal replacement therapy for end-stage renal disease, compared with the situation a little over a decade and a half before, when the disease was first recognized. Therapy with cyclosporin, glucocorticoids, and angiotensin-converting enzyme inhibitors provides the prospect of longer courses of renal insufficiency for patients with HIVN, and perhaps the hope of blunting progression of the disease when patients are treated early. Trials of patients with biopsy-proven HIVN are important to evaluate further the role of such newer therapies. HIV-infected patients with end-stage renal disease have been treated with hemodialysis, peritoneal dialysis, and renal transplantation. The course of therapy for dialysis patients may be improving, but ultimately depends on the stage of the viral illness. The disparities in the demographic composition of the patient populations probably underlies findings reported from different centers. Transplantation is currently a low-priority treatment option for HIV-infected patients with ESRD, but several studies provide fascinating insights into viral-host interactions.

Trypsinogen and other pancreatic enzymes in patients with renal disease: a comparison of high-efficiency hemodialysis and continuous ambulatory peritoneal dialysis.

Although serum amylase and lipase levels have been studied extensively in patients with renal disease, there are fewer data regarding trypsinogen levels in patients with end-stage renal disease (ESRD) treated with different dialytic modalities. We therefore evaluated the blood concentrations of trypsinogen, amylase, and lipase in asymptomatic patients with chronic renal insufficiency (CRI) and ESRD, to determine whether treatment modality or renal handling of these enzymes is important in determining steady-state levels in asymptomatic patients with chronic renal disease. Mean trypsinogen concentration levels were higher in hemodialysis (HD) patients and patients with CRI compared with normal subjects when values in the different groups were compared. There was no difference in the mean trypsinogen levels between patients treated with HD and those with CRI, between patients treated with chronic ambulatory peritoneal dialysis (CAPD) and those treated with HD, or between CAPD patients and patients with CRI. The mean circulating trypsinogen concentration was elevated more frequently and to a higher level than amylase or lipase in patients with CRI and ESRD. HD treatment did not result in a lowering of mean circulating pancreatic enzyme levels. We propose that decreased peripheral clearance, pancreatic overproduction, increased release from the pancreas, or a combination of these mechanisms is responsible, at least in part, for the increased plasma concentration of trypsinogen in patients with CRI, rather than simply a decrease in renal clearance.

Family structure and patient survival in an African-American end-stage renal disease population: a preliminary investigation.

Few studies have examined the influence of the family on the course of chronic illness in African-Americans. We explore the relationship between family structure, defined as marital status and household composition, and patient survival. Patient gender was examined as a possible moderator in this relationship. Using data from a survey of 476 African-American end-stage renal disease (ESRD) patients, a significant association between household composition and patient survival was found. Results from Cox proportional hazards model, controlling for patient age, indicated that patients who live in 'complex' households (i.e. those with a partner and/or others) are at greater risk for shortened survival as compared to those who live alone or with a spouse/partner (p < 0.05). When we examined whether patient gender moderates this relationship, female patients who live in these households were found to be at 2 times greater risk for shortened survival (p < 0.01) than female patients who live alone or with their spouse/ partner only. Family structure was not significantly associated with survival in male patients. Discussion and implications of findings are addressed.

Staff security and work pressure: contrasting patterns of stability and change across five dialysis units.

Differences among clinical care units in social dynamics and social organization are associated with differences in the clinical course of patients with a range of chronic illness. These differences are also associated with well-being of staff members. Recent attention has focused on understanding these differences among units with an eye towards correcting deficiencies and enhancing strengths of clinical care units. The current study sought to delineate the effect of social and organizational dynamics unique to each unit on staff perceptions of the security of their relationships with other staff and their perceived work pressure. The unit as a major source of differences among staff subjects was compared with the impact of ethnic identity, of work in the morning shift vs other shifts, and of professional role. Results confirmed that unit membership was, by far, the most important correlate of staff perceptions of the unit, particularly those concerning security of relationships with others and perceived work pressure. Moreover, the results suggested that unit differences in perceived security were due to differences among units in long standing turmoil within the unit or long standing problematic ties between the unit and the larger institution which controls it. However, perceived work pressure seems more transient and may reflect the challenge of shorter-term fluctuations in the demands of patient care.

Abnormal urinary protein excretion in HIV-infected patients.

HIV infection has been associated with a variety of renal diseases, although the pathogenesis of such dysfunction is unknown. To determine whether HIV-infection is associated with glomerular permeability defects, and if so, the prevalence of the finding, we studied patients with various stages of HIV infection. Urine samples from 505 outpatients with HIV infection (without hypertension, azotemia, or dipstick proteinuria), 41 normal controls and 40 febrile non-HIV positive, hospitalized patients with infectious diseases were analyzed for the urinary microalbumin/creatinine ratio (U microA/Cr), a sensitive indicator of incipient renal disease in diabetes mellitus and hypertension, and the urinary beta 2-microglobulin/creatinine ratio (U beta 2/Cr), an indicator of renal tubular function. Microalbumin concentration was measured by ELISA. Beta 2-microglobulin concentration was measured by an enzyme immunoassay. HIV-infected outpatients had higher mean U microA/Cr than normal subjects, but not febrile hospitalized controls. The prevalence of an increased U microA/Cr was 29.8% in the HIV-infected outpatient population. There was no difference in the ratio between Black and White HIV-infected outpatients, HIV-infected outpatients treated or untreated with zidovudine (AZT), or HIV infected outpatients untreated with any drug. There was no difference between U microA/Cr in stage II, III or IV HIV-infected patients when assessed by analysis of variance. A similar pattern was noted with U beta 2/Cr. The prevalence of an increased U beta 2/Cr ratio was 37.7% in HIV-infected outpatients. Increased urinary albumin and beta 2-microglobulin excretion, not associated with drug therapy, is present in patients with early HIV infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Zinc nutritional status modifies renal osteodystrophy in uremic rats.

BACKGROUND: Previous studies from our laboratories suggested that zinc depletion reduces the circulating level of 1,25-dihydroxycholecalciferol (1,25(OH)2D, calcitriol) in calcium- and phosphorus-depleted rats with normal renal function, and rats with uremia. Since calcitriol synthesis is in part dependent on renal function, we studied levels of circulating vitamin D metabolites, PTH response, mineral balance and bone histomorphometry in animals with different zinc nutritional and renal functional status. METHODS: Fifty-eight male Sprague-Dawley rats were pair-fed zinc-replete (+) or -deplete (-) diets for two weeks. Thereafter, half of each paired group underwent nephrectomy (N), while half had sham (S) operations. Animals were observed for eight weeks after surgery. External mineral balances of zinc, calcium, phosphate and magnesium were determined before surgery, and 1, 2 and 7 weeks after surgery. Plasma creatinine, zinc, calcium, phosphorus, magnesium, 25-hydroxycholecalciferol, calcitriol and PTH were determined at sacrifice. Static and dynamic bone histomorphometry was determined by standard techniques. RESULTS: After an 8-week observation period, zinc-depleted animals had lower plasma zinc levels, and nephrectomized animals had lower creatinine clearances than respective controls at sacrifice. Plasma calcium and phosphorus concentrations were similar in all four groups at sacrifice. Plasma magnesium concentrations were similar in groups with renal insufficiency, regardless of zinc nutritional status. Plasma 25-hydroxycholecalciferol and calcitriol levels were similar in all groups. There was no difference between mean PTH concentration in sham-operated animals, regardless of zinc nutritional status. Although nephrectomized groups' PTH levels were increased compared to S controls, PTH levels were increased in +Zn/N animals compared to the -Zn/N group. Zinc-deplete groups had consistent negative net zinc balance, however, there was no consistent effect of nephrectomy on external calcium, phosphorus, or magnesium balance, when nephrectomized groups of different zinc nutritional status were compared. Nephrectomized animals had histomorphometric changes indicative of higher bone turnover and abnormal mineralization. Zinc deficiency was associated with less evidence of increased parathyroid hormone activity on bone in nephrectomized rats. CONCLUSIONS: Zinc depletion limits the increase in plasma PTH concentration and the expression of secondary hyperparathyroid bone disease during the development of renal insufficiency in the renal ablation model of uremia in rats. The mechanism underlying this effect is unknown, but may involve a direct effect of zinc on the synthesis, release, metabolic clearance, and/or action of PTH on the cellular level, on the interrelationship of calcitriol and PTH, or a direct effect of zinc on bone mineral metabolism. These data highlight the potential relevance of zinc nutritional status to mineral metabolism in patients with chronic renal insufficiency and end-stage renal disease.