Renal Consequences of Diabetes After Kidney Donation.

Whether diabetes after kidney donation is associated with an accelerated GFR decay in the remaining kidney has not been studied. We determined the incidence of diabetes in kidney donors, and compared GFR change over time in diabetic to nondiabetic donors, in addition to the effect of diabetes mellitus (DM) on the development of proteinuria, hypertension, and end-stage renal disease (ESRD). Of the 4014 donors, 309 (7.7%) developed diabetes at a median age of 56.0 years and after a median of 18 years after donation. The difference in annual estimated GFR (eGFR) change between diabetic and nondiabetic donors in the 7 years before the development of DM was -0.08 mL/min/year; p = 0.51. After DM development, the difference was -1.10 mL/min/year for diabetic donors with hypertension and proteinuria, p < 0.001; -0.19 for diabetic donors with hypertension but no proteinuria, p = 0.29; -0.75 mL/min/year for diabetic donors with proteinuria but no hypertension, p = 0.19; and -0.09 mL/min/year for diabetic donors without proteinuria or hypertension, p = 0.63. When DM was considered as a time-dependent covariate, it was associated with the development of proteinuria (hazard ratio [HR] 2.65, 95% confidence interval [CI] 1.89-3.70; p < 0.001) and hypertension (HR 2.19, 95% CI 1.74-2.75; p < 0.001). It was not, however, associated with ESRD. eGFR decline after DM development exceeds that of nondiabetic donors only in diabetic donors with concomitant proteinuria and hypertension.

Associations of baseline characteristics with evolution of eGFR in a referred chronic kidney disease cohort.

BACKGROUND: Currently, most chronic kidney disease (CKD) classifications identify patients at different stages of CKD but do not identify risk of progression or adverse outcome. This analysis aims to describe associations between baseline characteristics and the evolution of estimated glomerular filtration rate (eGFR) and identify threshold values for clinical parameters that maximally discriminate progression to renal replacement therapy (RRT) in a referred cohort of patients with CKD stages 3-5. DESIGN AND METHODS: A longitudinal mixed-effect model was used to determine annualized estimated change in eGFR and classification tree analysis to identify threshold values that maximally discriminate progression to RRT. RESULTS: A total of 1316 patients were available for analysis with median follow-up of 33 months (interquartile range 20-60). Mixed model analysis suggested that the underlying diagnoses of autosomal dominant polycystic kidney disease and diabetic nephropathy exhibited on average a 2.7 (0.3) and 0.7 (0.3) ml/min/year faster rate of decline in eGFR, respectively, compared to those patients with biopsy-proven glomerulonephritis. In the regression tree analysis, we attempted to identify threshold values for clinical parameters that maximally discriminate progression to RRT. eGFR ≤24 ml/min was the first ranked discriminator, diastolic blood pressure appeared in the second and fourth rounds, eGFR appeared again in the third round together with cholesterol and systolic blood pressure, with basal metabolic index in the fourth. CONCLUSION: This analysis highlights risk factors for progressive kidney disease and demonstrates the variability in evolution of eGFR across the cohort as well as the importance of underlying renal disease type on the progression of CKD.

Epoetin use and Kidney Disease Outcomes Quality Initiative hemoglobin targets in patients returning to dialysis with failed renal transplants.

Patients with failed renal transplants represent an increasing proportion of the current dialysis population. Although their risk of anemia might be expected to be high, whether these patients receive adequate anemia therapy after returning to dialysis is unknown. We studied intravenous iron use, epoetin doses, and hemoglobin levels in patients with and without failed renal transplants who survived for 6 months after initiation of dialysis in the United States between 1996 and 2001. Of the study population (n=220 557), 9922 (4.5%) had failed renal transplants. In spite of a greater likelihood of receiving intravenous iron therapy (adjusted odds ratio (AOR) 1.47, P<0.0001) and epoetin (AOR 1.57, P<0.0001), patients with failed transplants were more anemic and had higher epoetin doses in each month of follow-up. During month 6, patients with failed transplants were more likely to have hemoglobin levels below 11 g/dl (AOR 1.50, P<0.0001) and to have epoetin-to-hemoglobin ratios above the population median of 1030 U/week per g/dl (AOR 1.73, P<0.0001). Patients who return to dialysis with failed transplants are at a higher risk of anemia than other patients who start dialysis; the pattern of lower hemoglobin levels and higher ratios of epoetin-to-hemoglobin suggests that relative epoetin resistance may be contributory.

Mortality studies comparing peritoneal dialysis and hemodialysis: what do they tell us?

Several recent large-scale epidemiological studies comparing mortality among end-stage renal disease (ESRD) patients receiving hemodialysis (HD) versus peritoneal dialysis (PD) show conflicting results. In this paper, we undertake a critical review of these studies. Our goal is to determine if there are any consistent trends in outcomes between HD and PD within select subgroups of patients once methodological differences have been accounted for. A total of six large-scale registry studies and three prospective cohort studies conducted in the United States (US), Canada, Denmark, and the Netherlands were reviewed. Summary findings from these studies are presented for comparative purposes. Additional summary analyses based on previously reported data on 398 940 incident US Medicare patients are included for the purpose of comparing results from this population of patients to those of the other select studies when similar methods of analysis are applied. Results are summarized in terms of the relative risk of death for PD versus HD (RR[PD:HD]). Differences in results between the nine studies can be attributed to the degree of case-mix adjustment carried out and to the use of different subgroups when comparing mortality between HD and PD. When these differences are accounted for, we found a remarkable degree of synergism in results between the registry studies and, to a lesser degree, the prospective cohort studies. PD was generally found to be associated with equal or better survival among non-diabetic patients and younger diabetic patients in all four countries. However, among older diabetic patients, results varied by country. The Canadian and Danish registries showed no difference in survival between PD and HD among older diabetics while in the US, HD was associated with better survival for diabetics aged 45 and older. All studies show a time-dependent trend in the RR of death with PD generally associated with equivalent or better survival during the first year or two of dialysis. However, results on longer-term survival varied according to study and to different subgroups within studies. Subgroup analyses in the prospective cohort studies were limited by small numbers of patients resulting in highly varied and somewhat controversial results when compared to the larger registry-based studies. Based on our review of recent publications and additional analyses of US Medicare data, we conclude that overall patient survival is similar for PD and HD but that important differences do exist within select subgroups of patients, particularly those subgroups defined by age and the presence or absence of diabetes.

Prevalence of hypogonadism in male patients with renal failure.

BACKGROUND: Hypogonadism in men may be secondary to renal failure and is well recognised in patients with end-stage renal disease. It is thought to contribute to the sexual dysfunction and osteoporosis experienced by these patients. However, the association between hypogonadism and lesser degrees of renal dysfunction is not well characterised. METHODS: The gonadal status of 214 male patients (mean age 56 (SD 18) years) attending a renal centre was studied; 62 of them were receiving haemodialysis and 22 continuous ambulatory peritoneal dialysis for end-stage renal disease, whereas 34 patients had functioning renal transplants and 96 patients were in the low-clearance phase. Non-fasting plasma was analysed for testosterone, follicle-stimulating hormone, luteinising hormone, sex hormone-binding globulin, parathyroid hormone and haemoglobin. Creatinine clearance was estimated in patients not on dialysis, and Kt/V and urea reduction ratio were assessed in patients on dialysis. Testosterone concentrations were classified as normal (>14 nmol/l), low-normal (10-14 nmol/l) or low (<10 nmol/l). RESULTS: 56 (26.2%) patients had significantly low testosterone levels and another 65 (30.3%) had low-normal levels. No significant changes were seen in sex hormone-binding globulin or gonadotrophin levels. Gonadal status was not correlated with haemoglobin level, parathyroid hormone level, creatinine clearance, or dialysis duration or adequacy. CONCLUSION: Over half of patients with renal failure, even in the pre-dialysis phase, have low or low-normal levels of testosterone, which may be a potentially reversible risk factor for osteoporosis and sexual dysfunction. These patients may be candidates for testosterone-replacement therapy, which has been shown to improve bone mineral-density and libido in men with low and low-normal testosterone levels.

Clinical epidemiology of pneumonia in hemodialysis patients: the USRDS waves 1, 3, and 4 study.

The clinical epidemiology of pneumonia in hemodialysis patients has received little attention. We linked the retrospective Waves 1, 3, and 4 Dialysis Morbidity and Mortality Study data sets (n=10 635) to Medicare claims to identify hospitalizations with pneumonia. Mean patient age was 60.3 years and duration of end-stage renal disease (ESRD) 3.8 years; 41.1% of patients had diabetes mellitus. Only 31.6% had received influenza vaccination in the 4 months preceding the study start date (January 1, 1994). The cumulative probability of pneumonia hospitalization was 0.09 at 1 year and 0.36 at 5 years. The main associations of hospitalization with pneumonia were age 45-64 years and >/=65 years (adjusted hazards ratio (AHR) 1.26 and 1.48 vs <45 years), chronic lung disease (AHR 1.62), ESRD duration >/=10 years (AHR 0.75 vs <5 years), body mass index (AHR 0.66 for 25.0-29.9, 0.58 for >/=30 vs <18.5 kg/m(2)), serum albumin (AHR 0.74 for >/=4.06 vs

Variation in dialysis patient mortality by Health Authority.

BACKGROUND: Maintenance dialysis is a relatively low prevalence, highly specialized, and labour-intensive treatment, which is usually delivered at regional centres serving many different health authorities. It is unknown whether a patient's health authority, in many ways an accident of birth, influences long-term dialysis outcomes. AIM: To study survival patterns in patients starting maintenance dialysis therapy in the north-west of England between 1990 and 1999. DESIGN: Retrospective analysis. METHODS: We analysed data from quarterly returns submitted to the West Pennine Health Authority from 10 dialysis centres, including health authority, dialysis centre, age, gender, mode of dialysis therapy, postal code and diabetic status. Postal codes were used to compute the distance from residence to dialysis centre and Carstairs index. RESULTS: There were 2458 patients from 18 health authorities. Survival on dialysis therapy differed by health authority (p < 0.0001). Health authorities were then grouped into socioeconomic families, using The Office of National Statistics health authority classification system (ONS1). ONS1 profiles at inception of dialysis therapy were also associated with disparities in survival, with subjects from Urban and Rural health authorities having longer survival than those from Mining and Industrial, Mature or Prospering health authorities (p < 0.0001). DISCUSSION: Survival on dialysis varies significantly by health authority. The interface between highly specialized, centralized, medical services and the health authorities they serve may be a major outcome determinant.

Should hemoglobin be normalized in uremic patients?

Cardiovascular disease is virtually a sine qua non of chronic kidney disease, as is poor quality of life. Dialysis patient for example, have cardiovascular death rates 10 - 20 times those of the general population. Recent estimates indicate that at least half of all patients starting dialysis therapy will have an admission for a major cardiovascular event within 5 years, of which cardiac failure is the most common. Both experimental and clinical studies suggest that the cardiovascular system in uremia is in a state of premature senescence, one which is poorly suited to the supraphysiological hemodynamic demands to which it is subjected. Most patients develop cardiomyopathy, which clearly predisposes to cardiac decompensation. Anemia and hypertension are the most obvious modifiable overload parameters in uremic patients. Several prospective observational studies have demonstrated anemia to be an independent risk factor for each step in the process leading from hemodynamic overload, through maladpative left ventricular enlargement to left ventricular failure and death. This process starts with declining renal function, long before end-stage renal disease, the traditional time at which intervention has started to be seriously considered. The case for normal hemoglobin in patients with chronic kidney disease is still greatly disputed. Observational studies, which examine left ventricular size, quality of life, functional status, hospitalization and survival, are overwhelmingly supportive. Intervention trials, to date, suggest clear benefits of a physiological approach to anemia management in terms of quality of life, and likely benefits in terms of left ventricular stress minimisation and associated remodelling. Whether these translate into a reduction in outcomes like cardiac failure or death remains an unanswered question.

Hypertension in end-stage renal disease.

Chronic renal failure is common. Recent estimates from the United States suggest that one in 10 adults has an elevated serum creatinine. Hypertension and renal disease are intimately connected at many levels, and clearly accelerate each other s course. Hypertension is an almost universal feature of end-stage renal disease, a state of frightening cardiovascular risk. Surprisingly, most recent observational studies have shown an association between low blood pressure and increased mortality, a result that may engender therapeutic nihilism in the absence of large randomised trials. This observation may be due to reverse causality, as the age and cardiovascular comorbidity of patients reaching end-stage renal disease is considerable. When outcomes other than death are considered, especially progressive left ventricular hypertrophy, but also ischaemic heart disease and congestive heart failure, more predictable and expected associations are seen, with rising blood pressure appearing to be a deleterious parameter. Uraemia appears to be a state of premature senescence, and arterial rigidity, whose clinical corollary is wide pulse pressure, is a characteristic feature. Recent observational studies have focused on pulse pressure, rather than the traditional approach of analysing its components, systolic and diastolic blood pressure, in isolation. High pulse pressure appears to be a marker of short survival in dialysis patients, but disentangling this association from old age and pre-existing cardiovascular conditions is challenging. Remarkably, and regrettably, no large scale randomised controlled studies examining strategies that tackle the issue of hypertension in dialysis patients have yet to be initiated.

Isolated sarcoid granulomatous interstitial nephritis: review of five cases at one center.

AIMS: To identify any clinical or biochemical parameters which determine prognostic outcome in isolated sarcoid granulomatous interstitial nephritis presenting with renal failure. METHODS: A review of five cases of renal failure due to isolated sarcoid granulomatous interstitial nephritis, which presented to Hope Hospital over the 7-year period 1994 to 2000. Follow-up averaged 35 months with a range of 11 to 73 months. RESULTS: Only one patient had an elevated serum ACE at presentation, reflecting the suboptimal sensitivity of this test as a marker in sarcoidosis and the limited extent of disease in these patients. Four of the five cases had a marked improvement in creatinine clearance within 10 days of starting oral prednisolone. Two patients required acute hemodialysis on presentation. Their renal failure responded to treatment with steroids, enabling withdrawal of dialysis within 10 days. All patients remained dialysis-independent although serum creatinine levels rose during follow-up. One patient experienced a relapse that responded to an increased dose of steroid. CONCLUSIONS: Serum ACE is not reliable in the diagnosis of renal failure due to sarcoid interstitial nephritis and the diagnosis can only be made on renal biopsy. First-line treatment with oral prednisolone results in a rapid improvement in creatinine clearance although prolonged treatment may be needed to prevent a relapse.

Anaemia, renal insufficiency and cardiovascular outcome.

Cellular models of cardiac hypertrophy and cardiac failure suggest that haemodynamic stresses lead to increased rates of cardiac myocyte apoptosis and fibrosis. Over the last 15 years, it has been become evident that the dramatically amplified exposure of patients with renal insufficiency to haemodynamic stress leads to maladaptive vascular and ventricular adaptations. Anaemia and hypertension are remediable haemodynamic stresses consistently associated with left ventricular enlargement in observational studies. Observational studies and clinical trials have shown consistently that treating the established, typically severe, anaemia of end-stage renal disease (ESRD) improves outcome. It has become clear that late intervention to normalize haemoglobin in patients with ESRD and cardiomyopathy achieves little. There is considerable observational evidence to suggest that intervention in haemodynamic risk factors, such as anaemia and hypertension, should coincide with their onset, which is typically years before renal replacement therapy. The optimum target haemoglobin, and timing of intervention, remain areas of intense speculation and research effort.

Effects of anaemia on cardiovascular status.

Cardiomyopathy is a common, heterogeneous and important cause of cardiac morbidity and mortality in uraemic patients. The risks of ischaemic heart disease, cardiac failure, and death increase progressively from lowest risk in patients with concentric left-ventricular hypertrophy, to medium risk in patients with left-ventricular dilatation but intact systolic function, to highest risk in patients with systolic dysfunction. Anaemia and hypertension are the reversible risk factors most consistently linked with the development of cardiomyopathy in these patients. Longitudinal data show that anaemia predisposes individuals to initial left ventricular dilatation, with compensatory hypertrophy, which may progress to systolic dysfunction. This process typically begins at glomerular filtration rates between 25 and 50 ml/min, and haemoglobin concentrations that are even slightly below normal are associated with progressive cardiac enlargement. Several observational studies have suggested that the correction of anaemia may reduce mortality and hospitalization rates in dialysis patients. The available evidence supports maintaining haemoglobin concentrations to greater than 11 g/dl. Whether a haemoglobin threshold exists above which no further benefit is seen remains controversial, partially because recent randomized controlled trials have intervened relatively late in the anaemia cardiomyopathy cardiac failure death continuum. One large randomized controlled trial showed no benefit from normalizing the haemoglobin concentration in haemodialysis patients with well-established cardiac disease; however, these patients had been exposed to anaemia for long periods of time and were at the extreme end of the cardiorenal disease spectrum. Other researchers have demonstrated a protective effect of normalizing the haemoglobin concentration in patients with asymptomatic, and hence presumably early, cardiomyopathy. The psychological benefits and improvements in exercise tolerance and quality of life resulting from normalization of the haemoglobin concentration are becoming clearer. However, conclusive evidence of the cardiovascular benefits of earlier, more aggressive treatment of renal anaemia as well as of the exact target haemoglobin concentration at which risk begins to develop is still lacking. The results of ongoing trials should help to clarify both of these issues within the next 5 years.

Changes in lipid profiles in non diabetic, non nephrotic patients commencing continuous ambulatory peritoneal dialysis.

This study examined the effect on patient lipid profile of commencing continuous ambulatory peritoneal dialysis (CAPD). We followed eighteen non diabetic, non nephrotic patients for 9 months before and after dialysis commencement and compared lipid profiles. Mean cholesterol levels rose from 4.98 mmol/L to 5.42 mmol/L (p < 0.05). This change was chiefly due to a rise in low density lipoprotein (LDL) cholesterol. The LDL cholesterol rose after dialysis commencement and continued to rise up to 9 months later. High-density lipoprotein (HDL) cholesterol remained stable. Serum albumin and body weight fell during follow-up, suggesting that the rise in cholesterol was not a reflection of enhanced nutritional status. This study highlights the pro-atherogenic change in lipids that results from commencing CAPD. This phenomenon is not seen in hemodialysis, and it should be considered when selecting a dialysis modality, given the increased risk of cardiovascular disease in the dialysis population.

Reducing cardiovascular morbidity and mortality from hypertension in end-stage renal disease.

Hypertension typically worsens with declining renal function, and is an almost universal feature of end-stage renal disease. Treating hypertension clearly reduces the likelihood of cardiovascular disease in nonrenal populations, with greater absolute benefit in those who have greater severity of underlying cardiovascular disease. Patients with chronic renal diseases are at enormous cardiovascular risk. Although our approach to hypertension in patients with early renal insufficiency has become more aggressive, the rationale has switched over the past decade from cardiovascular risk reduction to slowing the loss of renal function. Reliance on observational studies, especially using mortality as the outcome, has not allowed a consistent, rational approach to the treatment of hypertension in dialysis patients.

Long-term changes in left ventricular hypertrophy after renal transplantation.

BACKGROUND: Concentric and eccentric left ventricular hypertrophy are common progressive disorders in dialysis patients and are associated with cardiac failure and death. Although partial regression of these abnormalities is known to occur during the first post-transplant year, their long-term evolution is unknown. METHODS: A total of 143 of 433 dialysis patients participating in a long-term prospective cohort study received renal transplants. Laboratory parameters were assessed monthly. Echocardiography was performed annually. Left ventricular mass index (LVMI) and cavity volume index were calculated according to standard formulae. Multiple linear regression was used to model change in LVMI as a function of baseline clinical and laboratory variables. RESULTS: LVMI fell from 161 g/m2 at 1 year to 146 g/m2 (P=0.009) g/m2 after 2 years. No further regression was seen in years 3 and 4. Left ventricular volume index showed similar trends, with a decline from year 1 to year 2 (P=0.05) followed by stabilization in years 3 and 4. Older age, long duration of hypertension, need for more than one antihypertensive, high pulse pressure in normal-size hearts, and low pulse pressure in dilated hearts were significantly associated with failure of regression of LVMI between the first and second years (MLR, P<0.000001, r2=0.57). CONCLUSIONS: Regression of left ventricular hypertrophy continues beyond the first year after renal transplantation, reaching a nadir at 2 years and persisting into the third and fourth posttransplant years. Failure to regress was associated with older age, hypertension, high pulse pressure in normal-size hearts and low pulse pressure in dilated hearts.

Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy.

BACKGROUND: Hemoglobin levels below 10 g/dL lead to left ventricular (LV) hypertrophy, LV dilation, a lower quality of life, higher cardiac morbidity, and a higher mortality rate in end-stage renal disease. The benefits and risks of normalizing hemoglobin levels in hemodialysis patients without symptomatic cardiac disease are unknown. METHODS: One hundred forty-six hemodialysis patients with either concentric LV hypertrophy or LV dilation were randomly assigned to receive doses of epoetin alpha designed to achieve hemoglobin levels of 10 or 13.5 g/dL. The study duration was 48 weeks. The primary outcomes were the change in LV mass index in those with concentric LV hypertrophy and the change in cavity volume index in those with LV dilation. RESULTS: In patients with concentric LV hypertrophy, the changes in LV mass index were similar in the normal and low target hemoglobin groups. The changes in cavity volume index were similar in both targets in the LV dilation group. Treatment-received analysis of the concentric LV hypertrophy group showed no correlation between the change in mass index and a correlation between the change in LV volume index and mean hemoglobin level achieved (8 mL/m2 per 1 g/dL hemoglobin decrement, P = 0.009). Mean hemoglobin levels and the changes in LV mass and cavity volume index were not correlated in patients with LV dilation. Normalization of hemoglobin led to improvements in fatigue (P = 0.009), depression (P = 0.02), and relationships (P = 0.004). CONCLUSIONS: Normalization of hemoglobin does not lead to regression of established concentric LV hypertrophy or LV dilation. It may, however, prevent the development of LV dilation, and it leads to improved quality of life.

Comparative hospitalization of hemodialysis and peritoneal dialysis patients in Canada.

BACKGROUND: Most comparisons of hemodialysis (HD) and peritoneal dialysis (PD) have used mortality as an outcome. Relatively few studies have directly compared the hospitalization rates, an outcome of perhaps equal importance, of patients using these different dialysis modalities. METHODS: Eight hundred twenty-two consecutive patients at 11 Canadian institutions with irreversible renal failure had an extensive assessment of comorbid illness and initial mode of dialysis collected prospectively immediately prior to starting dialysis therapy. The cohort was assembled between March 1993 and November 1994. The mean follow-up was 24 months. Admission data were used to compare hospitalization rates in HD and PD. RESULTS: Thirty-four percent of patients at baseline and 50% at three months used PD. Twenty-five percent of HD and 32% of PD patients switched dialysis modality at least once after their first treatment (P = NS). Nine percent of HD patients and 30% of PD patients switched modality after three months (P < 0. 001). Total comorbidity was higher in HD patients at baseline (P < 0. 001) and at three months (P = 0.001). The overall hospitalization rate was 40.2 days per 1000 patient days after baseline and 38.0 days per 1000 patient days after three months. When an adjustment was made for baseline comorbid conditions, patients on PD had a lower rate of hospitalization in intention-to-treat analysis according to the type of dialysis in use at baseline (RR 0.85, 95% CI, 0.82 to 0.87, P < 0.001), but a higher rate according to the type of dialysis in use three months after study entry (RR 1.31, 95% CI, 1.27 to 1.34, P < 0.001). In analyses based on the amount of time actually spent on each treatment modality, PD was associated with a higher rate of hospitalization when analyzed according to the type of dialysis in use at baseline (RR 1.10, 95% CI, 1.07 to 1.13, P < 0.001) and according to the type of dialysis in use three months after study entry (RR 1.26, 95% CI, 1.23 to 1.30, P < 0.001). CONCLUSIONS: Conclusions regarding comparative hospitalization rates are heavily dependent on the analytic starting point and on whether intention-to-treat or treatment-received analyses are used. When early treatment switches are accounted for, HD is associated with a lower rate of hospitalization than PD, but the effect is modest.