Characteristics of high- and low-risk individuals in the PRIORITY study: urinary proteomics and mineralocorticoid receptor antagonism for prevention of diabetic nephropathy in Type 2 diabetes.

AIM: To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high- or low-risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis. RESULTS: A total of 1777 participants from 15 centres were included, with 12.3% of these having a high-risk proteomic pattern. Participants in the high-risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low-risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R2 < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin-angiotensin system-blocking agents remained significant determinants of the CKD273 high-risk group: area under the curve 0.72 (95% CI 0.68-0.75; P<0.01). CONCLUSIONS: In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012-000452-34 and Clinicaltrials.gov: NCT02040441).

Thrice-weekly in-center nocturnal hemodialysis: an effective strategy to optimize chronic dialysis therapy.

OBJECTIVES: Daily nocturnal hemodialysis (NHD) has been proposed as a valuable strategy to improve outcomes for patients on conventional hemodialysis (CHD), but it is burdened by high costs and logistic issues. Thrice NHD might represent a more affordable approach to improve hemodialysis patient outcome. METHODS: Here we retrospectively analyzed the data on blood pressure, body weight, and hematochemical parameters in a cohort of 7 patients (mean age 50.4-/+11.0 years, duration of CHD 14.3-/+11.5 years) who registered in the NHD program at the dialysis unit of Ospedali Riuniti, Bergamo, Italy. Data for the 2 first years of NHD were compared with those of the last year on CHD. RESULTS: At 2 years after start of NHD, we found a significant decrease in systolic (149.4-/+16.6 vs. 128.4+/-26.0 mm Hg, p<0.001) and diastolic (87.7-/+11.1 vs. 79.6-/+16.7 mm Hg, p<0.05) blood pressure, along with a significant reduction in the use of per-patient antihypertensive agents (1.17-/+1.19 vs. 0.47-/+0.89, p<0.05 and an increase in dry body weight (61.4-/+21.8 vs. 67.1-/+16.4 kg, p<0.001). Moreover, patients had a significant reduction in phosphate levels (6.2-/+2.4 vs. 5.4-/+3.0 mg/dL, p<0.01). The procedure was safe and well tolerated and did not require extra cost for ad hoc facilities. CONCLUSION: NHD is an effective approach to optimize chronic dialysis therapy.

Ways to boost kidney transplant viability: a real need for the best use of older donors.

Using kidneys from expanded criteria donors (ECD) increased transplant activity but resulted in a reduced graft survival. The relatively poor long-term outcome of ECD grafts may be the consequence of an imbalance between the number of viable nephrons supplied and the metabolic demand of the recipient. Providing more nephrons by dual transplants may improve outcomes but fails, per se, to confer the same benefit of single transplants from young donors. A biopsy-based score system has been presented by a panel of pathologists to assess whether kidneys from donors older than 60 years still contain enough viable nephrons to be made available for transplantation, and whether single or dual transplantation should be used. Allocating kidneys from older donors to a single or dual transplant on the basis of this scoring system allowed achieving a graft survival similar to that of single transplants from ideal donors and remarkably superior to that of single transplants from older donors not evaluated histologically before implantation. Thus, preimplantation histologic evaluation maximizes the success of ECD transplants and protects recipients from receiving organs at increased risk of premature failure. This may limit the number of patients who eventually must resume dialysis and need second transplants.

Time to abandon microalbuminuria?

The term microalbuminuria--a urinary albumin excretion (UAE) between 20 and 200 microg/min--has been introduced to identify subjects at increased risk of renal and cardiovascular disease. However, the relationship between albuminuria and risk is not restricted to the microalbuminuric range and extends to as low as 2-5 microg/min. On the contrary, the increase of UAE above 200 microg/min (macroalbuminuria) heralds the onset of proteinuria (urinary protein excretion above 0.5 g/24 h) and progressive renal and cardiovascular disease. Albuminuria is a component of the metabolic syndrome and may represent a marker of the increased risk of renal and cardiovascular disease associated with insulin resistance and endothelial dysfunction. Proteinuria is a sign of established kidney damage and plays a direct pathogenic role in the progression of renal and cardiovascular disease. Albuminuria reflects functional and potentially reversible abnormalities initiated by glomerular hyperfiltration, proteinuria, a size-selective dysfunction of the glomerular barrier normally associated with glomerular filtration rate (GFR) decline that may result in end-stage renal disease. Thus, the limit of 200 microg/min segregates patients with albuminuria or proteinuria who are at quite different risk. Among subjects with albuminuria, however, there is a continuous relationship between albumin excretion and risk and no lower bound between normal albuminuria and microalbuminuria can be identified that segregates subjects at different risk. Thus, the terms microalbuminuria and macroalbuminuria could be replaced by the concepts of albuminuria- and proteinuria-associated diseases. Future studies are needed to identify levels of albuminuria below which therapy is no longer beneficial.

Blood cyclosporine level soon after kidney transplantation is a major determinant of rejection: insights from the Mycophenolate Steroid-Sparing Trial.

Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C(0)) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C(2)) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C(0) levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C(2) levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.

[Hemolytic uremic syndrome]. / La sindrome emolitico uremica.

Hemolytic uremic syndrome (HUS) is a disease characterized by non immune hemolytic anemia, low platelet count and renal impairment. In children, the disease is most commonly triggered by Shiga-like toxin (Stx)-producing Escherichia coli (Stx-E. Coli): however, renal function recovers in up to 70% of patients. Plasma infusion or exchange reduces mortality and the risk of end-stage renal disease (ESRD) in adult patients. Non-Shiga toxin-associated HUS (non-Stx-HUS), accounting for only 5-10% of all disease cases, can be sporadic or familial. Collectively, non-Stx-HUS forms have a poor outcome. Up to 50% of cases progress to ESRD or have irreversible brain damage, and 25% can die during the acute phase of the disease. Genetic studies have recently documented that the familial form is associated with genetic abnormalities of complement regulatory proteins, and evidence is now emerging that similar genetic alterations can predispose to sporadic cases of non-Stx-HUS as well. Mutations of genes encoding for factor H, a glycoprotein that plays an important role in the regulation of the alternative pathway of complement and for MCP, a widely expressed transmembrane glycoprotein with an inhibitory role of activated C3, are reported in familial HUS. These mutations are more likely to predispose rather than to cause the disease directly.

Methods of cardio-renal protection in non-diabetic chronic nephropathies.

Angiotensin II (AII), the main effector of the Renin Angiotensin System (RAS), plays a central role in the hemodynamic and non-hemodynamic mechanisms of chronic renal disease and is currently the main target of interventions aimed to prevent the onset and progression of chronic nephropathies to end stage renal disease (ESRD). In addition to ameliorate glomerular hyperfiltration and size-selectivity, reduce protein traffic and prevent glomerular and tubulo-interstitial toxicity of ultrafiltered proteins, RAS inhibitors also limit the direct nephrotoxic effects of AII. Thus, both ACE inhibitors (ACEi) and AII antagonists (ATA) exert a specific nephroprotective effect in both experimental and human chronic renal disease. This effect is time-dependent and is observed across degrees of renal insufficiency. Forced ACEi or ATA up-titration above doses recommended to control arterial hypertension and combined treatment with both agents allow to optimise A II inhibition and maximize renoprotection. Multifactorial interventions combining RAS inhibition to treatments targeted also to non-RAS mechanisms may even achieve regression of glomerulosclerosis and chronic tubulo-interstitial injury. Studies are needed to assess whether renal damage can be reverted to such a point that renal function may be fully prevented from worsen, and possibly improve. The economic impact of even a partial improvement would be enormous. Moreover, chronic renal insufficiency is an independent risk factor for cardiovascular disease and effective nephroprotection may also decrease the excess cardiovascular morbidity and mortality associated with chronic nephropathies. In patients with renal insufficiency ACEi are even more cardioprotective than in those without, and are well tolerated. Thus, RAS inhibitor therapy should be offered to all renal patients without specific contraindications, including those closer to renal replacement therapy.

Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura.

The term thrombotic microangiopathy (TMA) defines a lesion of vessel wall thickening (mainly arterioles or capillaries), intraluminal platelet thrombosis, and partial or complete obstruction of the vessel lumina. Depending on whether renal or brain lesions prevail, two pathologically indistinguishable but somehow clinically different entities have been described: the hemolytic uremic syndrome (HUS) and the thrombotic thrombocytopenic purpura (TTP). Injury to the endothelial cell is the central and likely inciting factor in the sequence of events leading to TMA. Loss of physiological thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, abnormal von Willebrand factor release and fragmentation, and increased vascular shear stress may then sustain and amplify the microangiopathic process. Intrinsic abnormalities of the complement system and of the von Willebrand factor pathway may account for a genetic predisposition to the disease that may play a paramount role in particular in familial and recurrent forms. Outcome is usually good in childhood, Shiga toxin-associated HUS, whereas renal and neurological sequelae are more frequently reported in adult, atypical, and familial forms of HUS and in TTP. Plasma infusion or exchange is the only treatment of proven efficacy. Bilateral nephrectomy and splenectomy may serve as rescue therapies in very selected cases of plasma resistant HUS or recurrent TTP, respectively.

Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce urine protein excretion and slow the progression of renal disease. The beneficial effect in slowing the progression of renal disease is greater in patients with higher urine protein excretion at the onset of treatment. We hypothesized that the greater beneficial effect of ACE inhibitors on the progression of renal disease in patients with higher baseline levels of proteinuria is due to their greater antiproteinuric effect in these patients. METHODS: Data were analyzed from 1860 patients enrolled in 11 randomized controlled trials comparing the effect of antihypertensive regimens, including ACE inhibitors to regimens not including ACE inhibitors on the progression of non-diabetic renal disease. Multivariable linear regression analysis was used to assess the relationship between the level of proteinuria at baseline and changes in urine protein excretion during follow-up. The Cox proportional hazards analysis was used to assess the relationship between changes in urine protein excretion during follow-up and the effect of ACE inhibitors on the time to doubling of baseline serum creatinine values or onset of end-stage renal disease. RESULTS: Mean (median) baseline urine protein excretion was 1.8 (0.94) g/day. Patients with higher baseline urine protein excretion values had a greater reduction in proteinuria during the follow-up in association with treatment with ACE inhibitors and in association with lowering systolic and diastolic blood pressures (interaction P < 0.001 for all). A higher level of urine protein excretion during follow-up (baseline minus change) was associated with a greater risk of progression [relative risk 5.56 (3.87 to 7.98) for each 1.0 g/day higher protein excretion]. After controlling for the current level of urine protein excretion, the beneficial effect of ACE inhibitors remained significant [relative risk for ACE inhibitors vs. control was 0.66 (0.52 to 0.83)], but there was no significant interaction between the beneficial effect of ACE inhibitors and the baseline level of urine protein excretion. CONCLUSIONS: The antiproteinuric effects of ACE inhibitors and lowering blood pressure are greater in patients with a higher baseline urine protein excretion. The greater beneficial effect of ACE inhibitors on renal disease progression in patients with higher baseline proteinuria can be explained by their greater antiproteinuric effects in these patients. The current level of urine protein excretion is a modifiable risk factor for the progression of non-diabetic renal disease. ACE inhibitors provide greater beneficial effect at all levels of current urine protein excretion.

Drug-induced thrombotic microangiopathy: incidence, prevention and management.

The term thrombotic microangiopathy (TMA) describes syndromes characterised by microangiopathic haemolytic anaemia, thrombocytopenia and variable signs of organ damage due to platelet thrombi in the microcirculation. In children, infections with Shigella dysenteriae type 1 or particular strains of Escherichia coli are the most common cause of TMA; in adults, a variety of underlying causes have been identified, such as bacterial and viral infections, bone marrow and organ transplantation, pregnancy, immune disorders and certain drugs. Although drug-induced TMA is a rare condition, it causes significant morbidity and mortality. Antineoplastic therapy may induce TMA. Most of the cases reported are associated with mitomycin. TMA has also been associated with cyclosporin, tacrolimus, muromonab-CD3 (OKT3) and other drugs such as interferon, anti-aggregating agents (ticlopidine, clopidogrel) and quinine. The early diagnosis of drug-induced TMA may be vital. Strict monitoring of renal function, urine and blood abnormalities, and arterial pressure has to be performed in patients undergoing therapy with potentially toxic drugs. The drug must be discontinued immediately in the case of suspected TMA. Treatment modalities sometimes effective in other forms of TMA have been used empirically. Although plasma exchange therapy seems to be of value, the effectiveness of this approach has yet to be proved in multicentre, randomised clinical studies.

Remission achieved in chronic nephropathy by a multidrug approach targeted at urinary protein excretion.

Regardless of the pattern of renal involvement, increased urinary protein excretion rate is the best independent predictor of progression of chronic nephropathies and short-term reduction in proteinuria has been reported to be renoprotective in the long term. Despite such evidence, however, the therapeutic target in renoprotection is almost exclusively on blood pressure control. We report the clinical course of a patient with chronic nephropathy after the institution of a multidrug treatment titrated against urinary protein excretion to achieve renoprotection. The present findings indicate that adjusting renoprotective therapy according to the decline in protein excretion in a multidrug strategy may stabilize or even reverse renal disease progression. This approach should be formally explored in prospective studies.

Post-transplant renal artery stenosis: the hemodynamic response to revascularization.

BACKGROUND: Percutaneous transluminal angioplasty and stenting are relatively noninvasive approaches to treat post-transplant renal artery stenosis. However, the real impact of this procedure on renal function recovery has never been quantitated precisely to date. METHODS: In eight consecutive renal transplant patients with renal graft artery stenosis, blood pressure, body weight, and anatomical, functional, and Doppler ultrasound parameters were evaluated before and one month after renal artery transluminal angioplasty and stenting. On both occasions, glomerular filtration rate and renal plasma flow were evaluated by inulin and paraaminohippuric acid renal clearances, and glomerular size-selective function was evaluated by the fractional clearances of neutral dextran macromolecules. RESULTS: The correction of renal artery stenosis, by normalizing renal vascular resistances, fully restored kidney perfusion and decreased arterial blood pressure, relieved water and sodium retention, restored an almost laminar arterial blood flow, and normalized vascular shear stress without appreciable effects on glomerular barrier size-selective function and proteinuria. Preangioplasty and postangioplasty renal resistive indices and peak systolic blood velocity estimated by Doppler ultrasounds were significantly correlated with the effective renal plasma flow and the blood velocity calculated at the site of stenosis. All patients were discharged without sequelae one or two days after angioplasty. CONCLUSIONS: Percutaneous transluminal angioplasty and stenting are safe and effective procedures to normalize the functional changes sustained by hemodynamically significant artery stenosis after renal transplantation. Doppler ultrasound scanning is a reliable and reproducible technique to monitor the renal functional response to vascular reperfusion.