Proteomics and diabetic nephropathy

Diabetes mellitus is acknowledged to be a group of metabolic diseases and heterogeneous in natural history, pathogenesis, response to treatment, and disease progression and remission. Diabetic nephropathy (DN) accounts for approximately 40% of all newly diagnosed cases of endstage renal disease. The complexity of diabetes and its complications requires a broad-based, unbiased, scientific approach such as proteomics. Recently, proteomics (the systematic analysis of protein identity, quantity, and function) has been applied to the study of DN. Proteomic investigations into diabetic kidney disease have identified new mechanisms of diabetic renal pathology, as well as potential urinary markers of DN. Other current proteomic advances in understanding DN include identifying the role of advanced glycation end products in decreased mitochondrial respiration and also the rapid development of mass spectrometric methods for protein and peptide markers of DN development and markers to pharmacologic therapies. Proteomic analysis has only recently been applied to the study of DN, yet it has shown substantial potential.     

Kidney disease and the metabolic syndrome

The epidemic of metabolic syndrome contributes to the rapid growth of cardiovascular and renal diseases. Hyper-hemodynamics, impaired pressure natriuresis, excess excretory load, insulin resistance, endothelial dysfunction, chronic inflammation, and prothrombotic status individually and interdependently initiate renal injury in metabolic syndrome. The prevention and treatment of kidney disease require a multifactorial approach. Weight loss through diet control and exercise can reverse many pathophysiologic processes. Pharmacologic intervention includes insulin sensitizers, tight glycemic and lipid control, blockage of renin angiotensin aldosterone system, and anti-inflammatory and antithrombotic therapies. Each peroxisome proliferator-activated receptor isoform plays a distinct role in metabolic syndrome, and their agonists may prevent or reverse the early renal injuries.     

Hypertension: how comorbid disease influences the choice of therapy. Part 4 of a roundtable discussion.

Two categories of comorbid conditions affect the choice of therapy for hypertension: compelling indications, where outcomes data show improved survival, and indications where therapies may be beneficial but do not affect survival. In patients with diabetes, low-dose diuretics effectively lower blood pressure, but metabolic derangements may occur. A diuretic may exacerbate urinary incontinence and therefore may not be a first-choice therapy for some older women. Monotherapy is not effective in controlling blood pressures in patients with renal insufficiency. In patients with a history of MI, even those age 85 and older benefit from beta blockade. Lowering blood pressure over a 3- to 5-year period is effective in preventing left ventricular hypertrophy and congestive heart failure.     

Emerging therapies for heart failure: renal mechanisms and effects

Improved understanding of the pathophysiology of salt and water homeostasis has provided a foundation for explaining the renal mechanisms of emerging therapies for heart failure, as well as why renal function might potentially be improved or harmed. These aspects are reviewed in this article for a number of newer therapies including adenosine, endothelin, and vasopressin receptor antagonists, as well as extracorporeal ultrafiltration. An appreciation of the complexity and sometimes opposing pathways of these approaches may explain their limited efficacy in early trials, in which there has not been a substantial improvement in patient or renal outcomes. In that there is often a balance between beneficial and maladaptive receptor actions and neurohumoral responses, this physiologic approach also provides insight into the rationale for combining therapies. Multi-agent strategies may thus maximize their effectiveness while minimizing adverse effects and tolerance. In this paper, the theoretical impact of the emerging agents based on their mechanism of action and pathophysiology of the disease is initially addressed. Then, the available clinical evidence for each class of drugs is reviewed with special emphasis on their effect on kidney-related parameters. Finally, a general overview of the complexity of the interpretation of trials is offered along with a number of potential explanations for the observed results.     

Crohn's disease and kidney stones: much more than coincidence?

BACKGROUND: Crohn's disease is an inflammatory bowel disease associated with a wide variety of complications and manifestations secondary to the effects of underlie inflammatory process. In about 30% of the patients with Crohn's disease can be found extra-intestinals symptoms. Nephrolithiasis is one of them and the appearance of kidney stones, mainly of oxalate of calcium, is more common in these patients than in general population. AIM: To evaluate urinary metabolic factors potentially involved in renal stones formation on patients with Crohn's disease. METHODS: We evaluated 29 patients with Crohn's disease followed in the Outpatient Bowel Inflammatory Disease Clinics of State University Hospital, Londrina, PR, Brazil, from January to December of 2004. The metabolic evaluation included measured of blood and urine substances related to renal stones formation, kidneys, ureters and bladder ultrasonography and calculation of urinary supersaturation for calcium oxalate, uric acid and calcium phosphate. RESULTS: Twenty-nine of the evaluated patients were female or 65.5% and 34.5% were males. Among the metabolic urinary studied, we identified the following potential disturbances associated with nephrolithiasis: hypocitraturia in 21 patients (72.4%), hypomagnesuria in 12 (41.4%), hyperoxaluria in 4 (13.6%) and urinary volume low in 5 (17.2%). Renal stones were identified in 13 patients (44.8%). Oxalate urinary excretion was higher in patients submitted to bowel surgery and also in patients with ileum resection. The urinary supersaturation of calcium oxalate and brushita in patients with bowels surgery was higher than the other patients not submitted to any surgery. Data to compare patients who underwent to surgery or not were analyzed by Mann-Whitney test (U test), and Qui-square test or the accurate test of Fisher have been used to determine variables association. For all tests 5% of significance level was considered. CONCLUSION: This study shows that the frequency of renal stones in patients suffering from Crohns disease is higher than in general population and, also, higher than that described elsewhere for this disease. We identified hypocitraturia and hypomagnesiuria as the main factors which could explain our data. The impact of these metabolic disturbances can be also evaluated by means of the high supersaturation obtained for calcium oxalate and calcium phosphate which suggests the way those factors could be influencing crystal nucleation and, consequently, lead to renal stones formation in this group of patients.     

Proteinuria in diabetic nephropathy: Treatment and evolution

Diabetic nephropathy is characterized by increased urinary albumin excretion and loss of renal function. Increased urinary albumin (proteinuria) is a key component of this disease. Previously, its development led to end-stage renal disease with increased mortality and morbidity for diabetic patients versus nondiabetic patients. Several treatment strategies currently exist that can prevent, slow, and even reverse diabetic nephropathy. New trials suggest that a multidisciplinary approach focused on optimizing metabolic and hypertensive control, in addition to the use of angiotensin-converting enzyme inhibitors or angiotensin 2 receptor antagonists, is effective in halting the progression of disease. Screening and implementation of these strategies is needed to reverse the epidemic of diabetic renal disease.     

Interstitielle Nephritis

Drugs such as antibiotics, non-steroidal anti-inflammatory drugs and proton pump inhibitors, infections and systemic diseases can trigger interstitial nephritis. The clinical outcome varies from asymptomatic progression to acute kidney injury. Interstitial nephritis often leads to characteristic and detectable partial tubular disorders such as tubular proteinuria (α₁-microglobulin), phosphaturia with hypophosphatemia, aminoaciduria, diminished H⁺ secretion with metabolic acidosis with inadequate high urinary pH, glucosuria and salt loss. The main principle of treatment is avoidance of the inducing agent. In addition corticosteroids have been proven usable after exclusion of an infection so that a good prognosis can be expected for acute nephritis in the majority of cases. In chronic forms the interstitial nephritis involves the glomeruli as well as potentially resulting in end-stage renal failure in the long run. Supportive therapies are then required in the sense of chronic renal failure in order to prevent further functional loss up to end-stage renal disease.     

The association of nephrolithiasis with hypertension and obesity: a review

Kidney stones affect hypertensive patients disproportionately compared to normotensive individuals. On the other hand, some prospective data suggest that a history of nephrolithiasis was associated with a greater tendency to develop hypertension. Newer epidemiologic data also link obesity and diabetes, features of the metabolic syndrome, with nephrolithiasis. In this review, the association of hypertension, diabetes, and obesity with nephrolithiasis is reviewed, and possible pathogenic mechanisms are discussed. Patients with hypertension may have abnormalities of renal calcium metabolism, but data confirming this hypothesis are inconsistent. Higher body mass index and insulin resistance (i.e., the metabolic syndrome) may be etiologic in uric acid nephrolithiasis as increasing body weight is associated with decreasing urinary pH. The possibility that common pathophysiologic mechanisms underly these diseases is intriguing, and if better understood, could potentially lead to better therapies for stone prevention. Both hypertension and stones might be addressed through lifestyle modification to prevent weight gain. Adoption of a lower sodium diet with increased fruits and vegetables and low-fat dairy products, (for example, the dietary approaches to stop hypertension(DASH) diet), may be useful to prevent both stones and hypertension. In those patients in whom dietary modification and weight loss are ineffective, thiazide diuretics are likely to improve blood pressure control and decrease calciuria.     

Renal Kallikrein Excretion in Alcoholic Cirrhosis

Severe liver disease is often associated with renal hemodynamic changes, and these changes may involve vasoactive hormones. The vasodilatory renal kallikrein-kinin system has received little previous study in these patients. We measured urinary kallikrein in nine patients with alcoholic cirrhosis under rigid metabolic conditions and simultaneously evaluated renin, aldosterone and urinary prostaglandins. Plasma renin und aldosterone were generally increased as expected but urinary kallikrein was surprisingly diminished (13.3 ± 3.7 vs. 38.8 ± 11.1 SE, E.U./day. P < 0.05). despite adequate creatinine clearance (81 ± 9 ml./min.). Administration of prostaglandin inhibitors reduced urinary prostaglandin E by 72% and creatinine clearance by 56% but did not alter urinary kallikrein. Mineralocor-ticoid inhibition by spironolactone induced a natriuresis in four patients with ascites (from 1.4–140 mEq. Na⁺/day) but also failed to alter kallikrein. Thus, kallikrein excretion is paradoxically reduced and seemingly unresponsive to alterations in the prostaglandin and renin-aldosterone systems. If urinary kallikrein quantitatively reflects intrarenal kallikrein-kinin activity, the impairment in this vasodilatory system may mediate the altered renal hemodynamics of severe liver disease.     

Management of the patient with chronic renal failure in the evidence based era

Chronic renal failure is a growing problem with an increasing number of patients suffering from loss of kidney function. The morbidity and mortality of these patients is much higher than that of the general population. The patient with chronic kidney disease, even with only a moderate level of renal failure, falls in the highest risk category for cardiovascular disease. A proper evaluation and management of these patients is necessary to prevent further loss of kidney function, to prevent cardiovascular diseases and to manage the co-morbid conditions associated with renal failure and the complications due to renal failure. The therapies available for these purposes in adult patients with chronic renal disease not (yet) in dialysis, are presented in this article, with emphasis on blood pressure management, antiproteinuric therapies, correction of renal anaemia, approach of lipid disorders. A timely referral to a nephrologist is also shown to be important.     

Urinary acidification in a patient with glucose-6-phosphate dehydrogenase deficiency. A reevaluation of the role of the hexose monophosphate shunt in renal acid secretion

The relationship between renal metabolism and urinary acidification is poorly understood. During the past decade evidence has accrued to suggest that the hexose monophosphate (HMP) shunt might serve in the process of urinary acidification by providing reducing equivalents for a redox-coupled membrane-bound proton pump that could transport protons into the tubular lumen. The major support for this hypothesis has come from the finding that HMP shunt activity increases with acute and chronic metabolic acidosis. In the present study, we examine the urinary acidification capacity of a young man with severe erythrocyte glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and with unmeasurable G-6-PD activity in renal cortical tissue. We found that despite unmeasurable G-6-PD activity in renal tissue, the patient was capable of generating a maximally acid urine and increasing total acid secretion. Our findings suggest that the HMP shunt may not be necessary for the urinary acidification process.     

Urinary Tract Infections in Renal Transplant Recipients

Infection of the urinary tract is the most common infectious complication of renal transplantation. The microbiology of post-transplant urinary tract infections is similar to what is seen in the general population, although transplant patients may develop infections due to unusual or opportunistic pathogens. The optimal management of urinary tract infections in renal transplant recipients is poorly studied, but recommendations for treatment are available. Antibiotic prophylaxis can reduce the risk of bacterial infection of the urinary tract post-transplant but is not used in all transplant centers. The influence of urinary tract infection on graft survival requires further study.     

Minimizing urinary incontinence in the nursing home

In the nursing home, urinary incontinence is a common problem that all too often is treated as an irremediable "problem of aging" by physicians, nurses, and patients. Its etiologies are numerous, as are approaches to treatment in this setting. However, with a thoughtful approach to diagnosis and care, the primary care physician may be able to determine which patients, with which forms of urinary incontinence, will benefit from specific therapies.     

Immunosuppression and metabolic syndrome in renal transplant recipients

Cardiovascular disease is the major cause of death in renal transplant recipients. Renal transplant recipients share the same cardiovascular risk factors as the general population, including hypertension, hyperlipidemia, diabetes mellitus, smoking, and positive family history. However, renal transplant recipients are also exposed to transplant-specific risk factors such as chronic immunosuppression. Most renal transplant recipients receive combinations or permutations of immunosuppressive drugs including a calcineurin inhibitor (cyclosporine or tacrolimus), a mammalian target of rapamycin (mTOR) inhibitor (sirolimus), an antiproliferative drug (mycophenolate mofetil and azathioprine), and corticosteroids. Cyclosporine and tacrolimus can induce glucose intolerance, hypertension, and hyperlipidemia. Sirolimus can induce hyperlipidemia. Corticosteroids can induce glucose intolerance, hypertension, hyperlipidemia, and weight gain. Central to the development of metabolic complications in renal transplant recipients is insulin resistance induced by immunosuppressive drugs. Insulin resistance is considered to be the central pathophysiological feature of metabolic syndrome, which is linked to increased risk of cardiovascular disease and to chronic renal failure. Therefore, metabolic syndrome likely contributes to cardiovascular disease and chronic renal allograft dysfunction in renal transplant recipients. Treatment of metabolic complications in renal transplant recipients is difficult, as conversion to an alternate immunosuppressive drug may lead to introduction of new metabolic complications, and as discontinuation of immunosuppressive therapy may lead to rejection. Future research should focus on designing immunosuppressive regimens that have minimal effects on insulin resistance and metabolic complications but that are effective in preventing acute rejection and in prolonging both allograft and patient survival.     

Finerenona: completando el abordaje del paciente con enfermedad renal y diabetes

Despite current treatments, that include renin angiotensin system blockers and SGLT2 inhibitors, the risk of renal disease progression among patients with diabetes and chronic kidney disease (CKD) remains unacceptably high. The pathogenesis of CKD in patients with diabetes is complex and includes hemodynamic and metabolic factors, as well as inflammation and fibrosis. Finerenone is a nonsteroidal highly selective mineralocorticoid antagonist that, in contrast to current therapies, may directly reduce inflammation and fibrosis, supporting an added value in the management of these patients. In fact, finerenone decreased albuminuria and slowed CKD progression in persons with diabetes. We now review the mechanisms of action of finerenone, the results of recent clinical trials and a practical approach to integrate the kidney and cardiovascular protection afforded by finerenone in the routine care of patients with diabetes and CKD.     

Stand der Nierentransplantation im Jahr 2012

Triple immunosuppression including a calcineurin inhibitor, mycophenolic acid and steroids remains the standard of care after (renal) transplantation, while steroid-free immunosuppression and calcineurin inhibitor-free (mTOR inhibitor or belatacept-based) therapies are increasingly being used. In several transplant centers induction therapy with basiliximab or antilymphocyte globulin/antithymocyte globulin (ATG/ALG) is routinely used. Impairment of renal graft function necessitates a thorough investigation, often including a renal core biopsy and imaging studies for the assessment of vascular perfusion to allow adequate treatment for, e.?g. humoral, antibody-mediated rejection or polyomavirus type BK (BKV) nephropathy. Long-term survival of patients with functioning graft is largely determined by cardiovascular mortality. Therefore, aggressive preventive and therapeutic strategies are required in cardiovascular high-risk transplant patients. This comprises blood pressure control <140/90?mmHg, with calcium channel blocker, diuretic, angiotensin-converting enzyme (ACE) inhibitor, beta blocker as agents of first choice, statin treatment (fluvastatin, pravastatin most intensely studied), diabetes treatment (target HbA1c at 7%), avoidance of inadequate post-transplantation weight gain and nicotine abstinence. Tumor risk is increased 4-fold, especially skin tumors, post-transplant lymphoproliferative disorders (PTLD) and renal/bladder cancer. Besides standard tumor prevention protocols as suggested for the general population, regular dermatological and ultrasound studies (liver when viral hepatitis is present, native kidneys) are recommended. High-dose immunosuppression increases the risk of infection especially within the first 6 months. Transplantation-associated infections (catheter, wound, pneumonia, urinary tract infections with urinary bladder catheterization), de novo infections or endogeneous reactivation of viral infections, i.e. with herpes viruses (HSV, VZV, CMV) are most frequent. Due to the medical complexity of transplantation patients, an interdisciplinary approach and a close collaboration between transplant center and the primary care nephrologist is needed.     

Effects of sodium intake, furosemide, and infusion of atrial natriuretic peptide on the urinary and metabolic clearances of arginine vasopressin in normal subjects

Arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) have important influences on water and electrolyte metabolism, and studies on the interactions between these hormones may have important implications. We have investigated the effects of sodium intake, furosemide, and infusion of ANP on the urinary and metabolic (nonurinary) clearances of AVP in hydrated normal subjects. On a high sodium diet there was an increase in urine volume, sodium excretion, osmolal clearance, plasma ANP concentration, and urinary clearance and fractional excretion of AVP, with a decrease in PRA. The infusion of furosemide increased urine volume, sodium excretion, osmolal clearance, and PRA, but decreased circulating ANP levels and urinary clearance and fractional excretion of AVP. Since there was a positive correlation between circulating ANP and urinary clearance of AVP in these experiments, we infused human alpha ANP in physiological amounts and found increases in the urinary and metabolic (nonurinary) clearances of AVP. The changes in urinary clearance of AVP in all three experiments occurred even in relation to creatinine clearance. These observations demonstrate that urinary clearance of AVP does not correlate with urine volume, sodium or solute excretion, or PRA. The observations support a physiological role for ANP in modulating the renal action of AVP, probably at the level of the renal tubules, and indicate a need for caution when using plasma or urinary AVP as an indicator of AVP release from the neurohypophysis.     

Intensified inhibition of renin-angiotensin system: A way to improve renal protection?

Several large, randomized, multicenter studies in diabetic and nondiabetic patients with chronic proteinuric nephropathies have clearly demonstrated that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) are able to reduce urinary protein excretion and retard renal disease progression. However, the number of patients who reach end-stage renal failure is still considerable and there is a great need to identify therapies that can arrest evolution of kidney damage. Maximizing renin-angiotensin system (RAS) blockade through combined ACE inhibitor and ARB therapy has been shown to further increase antiproteinuric and nephroprotective effects of each drug class. However, in order to slow to the greatest extent progression of renal disease, the ideal therapeutic approach for patients with proteinuric nephropathies should be a multimodal strategy including dual RAS blockade, antialdosterone therapy, lipid-lowering agents, smoking cessation, and tight glucose control for diabetes.     

Intensified inhibition of renin-angiotensin system: A way to improve renal protection?

Several large, randomized, multicenter studies in diabetic and nondiabetic patients with chronic proteinuric nephropathies have clearly demonstrated that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) are able to reduce urinary protein excretion and retard renal disease progression. However, the number of patients who reach end-stage renal failure is still considerable and there is a great need to identify therapies that can arrest evolution of kidney damage. Maximizing renin-angiotensin system (RAS) blockade through combined ACE inhibitor and ARB therapy has been shown to further increase antiproteinuric and nephroprotective effects of each drug class. However, in order to slow to the greatest extent progression of renal disease, the ideal therapeutic approach for patients with proteinuric nephropathies should be a multimodal strategy including dual RAS blockade, antialdosterone therapy, lipid-lowering agents, smoking cessation, and tight glucose control for diabetes.