Treatment rationale for coronary heart disease in advanced CKD.

Chronic kidney disease (CKD) is accompanied by coronary artery disease (CAD) in most patients. In this article we describe differences in the pathogenesis, diagnosis, and treatment of CAD compared with patients without kidney impairment. The histological phenotype as well as the clinical presentation of acute and chronic coronary syndromes differ from those of patients with normal kidney function. The risk of cardiovascular events including death is strikingly increased with higher stages of CKD. Traditional but even more nontraditional cardiovascular risk factors are contributing to this increase. Screening and diagnostic procedures show limited sensitivity and specificity. Lifestyle modification is important for reducing the progression of both CKD and CAD. A special emphasis should be placed on physical exercising. Equally important is a strict antihypertensive therapy due to the very high incidences of hypertension in CKD patients. Blockade of the renin-angiotensin-system is imperative providing that adverse effects can be managed. Target blood pressure should be at 130 mm Hg systolic. Antiglycemic treatment should be implemented with metformin and SGLT2-inhibitors as first-line therapy, and glomerular filtration rate thresholds must be respected for both drugs. The risk of hypoglycemia is increased with worsening kidney function. Statins are indicated for up to stage 5 CKD. When a revascularization procedure is indicated (percutaneous intervention or bypass grafting), higher rates or peri-interventional morbidity and mortality must be anticipated. Taken together, the available literature on patients with CKD and CAD is clearly restricted compared with that on CAD patients with preserved kidney function. Mechanisms of arteriosclerosis and atheromatosis in CKD deserve more attention in the future. One major innovation in the field is SGLT2-inhibitor treatment with its concordant advantages for kidney and cardiac protection.

[Treatment of coronary artery disease in renal insufficiency]. / Therapie der koronaren Herzkrankheit bei Niereninsuffizienz.

The treatment of chronic but stable coronary artery disease is based on the stages of chronic kidney disease (CKD) stages G1-2 and stages G3-G5, distinguishing between advanced kidney disease (stages G3-G5) and end-stage kidney disease (G5D) treated by dialysis. In Germany, national guidelines are followed for patients with normal kidney function in addition to the recommendations of Kidney Disease - Improving Global Outcomes (KDIGO) for CKD patients. These guidelines focus on standard of care and include treatment with aspirin, statins, beta-blockers, inhibitors of the renin-angiotensin system, and sodium glucose cotransporters for patients with cardiovascular disease. Revascularization strategies follow a more pragmatic approach for the fragile, comorbid, and aging patient population. Younger patients appear to benefit from surgical interventions. Treatment of acute events is currently administered independent of the patient's kidney function, but there is no consensus yet on the best strategy. The focus of our efforts should be, via more controlled studies, to avoid "navigating through the darkness" to reach the end of the tunnel.

Safety and Efficacy of Induction Therapy With Thymoglobulin in AB0-Incompatible Kidney Transplantation.

INTRODUCTION: Data suggest an additional role of T cells in antibody-mediated rejections. In 2001 a protocol for AB0-incompatible kidney transplantation based on B-cell-depleting anti-CD20 antibody rituximab, antigen-specific blood group IgG immunoadsorption, intravenous immunoglobulins, and triple immunosuppression was introduced in Europe, which used induction therapy with the use of interleukin-2 receptor antibody (IL2-RA) basiliximab. We used thymoglobulin in AB0-incompatible patients as induction in the face of high immunologic risk. METHODS: We retrospectively evaluated a cohort of 9 AB0i living donation (LD) recipients from 2011 to 2014. Desensitization included blood group-specific immunoadsorption. Eighteen AB0-compatible LD recipients receiving induction therapy with thymoglobulin served as control subjects. Another control group consisted of 18 AB0-compatible LD recipients receiving basiliximab. Follow-up was 24 months. We captured graft function by estimating glomerular filtration rate (eGFR by Modification of Diet in Renal Disease formula), rejection episodes, and bacterial and viral infections. RESULTS: All patients experienced immediate graft function. No significant or clinical differences were observed regarding graft function, rejection rates, or infections between the groups, although there seemed to be slightly higher cytomegalovirus infection rates due to preemptive therapy strategy. CONCLUSIONS: Thymoglobulin appears to be similar in safety and efficacy to IL-2-antagonists in AB0i kidney transplantation.

First Treatment of Relapsing Rapidly Progressive IgA Nephropathy With Eculizumab After Living Kidney Donation: A Case Report.

BACKGROUND: IgA nephropathy (IGAN) rarely can present as a crescent and progressive form leading to end-stage renal disease (ESRD) in a short period of time. Recurrence of IGAN after kidney transplantation is frequent, and complement components such as C3, C4d, and C5 seem to be involved. We present a case of a young male patient with ESRD caused by rapidly progressive IGAN and who demonstrated rapid recurrence of crescentic IGAN after kidney donation. CASE REPORT: In September 2014, a 28-year-old male patient was hospitalized due to IGAN with 60% of crescents. Cyclophosphamide, steroids, and plasmapheresis did not prevent ESRD. After 8 months of peritoneal dialysis, the patient received a blood group-compatible living donor kidney from his 57-year-old mother. Immunosuppression consisted of tacrolimus, mycophenolic acid, and steroids without induction therapy. Acute graft failure occurred 2 months later, and graft biopsy results revealed recurrence of crescentic IGAN. Cyclophosphamide was added to tacrolimus and steroid treatment, but graft function could not be restored despite viable kidney tissue in repeated biopsy specimens. Rescue therapy with 4 single doses of eculizumab was introduced while hemodialysis had already been initiated. After a cumulative dose of 1800 mg of eculizumab, kidney function did not recover. CONCLUSIONS: In this case, eculizumab was not effective in treating IGAN recurrence after transplantation. Therapy was started late when hemodialysis had already been initiated; an earlier start of therapy might be more effective.

Successful Short-Term Intravenous Treatment of Disseminated Nocardia farcinica Infection with Severe Hyponatremia After Kidney Transplantation: A Case Report.

BACKGROUND: Nocardia is a genus of gram-positive Actinomycetes that are ubiquitous in decaying organic material, soil, and water. Some Nocardia species can infect humans, mainly by airborne transmission. Several reports describe disseminated infections, which are rare and mostly affect strongly immunocompromised patients because intact T-cell-mediated immunity is the major protective mechanism. CASE REPORT: We report a case of disseminated pulmonary, cerebral, and cutaneous infection with Nocardia farcinica in a 66-year-old kidney transplant recipient treated with low-dose triple immunosuppression. The patient was initially admitted because of severe hyponatremia and pneumonia with radiologic signs of pleural effusion. The infectious agent was isolated when cutaneous lesions developed. Oral trimethoprim/sulfamethoxazole treatment led to severe hyponatremia; therefore, long-term treatment with parenteral amikacin and minocycline was initiated. After 7 months of consistent intravenous treatment, the lesions completely resolved and treatment was stopped, against some expert suggestions. The patient had remained free of relapse at the time of writing. CONCLUSIONS: Disseminated Nocardia infection in immunocompromised patients is a rare but life-threatening disease. Owing to its infrequency, the variety of clinical patterns, antimicrobial resistance, and often fatal complications of standardized therapy, the diagnosis and treatment of this infection remain challenging and protracted.

[MRI after renal transplantation with dysfunctional allograft: are there typical diagnoses in the early and late postoperative phases?]. / MRT bei Nierentransplantatdysfunktion: Gibt es typische Diagnosen im frühen und späten postoperativen Verlauf?

PURPOSE: The aim of this study was to evaluate the different MRI diagnoses in the early and late post-operative period after renal transplantation with dysfunctional allograft. MATERIALS AND METHODS: Due to unknown transplant dysfunction, 49 patients (30-male, 19 female) received a total of 74 MRI studies. According to the date of examination all MRI studies were divided in an early (< or = 60 days, ETP) and a late post-transplant time period (> 60 days, LTP). All MRI studies were performed on 1.5 T MRI systems using a standardised imaging protocol consisting of a morphological (pre- and post-contrast enhanced T (1)- and T (2)-weighted TSE sequences), a vascular (contrast-enhanced 3D MRA) and a urographical part (Flash 3D sequences). Frequencies of diagnoses in ETP and LTP, and diagnoses within each transplant time period were analysed. RESULTS: 44/74 MRI studies were performed in ETP, 30/74 in LTP. In total 80 diagnoses were obtained: Renal artery stenosis (ETP, n = 21; LTP, n = 5), renal vein stenosis (ETP, n = 2), renal vein thrombosis (ETP, n = 2), renal perfusion defect (ETP, n = 11), rejection (ETP, n = 1; LTP, n = 2), abscess (ETP, n = 1), urinary outflow obstruction (LTP, n = 4), without MRI pathology (ETP, n = 11; LTP, n = 20). Renal artery stenosis was the most prevalent diagnosis in ETP, and a more frequent finding in ETP compared to LTP (p < 0.05). Renal perfusion defects were more frequent in ETP than in LTP (p < 0.05). In the ETP vascular diseases (34/49 diagnoses) were more frequent (p < 0.05) than uropathological diseases (0/49 diagnoses). CONCLUSIONS: Our results indicate that vascular diseases are a more frequent occurrence in the early post-operative course after renal transplantation than uropathological diseases. However, a transplant follow-up MRI study needs to contain a morphological, vascular and functional imaging part to answer combined clinical questions.

Prospective age-matching in elderly kidney transplant recipients--a 5-year analysis of the Eurotransplant Senior Program.

Renal transplantation faces challenges: the organ shortage resulting in extended waiting times and an aging population resulting in death with a functioning graft. The Eurotransplant Senior Program (ESP) allocates kidneys within a narrow geographic area from donors aged >/=65 years to recipients >/=65 years regardless of HLA. This analysis investigates the impact of the ESP on waiting time, graft and patient survival. The ESP group (n = 1406, old to old) was compared to two groups allocated via the Eurotransplant Kidney Allocation System (ETKAS) with either similar donor age (old to any [O/A], donor age >/=65, n = 446) or recipient age (any to old, [A/O], recipient age 60-64, n = 1687). All patients were transplanted between 1999 and 2004. Since initiation of the ESP (1999), availability of elderly donors doubled and waiting time for ESP patients decreased. Local allocation led to shorter cold ischemia time (11.9 vs. >17.0 h, p < 0.001) and less delayed graft function (DGF, ESP 29.7% vs. O/A 36.2%, p = 0.047) but 5-10% higher rejection rates. Graft and patient survival were not negatively affected by the ESP allocation when compared to the standard allocation. The ESP age matching of elderly donors and recipients is an effective allocation system for organs from elderly donors.

[Antiphospholipid antibody syndrome: a priori a contraindication to kidney transplantation?]. / Antiphospholipidantikörpersyndrom: a priori eine Kontraindikation zur Nierentransplantation?

BACKGROUND: The antiphospholipid antibody syndrome (APLS) is characterised by the presence of antiphospholipid antibodies in association with thrombotic disorders of the arterial and/or venous system, spontaneous abortion and thrombocytopenia. Several studies have shown that end-stage renal disease patients with APLS are at extremely high risk for graft thrombosis and graft loss after kidney transplantation. MATERIAL AND METHODS: We report on the treatment and clinical courses of 6 APLS renal transplant patients. RESULTS: Of 3 patients treated with low-dose subcutaneous heparin two had early graft loss due to venous graft thrombosis; of those patients treated by systemic heparin (PTT goal 45-55 s) and followed by coumadin (INR 2.5-3.0) only one had early graft loss whereas 2 grafts are doing well 2 years post-transplant. CONCLUSION: Our experience as well as recently published data suggest that kidney transplantation can be performed successfully in APLS patients if anticoagulation therapy is performed consistently. A general APL antibody screening prior to kidney transplantation does not seem to be justified at present. A prospective, randomised multicenter study is warranted to evaluate the management of these patients with respect to intensity, type and duration of anticoagulation therapy.

Haemodynamic effects of valsartan in acute renal ischaemia/reperfusion injury.

BACKGROUND: Acute deterioration of renal function is an important side-effect of angiotensin-converting enzyme (ACE) inhibitors, especially if accompanied by other nephrotoxic events. Angiotensin II receptor(1) blockers (ARB) are thought to have fewer side-effects on renal perfusion and function. We examined the effects of valsartan (VAL) on kidney function as well as the contribution of the nitric oxide (NO) system in a rat model of ischaemic acute renal failure (ARF). METHODS: ARF was induced by 40 min of clamping of both renal arteries in female Sprague-Dawley rats. Renal haemodynamic and tubular parameters were determined during post-ischaemic infusion of vehicle, VAL, VAL and the NO-synthase substrate L-arginine, and VAL together with inhibition of NO synthases (NOS) by L-NMMA. RESULTS: Clamping induced acute renal failure with marked decreases in glomerular filtration rate (GFR) and renal plasma flow (RPF) accompanied by a rise in renal vascular resistance (RVR) and fractional sodium excretion. Valsartan caused a slight but significant improvement of GFR and RPF without full recovery of renal function and caused a lowering of RVR and tubular sodium loss. L-arginine-co-administration had no additive beneficial effect. Valsartan-induced changes were not significantly depressed by unspecific inhibition of NOS. CONCLUSIONS: Inhibition of the angiotensin II-receptor(1) diminishes the deleterious effects of ischaemia and reperfusion on glomerular function and on the renal microcirculation. An involvement of the NO system could not be demonstrated.

Hormonal changes in brain death and immune activation in the donor.

Kidneys obtained from brain dead donors show inferior graft survival compared to living donation. The effects of brain death itself are thought to be partly responsible for these results. We, therefore, examined levels of catecholamines, the vasoconstricting hormones AT II, ET-1 and renin activity, pituitary hormones, and their correlation to pro-inflammatory cytokines and cytokine receptors. In 17 brain dead patients and 19 preoperative neurosurgical patients, these parameters were measured by HPLC, RIA and ELISA. Brain death resulted in massive increases in serum catecholamines, AT II and ET-1, as well as PRA, whereas thyroid and adrenal hormone levels remained unchanged. We found a significant correlation with rises in IL-6 and soluble TNF and IL-2 receptors as markers for the activation of immunological cascades. We concluded that these effects could be directly and indirectly responsible for the impaired organ perfusion and function observed in brain death.

Tacrolimus in acute renal failure: does L-arginine-infusion prevent changes in renal hemodynamics?

Nephrotoxicity is one of the main side effects of calcineurin-inhibitors. The influence of tacrolimus on the renal vasculature has not been well described. We have therefore examined the effects of tacrolimus on renal functional parameters as well as the contribution of the NO-system in a model of ischemic acute renal failure (ARF). Induction of ARF was achieved by clamping both renal arteries of female Sprague-Dawley rats. During the experiment, RBF, GFR, MAP, RVR and FENa were determined during infusion of vehicle, TAC, TAC and the NOS-activator L-arginine, and TAC and NOS-inhibition due to L-NMMA. TAC induced a significant rise in RVR with further decrease of RBF and GFR. Simultaneous L-arginine-infusion could reverse these effects during the infusion without complete restoration to preischemic levels. NOS-inhibition increased MAP and RBF without any effect on GFR. FENa did not differ significantly between the groups. Tacrolimus in the situation of ischemic acute renal failure causes vasoconstriction of pre- and postglomerular vessels with a further deterioration of renal function. L-arginine abolishes the functional deterioration, most likely due to increased NO-liberation.

Endotoxin-induced acute renal failure in the rat: effects of urodilatin and diltiazem on renal function.

Acute renal failure (ARF) due to endotoxins is a common problem in clinical medicine. Endotoxins are released from the outer membrane of the gram-negative bacterial envelope and are composed of lipopolysaccharides (LPS). Although systemic hypotension often is present, LPS-induced ARF is characterized by marked intrarenal vasoconstriction. Both calcium channel blockers and natriuretic peptides are able to antagonize vasoconstricting signals and have been reported to exert beneficial effects in toxic and ischemic ARF: We investigated the effects of diltiazem (Dil, 300 micrograms/kg) or urodilatin (Uro, 40 micrograms/kg) or a combination of both (same doses) on renal function in early LPS-induced ARF: One hour after induction of ARF by i.v. injection of LPS glomerular filtration rate (GFR, clearance of fluorescence-marked inulin) was distinctly reduced to about 54% of basal values. In the following infusion period (60 min) a significant increase of GFR was observed with diltiazem (1.54 +/- 0.11 ml/min), urodilatin (1.60 +/- 0.10 ml/min) and the combination of both drugs (1.66 +/- 0.04 ml/min) compared to controls (1.17 +/- 0.08 ml/min). Combined administration did not cause additive effects. Also 60 and 120 minutes after stopping of drug infusion elevated GFR could be maintained in all experimental groups. Due to their vasorelaxing activity both Uro and Dil induced a decrease of mean arterial blood pressure in comparison with controls and revealed remarkable diuretic and natriuretic activity. In conclusion our results underline that marked intrarenal vasoconstriction in LPS-induced ARF can be antagonized by the well known relaxing potency of Uro and Dil towards vascular smooth muscle and mesangial cells. Both Uro and Dil were capable of improving suppressed renal function in the early phase of LPS-induced ARF in the rat as long as severe systemic hypotension is absent.

Influence of nitric oxide on renal function in toxic acute renal failure in the rat.

Besides other mechanisms, nitric oxide (NO) plays a major role in maintaining the high renal blood flow (RBF) and is also involved in the regulation of glomerular hemodynamics and contractility of mesangial cells. We examined the hypothesis that L-arginine-derived NO exerts beneficial effects in toxic acute renal failure (ARF) in the rat. To induce ARF uranyl nitrate (UN) was given intravenously as a bolus injection (25 mg/kg over 5 min) following a basal period. After the initiation phase of ARF (3 h) saline in the control group (C) and drugs in the experimental groups (I-III, each n = 8) were administered for 60 min. Group I: Arg (= L-arginine, 300 mg/kg), group II: MeArg (= N-methyl-L-arginine, 30 mg/kg), group III: Arg + MeArg (300 mg/kg, 30 mg/kg respectively). The experiments were continued for additional 60 min following the infusion period. Glomerular filtration rate (GFR, inulin clearance) was reduced 3 h after UN to about 50% of normal values in group I-III and control group. After infusion of Arg GFR had significantly improved, but remained unchanged after MeArg in relation to control. One hour after the infusion period these effects were even more pronounced. We conclude that NO exerts beneficial effects on renal function in this animal model of ARF. These results underline the regulatory role of the L-arginine/NO pathway for renal function not only under basal conditions but also in ARF.

Effects of urodilatin and diltiazem on renal function in ischemic acute renal failure in the rat.

In humans as well as in experimental models the hallmark of ischemic acute renal failure (ARF) is a profound diminution in glomerular filtration rate (GFR) and renal blood flow. Both calcium antagonists and a-ANP have been reported to exert beneficial effects in ischemic ARF. No data, however, exist about combined administration of the natriuretic peptide urodilatin and calcium channel blockers. We therefore investigated the effects of urodilatin (URO, 40 micrograms/kg/h, i.v.) and diltiazem (DIL, 300 micrograms/kg/h, i.v.) in the rat given immediately after clamping of both renal arteries for 40 min. Compared to controls (0.07 +/- 0.01) depressed GFR (ml/min/100 g) was clearly elevated with URO (0.16 +/- 0.03), DIL (0.13 +/- 0.03) and URO + DIL (0.14 +/- 0.02) after the ischemic lesion. After cessation of drug delivery the beneficial effects were blunted in the URO group, in contrast to the DIL and URO + DIL group, where GFR was significantly elevated compared to controls even 3 h after starting reperfusion. Besides that also urine flow, sodium excretion and blood pressure were examined. In conclusion both URO and DIL exert beneficial effects in ischemic ARF in the rat while infused. In contrast to URO DIL showed prolonged beneficial effects even after cessation of drug delivery. An additional effect of both drugs could not be observed.

Toxic acute renal failure in the rat: effects of diltiazem and urodilatin on renal function.

Beneficial effects of natriuretic peptides have been reported in different models of acute renal failure (ARF). Calcium antagonists can also improve renal function, especially in ischemic models of ARF. The aim of our study was to investigate the effects of urodilatin and diltiazem alone and in combination in uranyl nitrate-induced toxic ARF in the rat. Three hours after induction of ARF glomerular filtration rate (GFR) was clearly diminished to about 50% compared to basal values. Intravenous infusion of diltiazem and urodilatin revealed a significant increase of GFR that even continued after cessation of drug delivery. Combined administration of urodilatin and diltiazem had no additional effect, probably due to a more pronounced fall in blood pressure in this group. Besides their vasorelaxing and blood pressure lowering effects both drugs also revealed diuretic activity. In conclusion both urodilatin and diltiazem are able to elevate GFR in the early phase of toxic ARF in the rat.

Toxic acute renal failure in the rat: effects of L-arginine and N-methyl-L-arginine on renal function.

Nitric oxide (NO) is generated from L-arginine (Arg) by different isoforms of nitric oxide synthase (NOS) and plays a major role in maintaining the high basal renal blood flow. NO also is involved in the regulation of glomerular haemodynamics and contractility of mesangial cells. We examined the hypothesis that L-arginine-derived NO modifies toxic ARF in the rat. After a basal period uranyl nitrate (UN) was given intravenously as a bolus injection (25 mg/kg over 5 min) to induce ARF. After the initiation phase of ARF (3 h) saline in the control group (C) and drugs in the experimental groups (I-III, each n = 8) were administered for 60 min. Group I, Arg (300 mg/kg); group II, MeArg (30 mg/kg); group III, Arg + MeArg (300 mg/kg, 30 mg/kg resp.). The experiments were continued for further 60 min following the infusion period. Glomerular filtration rate (GFR, inulin clearance) was reduced 3 h after UN to about 50% of normal values in groups I-III and control group (I, 0.52 +/- 0.06; II, 0.51 +/- 0.05; III, 0.49 +/- 0.05; C, 0.50 +/- 0.07 ml/min). After infusion of Arg GFR had significantly improved (0.64 +/- 0.07), but further declined after MeArg (0.46 +/- 0.06) in relation to control (0.47 +/- 0.07). This negative effect could be overcome by combined administration of Arg + MeArg (0.59 +/- 0.07). One hour after the infusion period these effects were even more pronounced (Arg, 0.71 +/- 0.06; MeArg, 0.43 +/- 0.05; Arg + MeArg, 0.65 +/- 0.07; C, 0.46 +/- 0.05). We conclude that the L-arginine/NO pathway is involved in toxic ARF of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)