Felix P. Brunner

Five-Year Survival for End-Stage Renal Disease Patients in the United States, Europe, and Japan, 1982 to 1987

We compared the 5-year survival for new end-stage renal disease (ESRD) patients accepted for renal replacement therapy (RRT) between 1982 and 1987 in the United States (n = 150,862), Europe (European Dialysis and Transplant Association [EDTA]) (n = 124,796), and Japan (n = 66,244). Given these large samples that approach a census in each of the three regions, all results are statistically significant. Our analysis showed that the US patients were older and more likely to be diabetic than the patients in either EDTA or Japan. After correction for patient differences in age composition and the percent diabetic, Japan had the highest survival, followed by EDTA, and then the US. Overall, the US 5-year survival was 40%. When comparison is done by age, only the youngest patients in the US (less than 15 years) have longer survival than their counterparts in Europe and Japan. For ages greater than 14 years, the survival differences between the US and EDTA and between the US and Japan grow larger with higher patient age. The comparisons of mortality by diagnosis showed that the differences between the US and EDTA and between the US and Japan were least for diabetes. For non-diabetic patients, the age adjusted relative risk (RR) of mortality for the US compared with EDTA was 1.22, ie, 22% higher in the US; for the US compared with Japan, the RR was 1.40. In contrast, the RR for diabetic patients in the US compared with EDTA was 1.07, and 1.23 for the US compared with Japan.(ABSTRACT TRUNCATED AT 250 WORDS)

A New Cause of Renal Thrombotic Microangiopathy: Yttrium 90-DOTATOC Internal Radiotherapy

The chelator somatostatin analogue dota-D-phe(1)-tyr(3)-octreotide (DOTATOC), which is stably labeled with the beta-emitting radioisotope yttrium 90 ((90)Y), is used as internal radiotherapy for the treatment of patients with advanced neuroendocrine tumors. We report 5 patients who developed chronic renal failure, caused in 3 patients by biopsy-proven thrombotic microangiopathy (TMA). Twenty-nine patients (14 men, 15 women) with normal renal function before therapy were treated with divided intravenous doses of (90)Y-DOTATOC approximately 6 weeks apart (mean normalized cumulative dose, 165.4 +/- 36.4 mCi/m(2)). Twenty-two of 29 patients were administered a normalized cumulative dose of 200 mCi/m(2) without side effects. Among the 7 patients (6 women, 1 man) administered a normalized cumulative dose greater than 200 mCi/m(2), 5 patients (4 women, 1 man) developed renal failure. Increasing serum creatinine levels were observed within 3 months after the last (90)Y-DOTATOC injection. The evolution was rapidly progressive in 3 patients, resulting in end-stage renal failure within 6 months. The remaining 2 patients developed chronic renal insufficiency (mean serum creatinine level, 300 micromol/L an average 16 months after the end of treatment). Renal biopsies performed in 3 patients showed typical signs of TMA involving glomeruli, arterioles, and small arteries. Patients treated with high-dose (90)Y-DOTATOC internal radiotherapy (cumulative dose > 200 mCi/m(2)) are at high risk to develop severe renal failure caused by TMA lesions. The histopathologic lesions are identical to those found after external radiotherapy, which suggests a causal relationship between (90)Y-DOTATOC and renal TMA.

Intravenous cyclosporine kinetics in renal failure

Kinetics of the novel immunosuppressive cyclosporine were determined in four patients with terminal renal failure. After a short intravenous infusion (2.05 to 3.5 mg/kg in 4 hr), blood and plasma concentrations were measured (HPLC and radioimmunoassay [RIA]) up to 36 hr. After infusion, concentration curves of the drug were characterized by a rapid initial fall (t½α 0.10 ± 0.03 hr), followed by a biphasic elimination phase with corresponding t½s of 1.08 ± 0.25 hr (t½β) and 15.8 ± 8.4 hr (t½γ). The volumes of distribution, calculated from whole blood concentrations (HPLC), were 0.140 ± 0.48 l/kg (volume of the central compartment) and 3.49 ± 2.65 l/kg (volume of distribution at steady state), whereas systemic clearances were 0.369 ± 0.08 l/hr/kg. Blood levels measured by RIA exceeded the HPLC values after the fourth hour by up to 100%, indicating the production of cross‐reacting cyclosporine metabolites. Plasma concentrations were considerably lower than in whole blood. Elimination of unchanged cyclosporine in patients with renal failure appears to be of the same order as in those with normal kidney function. Modification of the initial dosage regimens is therefore probably not required.

Karyomegalic interstitial nephritis: Further support for a distinct entity and evidence for a genetic defect

Karyomegalic interstitial nephritis was first described in 1979 by Mihatsch, who was reporting three such cases. We report here four additional cases as well as two family investigations. Our findings support the association of karyomegaly and interstitial nephritis as a distinct entity. Typical clinical features are asymptomatic progressive renal failure in the third decade of life and recurrent infections, mostly of the upper respiratory tract. Histologic alterations consist of markedly enlarged and hyperchromic nuclei in many tubular epithelial cells throughout the nephron accompanied by interstitial fibrosis in the surrounding atrophic tubules. Karyomegaly is not limited to the kidneys. In one case, autopsy revealed karyomegaly in epithelial and mesenchymal cells of many other organs. However, no association of karyomegaly with further histologic damage is evident except in the kidneys. Because of the familial clustering, karyomegalic interstitial nephritis seems to be an inherited disease. Examination of the nuclear proliferation-associated structures proliferating cell nuclear antigen/cyclin, Ki 67, and p53 suggests an inhibition of mitosis in karyomegalic cells. The finding of the same HLA haplotype, A9/B35, in four of six HLA-typed cases suggests the possibility of a genetic defect on chromosome 6, which is inherited and linked to the HLA locus.

Gentamicin-Induced Acute Renal Failure in the Rat

Acute renal failure was induced in rats by subcutaneous injection of 200 mg/kg body weight gentamicin on 3 consecutive days. Following the last gentamicin injection, the animals began to produce increased amounts of dilute urine and usually remained polyuric throughout the experimental period which lasted up to 2 weeks. Plasma concentrations of creatinine rose to values between 2 and 10 mg%, of urea to values between 100 and 1,000 mg% 5-7 days after the last gentamicin injection and returned to levels slightly above control after 14 days. Average proximal tubular pressure was slightly elevated to 13.7 +/- 0.5 mm Hg on the 2nd day after the last gentamicin dose, decreased to 6.1 +/- 0.4 mm Hg after 1 week, and returned to 11.8 +/- 0.2 mm Hg after 2 weeks (control proximal tubular pressure 11.6 +/- 0.2 mm Hg). These average values hide the fact that early in this model of gentamicin-induced acute renal failure many tubules had proximal tubular pressures increased to values between 18 and 25 mm Hg, suggesting tubular obstruction. Decreased proximal tubular pressures and the histological finding of wide-spread necrosis of proximal convolutions is suggestive of tubular leakage. Dehydration, similarly to other models of acute renal failure, markedly potentiated gentamicin-induced acute renal failure. Salt diuresis induced either by DOCA-saline or by furosemide failed to afford functional protection and increased the degree of morphological damage. No relation was found between the concentration of gentamicin in renal tissue and the degree of functional or morphological impairment.

Superficial Nephron Obstruction and Medullary Congestion after Ischemic Injury: Effect of Protective Treatments

90 min of renal artery occlusion in previously unilaterally nephrectomized rats produce acute renal failure (ARF) (plasma creatinine at 48 h after ischemia: 636 +/- 44 vs. 133 +/- 9 mumol/l in controls). Between 1 and 48 h after releasing the occlusion, two populations of superficial nephrons could be observed, one with dilated tubules and elevated proximal tubular pressures (PTP: 39 +/- 1 vs. 12 +/- 1 mm Hg in controls) and the other with collapsed tubules and decreased PTP (9 +/- 1 mm Hg). Proximal tubular passage time (PPT) could not be determined with the Lissamine green technique. Seven methods of pretreatment were tested, 5 of which provided partial functional protection (DOCA/NaCl/NaCl, furosemide infusion, inosine bolus, mannitol bolus and the combination of the last two). Neither renal renin levels nor urinary NaCl excretion were consistently correlated with protection. Functionally protected rats consistently showed no PTP increase and normal PPT in the tubules at the kidney surface. However, plasma creatinine at 48 h differed markedly within the 5 protected groups, ranging from 168 +/- 18 to 398 +/- 35 mumol/l. Extensive medullary congestion was seen at 1-6 h after ischemia only in those rats with obstructed, high pressure nephrons at the kidney surface. To conclude: (1) Functional protection from ischemic ARF, both with and without an accompanying increase in solute excretion, was achieved by the abolition of tubular obstruction. (2) Despite similar degrees of restoration of superficial nephron function, the persisting impairment of whole kidney function differed markedly between the protected groups. (3) Impairment of deeper nephron function must therefore play a major role, perhaps through persisting obstruction in the long loops of Henle. (4) High pressure nephrons may compromise medullary venous outflow in the outer zone of the outer medulla.

Cyclosporin a used alone or in combination with low-dose steroids in cadaveric renal transplantation

SummaryThe actual survival rate of 25 primary cadaveric kidney grafts in recipients treated initially with cyclosporin A (CyA) alone was 84%. The survival rate in 37 patients under conventional immunosuppression was 76%. The mean number of dialyses required in the first 4 weeks after transplantation was 1.2 per patient in both groups. At 15–28 months posttransplant, mean serum creatinine levels have remained stable at 175 µmol/l in the CyA group.The mean daily dose of steroids (including methylprednisolone i.v.) in the first two months was 2.07 mg/kg/d in patients under conventional immunosuppression and 0.76 mg/kg/d in the patients receiving CyA (p<0.001).The combination of CyA with low-dose steroids enabled the dose of CyA to be rapidly tapered off in once-weekly steps. CyA levels were monitored by determination of whole blood trough concentrations (target level: 300–800 ng/ml). At 60 days posttransplant the average dose of CyA was 6.0±0.5 mg/kg/d compared with an average daily dose of 11.4±0.9 as recommended for CyA alone in the protocol for the European multicentre study. This more rapid reduction in the CyA dose reduced nephrotoxicity (serum creatinine levels 174±14 as compared with 289±31 µmol/l) (p<0.05) and almost halved the number of methylprednisolone pulses given up to the end of the second month.We conclude from these results (1) that previously the dosage of CyA administered at this centre was probably too high, and (2) early adjustment of dose levels on the basis of blood concentrations and with low-dose prednisone cover appears to be safe and effective, but requires further verification.

Morphology of the renal medulla in ischemic acute renal failure in the rat.

In the initial phase of ischemic acute renal failure in the rat the outer medulla is characterized by widening of peritubular capillaries in the inner stripe and by accumulation of cytoplasmic blebs in dilated proximal straight tubules in the outer stripe. Both findings contribute to tubular obstruction. In the maintenance phase, outer and inner stripes show tubular necrosis mainly of proximal straight tubules and thick ascending loops of Henle. In both phases the papilla is apparently spared from damage. Protective measures act at least partly by prevention of peritubular capillary widening in the inner stripe of outer medulla.

Modular synthesis of simple cycloruthenated complexes with state-of-the-art performance in p-type DSCs

A modular approach based on Suzuki–Miyaura cross coupling and Miyaura borylation has been used to prepare two cyclometallated [Ru(N⁁N)2(C⁁N)]+ complexes which possess either a carboxylic or phosphonic acid group attached via a phenylene spacer to the 4-position of the pyridine ring in the C⁁N ligand. The key intermediate in the synthetic pathway is [Ru(bpy)2(1)]+ where bpy = 2,2′-bipyridine and H1 is 4-chloro-2-phenylpyridine. The crystal structure of [Ru(bpy)2(1)][PF6] is presented. Reaction of [Ru(bpy)2(1)][PF6] with 4-carboxyphenylboronic acid leads to [Ru(bpy)2(H6)][PF6], while the phosphonic acid analogue is isolated as the zwitterion [Ru(bpy)2(H5)]. The cyclometallated complexes have been characterized by mass spectrometry, multinuclear NMR spectroscopy, absorption spectroscopy and electrochemistry. [Ru(bpy)2(5)] adsorbs onto NiO FTO/NiO electrodes (confirmed by solid-state absorption spectroscopy) and its performance in p-type dye-sensitized solar cells (DSCs) has been compared to that of the standard dye P1; two-screen printed layers of NiO give better DSC performances than one layer. Duplicate DSCs containing [Ru(bpy)2(H5)] achieve short-circuit current densities (JSC) of 3.38 and 3.34 mA cm−2 and photoconversion efficiencies (η) of 0.116 and 0.109%, respectively, compared to values of JSC = 1.84 and 1.96 mA cm−2 and η = 0.057 and 0.051% for P1. Despite its simple dye structure, the performance of [Ru(bpy)2(H5)] parallels the best-performing cyclometallated ruthenium(II) dye in p-type DSCs reported previously (He et al., J. Phys. Chem. C, 2014, 118, 16518) and confirms the effectiveness of a phosphonic acid anchor in the dye and the attachment of the anchoring unit to the pyridine (rather than phenyl) ring of the cyclometallating ligand.

The angiotensin converting enzyme inhibitor enalapril in acute ischemic renal failure in rats

The influence of the renin-angiotensin system on renal hemodynamics, tubular pressure and tubulo-glomerular feedback was investigated with the angiotensin converting enzyme inhibitor MK 421 (enalapril), in uninephrectomized rats with and without ischemia-induced acute renal failure. In animals with normal renal function proximal tubular pressure and tubulo-glomerular feedback response were lowered by enalapril long-term treatment, whereas glomerular filtration rate and renal blood flow were not influenced by the drug. After 45 and 70 minutes ischemia there was no difference between treated and untreated animals in the severely impaired glomerular filtration rate. Renal blood flow remained unaffected by the treatment. The histological damage due to ischemia (tubular casts, tubular necrosis and medullary capillary congestion) was not influenced by enalapril. As tubulo-glomerular feedback had been significantly inhibited during renin-angiotensin inhibition, its importance in mediating acute renal failure remains doubtful; other factors such as tubular obstruction and medullary congestion may be crucial.