Letter to the Editor re: Are intravenous injections of contrast media really less nephrotoxic than intra-arterial injections?

UNLABELLED: In a recent paper, the authors oppose the opinion that " intra-arterial administration of iodinated-based contrast media (CM) appears to pose a greater risk of contrast-induced nephropathy (CIN) than intravenous administration" . As nephrologists, we are happy to have the opportunity to offer our expertise in the setting of renal disease aimed at optimizing diagnostic algorithm and preventive strategies. Our comment relies on the fact that, from a nephrologist's point of view, there is no doubt that renal damage following CM intra-venous administration in patients not in intensive care or emergency department and treated with conventional preventive strategies not only occurs with low frequency, but also appears of negligible clinical impact; it is confined to an asymptomatic increase of serum creatinine of 25% or 0.5 mg/dL lacking any prognostic negative impact, and in some case not significantly different from controls.True CIN, just related to intravenous CM injection for diagnostic purpose, has to be differentiated from all the other cause of renal involvement in people stricken with sudden and acute illness also receiving intra-arterial CM injection, in order to avoid patients being denied necessary radiological examinations due to an inappropriate fear of risk. KEY POINTS: • Contrast induced nephropathy (CIN) is not any nephropathy following contrast medium(CM). • CIN should only refer to renal damage strictly due to CM infusion. • True CIN following CM intravenous infusion is a clinically insignificant event. • Renal damage following intra-arterial CM infusion in compromised patients is not CIN. • Patients should not forego necessary radiological examinations for inappropriate understanding about risk.

[The Early Years of Nephrology at Molinette Hospital in Turin Told by Those Who Lived and Built Them].

This article, written by several authors, describes the birth and early development of the nephrology at Molinette Hospital in Torino, Italy. In particular, it supplies important information on Antonio Vercellone, very motivated and innovative clinician and one of the fathers of Italian nephrology, and on Giuseppe Piccoli, his right-hand man and then his successor. This article also shows the strong professional and human engagement that was requested to the young doctors who, in the early Sixties and Seventies of the past century, had chosen to devote their professional lives to the patients with kidney diseases: from endless workdays without schedules to the anguish caused by the shortage of artificial kidneys to the cure of very fragile and unfortunate patients, and much more.

Decreased kidney function and crystal deposition in the tubules after kidney transplant.

Adenine phosphoribosyltransferase (APRT) deficiency is an autosomal recessive purine enzyme defect that results in the inability to utilize adenine, which consequently is oxidized by xanthine dehydrogenase to 2,8-dihydroxyadenine (2,8-DHA), an extremely insoluble substance eventually leading to crystalluria, nephrolithiasis, and kidney injury. We describe a case of APRT deficiency not diagnosed until the evaluation of a poorly functioning kidney transplant in a 67-year-old white woman. After the transplant, there was delayed transplant function, urine specimens showed crystals with unusual appearance, and the transplant biopsy specimen showed intratubular obstruction by crystals identified as 2,8-DHA using infrared spectroscopy. APRT enzymatic activity was undetectable in red blood cell lysates, and analysis of the APRT gene showed 1 heterozygous sequence variant, a duplication of T at position 1832. The patient was treated with allopurinol, 300 mg/d, and transplant function progressively normalized. Because patients with undiagnosed APRT deficiency who undergo kidney transplant may risk losing the transplant because of an otherwise treatable disease, increased physician awareness may hasten the diagnosis and limit the morbidity associated with this disease.

Gadolinium-enhanced magnetic resonance imaging, renal failure and nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy.

First described in 2000, nephrogenic systemic fibrosis (NSF)/nephrogenic fibrosing dermopathy (NFD) is a recently defined and sometimes fatal condition that, so far, has occurred only in people with some degree of renal failure, either during the conservative phase of chronic renal disease, the dialysis phase, or the kidney transplantation phase. The association between NSF/NFD and gadolinium-based magnetic resonance (MR) examination is so strong that public health agencies have sent out warnings concerning the use of gadolinium-enhanced MR in patients with renal failure. The prolonged residence of some gadolinium-chelates in the uremic milieu may allow free toxic gadolinium released from its chelate to extravasate into the extravascular space where it may accelerate fibrillogenesis. The medical community must be apprised of the concern surrounding the use of gadolinium contrast agent in patients with even moderate renal failure, considering that the number of at risk persons is 20 times greater than that of patients needing dialysis/transplantation, remember that the risk is particularly high in patients with liver transplantation in the presence of functional renal impairment, and not to forget that MR examination remains one of the three pillars of molecular medicine.

Gadolinium-associated nephrogenic systemic fibrosis: the need for nephrologists' awareness.

Nephrogenic systemic fibrosis (NSF) / nephrogenic fibrosing dermopathy (NFD) is a recently described disease, occurring only in patients with variable degrees of renal failure (RF) previously exposed to gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging. Public advisories are consistent on some key points including that no cases of NSF/NFD have been reported in patients with normal renal function, and GBCAs may be toxic in patients with RF due to the prolongation of the half-time allowing dissociation and extravasation of highly toxic gadolinium-free ions, potentially linked to the scleroderma-like NSF/NFD, a systemic disabling disease with a mortality rate of up to 30%. The most intriguing feature remains which cofactor might be at play to explain why the disease occurs only in a minority of exposed patients. Therefore, renal dysfunction (substrate) and gadolinium chelates (trigger agent) are necessary but not sufficient. The challenge for nephrologists includes (a) evidence of transmetallation, such as gadolinium deposits in bone, increased urinary zinc excretion, iron-transferrin dissociation or "spurious hypocalcemia" in exposed people; (b) research for uremic cofactors such as increased serum calcium/phosphate, acidosis, use of phosphate-chelating agents able to act as efficient competitor ligands or other drugs; and (c) identification of at-risk patients (with moderate to severe renal dysfunction) and definition of the role of dialysis in removing gadolinium chelates, if any. Nephrologists are called to action to collect and organize information to identify cofactors for NSF/NFD, and therefore they must be aware of this new pathology, as the eye sees only what the mind knows.

Rubidium, salami and depression. You cannot have everything in life.

BACKGROUND: Depression may induce malnutrition, but, as a paradoxical hypothesis, malnutrition may induce depression. This relationship, of course, depends on how we define malnutrition. CURRENT KNOWLEDGE: Rubidium is a trace element strongly linked with depression, and is deficient in uremia sufferers. However, in uremic patients, rubidium deficiency is more evident during predialysis, as it is at least partially corrected during dialysis and after transplantation. It seems that diet restrictions might be the main cause of rubidium deficiency, as it is mainly found in red meat. CONCLUSION: If rubidium is found in salami, then the occasional slice could be more beneficial for people suffering from depression than taking a lot of medication.

Ciprofloxacin crystal nephropathy.

Ciprofloxacin is a widely used fluoroquinolone for the treatment of patients with complicated and uncomplicated infections. With rare exceptions, only immune-mediated interstitial nephritis was described, with direct renal damage reported only in case of overdose. Experimental studies indicated that crystalluria may be associated with the administration of this drug, but the likelihood that ciprofloxacin crystal nephropathy would occur in humans was believed to be very low on the basis of previous data showing that ciprofloxacin crystalluria depended on a urine pH greater than 6.8. However, we report 2 cases of ciprofloxacin crystal-induced nephropathy with a clinical pattern of acute reversible tubular damage and intratubular crystals identical to that previously described in elderly patients treated with ciprofloxacin dosages within therapeutic schedules. Crystals in the tubules were negative for both the von Kossa stain for phosphates and alizarin red stain for calcium.

Pregnancy in patients with kidney disease.

QUESTIONS: - To what extent can ailing kidneys adapt their functions to the demands of pregnancy? - What risks is the nephropathic patient prone to throughout pregnancy compared with those of the general population, and which specific risks does her kidney disease determine? - What risks is the baby of a nephropathic prone to throughout pregnancy compared with those of the general population? - What changes have occurred over recent years? CONCLUSIONS: Current knowledge allows to conclude that pregnancy in the nephropathic woman can be started, provided that: - best timing is considered; - women are informed about their risk factors: functional levels and presence of hypertension, regardless of type of nephropathy.

Guidelines audit may overcome disparities in health care: experience of an Italian region.

BACKGROUND: A clinical audit is used to verify the application of evidence-based clinical guidelines. Our regional section of the Italian Society of Nephrology was the first to establish a region-based program of clinical audits of compliance with guidelines for treating osteodystrophy and anemia of patients on chronic dialysis. This study summarizes the main results of the 2 audits of the Piemonte region. METHODS: Structured questionnaires were sent twice to all of the 22 dialysis centers of Piemonte and to the Center of Valle D'Aosta for an Audit on Osteodystrophy (in 2000 and 2004) and for the Audit on Anemia (2003). The questionnaires were meant to evaluate the clinical schedule of treatment relative to calcium-phosphate balance and anemia in dialysis patients. RESULTS: All centers responded, showing low levels of agreement with the targets of Italian guidelines. In sum, in 2000 only 27% of centers had more than 70% of patients with serum phosphate <5.5 mg/dL, but that rate had increased to 33% in 2004. Only 35% (in 2000) and 40% (in 2004) of the centers had more than 90% of patients with Kt/V >1.2. The Audit on Anemia showed a median of 42% of patients with hemoglobin between 11 and 12 g/dL, and only 2 centers had more than 70% of patients above this target. CONCLUSIONS: The first result of our pioneering experience was that we found that compliance with minimal levels of care was still inadequate, with regard to hyperphosphatemia, dialysis adequacy and anemia. Nevertheless, the 2nd Audit on Osteodystrophy showed a relative improvement in the results. But, most importantly, this open regional report has encouraged comparisons, and motivated centers to adopt a strategy of understanding, addressing and correcting inadequate levels of care, and furthermore increased satisfaction with the care being offered.

Blast from the past: the aluminum's ghost on the lanthanum salts.

Hyperphosphatemia is a common serious complication of chronic renal diseases, which needs appropriate continuous treatment in order to avoid ominous side effects. Therefore, oral chelating agents able to avoid phosphate absorption by the gut are mandatory. In the past, Aluminium salts, and more recently Calcium and Magnesium salts, and a synthetic resin polyallylamine hydrochloride have been employed, but Aluminium was later abandoned, because it has been a silent killer of many uremic patients, due to subtle absorption eventually leading to toxicity on Central Nervous System and bone, with allucinations, seizures, dementia, and osteomalacia, bone pain, fracturing osteodystrophy, and death. Recently, a new chelating agent able to bind dietary phosphate, namely Lanthanum carbonate has been introduced, with a proven efficacy profile for short-term treatment. However, after careful examination of the very few scientific papers available to date, we strongly advise caution before adopting, at present, lanthanum carbonate as a phosphate binder in uremic patients. In fact, notwithstanding minimized, some data are worrying: first, Lanthanum ions are absorbed, though at a minimal extent, by human gut; 2) pharmacokinetic evaluations show a greater exposure to Lanthanum in uremic patients;3) Lanthanum concentration is increased tenfold in blood and fivefold in bone after short-term supplementation in uremic patients; 4) there is no proofs that Lanthanum cannot cross the blood brain barrier in uremic patients; 5)Lanthanum has many biological effects and is potentially highly toxic. The Aluminum story should serve as cautionary tale when considering the use of new metal ions.

Long-term, low-dose, intravenous vitamin C leads to plasma calcium oxalate supersaturation in hemodialysis patients.

BACKGROUND: Ascorbate supplementation for patients on regular dialysis treatment (RDT) is advised to obviate deficiency and improve epoetin response in those with functional iron deficiency. However, clear-cut safety concerns regarding hyperoxalemia are still poorly understood. This study tries to establish safety/efficacy profiles of ascorbate and oxalate during long-term intravenous ascorbate supplementation. METHODS: A prospective study was performed in 30 patients on RDT showing ascorbate deficiency (plasma ascorbate < 2.6 mg/L [<15 micromol/L]): 18 patients were administered intravenous ascorbate during 18 months (250 mg/wk, subsequently increased to 500 mg), and 12 patients were taken as reference untreated cases. Plasma ascorbate and oxalate assays and dialytic balance determinations were performed (ion chromatography and reverse-phase high-performance liquid chromatography, respectively) at baseline, during treatment, and 12 months after withdrawal. RESULTS: Plasma ascorbate levels increased dose dependently with supplementation (1.6 +/- 0.8 mg/L [9.1 +/- 4.6 mumol/L] at baseline, 2.8 +/- 1.8 mg/L [15.9 +/- 10.1 micromol/L]) with 250 mg of ascorbate, and 6.6 +/- 2.8 mg/L [37.5 +/- 16.0 micromol/L] with 500 mg/wk of ascorbate), but only normalized with greater dosages for several months in 94% of patients. Baseline plasma oxalate levels increased from 3.2 +/- 0.8 mg/L (35.8 +/- 8.8 micromol/L) to 3.6 +/- 0.8 mg/L (39.5 +/- 9.1 micromol/L) and 4.5 +/- 0.9 mg/L (50.3 +/- 10.4 micromol/L) with 250 and 500 mg, respectively ( P < 0.001). The calcium oxalate saturation threshold was exceeded by 7 of 18 patients (40%) during 6 months therapy with 500 mg/wk. Ascorbate dialysis removal increased from 37.8 +/- 23.2 mg (215 +/- 132 micromol) to 99.6 +/- 51.7 mg (566 +/- 294 micromol) during supplementation (P < 0.001), with corresponding increases in oxalate removal from 82.5 +/- 33.2 mg (917 +/- 369 micromol) to 111.2 +/- 32.6 mg/L (1,236 +/- 362 micromol; P < 0.01). Withdrawal reverted plasma levels and dialysis removal to initial values. Values for untreated patients did not change during 1 year of follow-up. CONCLUSION: Patients on RDT may resolve ascorbate deficiency with intravenous supplementation of 500 mg/wk, but this implies a significant risk for oxalate supersaturation. Oxalate measurements are strongly recommended during long-term ascorbate therapy.

Pregnancy in kidney transplantation: satisfactory outcomes and harsh realities.

Since the first successful case of a pregnancy reported 40 yrs ago in a woman receiving a kidney transplant from her identical twin sister who did not receive immunosuppressive medications, the dream of a pregnancy in a renal transplant recipient has become reality. In women of childbearing age with a functioning transplant, the pregnancy rate has improved from 2 to 5%. Approximately 35% of pregnancies do not progress beyond the 1st trimester; the success rate is > 90% after the 1st trimester. In this review, different aspects of this topic are discussed: the consequences of pregnancy on renal grafts and maternal morbidity (hemodynamic changes, immunological problems, hypertension/preeclampsia, urinary tract infections and renal damage progression), the influence of renal grafts on pregnancy (perinatal mortality, prematurity, intrauterine growth retardation, low birth weight, malformations, handicaps and immunological problems) and the role of drugs used for renal transplants. A pregnancy can have a successful outcome if pre-conceptional graft function is good, if hypertension is absent and if the interval from grafting is at least 2 yrs. However, the majority of live-born outcomes are premature and many are low birth weight. Recipients must be advised that their offspring can also suffer from immunological abnormalities, malformations, long-term handicaps, and that the deleterious effects of pregnancy on long-term graft function cannot be excluded. In conclusion, women of childbearing age who have had renal transplantation should be counselled before conception about possibility and risks of pregnancy.

IgM antibodies against cytomegalovirus in SLE nephritis: viral infection or aspecific autoantibody?

Despite many studies on the subject, the causal relationships between viruses and presentation/exacerbation of autoimmune diseases are still elusive. The possibility of false positive IgM antibody tests for human cytomegalovirus (CMV) in patients with systemic lupus erythematosus (SLE) has been pointed out. Here we report a case of a patient who developed lupus nephritis, with biochemical and clinical markers of CMV infection with intestinal involvement. At first, the antibodies to CMV were regarded as spurious aspecific signs of autoimmune disease. The patient had had serious flare-ups of the disease, hemolytic-uremic syndrome with thrombotic microangiopathy superimposed on SLE nephritis, and life-threatening infections for three years until CMV infection was confirmed by the persistence of anti-CMV IgM-antibodies coupled with positive results of tests for viral replication. After therapy with ganciclovir, his clinical and biochemical condition improved and remained stable for three years, with only very low maintenance steroid coupled with hydroxychloroquine. IgM anti-CMV were no longer detectable in spite of the persistence of other autoantibodies such as anti-DNA and ANA. Keeping in mind that CMV-IgM has been reported in only 5% of patients with SLE nephritis, the history of our patient indicates that CMV infection must be carefully excluded before IgM antibodies against CMV can be simply classified as an aspecific sign of cross-reacting autoantibodies formed in SLE patients.

Recognizing purple bag syndrome at first look.

Purple urine bag syndrome is a clinical entity first described in 1978. Its typical discoloration is worrying for clinicians. In the past, these patients sometimes reached the emergency unit only because of this exceptional worrying urinary sign and underwent invasive diagnostic examinations including cystoscopy, without any abnormal finding. It is now clear that this astonishing phenomenon of double discoloration of the urine, appearing purple in the bag and dark blue in the test tube, results from the formation of 2 different pigments (indirubin and indigo) in very alkaline urines due to enzymes produced by gram-negative bacteria, such as indoxyl phosphatase/sulfatase, which can convert urinary metabolites of dietary tryptophan. Practicing physicians should identify purple urine bag syndrome as a usually benign medical condition diagnosed in asymptomatic patients, which only requires treatment of bacteriuria with antibiotics, prevention of constipation, substitution of catheter and acidification of the urine. After these measures, urine typically returns to its normal color.