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Background and Aims Sepsis is the main contributor to the development of acute kidney injury (AKI) in critically ill patients. Plasma soluble urokinase plasminogen activator receptor (suPAR) is a circulating risk factor for AKI and a new prognostic marker for renal outcome prediction. We analyzed the pathophysiological role and kinetic properties of suPAR in septic AKI in critically ill patients and in a murine model of septic AKI. Method 200 critically ill patients were enrolled prospectively after meeting Sepsis-3 criteria. Serum suPAR levels were measured at 0, 12, 24, 48, 72, 96, 120 and 168-hour after enrollment (n=1440) and the need for RRT within 7 days (predefined criteria) was assessed as the primary outcome measure. Polybacterial sepsis was induced by cecal slurry injection in three mouse strains, respectively wild type (WT, N=16), uPAR-knockout (KO, N=15), and suPAR transgenic overexpression (OE, N=14). Results No or mild AKI occurred in 62 patients (31.0%), moderate or severe AKI without the need for RRT in 102 patients (51.0%), criteria for RRT were met in 36 patients (18.0%) and 7 patients (3.5%) died within the 7-day period. Compared to all other maximum AKI stages and AKI disease courses within 7 days, patients requiring RRT showed significantly higher suPAR levels at all time-points. Patients with suPAR levels ≥ 12.7 ng/mL (highest quartile) had an unadjusted odds ratio (OR) of 9.73 (95% confidence interval [CI], 4.31-21.98) and an adjusted odds ratio of 5.22 (95% CI, 2.16-12.65) for the need for RRT; and 7.47 (95% CI, 3.54-15.74) and 4.44 (95% CI, 1.98-9.97) for RRT or death within 7 days compared to patients with levels < 12.7 ng/mL. Compared to KO mice, WT and OE mice showed a significantly greater impairment of renal function, structure and tubular apoptosis 24 hours after induction of sepsis. The inflammation levels with respect to Interleukin 6 were comparable between different strains. Kaplan-Meier analysis revealed a survival benefit of KO mice over OE mice within 24h (86.7% vs. 50.0%, p=0.033). Conclusion SuPAR distinguishes between divergent AKI stages/courses and the need for RRT at any time within 7 days after sepsis diagnosis. Our experimental data suggest that suPAR is a pathophysiological driver of septic AKI and may serve as a target for future interventional strategies.

Background and Aims An imbalance between CD4+-regulatory T-cells (Tregs) and CD4+-responder T-cells (Tresps) correlates with active disease flares in Systemic Lupus Erythematosus (SLE) patients. Both cell subsets consist of highly proliferative inducible T-cell co-stimulatory molecule expressing (ICOS+-) and less proliferating ICOS--Treg/Tresp cells. Method In this study we aimed to examine the role of age-dependent differentiation for maintaining the ICOS+-Treg/ICOS+-Tresp or ICOS--Treg/ICOS--Tresp balance in SLE remission patients compared to active disease patients and to evaluate the influence of proliferation inhibitor or glucocorticoid therapy concerning the maintenance of these equilibria. Results In 83 healthy volunteers, the ratio of ICOS+-Tregs/ICOS+-Tresps increased significantly with age, while that of ICOS--Tregs/ICOS--Tresps did not change. In 86 SLE remission patients, medication controlled disease activity was associated with an age-independently increased ratio of both ICOS+-Tregs/ICOS+-Tresps and ICOS--Tregs/ICOS--Tresps. In 13 active disease patients this increased ICOS+-Treg/ICOS+-Tresp ratio could not be maintained, due to an age-dependent earlier terminal differentiation of ICOS+-Tregs than of ICOS+-Tresps. The increased ratio of ICOS--Treg/ICOS--Tresp was maintained in active disease patients, but it decreased with age. This was attributable to an age-independent aberrant differentiation of ICOS--Tresps and a resulting loss of age-dependent differentiation of ICOS--Tregs. Especially the administration of proliferation inhibitors (azathioprine or mycophenolic acid) ensured prolonged differentiation and maintenance of functional ICOS+-Tregs with age. There was a similar but weaker effect of this medication on ICOS+-Tresps, causing a significant decrease of these cells with age. The proliferation capacity was neither affected in ICOS+-Tregs/Tresps nor in ICOS--Tregs/Tresps. As a result, the ratio of ICOS+-Tregs/ICOS+-Tresps increased significantly with age and kept the patients in remission. In contrast, glucocorticoids increased the differentiation of ICOS--Tregs especially in younger individuals, but had an adverse effect on their proliferation capacity. Conclusion Our data reveal a crucial role of the ICOS+-Treg/ICOS+-Tresp balance for the maintenance of self-tolerance and avoidance of disease flares in SLE. The used immunosuppressive therapy, especially the administration of proliferation inhibitors, has a decisive effect on the preservation of regular differentiation of all Treg/Tresp subsets with age, and most importantly avoids the terminal differentiation and immune senescence of ICOS+-Tregs.

The European Best Practice Guideline group (EBPG) issued guidelines on the evaluation and selection of kidney donor and kidney transplant candidates, as well as post-transplant recipient care, in the year 2000 and 2002. The new European Renal Best Practice board decided in 2009 that these guidelines needed updating. In order to avoid duplication of efforts with kidney disease improving global outcomes, which published in 2009 clinical practice guidelines on the post-transplant care of kidney transplant recipients, we did not address these issues in the present guidelines.The guideline was developed following a rigorous methodological approach: (i) identification of clinical questions, (ii) prioritization of questions, (iii) systematic literature review and critical appraisal of available evidence and (iv) formulation of recommendations and grading according to Grades of Recommendation Assessment, Development, and Evaluation (GRADE). The strength of each recommendation is rated 1 or 2, with 1 being a 'We recommend' statement, and 2 being a 'We suggest' statement. In addition, each statement is assigned an overall grade for the quality of evidence: A (high), B (moderate), C (low) or D (very low). The guideline makes recommendations for the evaluation of the kidney transplant candidate as well as the potential deceased and living donor, the immunological work-up of kidney donors and recipients and perioperative recipient care.All together, the work group issued 112 statements. There were 51 (45%) recommendations graded '1', 18 (16%) were graded '2' and 43 (38%) statements were not graded. There were 0 (0%) recommendations graded '1A', 15 (13%) were '1B', 19 (17%) '1C' and 17 (15%) '1D'. None (0%) were graded '2A', 1 (0.9%) was '2B', 8 (7%) were '2C' and 9 (8%) '2D'. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research.We present here the complete recommendations about the evaluation of the kidney transplant candidate as well as the potential deceased and living donor, the immunological work-up of kidney donors and recipients and the perioperative recipient care. We hope that this document will help caregivers to improve the quality of care they deliver to patients. The full version with methods, rationale and references is published in Nephrol Dial Transplant (2013) 28: i1-i71; doi: 10.1093/ndt/gft218 and can be downloaded freely from http://www.oxfordjournals.org/our_journals/ndt/era_edta.html.

Background Residual renal function (RRF) contributes to better patient survival in peritoneal dialysis (PD). It is known that glucose degradation products (GDP) and advanced glycation end-products (AGE) resorbed from the peritoneal cavity do not only cause local peritoneal toxicity but also systemic damage resulting in a loss of RRF. We hypothesize that GDP and AGE affect the structure and function of podocytes and investigate whether these effects can be rescued by human RAGE antibody (hRAGEab) to prevent AGE/RAGE interaction and podocyte damage. Methods Differentiated human podocytes were pre-incubated with ±hRAGEab to block the AGE/RAGE interaction and incubated afterwards either with control solution (control), PD fluid (PDF) or a GDP mixture (GDP) for 48 h. We analysed podocyte damage and rescue by hRAGEab using immunofluorescence, western blot, enzyme-linked immunosorbent assay and a functional migration assay. For quantitation, a semiquantitative score was used. Results When pre-incubating podocytes with hRAGEab, damage mediated by PDF and GDP was reduced. We observed lower expression of AGE in PDF and GDP as well as decreased levels of inflammation as shown by activation of nuclear factor kappa B and interleukin-6 release. The reorganization of the podocyte actin cytoskeleton was reduced in the presence of hRAGEab as well as ameliorated synaptopodin expression could be observed, both functionally associated with normal podocyte motility. Finally, podocytes underwent less apoptosis. Conclusions It has been investigated that GDP-containing PDF causes a loss of RRF in PD. Our findings suggest that hRAGEab confers protection against PDF- and GDP-induced podocyte dysfunction. Blocking the AGE/RAGE interaction provides specific protective effects against PDF- and GDP-induced cytoskeletal reorganization, dynamics and stabilizes podocyte survival; this might be an implication for the preservation of RRF in PD.

KDIGO (Kidney Disease: Improving Global Outcomes) is an international independent body aiming to 'improve the care and outcomes of kidney disease patients worldwide, through the development and implementation of clinical practice guidelines'. Recently, the KDIGO work group has produced comprehensive clinical practice guidelines for the care of kidney transplant recipients (KTRs). The guideline makes recommendations for immunosuppression, graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy and other complications that are common in KTRs, including haematological and bone disorders.Because most guidelines were 'soft' rather than 'strong', and because global guidelines need to be adapted and implemented into the regional context where they are used, the European Renal Best Practice (ERBP) Advisory Board appointed a work group of transplant nephrologists and surgeons to review the newest KDIGO guideline and comment on its relevance and applicability for European KTRs.In this article, we concentrate only on those guidelines which we considered worth amending or adapting. All guidelines not mentioned are fully endorsed. © 2010 The Author., SCOPUS: re.j, info:eu-repo/semantics/published

85% and 77%, respectively. The 1-, 3- and 5-year pancreas allograft survival rate after simultaneous pancreas– kidney transplantation was 86%, 79% and 71%, and patient survival was 95%, 91% and 86%, respectively (IPTR; http://www.iptr.umn.edu; [2]).

Organ transplantation is a well-established method for the therapy of end-stage organ failure. The emergence of novel immunosuppressive regimens has reduced the risk of rejection and extended the life expectancy of organ recipients. The long-term outcome of these patients is now challenged by life-threatening complications such as cardiovascular disease, infections and post-transplant malignancies. Malignancy is a well-recognized complication of transplantation and can manifest as de novo cancer, as a recurrence of a pre-existing malignancy or from transmission of malignancy from the donor. Recent studies show that tumour incidence increases with time after organ transplantation and is related to the intensity of immunosuppression [1,2]. Overall, a 3to 4-fold increased incidence of cancer has been observed in transplant patients compared with age-matched controls in the general population. During immunosuppressive therapy, there is a higher frequency of some relatively rare tumours that tend to be biologically more aggressive than those that occur in the general population [3]. The relative risk for developing skin cancer in allografted patients is increased up to 70% in regions with high sun exposure [4]. Post-transplantation lymphoproliferative disorder (PTLD) occurs in up to 11% of renal transplant recipients and holds the major cause for cancer-related mortality. There is a 400to 500-fold increase in Kaposi sarcoma compared with controls of the same ethnic origin and a 100-fold increase in vulval and anal carcinomas in transplant recipients [5]. The aetiology of post-transplant malignancy is believed to be multifactorial in nature and probably involves impaired immunosurveillance of the host, direct carcinogenic effects of some immunosuppressive agents and de

Background Several late sequelae of the administration of gadolinium (Gd)-containing MRI contrast agents have been described in patients with advanced renal failure. In an observational series, we found a remarkable frequency of peracute reactions after administration of Gd-DTPA used for cardiovascular evaluation before renal transplantation. Methods In a 26-month observational period, 13 of 136 haemodialyzed or CAPD patients exhibited onset of fever, chills and nausea within hours after administration of Gd-DTPA peracute. A minority showed persistent cessation of residual diuresis. We performed blood cultures in most patients and evaluated white blood cell (WBC) counts, eosinophils, CRP, heart rate and blood pressure. Results Within an average of 12 h (range 12-36 h) after Gd administration, the 13 patients (9 males, 4 females; median age 61 years, range 47-79) developed consistent symptomatology with fever (median 39.0 degrees C, range 37.5-39.5), chills, malaise, hypotension, vomiting, dyspnoea-initially raising suspicion of septicaemia. Subsequent blood cultures on bacterial contamination of the injected product remained negative throughout; bacterial or endotoxin contamination of the reagent was excluded. Steroids were tried in the first two patients without a noticeable effect. In all subsequent patients, symptoms were attenuated during the first 5 h dialysis (F60HPS with 280 ml/min blood flow) and disappeared within 72 h. CRP levels remained markedly elevated up to 14 days. Lymphopenia was seen in all patients, and polymorphic neutrophils (PMN) remained normal. Two polyuric patients developed persistent anuria. After a median of 16 months, none of these patients developed nephrogenic systemic fibrosis. Conclusion This series with unusually severe acute phase reactions was caused by one specific preparation. Such peracute reactions may be relevant for the so-far largely unresolved pathogenesis of the skin reaction to some Gd products in end-stage renal disease (ESRD) patients. It remains unresolved whether the reaction observed with Gd-DTPA do in principle also occur with other Gd reagents.

Background. Procalcitonin (PCT) is routinely measured to differentiate autoimmune disorders from infection. There are reports, however, where PCT is high in the absence of infection, i.e. in vasculitis. To investigate the value of PCT in Goodpasture’s syndrome, we reviewed the charts of patients with Goodpasture’s syndrome who were treated from 1996 to 2006. Methods. PCT (normal range

The population of incident dialysis patients is progressively ageing and dialysis outcome is particularly poor in the elderly. There is little documentation whether late referral is more frequent in the very elderly (or =75 years) as compared with non-elderly patients and whether it contributes, at least in part, to their particularly poor outcome.In a retrospective single center study we assessed all consecutive patients (n = 254) who had been admitted to haemodialysis between 1998 and 2001. Outcome in relation to the interval between the time of referral and start of dialysis was compared in very elderly and non-elderly patients. According to a previous analysis in our center major adverse outcome is seen in patients referredor =8 weeks before the start of dialysis. For the present study this time interval was therefore operationally defined as 'late referral'.Expectedly 1 year after start of dialysis mortality was higher (31%) in the very elderly compared with younger patients (19%). The interval between referral and first dialysis was less in patientsor =75 years (median interval 3.5 weeks) compared with patients75 years (median 20.5 weeks; P = 0.007). The difference in 1 year mortality between timely (8 weeks) vs late (or =8 weeks) referral, however, was as high in the very elderly (42% vs 16%) as in the younger patients (34% vs 9%). The relative risk of death conferred by late referral was also not significantly different in the very elderly (RR 1.80) compared with the younger (RR 2.32) patient. Using multivariate analysis timing of referral proves to be an independent factor with regard to the outcome and time of survival.We conclude that late referral is more frequent in the very elderly. Although the relative risk of death conferred by late referral is similar in the very elderly and non-elderly, due to higher frequency of late referral it accounts for a large proportion of excess mortality in the very elderly.

Background. It has been hypothesized that in renal failure, exogenous glycation compounds from food accumulate and play a major pathogenetic role when renal excretion is impaired. Methods. To address this, a diet containing a defined amount of the lysine Amadori product (AP) lactuloselysine was used. Plasma concentrations and cumulative urinary excretion of AP were assessed in 16 healthy subjects, 12 renal failure patients and 6 continuous ambulatory peitoneal dialysis (CAPD) patients. Amadori product was measured as furosine using reverse phase high performance liquid chromatography (RP-HPLC) after acid hydrolysis. Results. A diet low in glycation compounds significantly decreased excretion of APs in healthy subjects. In healthy individuals, ingestion of lactuloselysine bound to food proteins caused only a minor acute increase (8.24 ± 1.11 mg/day, 2% of the administered dose) of AP excretion in the urine; in patients with renal failure not yet on dialysis, the increase in AP excretion in the urine was significantly less (4.0 ± 0.51 mg/day) and the same was true in CAPD patients (0.21 ± 0.09 mg/day). The plasma concentration of total APs, i.e. the sum of APs as free amino acids and residues bound to plasma proteins, did not change in any of the three groups, however. Conclusion. Dietary APs do not accumulate in the blood even in advanced renal failure. The amount of APs measured as furosine excreted in the urine is significantly less, however, in renal failure and CAPD patients compared with healthy subjects. Although the findings exclude accumulation of lactuloselysine in renal failure, they do not generally exclude accumulation of other food-derived advanced glycation end products (AGEs).

Background. With the introduction of cyclosporine A (CsA) long-term allograft function has been significantly improved. Problems regarding limited therapeutic margins and CsA toxicity remain unsolved. Up to now there are no reliable, practical markers to measure the biological activity of CsA in vivo. Methods. Expression of nuclear factor of activated T lymphocytes (NFAT)-regulated genes in PMA/ ionomycin-stimulated peripheral blood from stable renal-transplant (n ¼ 25) recipients under CsA therapy were measured by quantitative real-time RT–PCR before and 2 h after drug intake. The relative expression of three NFAT-regulated genes was scored, averaged and presented as the multi-gene expression score ranging from 0 to 12 points. Gene expression data and CsA plasma levels were correlated. Results. A reliable and precise method to measure functional consequences of calcineurin inhibition in the individual patient was established. The individual decline in NFAT-regulated gene expression and the total drug exposure were in close relation ( ¼ 0.602). Conclusion. Quantitative measurement of NFATregulated gene expression in CsA-treated patients represents a potent new approach to assess the biological effectiveness of CsA therapy and has the potential to enable individualized immunosuppressive regimens.

Since the frequency of living-related and unrelated kidney donation has increased in the past decade, the risk of uninephrectomy should not be neglected. Major complications after kidney donation are rare. No serious problems like infection or bleeding are common with an overall perioperative complication rate of 14%. Risk of long-term mortality is lower compared to the expected mortality. Little decrease of glomerular filtration rate immediately after transplantation occurs with no further decline. Risk of end-stage renal failure in living donors is approximately 0.2-0.5%. Only a few patients develop proteinuria. After age adjustment, no increase of blood pressure is noted. The benefit of living kidney transplantation is superceding the potential risks. After careful work-up of the donor short- and long-term risks are minimal.

In Europe approximately 6% of all patients on chronic renal replacement therapy suffer from polycystic kidney disease. Survival of patients with polycystic kidney disease on renal replacement therapy is better than for other primary renal diseases, despite a similar cardiovascular risk profile. We documented a significantly higher erythropoietin level in polycystic patients even in advanced uraemia and on dialysis. A better haemoglobin level seems to improve long-term survival because of a possible beneficial effect on cardiac function. There is no increased risk of renal cell carcinoma in patients with autosomal dominant polycystic kidney disease. Polycystic patients on dialysis should be followed for cardiac valve abnormalities and cerebral aneurysms.

It has been claimed that anticipation occurs in ADPKD, i.e. endstage renal failure at progressively earlier age in successive generations. This observation might possibly point to unstable DNA as the molecular basis of ADPKD. We analysed 74 parent-offspring pairs of 148 families in Germany and Austria in whom (i) ADPKD was verified by appropriate imaging procedures and (ii) age at renal death was accurately known. The median difference for age at renal death between parent and offspring was 0 years, range - 26.3 to + 27.2 years. There was no deviation from normal (Gaussian) distribution according to the Shapiro-Wilk test (P=0.75). We conclude that systematic anticipation cannot be demonstrated with this sample which had sufficient size for meaningful biostatistical analysis.

The Han: SPRD Pkd rat mutant is an autosomal dominant rat model with incomplete penetration of polycystic renal transformation. Progressive renal failure occurs in heterozygous male animals. The mechanisms of progression have not been elucidated. To identify some pathogenetic factors involved we subjected male SPRD Pkd rats (and their non-affected littermates as controls) to uninephrectomy (UNX), castration or enalapril treatment. To assess progression S-urea at age 150 days was chosen as endpoint. (i) In uninephrectomized male Han: SPRD Pkd (n = 12 animals per group) S-urea at age 150 days was consistently above 300 mg/dl, while it was 245 mg/dl (191-290) in control Han: SPRD Pkd. (ii) In castrated male Han: SPRD median S urea at 150 days was 100 mg/dl (69-211) compared to sham-operated male Han: SPRD controls (245; 191-290). Castration did not, however, prevent accelerated progression after uninephrectomy. (iii) Enalapril (50 mg/l) in the drinking fluid did not significantly lower median systolic blood pressure (by plethysmography) in animals on 0.2% sodium diet (at 185 days 160 mmHg; 140-170 versus 170; 140-195 in non-enalapril controls), although circulating ACE was significantly inhibited (17 U; 11-33 versus 89; 52-108 in controls). S-urea at age 185 days was not significantly different in the 2 groups. In conclusion, the Han: SPRD Pkd model differs from human ADPKD to some extent. Uninephrectomy accelerates renal failure in the rat, but not in humans. On the other hand, in contrast to human ADPKD the renin system is suppressed in the rat model and ACE inhibition does not affect the course of renal failure.

) hashave a tri-segmented negative-sense single-stranded been implicated in a milder urban form of haemor-RNA genome. The virus reservoir was found to be rhagic fever with renal syndrome (HFRS) [3]. Furtherrodents and transmission occurs by aerosol of rodent studies revealed another antigenetically related virusdroppings. The diVerent types of hantavirus have co- (Puumala-PUU), which was isolated from the bankevolved with their specific rodent host through evolu- vole (

Anaemia is common after solid organ transplantation. Although many impressive experimental data about the organoprotective properties of erythropoietin (EPO) have been reported, there are only scant clinical and experimental data about EPO use after solid organ transplantation. Since the treatment targets of anaemia in chronic kidney disease cannot be transferred to organ recipients for several reasons (rejection, immunosuppression, infection), the recommendations for optimal targets in the treatment of anaemia remain uncertain. Moreover, further studies will be necessary to clarify whether EPO administration might have haemoglobin-independent beneficial effects.

Acute rejection episodes are now as low as 5-20% in the first year after renal transplantation; however, graft half-life has remained almost unchanged in the last decade. This statistic is mainly attributable to the side effects of immunosuppression, with loss of allografts due to the chronic allograft nephropathy that is a consequence of calcineurin inhibitor toxicity or hypertension. Patient death due to cardiovascular events, infections and malignancy also contribute to allograft loss. The introduction of the inhibitors of the mammalian target of rapamycin sirolimus and everolimus in renal transplantation has increased the repertoire of immunosuppressive protocols substantially. They have a different mode of action and a different side effect profile (i.e. lower nephrotoxicity, less hypertension and less neoplastic potential) than the calcineurin inhibitors. The inhibitors of the mammalian target of rapamycin therefore provide an especially promising alternative for the maintenance immunosuppression after renal transplantation. This overview provides a summary of the current literature on inhibitors of the mammalian target of rapamycin, with a special focus on sirolimus.

Since the beginning of organ transplantation, graft preservation has been one of the most important concerns. Ischemia reperfusion injury (IRI), which plays an important role in the quality and function of the graft, is a major cause for increased length of hospitalization and decreased long term graft survival. Among numerous attempts which have been made to minimize graft damage associated with IRI, the use of Thymoglobulin (TG) seems to offer potential benefits. TG is a polyclonal antibody which blocks multiple antigens related to IRI, in addition to its better known T cell depleting effects. This review will focus on the use of TG in preventing IRI in kidney transplantation (KTx) and liver transplantation (LTx). Different studies in experimental and clinical transplantation have shown that TG protects renal and liver grafts from IRI. Improvement in early graft function and decreased delayed graft function (DGF) rates are some of the clinical benefits of TG. Additionally, it is used in patients with hepatorenal syndrome to support the recovery of kidney function after LTx, by allowing reduced exposure to nephrotoxic calcineurin inhibitors as well as improving liver graft function by minimizing IRI. TG can reduce acute rejection rates in kidney and liver transplant recipients, decrease the length of hospital stay, and hence reduce transplantation costs. TG can play an important role in expanding the donor pool in both KTx and LTx by improving long-term graft and patient survival rates which increases the possibility of using marginal donors. Although controversial, the development of post-transplant lymphoproliferative disorder is a potential side effect of TG. No single optimal immunosuppressive regimen has given consistent results in decreasing the graft damage following IRI; however, TG usage in KTx and LTx appears to have some benefits in reducing IRI.

In the last decade the incidence of BK virus infection has increased in renal transplant recipients and become an important factor negatively influencing graft outcome. BK virus infection cannot be attributed to a single immunosuppressive agent or regimen. The risk of BKV infection is related to the overall load of immunosuppression, which is determined not only by immunosuppressive drugs but also by the humoral and cellular immunity of the recipient. Reduction in immunosuppression at this time appears to be the best available approach to the treatment of established BKVN. Assays are lacking that are able to measure the degree of immunosuppression in a given patient at a given time after transplantation. The balance between a sufficient yet nontoxic immunosuppressive regimen remains a major problem in preventing complications such as BK virus nephropathy. This article will focus on the influence of immunosuppressive medication on the development of BKVN. The role of other aspects such as viral virulence, humoral and cellular immunity or renal specificity will be shortly discussed.