A best-practice position statement on pregnancy after kidney transplantation: focusing on the unsolved questions. The Kidney and Pregnancy Study Group of the Italian Society of Nephrology

Kidney transplantation (KT) is often considered to be the method best able to restore fertility in a woman with chronic kidney disease (CKD). However, pregnancies in KT are not devoid of risks (in particular prematurity, small for gestational age babies, and the hypertensive disorders of pregnancy). An ideal profile of the potential KT mother includes “normal” or “good” kidney function (usually defined as glomerular filtration rate, GFR ≥ 60 ml/min), scant or no proteinuria (usually defined as below 500 mg/dl), normal or well controlled blood pressure (one drug only and no sign of end-organ damage), no recent acute rejection, good compliance and low-dose immunosuppression, without the use of potentially teratogen drugs (mycophenolic acid and m-Tor inhibitors) and an interval of at least 1–2 years after transplantation. In this setting, there is little if any risk of worsening of the kidney function. Less is known about how to manage “non-ideal” situations, such as a pregnancy a short time after KT, or one in the context of hypertension or a failing kidney. The aim of this position statement by the Kidney and Pregnancy Group of the Italian Society of Nephrology is to review the literature and discuss what is known about the clinical management of CKD after KT, with particular attention to women who start a pregnancy in non-ideal conditions. While the experience in such cases is limited, the risks of worsening the renal function are probably higher in cases with markedly reduced kidney function, and in the presence of proteinuria. Well-controlled hypertension alone seems less relevant for outcomes, even if its effect is probably multiplicative if combined with low GFR and proteinuria. As in other settings of kidney disease, superimposed preeclampsia (PE) is differently defined and this impairs calculating its real incidence. No specific difference between non-teratogen immunosuppressive drugs has been shown, but calcineurin inhibitors have been associated with foetal growth restriction and low birth weight. The clinical choices in cases at high risk for malformations or kidney function impairment (pregnancies under mycophenolic acid or with severe kidney-function impairment) require merging clinical and ethical approaches in which, beside the mother and child dyad, the grafted kidney is a crucial “third element”

Outcomes of pregnancies after kidney transplantation: lessons learned from CKD. A comparison of transplanted, nontransplanted chronic kidney disease patients and low-risk pregnancies: a multicenter nationwide analysis.

BACKGROUND: Kidney transplantation (KT) may restore fertility in CKD. The reasons why materno-foetal outcomes are still inferior to the overall population are only partially known. Comparison with the CKD population may offer some useful insights for management and counselling.Aim of this study was to analyse the outcomes of pregnancy after KT, compared with a large population of non-transplanted CKD patients and with low-risk control pregnancies, observed in Italy the new millennium. METHODS: We selected 121 live-born singletons after KT (Italian study group of kidney in pregnancy, national coverage about 75%), 610 live-born singletons in CKD and 1418 low-risk controls recruited in 2 large Italian Units, in the same period (2000-2014). The following outcomes were considered: maternal and foetal death; malformations; preterm delivery; small for gestational age baby (SGA); need for the neonatal intensive care unit (NICU); doubling of serum creatinine or increase in CKD stage. Data were analysed according to kidney diseases, renal function (staging according to CKD-EPI), hypertension, maternal age, partity, ethnicity. RESULTS: Materno-foetal outcomes are less favourable in CKD and KT as compared with the low-risk population. CKD stage and hypertension are important determinants of results. KT patients with e-GFR >90 have worse outcomes compared with CKD stage 1 patients; the differences level off when only CKD patients affected by glomerulonephritis or systemic diseases ('progressive CKD') are compared with KT. In the multivariate analysis, risk for preterm and early-preterm delivery was linked to CKD stage (2-5 versus 1: RR 3.42 and 3.78) and hypertension (RR 3.68 and 3.16) while no difference was associated with being a KT or a CKD patient. CONCLUSIONS: The materno-foetal outcomes in patients with kidney transplantation are comparable with those of nontransplanted CKD patients with similar levels of kidney function impairment and progressive and/or immunologic kidney diseas

The ideal blood pressure target to prevent cardiovascular disease in type 2 diabetes: a neutral viewpoint.

Type 2 diabetes mellitus (T2DM) and essential hypertension are often associated, and retrospective data analyses suggest an association between lower blood pressure (BP) values and lower cardiovascular (CV) risk in patients with T2DM. However, the most recent intervention trials fail to demonstrate a further CV risk reduction, for BP levels <130/80 mm Hg, when compared to levels <140/90 mm Hg. Moreover, a J-shaped, rather than a linear, relationship of BP reduction with incident CV events has been strongly suggested. We here debate the main available evidences for and against the concept of 'the lower the better', in the light of the main intervention trials and meta-analyses, with a particular emphasis on the targets to be pursued in elderly patients. Finally, the most recent guidelines of the scientific societies are critically discussed

The ideal blood pressure target to prevent cardiovascular disease in type 2 diabetes: A neutral viewpoint

Type 2 diabetes mellitus (T2DM) and essential hypertension are often associated, and retrospective data analyses suggest an association between lower blood pressure (BP) values and lower cardiovascular (CV) risk in patients with T2DM. However, the most recent intervention trials fail to demonstrate a further CV risk reduction, for BP levels <130/80 mm Hg, when compared to levels <140/90 mm Hg. Moreover, a J-shaped, rather than a linear, relationship of BP reduction with incident CV events has been strongly suggested. We here debate the main available evidences for and against the concept of 'the lower the better', in the light of the main intervention trials and meta-analyses, with a particular emphasis on the targets to be pursued in elderly patients. Finally, the most recent guidelines of the scientific societies are critically discussed. Copyright © 2014 Elsevier B.V. All rights reserved

Pregnancy outcomes after kidney graft in Italy: Are the changes over time the result of different therapies or of different policies? A nationwide survey (1978-2013)

BackgroundKidney transplantation is the treatment of choice to restore fertility to women on renal replacement therapy. Over time, immunosuppressive, support therapies and approaches towards high-risk pregnancies have changed. The aim of this study was to analyse maternal-foetal outcomes in two cohorts of transplanted women who delivered a live-born baby in Italy in 1978-2013, dichotomized into delivery before and after January 2000. MethodsA survey involving all the Italian transplant centres was carried out, gathering data on all pregnancies recorded since the start of activity at each centre; the estimated nationwide coverage was 75%. Data on cause of ESRD, dialysis, living/cadaveric transplantation, drug therapy, comorbidity, and the main maternal-foetal outcomes were recorded and reviewed. Data were compared with a low-risk cohort of pregnancies from two large Italian centres (2000-14; Torino and Cagliari Observational Study cohort). ResultsThe database consists of 222 pregnancies with live-born babies after transplantation (83 before 2000 and 139 in 2000-13; 68 and 121 with baseline and birth data, respectively), and 1418 low-risk controls. The age of the patients significantly increased over time (1978-99: age 30.7 \ub1 3.7 versus 34.1 \ub1 3.7 in 2000-13; P < 0.001). Azathioprine, steroids and cyclosporine A were the main drugs employed in the first time period, while tacrolimus emerged in the second. The prevalence of early preterm babies increased from 13.4% in the first to 27.1% in the second period (P = 0.049), while late-preterm babies non-significantly decreased (38.8 versus 33.1%), thus leaving the prevalence of all preterm babies almost unchanged (52.2 and 60.2%; P = 0.372). Babies below the 5th percentile decreased over time (22.2 versus 9.6%; P = 0.036). In spite of high prematurity rates, no neonatal deaths occurred after 2000. The results in kidney transplant patients are significantly different from controls both considering all cases [preterm delivery: 57.3 versus 6.3%; early preterm: 22.2 versus 0.9%; small for gestational age (SGA): 14 versus 4.5%; P < 0.001] and considering only transplant patients with normal kidney function [preterm delivery: 35 versus 6.3%; early preterm: 10 versus 0.9%; SGA: 23.7 versus 4.5% (P < 0.001); risks increase across CKD stages]. Kidney function remained stable in most of the patients up to 6 months after delivery. Multiple regression analysis performed on the transplant cohort highlights a higher risk of preterm delivery in later CKD stages, an increase in preterm delivery and a decrease in SGA across periods. ConclusionsPregnancy after transplantation has a higher risk of adverse outcomes compared with the general population. Over time, the incidence of SGA babies decreased while the incidence of 'early preterm' babies increased. Although acknowledging the differences in therapy (cyclosporine versus tacrolimus) and in maternal age (significantly increased), the decrease in SGA and the increase in prematurity may be explained by an obstetric policy favouring earlier delivery against the risk of foetal growth restriction

A meta-analysis and morphological review of cyclosporine-induced nephrotoxicity in auto-immune diseases

A meta-analysis and morphological review of cyclosporine-induced nephrotoxicity in auto-immune diseases.BackgroundThe risk-benefit ratio of cyclosporine A (CsA) is much more critical in some auto-immune diseases in comparison to transplantation medicine, due to its renal toxic potential. The present meta-analysis is based on an a priori defined methodology, and is linked with a review of CsA-induced morphological lesions, in order to draw relevant conclusions with regard to CsA-induced nephrotoxicity in auto-immune diseases.MethodsOnly controlled, randomized trials with a treatment period of two months or more, published from January 1979 to August 1996, were selected for the evaluation of functional renal impairment due to CsA treatment. To assess the risk of developing nephrotoxicity during CsA therapy, individual peak rises in serum creatinine level were compared between the CsA-treated group and the control group. Nephrotoxicity was defined as an increase in serum creatinine level of 50% or more above baseline at least once during the study period. Papers reporting CsA-induced renal morphological lesions were reviewed.ResultsA risk difference of 20.9% for developing nephrotoxicity, between a therapy with CsA and an alternative therapy, was found. Already after a treatment period of 12months with low dose CsA (≤5mg/kg/day), de novo nonspecific morphological damage could be induced in patients with auto-immune diseases.ConclusionsFrom this analysis of the literature, it is obvious that a therapy with CsA in patients affected by auto-immune diseases is not without risk. A rigorous evaluation of the risk-benefit ratio is strongly recommended for each patient, with strict monitoring of serum creatinine and CsA trough levels during treatment. Renal biopsies during treatment must be seriously taken into consideration in patients who develop even a slight renal functional impairment, particularly when prolonged therapy of longer than one year, even with low dose CsA (≤5mg/kg/day), is given